ABCMdb

ABCC7 p.Gly542*

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Publications

PMID: 16442101 [PubMed] Frelet A et al: "Insight in eukaryotic ABC transporter function by mutation analysis."

No. Sentence Comment

314 [142] G542X, W1316X G542X and W1316X nonsense mutants fail to generate functional CFTR Cl-channels. Login to comment

PMID: 10050655 [PubMed] Lissens W et al: "Molecular analysis of the cystic fibrosis gene reveals a high frequency of the intron 8 splice variant 5T in Egyptian males with congenital bilateral absence of the vas deferens."

No. Sentence Comment

32 Initially, eight of the males` samples were analysed by a commercial kit allowing the detection of eight mutations in the CFTR gene: ∆F508, ∆I507, G542X, G551D, R553X, 1717-1G→A, W1282X and N1303K (INNO-LiPA CF, Innogenetics, Zwijnaarde, Belgium). Login to comment
52 None of the other individuals showed a mutation except the male with the ectopic pelvic kidney (patient ii in the previous paragraph) who had neither a normal nor a mutated band at the G542X site when studied by the INNO-LiPA CF kit. Login to comment
55 This base substitution probably inhibits the binding of the exon 11 PCR fragment to the normal (and mutant) sequence at the G542X locations in the INNO-LiPA CF kit. Login to comment

PMID: 10077727 [PubMed] Loumi O et al: "Analysis of the complete coding region of the CFTR gene in ten Algerian cystic fibrosis families."

No. Sentence Comment

37 The V754M (G to A at position 2392) mutation has previously been reported to the Cystic Fibrosis Genetic Analysis Consortium by Roger Mountford and seems to confer moderate disease when it is associated either with 1812 - 1G→A or G542X. Login to comment
43 Surprisingly, none of the defined mutations (G542X, R553X, G551D, 1717 - 1G→A) which occur relatively frequently in exon 11 in Caucasian populations was identified in our Algerian population. Login to comment

PMID: 10099982 [PubMed] Dohle GR et al: "The complex relationships between cystic fibrosis and congenital bilateral absence of the vas deferens: clinical, electrophysiological and genetic data."

No. Sentence Comment

58 CFTR mutation analysis was performed for 10 mutations: we analysed for the mutations R117H, A455E, ∆F508, 1717-1G→A, G542X, R553X, R1162X, S1251N, W1282X, and N1303K. Login to comment

PMID: 10223721 [PubMed] Mansoura MK et al: "Fluorescent chloride indicators to assess the efficacy of CFTR cDNA delivery."

No. Sentence Comment

249 Cl2 INDICA TOR APPLICATION TO STUDY CFTR FUNCTION (CONT`D ) Cell or tissue Protocol Cell SPQ Quench Findings/significance type Descriptiona loading ion Ref. Deletion of 19 residues HEK 293- Embryonic kidney cell line Passive Cl Xie et al. in the loop between EBNA 5 mM (1995) TM4 and TM5 12±18 hr eliminated Cl transport Coexpression of the N HeLa Cervical carcinom a (epithelial) Passive I Ostedgaard and C halves of CFTR 10 mM et al. resulted in functional 12±18 hr (1997) Cl channels C orrection of C F phenotype by pharmacological maneuvers Increased [IBMX] L cells Mouse fibroblasts Hypotonic I Yang et al. improved D F508 12 hr (1993) response; reduced temperature improved D F508 and G551D Transfer of purified CHO-CFTR Chinese hamster ovary Passive I Marshall CFTR protein induced FRT-CFTR Fisher rat thyroid epithelial 10 mM et al. Cl2 transport LLCPK1 Pig kidney epithelial 12±18 hr (1994) Overexpression of CFPAC-1 Pancreatic duct adenocarcinoma Passive or I Cheng et al. D F508 with sodium JME/CF15 (D F/D F) Hypotonic (1995) butyrate resulted in 1° culture Transformed CF airway 10 mM detectable Cl2 transport epithelial CF airway epithelial Chemical chaperones Swiss 3T3 Mouse embryo fibroblast Passive Cl Brown et al. (glycerol, D2O, TMAO) 5 mM (1996) corrected the CF 12±18 hr phenotype Aminoglycosid e antibiotics HeLa Cervical carcinom a (epithelial) Hypotonic I Howard et al. overcam e premature 10 mM (1996a) stop codons and 10 min corrected CF phenotype Deoxyspergualin C127-CFTR Mouse mammary epithelial Hypotonic I Jiang et al. delivered D F508 to JME/CF15 Transformed CF airway 10 mM (1998) plasma membrane and IBE-1 epithelial 4 min partially restored Cl2 Transformed intrahepatic transport (D F/G542X) Abbreviations: wt, wildtype; PKA, protein kinase A; TM, transmembrane ; TMAO, trimethylamine -N-oxide. Login to comment
252 The efficacy of aminoglycoside s in promoting read-through in the CFTR nonsense mutations G542X and R553X was shown using Cl2 indicators (Howard et al., 1996a). Login to comment

PMID: 10229049 [PubMed] Lecoq I et al: "Blood immunoreactive trypsinogen concentrations are genetically determined in healthy and cystic fibrosis newborns."

No. Sentence Comment

61 Twins or unrelated patients with identical genotype had very similar neonatal IRT concentrations: DF508/I148T (twins), 1040 and 1055 mg LÀ1 ; N1303K/G149R (twins), 1600 and 1725 mg LÀ1 ; DF508/E585X, 900 and 945 mg LÀ1 ; DF508/ G542X, 1535 and 1660 mg LÀ1 ; DF508/L206W, 980, 1090 and 1100 mg LÀ1 . Login to comment
72 In this study, CF newborns with one mutation in an exon encoding for either NBD1 or NBD2 (DF508, G542X, G551D, E585X, N1303K, etc.) and the other affecting one of the MSD (R117H, 574delA, I148T, G149R, L206W, etc.) had significantly lower IRT concentrations than CF neonates with both mutations located in NBD. Login to comment

PMID: 10325788 [PubMed] Sarles J et al: "Blood concentrations of pancreatitis associated protein in neonates: relevance to neonatal screening for cystic fibrosis."

No. Sentence Comment

77 Other genotypes were F508/G542X (n=4), F508/N1303K (n=2), F508/I148T (n=2), F508/R117H, F508/R553X, F508/1717-1G->A, F508/ 1078delT, F508/2789+5G->A, F508/ E1308X (a novel CFTR mutation), R553X/ 394delTT, and N1303K/R553X. Login to comment

PMID: 10330420 [PubMed] Kalin N et al: "DeltaF508 CFTR protein expression in tissues from patients with cystic fibrosis."

No. Sentence Comment

12 Skin biopsies were taken from the right shoulder of 5 healthy volunteers, 4 ∆F508 homozygous CF patients, and 3 CF patients homozygous for the stop mutations R553X (n = 1) and G542X (n = 2). Login to comment
65 Three skin biopsies from patients homozygous for the CFTR stop mutations R553X and G542X and 1 rectal suction biopsy homozygous for an out-of-frame deletion of exons 2 and 3 (biopsy and mutation analysis provided by F. Mekus, Medizinische Hochschule Hannover) that results in a stop in exon 4 were analyzed by CFTR immunohistochemistry 1380 The Journal of Clinical Investigation | May 1999 | Volume 103 | Number 10 Figure 1 CFTR antibodies PAC13, PAC865, MATG1104, and M3A7 detect the characteristic immunoreactive CFTR bands in immunoblot analysis of T84 cells. Login to comment
133 3a, 3b, 4a, 4b, 5a, 5b: ×6,168. ing was demonstrated by common negative controls and the absence of specific signals in skin biopsies homozygous for the stop mutations G542X and R553X (n = 3). Login to comment

PMID: 10341008 [PubMed] Boucher D et al: "Screening for cystic fibrosis transmembrane conductance regulator gene mutations in men included in an intracytoplasmic sperm injection programme."

No. Sentence Comment

51 Each patient was tested for the nine most frequent cystic fibrosis-causing CFTR mutations: ∆F508, ∆I507, 1717-1G→A, G542X, G551D, R553X, W1282X, N1303K, 621ϩ1G→T and the three most frequent CFTR mutations involved in CBAVD (∆F508, R117H and the IVS8 polyT). Login to comment
53 The other mutations were detected using either heteroduplex analysis (∆I507), allele specific oligonucleotide (ASO) hybridization (G542X, 1717-1G→A, IVS8 polyT) (Kerem et al., 1990), restriction endonuclease analysis (G551D, R553X, W1282X) (Zielenski et al., 1991) or polymerase chain reaction (PCR)-mediated site-directed mutagenesis (621ϩ1G→T, R117H, N1303K) (Friedman et al., 1991). Login to comment
67 ASO hybridization PCR-amplified DNA (6 µl) of exon 9 or exon 11 was denatured and vacuumblotted onto nylon membrane(Hybond Nϩ, Amersham Pharmacia Biotech, Orsay, France) and hybridized with oligonucleotides which recognize the presence of 5T, 7T or 9T for detection of the IVS8 polyT-stretch, normal or mutated allele for 1717-1G→A and G542X. Login to comment
94 Methods for detecting mutations Mutation Method R117H PCR-mediated-site-directed mutagenesis, HaeII digestion N: 113 ϩ 24 bp R117H: 137 bp 621ϩ1G→T MseI digestion N: 269 ϩ 33 bp 621ϩ1G→T: 215 ϩ 54 ϩ 33 bp IVS8polyT ASO hybridization: hybridization at 50°C 5T: TGT GTG TGT TTT TAA CAG washing at 55°C 7T: TGT GTG TTT TTT TAA CAG washing at 51°C 9T: GTG TGT TTT TTT TTA ACA G washing at 55°C ∆I507 Heteroduplex DNA formation ∆F508 Heteroduplex DNA formation (see Figure 1) 17171G→A ASO hybridization, hybridization at 42°C, washing at 54°C N: TTT GGT AAT AGG ACA TCT CC 17171G→A: TTT GGT AAT AAG ACA TCT CC G542X ASO hybridization, hybridization at 42°C, washing at 49°C N: ACC TTC TCC AAG AAC T G542X: ACC TTC TCA AAG AAC T G551D DpnII digestion: N: 425 bp G551D: 243 ϩ 182 bp R553X HincII digestion N: 239 ϩ 186 bp R553X: 425 bp W1282X MnlI digestion N: 178 ϩ 172 ϩ 123 bp W1282X: 301 ϩ 172 bp N1303K PCR-mediated-site-directed mutagenesis, BstNI digestion N: 266 ϩ 23 bp N1303K: 289 bp The underlining indicates the location of nucleotide substitution in normal and mutated allele. Login to comment

PMID: 10376575 [PubMed] Mak V et al: "Proportion of cystic fibrosis gene mutations not detected by routine testing in men with obstructive azoospermia."

No. Sentence Comment

28 Analysis for 31 of the most common CFTR mutations found within the white CF population,60 consisting of ⌬F508, W1282X, G542X, G551D, N1303K, R553X, G85E, R117H, S549N, V520F, R334W, A455E, R347P, R1162X, Y122X, S549R, 621+1G→T, ⌬I507, R560T, R347H, 3659delC, Q493X, 1898+1G→T, 711+1G→T, 3849+10C→T, 1717-1G→A, 3849+4A→G, 3905insT, 1078delT, 2183AA→G, and 2789+5G→A. Briefly, the technique involved amplification by polymerase chain reaction61 of the relevant exons, followed by digestion with appropriate restriction endonucleases and acrylamide gel electrophoresis with ethidium bromide staining. Login to comment
35 Two CFTR mutations(⌬F508,G542X)wereidentifiedby analysisusingthe31CFTRmutationpanel (TABLE2).TheIVS8-5Tvariantwasiden- tifiedin5alleles.Twomutations(theiden- tical ⌬F508 and G542X mutations detected by the 31 mutation panel) were identifiedthroughscreeningofallCFTR exons and splice sites. Login to comment
45 (%) Men With 2 Mutations ⌬F508/IVS8-5T 7 (11) ⌬F508/IVS8-5T 1 (10) ⌬F508/IVS8-5T 1 (1.8) ⌬F508/R117H 6 (9) W1282X/IVS8-5T 1 (1.8) ⌬F508/L206W 1 (1.6) G544S/IVS8-5T 1 (1.8) ⌬F508/M952T 1 (1.6) V754M/-741T→G 1 (1.8) ⌬F508/P67L 1 (1.6) R75Q/R258G 1 (1.8) ⌬F508/S549R 1 (1.6) R334W/R334W 1 (1.6) R117H/R117H 1 (1.6) R117H/IVS8-5T 1 (1.6) R347P/IVS8-5T 1 (1.6) N1303K/IVS8-5T 1 (1.6) 1677delTA/IVS8-5T 1 (1.6) R117L/IVS8-5T 1 (1.6) D979A/IVS8-5T 1 (1.6) IVS8-5T/IVS8-5T 1 (1.6) Men With 1 Mutation IVS8-5T/N 10 (16) ⌬F508/N 1 (10) IVS8-5T/N 9 (16) ⌬F508/N 1 (2) ⌬F508/N 6 (9) IVS8-5T/N 1 (10) ⌬F508/N 1 (1.8) G542X/N 1 (2) W1282X/N 2 (3) R75Q/N 1 (1.8) IVS8-5T/N 5 (10) L206W/N 1 (1.6) W1282X/N 1 (1.8) 4016insT/N 1 (1.6) R117H/N 1 (1.8) 2423delG/N 1 (1.8) Men With No Mutations 18 (28) 7 (70) 37 (66) 42 (86) *N indicates that no CFTR mutations or variants were detected. Login to comment
58 (%) 31 Mutation panel† ⌬F508 23 (18) ⌬F508 2 (10) ⌬F508 2 (1.8) ⌬F508 1 (1) R117H 9 (7) W1282X 2 (1.8) G542X 1 (1) W1282X 2 (1.6) R117H 1 (0.9) R334W 2 (1.6) S549R 1 (0.8) R347P 1 (0.8) N1303K 1 (0.8) Extensive screen† ⌬F508 23 (18) ⌬F508 2 (10) ⌬F508 2 (1.8) ⌬F508 1Mutations included in R117H 9 (7) W1282X 2 (1.8) G542X 131 mutation panel W1282X 2 (1.6) R117H 1 (0.9) R334W 2 (1.6) S549R 1 (0.8) R347P 1 (0.8) N1303K 1 (0.8) L206W 2 (1.6)‡ R75Q 2 (1.8)‡Mutations not included in P67L 1 (0.8)‡ G544S 1 (0.9)‡31 mutation panel 1677delTA 1 (0.8)‡ 2423delG 1 (0.9)‡ R117L 1 (0.8)‡ V754M 1 (0.9)‡ 4016insT 1 (0.8)‡ -741T→G 1 (0.9)‡ D979A 1 (0.8)§ R258G 1 (0.9)§ M952T 1 (0.8)¶ IVS8-5T 25 (20)# 2 (10) 12 (11) 5 (5) Detectable mutations 72 (56)# 4 (20) 24 (21)# 7 (7) Detectable mutations missed by 31 mutation panel 33 (46) 2 (50) 19 (79) Detectable non-IVS8-5T mutations missed by 31 mutation panel 8 (17) 0 (0) 7 (58) *Percentages indicate allele frequency. Login to comment

PMID: 10388469 [PubMed] Castaldo G et al: "Detection of five rare cystic fibrosis mutations peculiar to Southern Italy: implications in screening for the disease and phenotype characterization for patients with homozygote mutations."

No. Sentence Comment

13 A few mutations (i.e., ⌬F508, N1303K, G542X, and R553X) are frequent worldwide; the other mutations are regional or "private" mutations. Login to comment
36 All patients were first analyzed for eight CF mutations, i.e., ⌬F508, N1303K, G542X, W1282X, 1717-1G3A, R553X, 2183AA3G, and I148T (9). Login to comment
39 methods The eight CF mutations (i.e., ⌬F508, N1303K, G542X, W1282X, 1717-1G3A, R553X, 2183AA3G, and I148T) were identified with a semi-automated procedure based on a single multiplex PCR amplification followed by the allele-specific oligonucleotide (ASO) identification we described previously (9). Login to comment

PMID: 10402399 [PubMed] Jakubiczka S et al: "Frequency of CFTR gene mutations in males participating in an ICSI programme."

No. Sentence Comment

13 Materials and methods CFTR screening included the most frequent CFTR mutations in the German population (R347P, ∆F508, G542X, S549I,N,R(A→C), G551D, R553X, N1303K, and 3849ϩ10kbC→T) (Do¨rk et al., 1994) as well as the mutation R117H and the analysis of the IVS8-T haplotype. Login to comment
40 The most obvious difference between the studies lies in the frequency of the mutation G542X, accounting for eight out of 18 mutations detected among 101 males by van der Ven et al. (1996) but not found in any of our probands. Login to comment

PMID: 10439967 [PubMed] Liechti-Gallati S et al: "Two buffer PAGE system-based SSCP/HD analysis: a general protocol for rapid and sensitive mutation screening in cystic fibrosis and any other human genetic disease."

No. Sentence Comment

20 The distribution of analysed known mutations is similar to that of the total number of mutations in the entire CFTR gene: missense mutations account for 35% (G27E, G85E, R117H, A120T, I148T, H199Y, R334W, T338I, R347P, R347H, A455E, M718K, S5449N, S5449I, G551D, R560T, R560S, S945L, S977P, I1005R, R1066C, R1070Q, M1101K, D1152H, S1235R, R1283M, N1303K, N1303H), followed by 28% of frameshift mutations (175delC, 394delTT, 457TAT- > G, 905delG, 1078delT, I507, F508, 1609delCA, 1677delTA, 2143delT, 2176insC, 218delA, 2184insA, 2869insG, 3659delC, 3732delA, 3821delT, 3905insT, 4016insT, 4172delGC, 4382delA), 21% of nonsense mutations (Q30X, Q39X, Q220X, W401X, Q525X, G542X, Q552X, R553X, V569X, E585X, K710X, R792X, Y1092X, R1162X, S1255X, W1282X, E1371X), and 16% of splice site mutations (621 + 1G- > T, 711 + 1G- > T, 711 + 5G- > A, 1717-1G- > A, 1898 + 1G- > A, 1898 + 5G- > T, 2789 + 5G- > A, 3271 + 1G- > A, 3272-26A- > G, 3601-17T- > C, 3849 + 4A- > G, 3849 + 10kbC- > T, 4374 + 1G- > T). Login to comment
34 Intron 19, all 27 exons and their exon-intron boundaries, including the 24 most common mutations worldwide (G85E, R117H, 621 + 1G- > T, 711 + 1G- > T, 1078delT, R334W, R347P, A455E, I507, F508, 1717-1G- > A, G542X, S549N, G551D, R553X, R560T, 1898 + 1G- > A, 2184delA, 2789 + 5G- > A, R1162X, 3659delC, 3849 + 10kbC- > T, W1282X, N1303K) (Cystic Fibrosis Genetic Analysis Consortium 1994), and the 15 most common mutations in our population (I148T, 1078delT, R334W, R347P, F508, 1717-1G- > A, G542X, R553X, 2347delG, D1152H, R1162X, 3849 + 10kbC- > T, 3905insT, W1282X, N1303K), were considered in this study. Login to comment
61 The slots C present wild type (wt) sequences, 1-8 present amplification products from CF patients with the following genotypes: 1 = R553X/R553X; 2 = 1717-1G- > A/wt; 3 = R553X/wt; 4 = G542X/wt; 5 = G542X/1717-1G- > A; 6 = G551D/wt; 7 = R560T/wt; 8 = S549N/wt. Login to comment
92 The technique developed demonstrates excellent single-strand separation and non-radioactive visualisation on polyacrylamide gels, and is time-saving and directly Table 2 Known mutations identified in 198 CF patients analysed investigatively Exon (E) Number of CFTR mutations intron (I) chromosomes Patient`s nationality Highest prevalence ∆F508 E10 212 miscellaneous 3905insT E20 025 Swiss Swiss, Amish, Arcadian R553X E11 020 Swiss, German German 1717-1G->A I10 017 Swiss, Italian Italian N1303K E21 011 Swiss, French, Italian Italian W1282X E20 014 Swiss, Italian, Israelit Jewish-Askhenazi G542X E11 009 Swiss, Spanish, Italian Spanish 2347delG E13 008 Swiss R1162X E19 006 Swiss, Italian, Russian Italian 3849+10kbC->T I19 005 German, French R347P E07 004 Swiss T5 I08 004 Swiss R334W E07 003 Swiss Q525X E10 003 Swiss 3732delA E19 003 Swiss S1235R E19 003 Italian, Turkish G85E E03 002 Italian, Greek I148T E04 002 Austrian, Turkish French-Canadian 621+1G->T I04 002 French French-Canadian 1078delT E07 002 Swiss E585X E12 002 Italian 2176insC E13 002 Swiss, Italian 2789+5G->A I14b 002 Italian Spanish D1152H E18 002 Swiss, French 4016insT E21 002 Turkish Q39X E02 001 Swiss 394delTT E03 001 Swiss Nordic, Finnish R117H E04 001 Swiss A120T E04 001 Swiss G126D E04 001 Swiss 711+5G->A I05 001 Russian M348K E07 001 Italian L568F E12 001 Italian 2183AA->G E13 001 Italian Italian K710X E13 001 Swiss S945L E15 001 French 3272-26A.->G I17a 001 Swiss M1101K E17b 001 Swiss Huttite 3601-17C->T I18 001 Swiss R1158X E19 001 Swiss 4005+1G-A I20 001 Italian applicable to early diagnostic testing, carrier detection and prenatal diagnosis. Login to comment

PMID: 10444722 [PubMed] Gasparini P et al: "Analysis of 31 CFTR mutations by polymerase chain reaction/oligonucleotide ligation assay in a pilot screening of 4476 newborns for cystic fibrosis."

No. Sentence Comment

8 Other common mutations included G542X (16 of 144), which was particularly common in southern Italy (14 of 49), N1303K (8 of 144), and R117H (8 of 144), detected only in the northern centres. Login to comment
45 Other mutations found with greater than normal frequency were G542X, which is particularly common in southern Italy (14 of 49 individuals from San Giovanni Rotondo), N1303K (8 of 144), and R117H (8 of 144), which was detected only in the northern centres. Login to comment
46 Table 1 Mutations analysed in the CFTR gene using polymerase chain reaction/oligonucleotide litigation assay/sequence coded separation Mutation Location Nucleotide Result F508 Exon 10 3 bp deletion Deletion of Phe-508 I507 Exon 10 3 bp deletion Deletion of Ile-507 (or -506) Q493X Exon 10 C-1609 →→ T Gln-493 → Stop V520F Exon 10 G-1690 → T Val-520 → Phe 1717-1G → A Intron 10 G-1717-1 → A 3`-splice site mutation G542X Exon 11 G-1756 → T Gly-542 → Stop G551D Exon 11 G-1784 → A Gly-551 → Asp R553X Exon 11 C-1789 → T Arg-553 → Stop R560T Exon 11 G-1811 → C Arg-560 → Thr S549R Exon 11 T-1779 → G Ser-549 → Arg S549N Exon 11 G-1778 → A Ser-549 → Asn 3849+10 kb C → T Intron 19 C-3849+10 kb → T Splice mutation 3849+4A → G Intron 19 A-3849+4 → G Splice mutation R1162X Exon 19 C-3616 → T Arg-1162 → Stop 3659delC Exon 19 1 bp deletion Frameshift W1282X Exon 20 G-3978 → A Trp-1282 → Stop 3905insT Exon 20 1 bp insertion Frameshift N1303K Exon 21 C-4041 → G Asn-1303 → Lys G85E Exon 3 G-386 → A Gly-85 → Glu 621+1G → T Intron 4 G-621+1 → T 5`-splice site mutation R117H Exon 4 G-482 → A Arg-117 → His Y122X Exon 4 T-498 → A Tyr-122 → Stop 711+1G → T Intron 5 G-711+1 → T 5`-splice site mutation 1078delT Exon 7 1 bp deletion Frameshift R347P Exon 7 G-1172 → C Arg-347 → Pro R347H Exon 7 G-1172 → A Arg-347 → His R334W Exon 7 C-1132 → T Arg-334 → Trp A455E Exon 9 C-1496 → A Ala-455 → Glu 1898+1G → A Intron 12 G-1898+1 → A 5`-splice site mutation 2184delA Exon 13 Deletion A-2184; A-2183 → G Frameshift 2789+5G → A Intron 14B G-2789+5 → A Splice mutation Table 2 Summary of cystic fibrosis screening results No of samples analysed Normal subjects Carriers Carrier frequency Turin 1574 1521 53 1/29.7 Pavia 1341 1299 42 1/31.9 San Giovanni Rotondo 1561 1512 49 1/31.8 Total 4476 4332 144 1/31.1 Table 3 Detailed list of mutations detected in the Italian population Centre F508 G542X R347P 2183-AG N1303K 711+1GT 1717-1A R347H R117H 1898+1G 2789+5G W1282X R1162X I507 Other TO 33 2 1 1 5 1 1 2 3 2 2 - - - PV 27 - - 1 2 - 1 - 5 - 1 2 1 1 SGR 30 14 2 1 1 1 - - - - - - - - TO, Dipartimento di Patologia Clinica, Ospedale Infantile "Regina Margherita, Torino; PV, Istituto di Anatomia Patologica, Sezione di Anatomia Patologica, Università di Pavia, Pavia; SGR, Servizio di Genetica Medica and Divisione di Neonatologia, IRCCS Casa Sollievo della SoVerenza, San Giovanni Rotondo, Foggia. Login to comment

PMID: 10456926 [PubMed] Parad RB et al: "Pulmonary outcome in cystic fibrosis is influenced primarily by mucoid Pseudomonas aeruginosa infection and immune status and only modestly by genotype."

No. Sentence Comment

51 Genomic DNA isolated from each subject was evaluated for the presence of any of twelve CFTR gene mutations (⌬F508, G551D, G542X, 621ϩ1G3T, ⌬I507, 1717-1 G3A, R117H, N1303K, W1282X, R560T, R553X, and 3849ϩ10kb C3T) by one of three standard assays (10, 11, 32). Login to comment
101 Of these 12, 9 had one ⌬F508 CFTR gene allele, but the second allele was identified for only 2 of these 9 subjects (N1303K and G542X); the remaining 7 subjects carried a second CFTR gene allele that was not among the 12 most common ones we screened for. Login to comment
102 Two uninfected patients lacking any opsonic antibody were also compound heterozygotes with one of the two alleles not identified and the second allele being either G542X or G551D. Login to comment
118 with overall opsonic antibody titer of Ն5 26 14 Ͻ0.001 a Distribution of non-⌬F508 CFTR gene alleles in the uninfected group: G542X, 3 alleles; G551D, 1 allele; W1282X, 1 allele; N1303K, 1 allele; and not identified, 14 alleles. Login to comment
119 Distribution in the infected group was as follows: G542X, 2 alleles; G551D, 2 alleles; 621ϩ1G3T, 1 allele; and not identified, 7 alleles. Login to comment

PMID: 10480369 [PubMed] Romey MC et al: "Complex allele [-102T>A+S549R(T>G)] is associated with milder forms of cystic fibrosis than allele S549R(T>G) alone."

No. Sentence Comment

48 Five patients were compound heterozygotes for the complex allele and another mutation, two with ∆F508 and three with, R334 W, G542X, or S945L, respectively, and one patient was homozygous for the [-102T>A+S549R(T>G)] complex allele. Login to comment
50 5 months - 5 years 1 year 4 months 8 months 1.5 years - - 3 months 3 years 1 year 3 months 3 months 1 month 1 month (age of onset) Meconium ileus No No No No No No No No No No No No No No No No Pancreatic Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes insufficiency Table 2 Clinical characteristics of six patients carrying the complex allele: [-102T>A+S549R(T>G) (ND no data, FEV1 forced expiratory volume in 1 s, FVC forced vital capacity) Characteristic Patient P1 P2 P3 P4 P5 P6 Genotype -102T>A+S549R(T>G) -102T>A+S549R(T>G) -102T>A+S549R(T>G) -102T>A+S549R(T>G) -102T>A+S549R(T>G) -102T>A+S549R(T>G) -102T>A+S549R(T>G) R334 W ∆F508 ∆F508 G542X S945L Geographic background South of France South of Spain South of France North of France North of France South of France Ethnic background Jews of Algeria ND Jews ND North of Africa Jews Gender F F F F M M Current age (years) 34 38 6 31 23 18 Age at diagnosis 6 years 35 years 3.5 years 2 months 4 months 9 years Age of first clinical symptoms 5 years ND 3 years 2 months 4 months 5 years First clinical symptoms Episodic bronchitis Dyspnea Pulmonary disease Pulmonary disease Cough Pulmonary disease Sweat Cl- (mmol/l) ND < 60 122 66 72 85 Height (percentile) 60 50 ND 60 26 30 Weight (percentile) 60 50 ND 40 12 < 25 Shwachman-Kulczycki score 85 ND 85 ND 60 85 FEV1 (% predicted) 30 19.3 89 60 59 89 FVC (% predicted) 50 38.7 96 100 76 115 Lung colonization Yes No Yes Yes Yes Yes Pseudomonas aerug. Login to comment
64 As opposed to 100% of S549R(T>G)/S549R(T>G) patients, 50% of patients carrying the (-102T>A) sequence alter- 148 Table 3 Comparison of clinical features between CF patients carrying the complex allele [-102T>A+ S549R(T>G) and those carrying S549R(T>G) only Feature Patients with [-102T>A+ S549R(T>G)] Patients with S549R(T>G) P value (n = 6) (n = 16) Mean ± SD Median (5th-95th Mean ± SD Median (5th-95th (no. studied) percentile) (no. studied) percentile) Current age (years) 25 ± 11.8 (6) 27 (6-38) 5 ± 3.35 (13) 5 (2-12) 0.0032 Age at diagnosis (years) 9.0 ± 13.2 (6) 4.75 (0.16-35) 0.88 ± 1.0 (16) 0.41 (0.08-3.5) NS Sweat Cl- (mmol/l) 79.0 ± 27.13 (5) 72 (50-120) 117.2 ± 25.1 (14) 120 (70-155) 0.028 Shwachman-Kulczycki score 78.8 ± 12.5 (4) 85 (60-85) 50.0 ± 7.3 (15) 50 (35-60) 0.004 Age at onset of lung colonization 11.5 ± 6.7 (5) 11 (3.5-22) 1.0 ± 1.43 (13) 0.41 (0.08-5) 0.0022 Lung colonization 5/6 (83) 13/16 (81) NS (no. positive/no. studied) (%) Pancreatic insufficiency 3/6 (50) 16/16 (100) 0.013 (no. positive/no. studied) (%) Table 4 CFTR haplotypes for seven [-102T>A+ S549R(T>G)] chromosomes (parentheses indicate unknown phase) P1 [-102T>A+S549R(T>G)] 1 2 1 23 7 1 34 13 1 1 [-102T>A+S549R(T>G)] 1 2 1 23 7 1 34 13 1 1 P2 [-102T>A+S549R(T>G)] (1) (2) (1) 23 7 (1) 34 13 1 1 R334W (2) (1) (2) 17 7 (2) 46 13 1 1 P3 [-102T>A+S549R(T>G)] 1 2 1 23 7 1 34 13 1 1 ∆F508 1 2 1 23 9 1 31 13 1 1 P4 [-102T>A+S549R(T>G)] 1 2 1 23 7 1 34 13 1 1 ∆F508 1 2 1 23 9 1 32 13 1 1 P5 [-102T>A+S549R(T>G)] 1 2 1 23 7 1 34 13 1 1 G542X 1 2 1 22 9 1 33 13 1 1 P6 [-102T>A+S549R(T>G)] 1 2 1 23 1 34 13 1 1 S945L 2 1 2 16 7 2 29 13 1 1 Patient Genotype XV-2c KM-9 J44 IVS8CA IVS8(T)n M470V IVS17BTA IVS17BC 3601-65C/A J3.11 ation were pancreatic insufficient (P = 0.013). Login to comment

PMID: 10549060 [PubMed] Reynaud-Gaubert M et al: "[Respiratory disease in cystic fibrosis: from physiopathology to therapy. Kinesitherapy and pulmonary transplantation excluded]."

No. Sentence Comment

65 MUTATIONS DE LA CFTR Classification Les progrès récents de compréhension de la pathologie au niveau moléculaire ont permis de classer les anomalies de codage du gène en diverses classes, selon qu`elles affectent la transcription du gène, la translation, le transport ou la structure de la CFTR [14] : - Classe I : défaut de biosynthèse, générant une protéine altérée (tronquée ou aberrante) (ex : mutation G542X présente dans 3,4 % des cas). Login to comment

PMID: 10609658 [PubMed] Zuckerman JB et al: "A phase I study of adenovirus-mediated transfer of the human cystic fibrosis transmembrane conductance regulator gene to a lung segment of individuals with cystic fibrosis."

No. Sentence Comment

87 STU DY DESIGN A ND DO SE OF ADEN OVIRA L VECTOR H5.001CBCFTRa Baseline FEV1 Subject Dose (particles) a Region dosed Age/sex Genotype (% Pred) 1 2.1 3 109 Left lower lobe 20/M D F508/unknown 85 2 2.1 3 109 Right lower lobe 21/M D F508/G542X 67 3 7.0 3 109 Left lower lobe 23/F D F508/unknown 71 4 7.0 3 109 Left lower lobe 25/F D F508/R347P 48 5 2.1 3 1010 Left lower lobe 20/F D F508/unknown 89 6 2.1 3 1010 Right lower lobe 26/M D F508/unknown 95 7 7.0 3 1010 Right lower lobe 19/M D F508/unknown 108 8 7.0 3 1010 Left lower lobe 25/F D F508/D I507 70 9 2.1 3 1011 Left lower lobe 47/M D F508/unknown 90 10 2.1 3 1011 Right lower lobe 35/M D F508/R117H 61 11 2.1 3 1011 Right lower lobe 24/F D F508/unknown 107 a The dose is reported in total viral particles in a 7-ml suspension. Login to comment

PMID: 10627945 [PubMed] Gundry CN et al: "Rapid F508del and F508C assay using fluorescent hybridization probes."

No. Sentence Comment

149 Other clinically significant mutations (e.g., G542X, R553X, R1162X, N1303K, W1282X, G551D, G5151X, etc.) Login to comment

PMID: 10712334 [PubMed] Wilschanski M et al: "A pilot study of the effect of gentamicin on nasal potential difference measurements in cystic fibrosis patients carrying stop mutations."

No. Sentence Comment

29 Four patients were homozygous for the W1282X mutation, three were compound heterozygous W1282X/ G542X, one patient was compound heterozygous W1282X/3849 ϩ 10kb C→T, and one patient was compound heterozygous W1282X/ ⌬F508. Login to comment
70 Age (yr) FEV1 (% pred) Genotype 1 18 62 W1282X/W1282X 2 46 30 W1282X/W1282X 3 18 97 W1282X/W1282X 4 13 87 W1282X/W1282X 5 17 62 W1282X/G542X 6 23 60 W1282X/G542X 7 28 80 W1282X/G542X 8 38 44 W1282X/3849 ϩ 10kbC→T 9 12 73 W1282X/⌬F508 of gentamicin to increase the frequency of erroneous insertion of nonsense codons, thereby permitting the translation of CFTR alleles carrying missense mutations to continue reading to the end of the gene. Login to comment
84 Quantification studies have shown that after aminoglycoside incubation, the amount of full-length CFTR produced is as much as 25% (in the R553X mutation) to 35% (in the G542X mutation) of that observed in cells transfected with a wild-type CFTR complementary DNA (cDNA) (9, 10). Login to comment

PMID: 10733236 [PubMed] Zebrak J et al: "Partial CFTR genotyping and characterisation of cystic fibrosis patients with myocardial fibrosis and necrosis."

No. Sentence Comment

59 The latter was negative for 14 other mutations: DI507, 1717-1GA, G542X, G551D, R553X, R560T, 3849+10kbCT, N1303K, W1282X, S549I, S549N, 621+1GT, 2789+5GA, R117H. Login to comment

PMID: 10755189 [PubMed] Stuhrmann M et al: "CFTR gene mutations and male infertility."

No. Sentence Comment

84 CFTR mutations and male fertility Disorder Number of Proportion of Most frequent mutations (%) patients mutated alleles (%) Ethnic origin Reference CBAVD 17 20.6* DF508 (20.6) French Dumur et al. (1990b) CBAVD 25 38.0 DF508 (26.0) Northern European Anguiano et al. (1992) CBAVD 12 41.7 DF508 (20.8) French Culard et al. (1994) CBAVD 49 45.9 DF508 (32.6), R117H (6.1) Caucasians Oates & Amos (1994) CBAVD 47 21.3 DF508 (8.5), D1152H (3.2) Mostly Askenazim Augarten et al. (1994) CBAVD 30 41.7 DF508 (15.0), G542X (6.7), R117H (3.3) Spanish Casals et al. (1994) CBAVD 67 44.8 DF508 (20.9), R117H (4.5), W1282X (3.7) French Mercier et al. (1995) CBAVD 102 65.7+a DF508 (21.6), 5T (21.1), R347H (2.4) Caucasians Chillon et al. (1995) CBAVD 45 75.6+b DF508 (25.6), 5T (25.6), R117H (3.3), W1282X (3.3) French Costes et al. (1995) CBAVD 25 52.0+c 5T (26.0), DF508 (12.0), R117H (6.0) Caucasian Jarvi et al. (1995) CBAVD 70 68.6+d 5T (25.7), DF508 (19.3), W1282X (7.9) Mostly Caucasian Zielenski et al. (1995) CBAVD 101 79.2+e DF508 (26.2), R117H (11.4), 5T (12.9) Mostly German Do¨rk et al. (1997) CUAVD 10 5.0 DF508 (5.0) Spanish Casals et al. (1995) CUAVD 21 19.0 DF508 (9.5), R117H (4.8) Caucasian Mickle et al. (1995) BEDO 7 78.6 DF508 (28.5), 5T (21.4), R117H (14.3) Mostly German Meschede et al. (1997) IASV 16 3.1 I1139V (3.1) Mostly German Meschede et al. (1997) Azoospermia† 17 23.5+c 5T (14.7), R117H (5.9) DF508 (2.9) Caucasian Jarvi et al. (1995) Azoospermia 21 9.5 DF508 (2.4), G551D (2.4), R117H (2.4), G542X (2.4) Caucasian van der Ven et al. (1996) Spermatogenic failure 18 5.5+c G542X (2.8), 5T (2.8) Caucasian Jarvi et al. (1995) Spermatogenic failure 80 8.7 G542X (4.4), DF508 (3.1) Caucasian van der Ven et al. (1996) Spermatogenic failure 75 2.7+f DF508 (1.3), R117H (0.6), 5T (0.6) Dutch Tuerlings et al. (1998) *Testing only for DF508; +testing included the 5T allele; a-f, frequency of the 5T allele in the general population: a5.2%, n=498; b5.3%, n=131; c,dnot determined; e4.8%, n=186; f3.7%, n=212; †azoospermia with normal vas deferens and bilateral epididymal obstruction. Login to comment
95 Most patients are of German origin CFTR genotype (mutation class in brackets) Patients with typical CF (%) Patients with CBAVD (%) DF508 (2)/DF508 (2) 247 (59.4) 0 DF508 (2)/N1303K (2) 17 (4.1) 0 DF508 (2)/R347P (4) 13 (3.1) 0 DF508 (2)/R553X (1) 11 (2.6) 0 DF508 (2)/G542X (1) 11 (2.6) 0 DF508 (2)/G551D (3) 11 (2.6) 0 DF508 (2)/R1162X (1) 10 (2.4) 0 DF508 (2)/3849+10 KbC T (5) 9 (2.2) 0 DF508 (2)/2789+5G A (5) 9 (2.2) 0 DF508 (2)/3272-26 A G (5) 7 (1.7) 2 (2.6) DF508 (2)/1717-1G A (1) 6 (1.4) 0 DF508 (2)/CFTRdel21Kb (1) 5 (1.2) 0 DF508 (2)/R117H (4) 3 (0.7) 21 (26.9)* DF508 (2)/IVS8-5T (5) 2 (0.5) 9 (11.5)* DF508 (2)/other 33 (7.9) 20 (25.6) Other/other 22 (5.3) 26 (33.3) *Including one CUAVD patient each. Login to comment
140 One further aspect, not discussed by van der Ven et al. (1996), was thatbe caused by CFTR mutations was further substantiated by Meschede et al. (1997) who screened the increase in CFTR mutation frequency in males with reduced sperm quality was almost exclusively affected in a subset of CBAVD patients with CFTR mutations (e.g. IVS8-5T), whereas in other casesdue to the identification of mutation G542X on seven of 160 CFTR alleles (4.3%), which is 20 no disturbances of sperm maturation occur. Login to comment
141 times higher than the frequency of G542X in the general population of this area (0.2%). Login to comment
142 G542X is Genotype phenotype correlations particular frequent in Spain and Italy (The Cystic Fibrosis Genetic Analysis Consortium, 1994; The expression of CF disease is highly heterogeneous among different patients. Login to comment
146 The same mutation G542X was present in one of the 18 often monosymptomatic CF. Login to comment

PMID: 10756209 [PubMed] Lishanski A et al: "Branch migration inhibition in PCR-amplified DNA: homogeneous mutation detection."

No. Sentence Comment

126 Genotype Without reference DNA With reference DNA Wild-type homozygotes wt/wt 1.4 (1.2) 2.4 wt/wt 1.6 (1.3) 2.1 wt/wt 2.0 (1.5) 2.4 wt/wt 2.1 (1.4) 2.0 wt/wt 1.6 (1.2) 3.2 wt/wt 1.7 (1.4) 1.5 Heterozygotes G542X/wt G→T 41 (42) 38 G542X/wt G→T 73 (90) 66 G551D/wt G→A 83 (84) 93 G551D/wt G→A 99 (69) 76 R553X/wt C→T 92 (84) 57 R553X/wt C→T 105 (95) 61 R560T/wt G→C 130 (123) 70 R560T/wt G→C 109 (135) 111 G551D/R553X G→A/C→T 134 (134) 193 G551D/R553X G→A/C→T 134 (144) 235 Mutant homozygotes G542X/G542X G→T 1.5 (1.4) 174 G542X/G542X G→T 1.4 (1.5) 133 Blank (no target DNA) 1.6 Figure 3. Login to comment
139 Genotype Without εAεAG With εAεAG wt/wt 37 1.4 wt/wt 39 1.4 wt/wt 41 1. wt/wt 41 1.5 G542X/wt 121 126 G551D/wt 100 93 R553X/wt 82 85 R560T/wt 97 96 vi A PCR modification similar to the use of nested primers provided a powerful alternative method for reducing background signals. Login to comment

PMID: 10773783 [PubMed] Zielenski J et al: "Genotype and phenotype in cystic fibrosis."

No. Sentence Comment

165 Both studies showed that certain mild alleles (R117H; A455E; 3849+10kbC→T) from class IV or V tend to be associated with significantly lower Cl sweat levels than those for severe alleles ('F508; 621+1G→T; G542X; R553X, etc.). Login to comment

PMID: 10777364 [PubMed] Wang J et al: "A novel mutation in the CFTR gene correlates with severe clinical phenotype in seven Hispanic patients."

No. Sentence Comment

292 The frequency of this mutation in the Hispanic CF patients attending CHLA is similar to that of G542X, only second to F508. Login to comment

PMID: 10777368 [PubMed] Rivard SR et al: "Correlation between mutations and age in cystic fibrosis in a French Canadian population."

No. Sentence Comment

292 The frequency of this mutation in the Hispanic CF patients attending CHLA is similar to that of G542X, only second to F508. Login to comment

PMID: 10794365 [PubMed] Bernardino AL et al: "Molecular analysis in Brazilian cystic fibrosis patients reveals five novel mutations."

No. Sentence Comment

6 Another fifteen mutations (previously reported) were detected: G542X, R1162X, N1303K, R334W, W1282X, G58E, L206W, R553X, 6211 1GRT, V232D, 1717-1GRA, 2347 delG, R851L, 27891 5GRA, and W1089X. Login to comment
51 The next most common mutations were: G542X (8.8%), R1162X (2.5%), N1303K (2.5%), R334W (2.5%), W1282X (1.3%), G58E (1.3%), L206W (0.6%), and R553X (0.6%). Login to comment
81 In this study, 16 mutations were identified: D F508, G542X, R1162X, N1303K, R334W, W1282X, G58E, L206W, R553X, 6211 1GRT, V232D, 1717-1GRA, 2347 delG, R851L, 27891 5GRA, and W1089X. Login to comment
84 GEN OTYPES, FREQUENCIES, AN D PRESENCE OF PI FRO M 160 CF PATIE NTS (320 CF CHROM OSOM ES) Number and frequency (%) Genotype Number Frequency (%) of patients with PI D F508/D F508 47 29.40 47 (100%) D F508/G542X 13 8.10 13 (100%) D F508/R1162X 6 3.80 6 (100%) D F508/R334W 5 3.10 3 (60%) D F508/N1303K 3 1.90 3 (100%) D F508/W1282X 2 1.20 2 (100%) D F508/G58E 2 1.20 1 (50%) D F508/L206W 1 0.62 0 D F508/R553X 1 0.62 1 (100%) D F508/R851L 1 0.62 0 D F508/2789 1 5g ® A 1 0.62 0 D F508/3617delGA 1 0.62 1 (100%) D F508/3171delC 1 0.62 1 (100%) D F508/2686insT 1 0.62 1 (100%) D F508/Y275X 1 0.62 1 (100%) D F508/U 22 13.80 14 (64%) G542X/G542X 3 1.90 3 (100%) G542X/N1303K 3 1.90 2 (67%) G542X/R1162X 1 0.62 1 (100%) G542X/U 5 3.10 4 (80%) N1303K/R1162X 1 0.62 1 (100%) N1303K/G58E 1 0.62 0 2347delG/2347delG 1 0.62 1 (100%) R334W/V232D 1 0.62 0 R334W/W1089X 1 0.62 1 (100%) R334W/U 1 0.62 1 (100%) W1282X/U 1 0.62 1 (100%) G58E/U 1 0.62 1 (100%) R553X/U 1 0.62 1 (100%) L206W/U 1 0.62 0 621 1 1G ® T/U 1 0.62 1 (100%) 1717-1G ® A/U 1 0.62 Not known V201M/U 1 0.62 0 U/U 27 16.90 12 (44%) Total 160 100 - U, Unknown CF mutation. Login to comment
88 The second most common mutation, G542X, which occurred in 8.8% of our patients, is also the second most frequently reported in Spanish Mediterranean coastal areas (8.0%) (Casals et al., 1993). Login to comment
104 However, one of our compound heterozygote patients for severe mutations (N1303K/G542X), has PS. Login to comment
110 Unexpectedly, however one compound heterozygote (N1303K/G542X) CF patients (who was referred to above as having PS) was the son of first cousins, which is compatible with the high frequency of CFTR heterozygotes in the population. Login to comment

PMID: 10798368 [PubMed] Orozco L et al: "Spectrum of CFTR mutations in Mexican cystic fibrosis patients: identification of five novel mutations (W1098C, 846delT, P750L, 4160insGGGG and 297-1G-->A)."

No. Sentence Comment

17 We previously reported that only 39% of CF chromosomes from Mexican patients with Mestee ethnic background carry the ∆F508 mutation (Orozco et al. 1993) and 7.2% carry the G542X mutation (Villarreal et al. 1996), which is common in the Spanish population (Casals et al. 1997). Login to comment
27 Detection of known mutations ∆F508, G542X, N1303K, ∆I507 and 2869insG were screened by PCR-mediated site directed mutagenesis (PSM) as previously described (Friedman et al. 1991). Login to comment
41 The second most common mutation was G542X, present in 6.1% of CF chromosomes, followed by ∆I507 and S549N (each 2.5%), N1303K (2.06%) and 2055del→A (1.03%). Login to comment
69 First, we tested these patients for 12 mutations selected for the following reasons: five are the most common mutations worldwide (∆F508, G542X, N1303K, G551D and R553X; CFGAC 1994); 362 Table 1 Frequency of the CFTR gene mutations in 97 (194 chromosomes) Mexican patients Mutation Number of Frequency affected alleles (%) ∆F508 79 40.72 G542X 12 6.18 ∆I507 5 2.57 S549N 5 2.57 N1303K 4 2.06 R75X 3 1.54 406-1G→A 3 1.54 I148T 3 1.54 2055del9→A 2 1.03 935delA 2 1.03 I506T 2 1.03 3199del6 2 1.03 2183AA→G 2 1.03 G551D 1 0.51 R553X 1 0.51 1924del7 1 0.51 G551S 1 0.51 1078delT 1 0.51 Y1092X 1 0.51 R117H 1 0.51 G85E 1 0.51 3849+10KbC→T 1 0.51 1716G→A 1 0.51 W1204X 1 0.51 W1098Ca 1 0.51 846delTa 1 0.51 P750La 1 0.51 V754M 1 0.51 R75Q 1 0.51 W1069X 1 0.51 L558S 1 0.51 4160insGGGGa 1 0.51 297-1G→Aa 1 0.51 H199Y 1 0.51 2869insG 0 0 R1162X 0 0 3120+1G→A 0 0 Total 34 145 74.58% aNovel mutations detected in this study Fig.1 Sequencing ladders showing the CFTR novel mutations. Login to comment
74 The G542X mutation has a frequency higher (6.1%) than that reported to the CFGAC, but similar to Spanish patients (Casals et al. 1997). Login to comment

PMID: 10819640 [PubMed] Kilinc MO et al: "Genotype-phenotype correlation in three homozygotes for the cystic fibrosis mutation 2183AA-->G shows a severe phenotype."

No. Sentence Comment

446 The clinical data presented for three patients homozygous for the mutation and eight compound heterozygous patients who carry a severe mutation ( F508, G542X, and G1244E) on the other CFTR chromosome indicate that the mutation causes a severe CF phenotype. Login to comment

PMID: 10820156 [PubMed] Claass A et al: "Applicability of different antibodies for immunohistochemical localization of CFTR in sweat glands from healthy controls and from patients with cystic fibrosis."

No. Sentence Comment

33 Materials and Methods Tissue Samples Full-thickness skin biopsies were taken from the right shoulder of six healthy volunteers, four ⌬F508 homozygous CF patients, and four patients bearing two nonsense mutations within the CFTR gene (G542X/G542X; nϭ2; R553X/ R553X; and G542X/W1282X). Login to comment
114 No signals are observed with MATG 1104 (1:2400; Ba) in G542X/ G542X tissue; isotype control (Bb). Login to comment
115 G542X/W1282X is shown with cc24 (1:100; Ca; specific peptide competition, Cb); again, no labeling above the negative control is observed. Login to comment
130 Although overreading of stop codons has been reported to occur in mammalian cells (McCaughan et al. 1995), ample evidence exists that the nonsense mutations R553X and G542X of the CFTR gene result in reduced to undetectable levels of mRNA transcripts (Hamosh et al. 1992; Will et al. 1995) and absence of full-length protein (Howard et al. 1996). Login to comment
163 J Clin Invest 95:1601-1611 Gregory RJ, Cheng SH, Rich DP, Marshall J, Paul S, Hehir K, Ostedgaard L, Klinger KW, Welsh MJ, Smith AE (1990) Expression and characterization of the cystic fibrosis transmembrane conductance regulator. Nature 347:382-386 Hamosh A, Rodenstein BJ, Cutting GR (1992) CFTR nonsense mutations G542X and W1282X associated with severe reduction of CFTR mRNA in nasal epithelial cells. Login to comment

PMID: 10844532 [PubMed] Moss RB et al: "Cytokine dysregulation in activated cystic fibrosis (CF) peripheral lymphocytes."

No. Sentence Comment

30 Except for one patient who was heterozygous for G542x, the remainder (50%) were heterozygous for dF508, with other identified mutations including 3659delC (n 1), G85E (n 2), W1282X (n 1), 1898 1 1 (n 1), 2184delA (n 1), and G542X (n 1); six patients carried an unidentified mutation at the second allele. Login to comment

PMID: 10875853 [PubMed] Casals T et al: "Heterogeneity for mutations in the CFTR gene and clinical correlations in patients with congenital absence of the vas deferens."

No. Sentence Comment

55 ∆F508 and G542X were the most frequently patients (30 CBAVD, 10 CUAVD) were reported previously (Casals identified CF mutations, but at lower frequencies than in CF et al., 1995). Login to comment
59 Mutations ∆F508 and in CAVD than in CF patients [4.0% versus 0.6% (χ2 ϭ 20.09, G542X (Kerem et al., 1989, 1990) were analysed in all patients, as P Ͻ 0.001) and 3.6% versus 0.3% (χ2 ϭ 28.45, P Ͻ 0.001)they are the most common mutations in Spanish CF patients, 53% respectively].and 8% respectively (Casals et al., 1997). Login to comment
62 Recently, direct analysis of 31 CFTR mutations (PCR/OLA Cystic Fibrosis Assay; Perkin Elmer, Foster City) was 6(5T), ∆F508, G542X, L206W and R117H are the most performed in 30 of these infertile men. Login to comment
70 Thethe vas deferens M470V variant in exon 10 was analysed in 82 patients (98 Mutation CBAVD CUAVD Total alleles M470 and 66 V470), (TTGA)n in intron 6a which (n ϭ 42) 156 alleles (%) 14 alleles (%) 170 alleles (%) presented the higher frequency of seven repeats (129/272 alleles), T854T in exon 14a (72/272 alleles), 4521G→A in 5T 50a (32) 6 (43) 56 (33) exon 24 (62/272) and 3601-65C/A in intron 18 (48/272) were∆F508 40 (26) 3 (21) 43 (25) G542X 10 (6) 1 (7) 11 (6) the most frequent. Login to comment
95 CFTR genotypes in 24 patients with congenital unilateral absenceTable III. CFTR genotypes in 110 patients with congenital bilateral absence of the vas deferens of the vas deferens Mutations IVS8-6(T) n (%)Mutations IVS8-6(T) n (%) Two CFTR mutations 62 (56) Two CFTR mutations 5 (21) ∆F508/- 5T/9T 2 (8)∆F508/- 5T/9T 17 (15) G542X/- 5T/9T 6 (5) G542X/- 5T/9T 1 3732delA/- 5T/7T 1∆F508/L206W 9T/9T 6 (5) ∆F508/D1270NϩR74W 7T/9T 3 (3) L383S/- 5T/7T 1 One CFTR mutation 4 (17)∆F508/R117H 7T/7T 1 ∆F508/P1021S 7T/9T 1 ∆F508/-a 7T/9T 1 3732delA/-a 7T/7T 1∆F508/M952T 7T/9T 1 ∆F508/D110Y 7T/9T 1 Q890R/- 7T/7T 1 -/-a 5T/7T 1∆F508/S50P 5T/9T 1 ∆F508/2751ϩ3A→G 5T/9T 1 Negative CFTR mutations 15 (62) -/- 7T/7T 10 (42)G542X/R117H 7T/9T 1 G542X/2789ϩ5G→A 7T/9T 1 -/- 7T/9T 3 (12) -/- 9T/9T 2 (8)R117H/2789ϩ5G→A 7T/7T 1 R117H/712-1G→T 7T/9T 1 R117H/∆I507 7T/7T 1 aThree carrier patients with renal agenesis. Login to comment
101 Azoospermia was more frequent in CUAVD ∆F508/- 9T/9T 3 (3) patients with CFTR mutations (7/9) than in those without-/- 5T/9T 2 (2) G542X/- 7T/9T 2 (2) mutations (8/13), and sperm concentration was higher in the 2789ϩ5G→A/- 7T/7T 2 (2) latter group. Login to comment

PMID: 10918483 [PubMed] Hyde SC et al: "Repeat administration of DNA/liposomes to the nasal epithelium of patients with cystic fibrosis."

No. Sentence Comment

24 Genotype Dose Sex Age (years) FEV1 (litres) Clinical score A1 ⌬F508/1078delT CFTR M 22.7 3.25 85 A2 ⌬F508/⌬F508 CFTR M 22.9 3.4 90 A3 ⌬F508/G542X CFTR M 28.5 1.75 70 A5 ⌬F508/F945L CFTR M 30.3 3.05 70 A6 ⌬F508/⌬F508 CFTR M 24.4 1.25 70 B1 ⌬F508/⌬F508 CFTR M 17.6 3.8 90 B3 ⌬F508/1898+1(GϾA) CFTR F 16.9 2.15 80 B4 ⌬F508/G551D CFTR M 32.8 1.8 55 B6 ⌬F508/⌬F508 CFTR M 18.8 3.5 95 A4 ⌬F508/G551D Placebo F 16.5 2.65 95 B5 ⌬F508/3659delC Placebo M 16.4 2.8 85 All patients were pancreatic insufficient. Login to comment

PMID: 10922396 [PubMed] Teder M et al: "Distribution of CFTR gene mutations in cystic fibrosis patients from Estonia."

No. Sentence Comment

7 First, several known mutations were tested directly by the heteroduplex analysis (HA; F508, 394delTT, polyT variants in IVS8), restriction digestion (RD; G551D, R553X, 1811+1.6kbA→G, L206W, 3849+10kbC→T), and amplification refractory mutation system (ARMS, kits from Cellmark Diagnostics, UK; G542X, 621+1G→T, N1303K). Login to comment
66 This is the second most frequent mutation in several Nordic populations, with a relative frequency of 1.9% in Denmark,2 3.2% in Flanders,32 6.5% in Sweden,2 2.2-5.5% in Norway,2 and 30% in Finland.3 It was also found on 1.5% of the CF chromosomes in Russia.32 We did not find any of the mutations more common in European populations, such as G542X (2.6%), N1303K (1.6%), G551D (1.5%), or W1282X (1.0%),4 which is not surprising, as the relative frequency of these mutations is less than 1% in Nordic countries also. Login to comment

PMID: 10923221 [PubMed] Dawson KP et al: "The geographic distribution of cystic fibrosis mutations gives clues about population origins."

No. Sentence Comment

12 Eur J Pediatr (2000) 159: 496±499 Ó Springer-Verlag 2000 K. P. Dawson (&) Department of Paediatrics, Faculty of Medicine and Health Sciences, UAE University, PO Box 17666, Al Ain, United Arab Emirates P. M. Frossard Department of Pathology, Faculty of Medicine and Health Sciences, UAE University, PO Box 17666, Al Ain, United Arab Emirates We present here population genetics data that has been gathered about the DF508 mutation and information with regards to two other common mutations, namely G542X and N1303K. Login to comment
45 The G542X mutation G542X, a nonsense mutation, is the second most common mutation after DF508. Login to comment
49 Kerem et al. [10] described the G542X in their major paper on the identi®cation of the CF gene. Login to comment
53 They have produced a fascinating hypothesis that the areas with an elevated frequency of the G542X mutation correspond to ancient sites of occupation by the occidental Phoenicians. Login to comment
56 Thus the evidence to date suggests that the G542X mutation may provide another link in the story of the spread of the CF gene mutations and in the de®nition of their geography [1]. Login to comment
60 Microsatellite markers indicate that the mutation is about 35,000 years old (similar to G542X) and again diusion through Europe from an Asian origin is suggested by these recent ®ndings [8]. Login to comment
104 Loirat F, Hazout S, Lucotte G (1997) G542X as probably Phoenician cystic ®brosis mutation. Login to comment

PMID: 10940786 [PubMed] Zeitlin PL et al: "Future pharmacological treatment of cystic fibrosis."

No. Sentence Comment

22 Examples of CFTR mutations organized by classification of the defect in CFTR biosynthesis Type Genotype Phenotype Defect Cell diagram Drugs that may improve phenotype G542X 621+1 G → T 3905insT W1282X R553X 1717-1 G → A PI no CFTR protein no cell surface chloride transport gentamicin G418 Class II [64] 'F508 N1303K (P574H)a (A455E)a PI defective CFTR processing defective CFTR trafficking no cell surface chloride transport chemical chaperones CPX phenylbutyrate deoxyspergualin Class III [64] G551D G551S PI defective chloride channel regulation reduced or absent cell surface chloride transport genistein pyrophosphate Class IV [64, 66] R117H R334W G314E R347P ('F508)a P574H PS reduced chloride conductance reduced levels of cell surface chloride transport genistein milrinone phenylbutyrate Class V [64] 3849+10 kb C → T 2789+5 G → A 3272-26 A → G A455E 3120+1 G → A 1811+1.6 kb A → G 5Tb PS normal CFTR channels reduced numbers of normal CFTR reduced cell surface chloride transport genistein milrinone phenylbutyrate a Some mutants have features of more than one class of defect. Login to comment

PMID: 10950058 [PubMed] Ockenga J et al: "Mutations of the cystic fibrosis gene, but not cationic trypsinogen gene, are associated with recurrent or chronic idiopathic pancreatitis."

No. Sentence Comment

53 Using the ARMS technology (elucigene CF20, Zeneca Diagnostics, Oxfordshire, UK) all samples were tested additionally for the mutations E60X, R347P, A455E, 1078delT, 2183AA3G, G542X, G551D, N1303K, W1282X, 1717-1G3A, R553X, 621ϩ1G3T, R117H, R1162X, 3849ϩ10kbC3T, R334W, S1251N, and 3659delC. Login to comment

PMID: 10952679 [PubMed] Mall M et al: "Effect of genistein on native epithelial tissue from normal individuals and CF patients and on ion channels expressed in Xenopus oocytes."

No. Sentence Comment

26 Eight CF patients presenting with nasal polyps were tested for six common mutations: DF508, R553X, N1303K, G542X, G551D and R347P. Login to comment
30 In all CF patients from whom rectal biopsies were studied DNA analysis was carried out for the following CFTR mutations: DF508; R117H and S108F in exon 4; R347P, R347H, I336K and T338I in exon 7; S549N, G551D, R553X, G542X, Q552X, 1717-1 G?A in exon 11; W1282X and 3905insT in exon 20; N1303K in exon 21 and 3849+10kB C?T in intron 19. Login to comment

PMID: 10971545 [PubMed] Lader AS et al: "Increased circulating levels of plasma ATP in cystic fibrosis patients."

No. Sentence Comment

65 other CF mutations including R117H (n 3), G551D (n 1), G542X (n 1) and W1282X (n 1), had an encompassed plasma ATP level of 1á22 0á22 lM (n 10), thus similar to control values (P<0á4). Login to comment
66 Of these genotypes, the G551D mutation had the highest plasma ATP concentration (2á25), while the W1282X, G542X, and R117H mutations had plasma ATP concentrations of 1á6, 0á75 and 0á68, respectively. Login to comment

PMID: 10973878 [PubMed] Costes B et al: "Prenatal detection by real-time quantitative PCR and characterization of a new CFTR deletion, 3600+15kbdel5.3kb (or CFTRdele19)."

No. Sentence Comment

51 The mutations tested were S549N, S549R, R553X, G551D, V520F, ⌬I507, ⌬F508, Q493X, 1717-1G3A, G542X, R560T, R347P, R347H, 3849ϩ4A3G, W1282X, R334W, 1078delT, 3849ϩ10kbC3T, R1162X, N1303K, 3659delC, 3905insT, A455E, R117H, Y122X, 2183AA3G, 2789ϩ5G3A, 1898ϩ1G3A, 621ϩ1G3T, 711ϩ1G3T, and G85E. Login to comment

PMID: 11000267 [PubMed] Thelwell N et al: "Mode of action and application of Scorpion primers to mutation detection."

No. Sentence Comment

39 We have used Scorpion primers to detect five common ABCC7 mutations, ∆F508 (11-13), N1303K (15), W1282X (12), G542X (12) and G551D (12,16) (Table 1). Login to comment
60 Mutation site Base change Probe-target mismatch ∆F508 M55115 436-438 CTT del - N1303K M55128 329 C→G C-C W1282X M55127 395 G→A C-A G551D M55116 362 G→A C-A G542X M55116 334 G→T C-T All PCR reactions were carried out on a Roche LightCycler. Login to comment
72 Oligo name Code Oligo sequence MTHFR forward primer BPF 5'-CTGACCTGAAGCACTTGAAGG-3' MTHFR reverse primer BPR 5'-ATGTCGGTGCATGCCTTCAC-3' MTHFR Molecular Beacon MMB 5'-FAM GCGAGTGCGGGAGCCGATTTCTCGC MR-3' MTHFR TaqMan MT 5'-FAM TGCGGGAGCCGATTT TAMRA-3' MTHFR Scorpion MS 5'-FAM CCCGCGGAAATCGGCTCCCGCACCGCGGG MR HEG CTGACCTGAAGCACTTGAAGG-3' ∆F508 normal Scorpion 508S 5'-FAM CCGCGCAAACACCAAAGATGATATTTTCTGCGCGG MR HEG AGTTTTCCTGGATTATGCCT-3' ∆F508 mutant Scorpion 508M 5'-ROX CCGC(F)GCAAACACCAATGATATTTTCTGCAGCGG MR HEG AGTTTTCCTGGATTATGCCT-3' ∆F508 reverse primer 508R 5'-TTGGGTAGTGTGAAGGGTTC-3' ∆F508 forward primer 508F 5'-AGTTTTCCTGGATTATGCCT-3' Hybrid Scorpion HS 5'-FAM CCGCGCAAACACCAAAGATGATATTTTCTGCGCGG MR HEG CTTGGAGAAGGTGGAATCAC-3' N1303K Scorpion N13S 5'-FAM CCCGCGCGGAACATTTAGAAAAAACTTGGATCCCGCGCGGG MR HEG TTTCTTGATCACTCCACTGTTC-3' N1303K reverse primer N13R 5'-CATACTTTCTTCTTCTTTTCTTT-3' W1282X Scorpion W12S 5'-FAM CCCGCGCCTTTCCTCCACTGTTGCGCGCGGG MR HEG ATGGTGTGTCTTGGGATTCA-3' W1282X reverse primer W12R 5'-GGCTAAGTCCTTTTGCTCAC-3' G551D Scorpion 551S 5'-FAM CCCGCGCCTCGTTGACCTCCACTCGCGCGGG MR HEG CTTGGAGAAGGTGGAATCAC-3' G551D reverse primer 551R 5'-AAATGCTTGCTAGACCAATA-3' G551D forward primer 551F 5'-CTTGGAGAAGGTGGAATCAC-3' G551D-DIST Scorpion (90 bases between 3'-end of Scorpion primer and 5'-end of probe target) G90 5'-FAM CCCGCGCCTCGTTGACCTCCACTCGCGCGGG MR HEG CAGATTGAGCATACTAAAAG-3' G542X Scorpion G542S 5'-FAM CCGCGCACCTTCTCCAAGAACTAGCGCGG MR HEG CCAAGTTTGCAGAGAAAGAC-3' G542X reverse primer G542R 5'-AAATGCTTGCTAGACCAATA-3' Table 3. Login to comment
73 Annealing and fluorescence monitoring temperatures used for each locus Loci/test Annealing temperature (°C) Monitoring temperature (°C) ∆F508 48 51 N1303K 44 61 W1282X 49 53 G551D 47 55 G551D-DIST 46 55 G542X 48 53 Unimolecular versus bimolecular test 47 51 Distance constraints G90 Scorpion 46 55 G551DS Scorpion 47 55 MTHFR 58 58 described in Results were 95°C for 30 s, 58°C for 60 s and 72°C for 30 s. Login to comment

PMID: 11025834 [PubMed] Wang X et al: "Mutation in the gene responsible for cystic fibrosis and predisposition to chronic rhinosinusitis in the general population."

No. Sentence Comment

11 Results Eleven CRS patients were found to have a CF mutation (⌬F508, n=9; G542X, n=1; and N1303K, n=1). Login to comment
30 Analysis of CFTR Genes Genomic DNA samples extracted from the blood of participants were screened for 16 mutations (R117H, 621+1G→T, R334W, R347P, A455E, ⌬I507, ⌬F508, 1717-1 G→A, G542X, S549N, G551D, R553X, R560T, 3849+10 Kb C→T, W1282X, and N1303K) that account for 85% of CF alleles in the white population using the multiplex reverse dot hybridization system (Roche Molecular Systems, Alameda, Calif).16,17 This test also identified the 5T, 7T, and 9T variants of the splice acceptor site in intron 8 and F508C, I507V, and I506V (exon 10) polymorphisms of the CFTR gene. Login to comment
46 Eleven CRS patients were found to have CF mutations (TABLE 1); 9 had the common mutation, ⌬F508, 1 had G542X, and 1 had N1303K. Login to comment
53 Using this technique, we previously demonstrated that at least 96% of mutations in the exons and flanking intron regions of the CFTR gene can be detected.16 A 97% sensitivity was achieved using 115 samples with previously identified mutations16 in this study.Sequenceanalysisofsampleswith anabnormalDGGEpatternidentifiedan R75Q mutation in the N1303K carrier and an L967S mutation in the G542X carrier. Login to comment
59 Patient 1386 had changes in exon 10 (M470V), exon 15 (L967S), and exon 11 (G542X), and pedigree analysis was used to show that the M470V variant and the L967S variant segregated independently of G542X. Login to comment
67 Cystic Fibrosis (CF) Mutations and Cystic Fibrosis Transmembrane Regulator (CFTR) Variants in Chronic Rhinosinusitis (CRS) Patients and Controls* CRS, No. (%) Non CRS, No. (%) P Value (n = 147) (n = 123) CF mutations ⌬F508/+ 1 2 ⌬F508/M470V 7 0 G542X/M470V, L967S 1 0 N1303K/+; M470V/M; R75Q/+† 1 0 (⌬F508/2789+5G→A)‡ 1 0 Frequency of CF carriers 10 (7) 2 (2) .04§ (n = 136) (n = 121) CFTR variants 5T Variant in non-CF carriers࿣ 5T/+ 11 (9) 6 (6) .25§ Codon 470 genotypes among non-CF carriers࿣ M/M 21 (16) 23 (19) M/V 55 (40) 64 (53) .03¶ V/V 60 (44) 34 (28) *Plus (+) indicates wildtype. Login to comment
87 1386 M G542X/M470V, L967S 16 14 + Asthma, Pseudomonas aeruginosa pneumonia§ Normal Ͻ15 Fathered 3 children, genetically confirmed 1379 F ⌬F508/M470V Ͻ10 8 - Normal Normal 31 Problem conceiving 1380 M ⌬F508/M470V 59 2 + Asthma Normal 39 Fathered 2 children 1468 F ⌬F508/M470V 20 2 - Normal Normal 29 Problem conceiving 1509 F ⌬F508/M470V 26 None - Asthma Normal 21 . Login to comment

PMID: 11076060 [PubMed] Tanackovic G et al: "The incidence of cystic fibrosis (CF) mutations among patients from Croatia."

No. Sentence Comment

5 After DNA isolation (2), we screened the samples for the 16 most common CFTR mutations: DF508, DI507 [heteroduplex analysis (3)] G542X, G551D, W1282X, N1303K, 3849+10kbCT, R553X, 621+1GT, R1162X, 1717-1GA, 2789+ 5GA, 3849+4AG, 1898+1GA, R117H [restriction fragment length polymorphism, (4-7)] and 3905insT [single-strand conformational polymorphism analysis (8)]. Login to comment
7 The presence of six different mutations was observed on 60 CF chromosomes: DF508, G542X, 1717-1GA, R117H, N1303K and R1162X (Table 1). Login to comment
14 The second most common mutation among Croatian CF patients was G542X with a relative frequency of 5.0%. Login to comment
16 The frequency of mutation G542X in two neighbouring countries was, however, lower: Slovenia (3.3%) (17) and Hungary (2.4%) (12, 18). Login to comment

PMID: 11095651 [PubMed] Persu A et al: "CF gene and cystic fibrosis transmembrane conductance regulator expression in autosomal dominant polycystic kidney disease."

No. Sentence Comment

52 Genomic DNA samples were screened using the Elucigene CF12 kit (based on Amplification Refractory Mutation System technology; Zeneca Diagnostics, Abingdon, UK), to detect the following 12 CFTR mutations: 1717-1G3A, G542X, W1282X, N1303K, ⌬F508, 3849ϩ10kbC3T, 621ϩ1G3T, R553X, G551D, R117H, R1162X, and R334W. Login to comment
99 Characteristics of the 12 mutations of the CF gene screened for among the patients with ADPKD and the control subjectsa Name Location Nucleotide Change CFTR Domain Consequence R117H Exon 4 G3A at 482 TM2 Arg3His at 117 621ϩ1G3T Intron 4 G3T at 621ϩ1 mRNA splicing mutation R334W Exon 7 C3T at 1132 TM6 Arg3Trp at 334 ⌬F508 Exon 10 3-bp deletion between 1652 and 1655 NBD1 Phe-508 deletion 1717-1G3A Intron 10 G3A at 1717-1 NBD1 mRNA splicing mutation G542X Exon 11 G3T at 1756 NBD1 Gly3Stop at 542 G551D Exon 11 G3A at 1784 NBD1 Gly3Asp at 551 R553X Exon 11 C3T at 1789 NBD1 Arg3Stop at 553 R1162X Exon 19 C3T at 3616 Arg3Stop at 1162 3849ϩ10kbC3T Intron 19 C3T in a 6.2-kb EcoRI fragment 10 kb from 19 NBD2 Creation of a splice acceptor site W1282X Exon 20 G3A at 3978 NBD2 Trp3Stop at 1282 N1303K Exon 21 C3G at 4041 NBD2 Asn3Lys at 1303 a Modified from reference 16. Login to comment

PMID: 11100963 [PubMed] Choo-Kang LR et al: "Type I, II, III, IV, and V cystic fibrosis transmembrane conductance regulator defects and opportunities for therapy."

No. Sentence Comment

22 The nonsense mutations G542X, W1282X, R553X, Q39X, E60X, R75X, L719X, Y1092X, and S1196X significantly reduce the levels of mutant CFTR mRNA to 5 to 30% of wild-type levels [28]. Login to comment
37 Molecular fate of CFTR protein Type of genetic defect and example Class-specific potential therapeutic approach Specific clinical examples I No synthesis Nonsense G542X Frameshift 394delTT Splice junction 1717-1G→A Aminoglycoside readthrough of premature termination site Gentamicin II Trafficking block AA deletion ∆F508 Missense N1303K Manipulation of intracellular folding environment (chemical or molecular chaperones) Phenylbutyrate, CPX III Block in regulation Missense G551D Stimulation of membrane localized mutant channel Genistein, MPB- compounds IV Altered conductance Missense R117H Augmentation of mutant channel conductance Milrinone, adenosine nucleotides V Reduced synthesis of normal protein Missense A455E Alternative splicing 3849+10kbC→T Maximal activation of decreased but functionally normal channels Stimulation of mRNA and protein synthesis ? Login to comment

PMID: 11101688 [PubMed] Jezequel P et al: "Molecular screening of the CFTR gene in men with anomalies of the vas deferens: identification of three novel mutations."

No. Sentence Comment

54 The three men with CUAVD wereTotal genomic DNA was isolated from the patients` peripheral blood cells and analysed for mutations in the whole CFTR region and splice compound heterozygotes (G542X/R1070W, ∆F508/R117H, junctions. Login to comment
60 Tworegions (1, 2, 5, 6a, 6b, 7, 10, 11, 12, 14a, 14b, 15, 16, 17a, 17b, 18, 20, 22, 23, 24) were amplified with a GC-clamp primer and six exons mutations were found in 31.9% of patients, 31.9% had one Table I. Summary of the clinical and biological findings of a population of men with congenital bilateral absence of the vas deferens (CBAVD, n ϭ 37), congenital unilateral absence of the vas deferens (CUAVD, n ϭ 3) and obstructive azoospermia (Obs A, n ϭ 7) Patient Phenotype Surgical Age Weight Height Sweat test Other clinical CFTR exploration (years) (kg) (m) (Cl- mEq/l) manifestation genotype 1 CBAVD ϩ 40 63 1.72 72 ∆F508/T5 2 CBAVD ϩ 31 66 1.76 40 L1227S/3272-26A→G 3 CBAVD ϩ 29 ∆F508/T5 4 CBAVD 29 sinusitis -/- 5 CBAVD 32 50 1.60 ∆F508/T5 6 CBAVD 35 64 1.66 ∆F508/T5 7 CBAVD ϩ 28 ∆F508/R117H 8 CBAVD ϩ 34 69 1.80 24 ∆F508/R117H 9 CBAVD ϩ 35 65 1.70 R117H/T5 10 CBAVD ϩ 32 50 1.70 31 asthma ∆F508/T5 11 CBAVD ϩ 26 left hydrocele T5/- 12 CBAVD ϩ 23 left varicocele, G551D/T5 asthma, anosmia 13 CBAVD ϩ 29 ∆F508/T5 14 CBAVD ϩ 36 63 1.64 52 ∆F508/R117H 15 CBAVD ϩ 37 60 1.76 ∆F508/T5 16 CBAVD ϩ 34 70 1.65 24 ∆F508/A1067V 17 CBAVD 35 61 1.73 42 ∆F508/R117H 18 CBAVD 25 72 1.82 86 2183AA→G/T5 19 CBAVD 28 88 1.76 7 -/- 20 CBAVD ϩ 29 ∆F508/T5 21 CBAVD 31 48 epididymite -/- 22 CBAVD 28 ∆F508/T5 23 CBAVD ϩ 32 68 1.76 36 flatulence ∆F508/R1070W 24 CBAVD ϩ 31 64 1.76 39 R1162X/T5 25 CBAVD 30 17 asthma R117H/L375F 26 CBAVD ϩ 36 62 1.70 ∆F508/R1070W 27 CBAVD 30 6 -/- 28 CBAVD 35 85 1.70 R1070W/- 29 CBAVD 39 bronchectasis -/- 30 CBAVD ϩ 29 ∆F508/- 31 CBAVD 31 bronchectasis, -/- deafness 32 CBAVD ϩ 26 asthma, otitis -/- 33 CBAVD ϩ 28 allergy -/- 34 CBAVD 37 36 R117H/- 35 CBAVD 33 -/- 36 CBAVD ϩ 30 64 1.68 R117H/T5 37 CBAVD ϩ 37 71 1.78 31 pancreatitis, 621ϩ1G→T/I980K alcoholism 38 CUAVD 43 62 1.68 40 allergy G542X/R1070W 39 CUAVD ϩ 35 allergy ∆F508/R117H 40 CUAVD ϩ 34 hydrocele L375F/G551D 41 Obs A ϩ 32 26 T5/- 42 Obs A 23 60 sinusitis ∆F508/2789ϩ2insA 43 Obs A ϩ 25 80 sinusitis, chronic ∆F508/4428insGA 44 Obs A ϩ 30 bronchitis -/- anosmia 45 Obs A 29 50 -/- 46 Obs A 29 75 1.77 ∆F508/T5 47 Obs A ϩ 30 82 1.66 -/- mutation and the T5 allele, 10.7% had only one mutation and clinical palpation. Login to comment
73 This mutation creates a stop codon 43 nucleotides 26 ∆F508/R1070W (TG)10T9/(TG)10T7 downstream leading to the deletion of 33 C-terminus amino 16 ∆F508/A1067V (TG)10T9/(TG)10T7 acids of the CFTR protein including the TRL-COOH domain.42 ∆F508/2789ϩ2insA (TG)10T9/(TG)10T7 43 ∆F508/4428insGA (TG)10T9/(TG)11T7 This highly conserved proteic site is a perfect match for the 25 R117H/L375F (TG)10T7/(TG)10T7 binding consensus domain of the Naϩ-Hϩ exchanger regulatory 38 G542X/R1070W (TG)10T9/(TG)11T7 factor (NHE-RF), a cytoplasmic phosphoprotein that may play40 L375F/G551D (TG)10T7/(TG)10T7 37 621ϩ1G→T/I980K (TG)10T9/(TG)10T9 an important regulatory role in CFTR function (Wang et al., 2 L1227S/3272-26A→G (TG)10T9/(TG)12T7 1998). Login to comment

PMID: 11116277 [PubMed] Roomans GM et al: "Pharmacological treatment of the ion transport defect in cystic fibrosis."

No. Sentence Comment

219 5.6 Gentamicin The aminoglycoside antibiotic gentamicin has been shown to suppress two premature stop mutations (G542X and R553X) [114]. Login to comment

PMID: 11139834 [PubMed] Shah PL et al: "Update on clinical trials in the treatment of pulmonary disease in patients with cystic fibrosis."

No. Sentence Comment

43 A pilot study has thus far treated eight patients with the G542X mutation with iv. Login to comment
57 (Genetech, Roche, NIH) & University of Cornell Repeated dosing, every 30 days to the Lungs Age > 15 years FEV1 > 40% predicted 26 Degree of transfection, duration and stability of expression Adenovirus vector Phase II University of Iowa Repeated administration to the lung NK NK Degree of transfection, duration and stability of expression Adeno-associated viral vector Phase I Targeted Genetics, Medeva, Stanford University, University of Washington & Boston Children Hospital Aerosol to lung Age > 15 years FVC > 40% predicted CF genotypes: DF508, G551D, W1282X, and G542X 12 Degree of transfection Cationic lipids, Cytofectins Phase I Genzyme, Vical, University of Alabama Lung Age > 18 years FEV1 > 40% predicted NK Degree of transfection Liposomal DNA complexes Phase II NHLI, UK Inhalation to lung Male FEV1 > 70% 16 i) functional correction ii) degree of transfection iii) bacterial adherence NHLI: National Heart & Lung Institute (Imperial College, UK); NIH: National Institute of Health (USA); NK: Not known. Login to comment

PMID: 11157821 [PubMed] McCallum T et al: "Unilateral renal agenesis associated with congenital bilateral absence of the vas deferens: phenotypic findings and genetic considerations."

No. Sentence Comment

60 Therereflects the 26 mutation/5T allele polymorphism assessment at the was no history of maternal diabetes, obvious teratogen exposurepresent time at Boston University Center for Human Genetics: or evidence of known congenital syndromes in themselves, orR117H; 1717-1G→A; G542X; 621ϩ1; S549N; R560T; I507; G551D; their families, that the men in either group could recall. Login to comment

PMID: 11158459 [PubMed] Wine JJ et al: "Comprehensive mutation screening in a cystic fibrosis center."

No. Sentence Comment

16 Mutations detected in both groups included 7 missense mutations (S13F, P67L, G98R, S492F, G970D, L1093P, N1303K) and 9 deletion, frameshift, nonsense or splicing mutations (R75X, G542X, ⌬F508, 451-458⌬8 bp, 5T, 663⌬T, exon 13 frameshift, 1261؉1G3A and 3272-26A3G). Login to comment
86 Mutations in the Stanford CF Mutation Database After Screening With the Genzyme70 Assay Mutation n % n % ⌬F508 353 67.11% 353 67.11% Splice mutations 16 3.04% 621ϩ1 G3T 5 0.95% 1717-1 G3A 5 0.95% 2789ϩ5 G3A 1 0.19% 1898ϩ1 G3A 1 0.19% 3849ϩ10 kb C3T 4 0.76% Stop mutations 31 5.89% Q493X 1 0.19% G542X 13 2.47% R553X 4 0.76% R1162X 1 0.19% W1282X 10 1.90% S1455X 2 0.38% Insertions/deletions 9 1.71% 681 del C 1 0.19% 2184 del A 2 0.38% 3859 del C 5 0.95% 3905 ins T 1 0.19% Missense mutations 33 6.27% G85E 4 0.76% R117H 3 0.57% R334W 6 1.14% G551D 14 2.66% R560T 3 0.57% N1303K 3 0.57% Unknown mutations 84 15.97% 84 15.97% Total 526 100.00% 526 100.00% ARTICLES tients with positive sweat tests were selected for SSCP/HA analysis based on clinical status, ethnicity, and previous screening with the Genzyme70 assay. Login to comment
155 PS none - SN3 unk/unk 10-15 PS none GATT6/6, 1001ϩ11 C3T, TG10, T9 homozygous all SN4 unk/unk 25 PI None M470V (10), (GT)11/10 GATT7/7, 1896ϩ152 A/T (I12); 2694T/G (14a), 4521G3A (24) SN5 G542X unk 25 PS none M470V (10), TG11, T7 SN6 unk*/unk* 48 PS P67L (3) 1261ϩIG3A (I13) 1898ϩ174 ins A (I12), 2694T3G (14a) 4521G3A (24) 1812-3 ins T, (I11), homozygous SN7 unk/unk 40 PS None found - Notation as for Table 1. Login to comment

PMID: 11168023 [PubMed] Goldman A et al: "The molecular basis of cystic fibrosis in South Africa."

No. Sentence Comment

6 DF508 accounts for 76% of the CF chromosomes in this group, with 3272-26AG, 394delTT and G542X occurring at the following frequencies: 4, 3.6 and 1.3%, respectively. Login to comment
27 Five other mutations were identified in the white population, G542X, R553X, S549N, 621+lGT and N1303K which together account for a further 3% of mutations (5). Login to comment
40 White and coloured patients with unidentified CF mutations were tested for 15 mutations including 394delTT, Q493X, 3272-26A G, 3120+1GA as well as 11 other mutations, R117H, R334W, G542X, G551D, R553X, 621+ 1GT, W1282X, N1303K, 1717-1GA, R1162X, 3849+10kbCT. Login to comment
58 Frequency of CFTR mutations in white CF chromosomes Mutation Number of chromosomes Frequency (%) DF508 291 76 3272-26AG 16 4 394delTT 14 3.6 G542X 5 1.3 R553X 4 1 1W1282X 4 14N1303K G551D 3 0.8 3120+1GA 2 0.5 R117H 1 0.3 Q493X 1 0.3 S549N 1 0.3 621+1GT 1 0.3 1717-1GA 1 0.3 2789+5GA 1 0.3 91Total 349/384 Table 2. Login to comment
59 Genotypes of South African coloured CF patients Genotype Number of patients 2DF508/DF508 DF508/3120+1GA 5 1DF508/G542X DF508/U 2 3120+1GA/R1162X 1 13120+1GA/G551D 3120+1GA/U 1 1U/U 14Total U=unidentified mutation. Login to comment
81 The G542X mutation accounted for 1.3% of mutations. Login to comment
85 The R1162X, G551D and G542X mutations were each found on one chromosome. A total of 82% (23/28 chromosomes) of mutations have been identified. Login to comment

PMID: 11243954 [PubMed] Marchand E et al: "Frequency of cystic fibrosis transmembrane conductance regulator gene mutations and 5T allele in patients with allergic bronchopulmonary aspergillosis."

No. Sentence Comment

6 All subjects in the study were screened for the presence of 13 mutations in the CFTR gene (R117H, 621 ؉ 1G->T, R334 W, ⌬F508, ⌬I507, 1717-1G->A, G542X, R553X, G551D, R1162X, 3849 ؉ 10kbC->T, W1282X, and N1303K). Login to comment
11 Results: Six patients with ABPA were found to be heterozygous for one CFTR mutation, including ⌬F508 (n ‫؍‬ 2), G542X (n ‫؍‬ 1), R1162X (n ‫؍‬ 1), 1717-1G->A (n ‫؍‬ 1), and R117H (n ‫؍‬ 1). Login to comment
42 Genomic DNA samples were screened for the following CFTR mutations: R117H/ exon 4, 621 ϩ 1G-ϾT/intron 4, R334 W/exon 7, ⌬F508/exon 10, ⌬I507/exon 10, 1717-1G-ϾA/intron 10, G542X/exon 11, R553X/ exon 11, G551D/exon 11, R1162X/exon 19, 3849 ϩ 10kbC-ϾT/ intron 19, W1282X/exon 20, and N1303K/exon 21. Login to comment
58 Six patients (patients 1 to 6) were identified to carry one CFTR mutation, including ⌬F508 (n ϭ 2), G542X (n ϭ 1), R1162X (n ϭ 1), 1717-1G-ϾA (n ϭ 1), and R117H (n ϭ 1). Login to comment
99 Sweat Chloride,† mEq/L CFTR Mutation Intron 8 Polythymidine Tract Alleles 1 17 ⌬F508 7T/9T 2 33 ⌬F508 7T/9T 3 6 G542X 7T/9T 4 38 R1162X 7T/7T 5 54 1717-1G3A 7T/7T 6 8 R117H 7T/9T 7 36 - 7T/7T 8 23 - 7T/7T 9 14 - 7T/7T 10 19 - 7T/7T 11 37 - 7T/7T 12 NA - 7T/7T 13 40 - 7T/7T 14 38 - 7T/7T 15 14 - 7T/7T 16 19 - 7T/7T 17 32 - 7T/7T 18 15 - 7T/7T 19 34 - 7T/9T 20 13 - 7T/7T 21 34 - 7T/7T *See Table 1 for expansion of abbreviation. Login to comment

PMID: 11274414 [PubMed] Zhong XB et al: "Visualization of oligonucleotide probes and point mutations in interphase nuclei and DNA fibers using rolling circle DNA amplification."

No. Sentence Comment

32 Cell lines with mutations at the G542X locus of the cystic fibrosis transmembrane conductance regulator (CFTR) gene (GM11497, heterozygous mutation; GM11496; homozygous mutations), a cell line (CTL2337) with a single C insertion between nucleotides 5382 and 5383 of the BRCA1 gene, and standard HeLa cell lines, were obtained from the American Tissue Type Collection (Corriel Cell Repositories, Camden, NJ). Login to comment
54 A mixture of 500 nM decorator probes (Det3-Cy3 for ⌬F508, Det1c-FITC, Det1d-FITC for G542X, Det4-Cy5 for M1101K) in 2 ϫ SSC, 1% BSA, and 0.1% Tween 20 was applied to the slides. Login to comment
68 Physical mapping of three loci in the CFTR gene region by RCA Locus ODN sequences ⌬508 Probe-primer PRP3 (89): 3Ј-CCCTCTTGACCTCGGAAGTCTCCCATTTTAATTCGTGTCACCTTCTTAAAtttt(CH2)18tttttACGTCATCATGAACATTACACGTTCCAC-3Ј Circle3 (78): GTGGAACGTGTAATGTTCATGATGACGTGCATCCTTGACAGCCGATGAGGCTGGCATCCTTGACAGCCGATGAGGCTG Decorator probe: Det3-Cy3 (24): 5Ј-Cy3-GCATCCTTGACAGCCGATGAGGCT-3Ј G542X Probe-primer PRP1 (89): 3Ј-GAACCTCTTCCACCTTAGTGTGACTCACCTCCAGTTGCTCGTTCTTAAAGtttt(CH2)18tttttATGATCACAGCTGAGGATAGGACATGCGA-3Ј Circle1 (78): CGCATGTCCTATCCTCAGCTGTGATCATCAGAACTCACCTGTTAGACGCCACCAGCTCCAACTGTGAAGATCGCTTAT Decorator probe: Det1c-FITC (18): 5Ј-FITC-TCAGAACTCACCTGTTAG-3Ј; Det1d-FITC (18): 5Ј-FITC-ACTGTGAAGATCGCTTAT-3Ј M1101K Probe-primer PRP4 (89): 3Ј-GACGGTTGACCAAGAACATGGACAGTTGTGACGCGACCAAGGTTTACTCTtttt(CH2)18tttttCTTGTACATGTCTCAGTAGCTCGTCAGT-3Ј Circle4 (78): ACTGACGAGCTACTGAGACATGTACAAGGAGCAGTCCTGT˙CAGCTAGGTCACGGAGCAGTCCTGTCAGCTAGGTCACG Decorator probe: Det4-Cy5 (24): 5Ј-Cy5-GAGCAGTCCTGTCAGCTAGGTCACG-3Ј Bold type: probe sequence; lowercase tttt(CH2)18ttttt: linker; standard type: RCA primer, circle, and decorator ODN sequences. Note that probe-primer and AD-P2-ODNs have polarity reversal and two 3Ј ends. Login to comment
75 Human genomic DNA fibers were stretched from freshly cultured normal peripheral blood lymphocytes and GM11496 cells (homozygous G542X mutation). Login to comment
93 A mixture of 500 nM decorator probes (Det3-Cy3 for ⌬F508, Det1c-FITC, Det1d-FITC for G542X, Det4-Cy5 for M1101K) in 2 ϫ SSC, 1% BSA, and 0.1% Tween 20 was applied to the slides. Login to comment
100 Experiments designed for allele discrimination at the G542X locus did not use the PAC prehybridization step outlined above. Login to comment
101 Instead, the P1 anchor ODN and the pair of P2 AD-ODNs for the G542X locus were cohybridized with the 50-mer non-AD-ODN probes for the ⌬508 and M1101K loci, which acted as reference markers. Login to comment
102 The hybridization, ligation, RCA reactions, washes, and signal detection conditions were carried out as described for the detection of G542X mutations in interphase cells. Login to comment
122 To test the ability of RCA to detect small genomic DNA sequences within interphase nuclei and stretched DNA fibers we chose three 50-bp targets at the ⌬508, G542X, and M101K mutation loci within the CFTR gene. Login to comment
131 In Fig. 2A, the RCA products from the ⌬508, G542X, and M11101K probes were detected by Cy3-, FITC-, and Cy5-labeled decorator ODNs, respectively. Login to comment
136 The overall RCA detection efficiency at the ⌬508, G542X, and M1101K loci averaged 37%, 45%, and 35%, respectively. Login to comment
140 (A) RCA detection of probes targeted to the G542X locus (FITC), the ⌬508 locus (Cy-3), and the M1101K locus (Cy5) in normal human lymphocytes. Login to comment
143 (C) Cohybridization of two PAC clones (extended green and red signals) with ⌬508 (yellow), G542X (green), and M1101K (white) oligomer probes. Login to comment
153 The overall efficiency in detecting RCA signals at the ⌬508, G542X, and M1101K loci were 48%, 44%, and 36% respectively. Login to comment
157 The sequences of the P1 and the two AD-P2 ODNs designed to detect mutations at the G542X locus of the CFTR gene are given in Table 2. Login to comment
172 Detection of the G542X mutation also was done on stretched DNA fibers prepared from normal lymphocytes and the GM11496 cell line homozygous for the G542X mutation (Fig. 3B). Login to comment
176 RCA detection of wt and mu alleles at the G542X locus of the CFTR gene. Login to comment
178 (B) Discrimination of wt and mu alleles of the G542X locus on stretched DNA fibers. Login to comment
183 The wt G542X allele is labeled with Cy5 while the mu allele is labeled with Cy3. Login to comment
184 The merged image (Com) shows a yellow-blue-white hybridization pattern when the G542X allele is wt and a yellow-green-white pattern when G542X is a mu allele. Login to comment
186 It was apparent, however, that wt and mu alleles at the G542X could be readily detected as many fibers showing the hybridization profiles illustrated in Fig. 3B were observed. Login to comment

PMID: 11298840 [PubMed] Attardo T et al: "Genetic, andrological and clinical characteristics of patients with congenital bilateral absence of the vas deferens."

No. Sentence Comment

49 We investigated the following 11 CFTR mutations: DF508, G542X, R553X, N1303K, W1282X, R347P, L1077P, 2183AA ® G, 1717±1G > A, R1162X, and R117H. Login to comment
61 The other mutations found were: W1282X in four patients, G542X in two patients, R347P in one patient and R553X in one patient. Login to comment
63 The patient with CUAVD had the G542X mutation associated with the 5T allele (Table 1). Login to comment
66 Four wives (14.8%) had the 5T allelic variant and of their husbands, two had the alleles G542X or W1282X and two had no mutations. Login to comment
87 38) with CUAVD Patient Age (years) Mutation/ 5T allele Sweat test Steatocrit FEV1 Other clinical features 1 38 R347P/ND Normal ND ND ND 2 29 DF508/ND ND ND ND ND 3 37 ±/ND ND ND ND ND 4 38 ±/ND ND ND ND ND 5 29 DF508/ND Normal ND = ND 6 40 ±/ND Normal ND = ND 7 32 DF508/ND Borderline ND = ND 8 29 DF508/ND ND ND ND ND 9 41 ±/ND Borderline ND ¯ ND 10 32 DF508/± Normal = = RB 11 35 R553X/± Borderline - = RB 12 29 ±/ND Borderline - = Diarrhoea 13 37 ±/ND Abnormal = = Sinusitis 14 36 W1282X/± Normal - = Recurrent bronchitis 15 35 G542X/± Abnormal = ¯ ± 16 34 W1282X/5T Abnormal = = Diarrhoea 17 31 ±/5T Abnormal = = ± 18 22 ±/± Borderline - = Diarrhoea 19 27 G542X/± Abnormal = = Recurrent bronchitis 20 35 ±/± Abnormal - = Recurrent bronchitis 21 33 W1282X/± Abnormal = ND Sinusitis, diarrhoea 22 30 DF508/5T Abnormal - = ± 23 20 ±/± Abnormal = = Sinusitis, diarrhoea 24 39 ±/± Normal = ¯ Asthma, collapse 25 35 ±/5T Normal - ¯ Sinusitis, diarrhoea 26 26 W1282X/5T Abnormal - = ± 27 35 ±/± Normal - = ± 28 30 DF508/5T Normal - = ± 29 29 DF508/ND ND ND ND Collapse 30 35 ±/5T Normal = ¯ ± 31 36 DF508/5T Borderline = ¯ Sinusitis, asthma, collapse, polyps 32 41 ±/5T Normal - ¯ Recurrent respiratory infection 33 39 ±/5T Normal = ¯ Sinusitis 34 27 DF508/5T Borderline - = ± 35 39 ±/± Normal ND ¯ Diarrhoea 36 37 ±/± Normal - = Polyps 37 40 ±/± Abnormal - ¯ Asthma, recurrent respiratory infection 38 29 G542X/5T Borderline - ¯ Diarrhoea ND: Not determined; ±: absence of mutations or clinical features; =: unchanged; -: increased; ¯: decreased. Login to comment
97 As shown elsewhere (Dumur et al., 1990; Anguiano et al., 1992), the presence of DF508 was the commonest mutation observed in patients with CBAVD, followed by W1282X and G542X. Login to comment
98 DF508 is also the most frequent mutation found in patients with CF, followed by G542X and W1282X (F. Mollica et al., unpublished data). Login to comment
114 The patient with CUAVD presented with a G542X/5T genotype and had also an abnormal sweat test, reduced FEV1, steatorrhoea and symptoms of digestive dysfunction. Login to comment

PMID: 11307750 [PubMed] Scheid P et al: "Inflammation in cystic fibrosis airways: relationship to increased bacterial adherence."

No. Sentence Comment

140 Group 1 (n=13) with mistraf- ®cking mutations on both alleles (DF508 homozygotes and a DF508/I507 compound heterozygote), group 2 (n=6) with only one mistraf®cking mutation (DF508 compound heterozygotes, the second mutation being R553X62, 1717-1GAA, 621+1GAT, G551D62), and group 3 (n=3) without mistraf®cking mutations (genotypes being G542X/3849+10kB GAT, G542X/ R533X, 1717-1GAA/G551D). Login to comment

PMID: 11313771 [PubMed] Henry MT et al: "An alpha1-antitrypsin enhancer polymorphism is a genetic modifier of pulmonary outcome in cystic fibrosis."

No. Sentence Comment

66 1237G group: G551D (10); R117H (3); R560T (3); D1507 (2); E60X (2); N1303K (1); 1717-1 (1); 621H (1); G542X (1); POL 400 (1); R352Q (1); RT0F (1); 621+G4T (1); Unknown (15). Login to comment

PMID: 11336401 [PubMed] Orgad S et al: "Prevalence of cystic fibrosis mutations in Israeli Jews."

No. Sentence Comment

33 These were: delF508 (Kerem et al., 1989), W1282X (Vidaud et al., 1990), G542X, 1717-1G R A, S549R (Kerem et al., 1990), N1303K (Osborn et al., 1991), 3849 1 10Kb C R T (Highsmith et al., 1994), T359K/Q360K (Shoshani et al., 1992), G85E (Zielenski et al., 1991), 405 1 1G R A (Dork et al., 1993), W1089X (Shosani et al., 1994), and D1152H (Highsmith et al., 1993). Login to comment
45 There were 173 (46.3%) carriers of the W1282X mutation; 110 (29.4%) carriers of delF508; 23 (6.1%) carriers of G542X; 10 (2.7%) carriers of N1303K; and 22 (5.9%) carriers of 3849 1 10KbC R T. Twenty (5.3%) were found to carry D1152H; 11 (2.9%) carried 405 1 1G R A; 4 (1.1%) carried W1089X; and 1 (0.3%) carried S549R. No carriers were detected for the mutations 1717-1G R A, G85E, and T360K, which were tested for in 7,383, 1,436, and 41 individuals, respectively. Login to comment
52 Mutations tested for all individuals in the cohort North Total Ashkenazi Sephardi Africa Eastern number of Mutation no. 6850 no. 933 no. 1146 no. 468 carriers W1282X 142 17 8 6 173 delF508 86 12.25 11.5 0.25 110 G542X 20.25 0.5 1.75 0.5 23 N1303K 7.5 1.5 0.25 0.75 10 3849110Kb 17 2 2 1 22 C® T B. Mutations tested for individuals of non-Ashkenazi origin, mixed origin, and of spouses of carriers Type of Total number mutation Number tested Ashkenazi Sephardi North Africa Eastern of carriers D1152H Number tested 1,305 458.25 722.75 280 Carriers 11.5 4.5 3.5 0.5 20 405 Number tested 425.75 372 633.5 119 11G® A Carriers 0.5 1 9.5 0 11 W1089X Number tested 539.25 345 638.5 135 Carriers 2 0.5 1 0.5 4 S549R Number tested 534.5 385.5 686 110 Carriers 0 1 0 0 1 a Ethnic origin was classified according to the country of origin of the four grandparents of each individual. Each grandparent was calculated as contributing a quarter of his/her gene pool and these were summed up for each ethnic origin. Login to comment
74 Therefore, Ashkenazi Jews would have been tested for the five main mutationsonly: delF508,W1282X, G542X, N1303K, and 3849 1 10KbC R T. The mutations D1152H and W1089X would not have been included in the test panel in Ashkenazi Jews. Login to comment

PMID: 11345141 [PubMed] Modolell I et al: "Gastrointestinal, liver, and pancreatic involvement in adult patients with cystic fibrosis."

No. Sentence Comment

45 The second most prevalent mutation was G542X, present in eight patients. Login to comment
50 In the remaining 14 patients, ⌬F508 was carried with G542X, R1162X, N1303K, L206W, 1717-1G>A, 711+1G>T, or an unidentified mutation. Login to comment
51 In the 10 patients of group A without ⌬F508, the mutations identified were: G542X (present in five), R1162X, Q890X, ⌬I507, 2183A, and 1609-CA. Login to comment
56 5T, G542X, R334W, N1303K, L206W, 3659-C, and G85E were identified in the remaining nine patients. Login to comment
64 Other genotypes present in our series ⌬F508/711+1G>T 2A 5T/5T 1B ⌬F508/5T 2B ⌬1507/- 1A ⌬F508/R117H 2B R1162X/1898+1G>A 1A ⌬F508/R1162X 1A 2183A/- 1A ⌬F508/N1303K 1A 1609-CA/1811+1.6kbA>G 1A ⌬F508/3272-26A>G 1B 1609-CA/R347P 1A ⌬F508/D836Y 1B Q890X/- 1A ⌬F508/1717-1G>A 1A R334W/- 1B G542X/W1282X 1A N1303K/2789+5G>A 1B G542X/2789+5G>A 1B 3659-C/- 1B G542X/P205S 1B G85E/- 1B G542X/D1270N 1B Negative 1A, 20B L206W/- 1B Unknown 2A creatic insufficiency was highly prevalent, affecting 33 patients (84.6%). Login to comment
98 The second most prevalent mutation, G542X, was present in eight patients (8.98%), a prevalence similar to that described in the literature. Login to comment
135 The four patients in our series ⌬F508/G542X all belonged, as expected (28), to group A and three of them had pancreatic insufficiency. Login to comment

PMID: 11379874 [PubMed] Le Marechal C et al: "Complete and rapid scanning of the cystic fibrosis transmembrane conductance regulator (CFTR) gene by denaturing high-performance liquid chromatography (D-HPLC): major implications for genetic counselling."

No. Sentence Comment

140 For example, if only the ∆F508 and the other most common mutations (G551D, G542X, W1282X, 1717-1 G→A) are sought, the detection rate is 70% and the residual risk is around 1/3. Login to comment

PMID: 11388756 [PubMed] Heim RA et al: "Improved detection of cystic fibrosis mutations in the heterogeneous U.S. population using an expanded, pan-ethnic mutation panel."

No. Sentence Comment

109 More strikingly, the five mutations reported to account for 97% of Ashkenazi Jewish chromosomes (⌬F508, G542X, W1282X, N1303K, and 3849 ϩ 10 kbCϾT)16 accounted for only 39/48 chromosomes in this study (81.3%). Login to comment

PMID: 11401894 [PubMed] Clancy JP et al: "Evidence that systemic gentamicin suppresses premature stop mutations in patients with cystic fibrosis."

No. Sentence Comment

61 Nasal cells from a G542X/ ⌬F508 patient (A, B, C) and a ⌬F508/⌬F508 patient (E, F ) in increasing concentrations of gentamicin: (A) G542X/⌬F508 0 ␮gm/mlgentamicin;(B)G542X/ ⌬F508 10 ␮gm/ml gentamicin; (C) G542X/⌬F508 100 ␮gm/ ml gentamicin; (D) G542X/⌬F508 no gentamicin, no primary antibody (control); (E) ⌬F508/⌬F508, no gentamicin; (F) ⌬F508/⌬F508, 100 ␮gm/ml gentamicin. Login to comment
86 STUDY PATIENT DEMOGRAPHICS* Age/Sex Premature Stop CF Subjects Control CF Subjects Genotype P.a FEV1 (% pred) Age/Sex Genotype P.a FEV1 (% pred ) 18/M G542X/⌬F508 (ϩ) 52 23/F ⌬F508/⌬F508 (ϩ) 38 18/M G542X/⌬F508 (ϩ) 76 18/F ⌬F508/⌬F508 (ϩ) 29 15/F W128X/⌬F508 (ϩ) 105 30/M ⌬F508/G55ID (ϩ) 19 28/M G542X/⌬F508 (ϩ) 25 26/F ⌬F508/⌬F508 (ϩ) 53 13/F R553X/621G-T (ϩ) 40 28/F ⌬F508/⌬F508 (ϩ) 34 18.4 yr (5.77)† 59.6 (31.5)† 25 yr (4.69)† 34.6 (11.8)† * Age (yr, mean Ϯ SD), sex (M ϭ male, F ϭ female), bacterial colonization (P.a ϭ Pseudomonas aeruginosa), FEV1 (forced expiratory volume in 1 s, %pred. Login to comment
90 (A) Cells from a G542X/⌬F508 patient (open symbols) and a ⌬F508/⌬F508 patient (closed symbols) were isolated, grown, and loaded with SPQ as described in METHODS. Login to comment
94 A positive response was obtained for 5/44 G542X/⌬F508 cells treated with 10 ␮gm/ml gentamicin and 42 of 44 cells treated with 100 ␮gm/ml gentamicin, and the means of these responding cells are plotted (Ϯ S.E.M.). Login to comment
95 No responding cells were identified in the G542X/⌬F508 cells without gentamicin treatment (n ϭ 40), or any of the ⌬F508/⌬F508 cells (n Ͼ 80 cells tested in each condition). Login to comment
97 (B) The percent of positive cells in each condition are shown for the ⌬F508/⌬F508 (left) and G542X/ ⌬F508 cells (right) in the increasing concentrations of gentamicin. Login to comment
112 To investigate the effects of gentamicin on CFTR biosynthesis in human tissues, nasal cells from a G542X/⌬F508 patient with CF were grown on glass coverslips and exposed to medium with gentamicin at 0, 10, and 100 ␮g/ml for 16 h followed by immunohistochemical staining for surface-localized CFTR. Login to comment
114 Figures 1A-1C identify CFTR antigen at the cell membrane from G542X/⌬F508 nasal cells with increasing gentamicin concentrations. Login to comment
118 In a parallel set of experiments, nasal cells isolated from a G542X/⌬F508 patient with CF were grown on glass coverslips and studied for evidence of halide transport, using the fluorescent dye SPQ. Login to comment
120 Figure 2 shows that G542X nasal cells exposed to gentamicin at 10 and 100 ␮g/ml had increased halide efflux in response to stimulation with a cAMP-elevating cocktail, compared with cells with no gentamicin exposure. Login to comment
122 Similar (immunocytochemical and functional) results have been observed for airway cells derived from other patients with premature stop mutations (G542X/⌬F508 and R553X/⌬F508 ([23] and our unpublished observations). Login to comment
180 Similar observations were made with transient expression systems for other CF-associated premature stop mutations, including G542X, R553X, and R1162X mutations, in addition to W1282X (12, 13). Login to comment

PMID: 11404347 [PubMed] Slatkin M et al: "The use of intraallelic variability for testing neutrality and estimating population growth rate."

No. Sentence Comment

253 the recent growth rate of European populations is not TABLE 2 Parameters and results for the CFTR data sets p n N0 ␮ ϭ 0.0001 ␮ ϭ 0.0005 ␮ ϭ 0.001 ␮ ϭ 0.0005 Mutation (ϫ10-4 ) i So (ϫ103 ) (ϫ107 ) (single) (single) (double) (double) ⌬F508 132 2112 59 160.0 20.0 0.0 0.0 6.0 ϫ 10-73 6.3 ϫ 10-21 ⌬F508 132 2112 118 160.0 20.0 0.0 5.5 ϫ 10-91 4.4 ϫ 10-39 1.0 ϫ 10-4 G542X 6.8 116 9 170.6 5.82 8.9 ϫ 10-8 0.012 0.231 0.907 N1303K 5.6 59 7 105.3 5.18 5.9 ϫ 10-4 0.180 0.639 0.977 1717-1G-A 3.2 24 3 75.0 4.38 0.031 0.370 0.695 0.945 R1162X 2.2 68 4 309.1 5.18 3.4 ϫ 10-4 0.082 0.313 0.829 Definitions are as in Table 1, except the mutation rates. Login to comment
271 TABLE 3 Values of ␹2 ϭ -2 log(L0/L*) calculated as described in the text for each allele at CFTR compared to the rest ␮ ϭ 0.00028: ␮ ϭ 0.00028: ␮ ϭ 0.00084: ␮ ϭ 0.00084: Mutation So ϭ 59 So ϭ 118 So ϭ 59 So ϭ 118 ⌬F508 20.3 11.0 19.6 4.6 G542X 5.8 1.4 5.4 0.8 N1303K 8.4 3.8 7.9 3.0 1717-1G-A 3.4 0.5 3.5 1.0 R1162X 1.8 0.6 1.6 0 So was estimated by using a parsimony algorithm to infer because they depend on assumed values of parameters and on a simplified model of past population growth.the minimum number of mutations necessary to gener- The results for CFTR are compatible with those for PAHate the observed haplotypes. Login to comment

PMID: 11462247 [PubMed] Castellani C et al: "Analysis of the entire coding region of the cystic fibrosis transmembrane regulator gene in idiopathic pancreatitis."

No. Sentence Comment

41 Genetic analysis Phase 1 - Patients were tested for the following mutations: F508del, I507del, R117H, R1162X, 2183AA>G, N1303K, 3849+10KbC>T, G542X, 1717-1G>A, R347P, R352Q, R553X, Q552X, G85E, 711+5G>A, W1282X, 3132delTG and 2789+5G>A, plus the CFTR intron 8 poly(T) tract length. Login to comment

PMID: 11466205 [PubMed] Larriba S et al: "Adenosine triphosphate-binding cassette superfamily transporter gene expression in severe male infertility."

No. Sentence Comment

87 Phenotypical and genotypical description of CAVD and non-CAVD infertile patients.a No. patient Phenotype FSH (U/L) Non-CFTR infertility-associated factors Testicular biopsy CFTR mutation M470V polymorphism CAVD infertility 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 CBAVD CBAVD CBAVD CBAVD CBAVD CBAVD CBAVD CBAVD CBAVD CBAVD CBAVD CBAVD CBAVD CBAVD CBAVD CBAVD CUAVD CUAVD CUAVD CUAVD 3.1 7.3 3.1 2.4 1.9 3.5 5.7 4.3 3.6 ND 2.2 4.8 11.3 2.1 ND 7.6 5.3 6.5 3.9 21.4 None None None None None None None None None None None None None None None None None None None Yes 1 Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes V232D/V232D F508del/R117H F508del/R117H G542X/2789ϩ5GϾA F508del/D1270N ϩ R74W F508del/D1270N ϩ R74W S945L/R258G F508del/5T F508del/5T L206W/5T R117H/N F508del/N Y1014C/N 5T/N N/N N/N Y1092X/R258G 621ϩ1GϾT/5T Q890R/N N/N M/M M/M M/M M/M M/V M/V M/V M/M M/V M/V M/V M/V M/V M/V M/M V/V V/V M/V V/V M/M Non-CAVD infertility 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 TF (SA) TF (SA) TF (SA) TF (SA) TF (SA) TF (SA) TF (SA) TF (SA) TF (SA) TF (SSO) TF (SSO) TF (SSO) TF (SSO) TF (SSO) TF (SSO) TF (SSO) TF (SSO) TF (SSO) TF (SSO) TF (SA) TF (SA) TF (SSO) OA OA OA OA OA OA OA OA 42.0 15.9 34.8 8.9 26.3 6.4 7.8 15.6 8.7 3.2 3.9 12.6 4.7 1.3 5.6 3.9 6.1 9.3 8.8 19.3 9.6 ND 3.3 5.9 6.6 3.6 1.9 4.2 2.0 4.4 None None None None None None None None None None None None None None None None Yes 2 Yes 2 Yes 2, 3 Yes 4 Yes 5 Yes 6 None None None None None Yes 1 Yes 7 Yes 8 Yes Yes Yes Yes No Yes Yes Yes Yes Yes Yes Yes Yes No No No No No No Yes Yes Yes Yes Yes Yes Yes No Yes Yes Yes F508del/N R334W/N N/N N/N N/N N/N N/N N/N N/N R75Q/N N/N N/N N/N N/N N/N N/N N/N N/N N/N N/N N/N N/N 5T/5T N/N N/N N/N N/N N/N N/N N/N M/M V/V M/V M/V M/V M/V V/V V/V V/V V/V M/V M/V M/V ND V/V M/M M/V M/M M/V M/M M/V V/V M/V M/V M/V V/V V/V M/V M/V V/V a CFTR mutations and M470V allele are also described for each patient. Login to comment
94 CFTR Analysis We have identified 14 different CFTR mutations (R117H, L206W, V232D, R258G, F508del, G542X, 621ϩ1GϾT, Q890R, S945L, Y1014C, Y1092X, D1270N, 2789ϩ5GϾA, IVS8-6[5T]) in 17 of 20 patients of the CAVD group, giving a CFTR mutation frequency of 85%. Login to comment

PMID: 11472971 [PubMed] Bals R et al: "Salt-independent abnormality of antimicrobial activity in cystic fibrosis airway surface fluid."

No. Sentence Comment

35 R347P, and one ⌬F508/unknown; plus one G542X/unknown, one 621 ϩ 1G Ͼ T/W1282X, and four unknown) and their bacteriology (three Staphylococcus aureus positive, three Pseudomonas aeruginosa positive, and four other positive results). Login to comment

PMID: 11484207 [PubMed] Orozco L et al: "XV-2c/KM-19 haplotype analysis of cystic fibrosis mutations in Mexican patients."

No. Sentence Comment

43 DF508 and G542X chromosomes (56% of all CF chromosomes) were highly associated with haplotype B (97.2% and 72.7%, respectively). Login to comment
47 Carrier Detection XK haplotype analysis of families with at least one unknown CF allele or with uncommon mutations was TABLE I. Distribution of XK Haplotype on Cystic Fibrosis (CF) and Normal Chromosomes A B C D DF508 N 72 70 (97.2%) 2 (2.8%) G542X N 11 1 (9.09%) 8 (72.72%) 2 (18.18%) Others N 32 13 (40.6%) 5 (15.6%) 9 (28.1%) 5 (15.6%) Unknown N 33 18 (54.5%) 1 (3.0%) 13 (39.4%) 1 (3%) CF chromosomes N 148 32 (21.6%) 84 (56.7%) 22 (14.9%) 10 (6.8%) Normal N 110 54 (49.1%) 8 (7.3%) 35 (31.8%) 13 (11.8%) useful to determine the carrier status of siblings in 18 families (24.3%), as illustrated in Figure 1. Login to comment
51 This difference is mainly due to the high frequency of mutations DF508 and G542X, associated with haplotype B in 97.2% and 72.7% of chromosomes, respectively. Login to comment
72 G542X is the second most common CF mutation worldwide. Login to comment
74 It has been suggested that G542X was introduced into Europe by the occidental Phoenicians 2,000 or 3,000 years ago [Loirat et al., 1997]. Login to comment
75 In the Mexican population, G542X is also the second most common mutation (6.1%), and was found to be most frequently associated with haplotype B (72.2%), but also with haplotypes A (9.09%) and D (18.18%). Login to comment
77 Recombination on the original G542X chromosome. Login to comment
82 The fact that G542X was found in Native American populations of the U.S. Southwest such as the Pueblo [Grebe et al., 1992] supports the latter hypothesis. Login to comment

PMID: 11485629 [PubMed] Joseph PM et al: "Aerosol and lobar administration of a recombinant adenovirus to individuals with cystic fibrosis. I. Methods, safety, and clinical implications."

No. Sentence Comment

170 DAY 1 CLINICAL CHARACTERISTICS OF SUBJECTS RECEIVING LOBAR ADMINISTRATION OF VECTOR Age FEV1 Dose Subject Sex (years) (% pred) NIH score Genotype Vector (IU) 1 M 31 2.31/50 69 DF508/DF508 Ad2/CFTR2 8 3 106 2 M 26 3.92/81 87 DF508/R117H Ad2/CFTR2 8 3 106 3 M 23 1.59/38a 67 DF508/DF508 Ad2/CFTR2 8 3 106 4 F 23 1.55/46 65 DF508/R117H Ad2/CFTR2 2.5 3 107 5 M 30 3.19/79 85 DF508/DF508 Ad2/CFTR2 2.5 3 107 6 M 27 4.18/99 87 DF508/W1282X Ad2/CFTR2 2.5 3 107 7 F 33 1.47/50 70 DF508/R3342 Ad2/CFTR2 8 3 107 8 F 28 2.0968 78 G542X/Other Ad2/CFTR2 8 3 107 9 M 15 3.80/94 93 DF508/A455L Ad2/CFTR2 8 3 107 10 F 33 2.47/75 92 DF508/Other Ad2/CFTR2 2.5 3 108 11 M 17 3.82/84 95 DF508/DF508 Ad2/CFTR2 2.5 3 108 12 F 22 1.71/53 77 DF508/Other Ad2/CFTR2 2.5 3 108 13 F 23 1.72/58 85 DF508/DF508 Ad2/CFTR8 2.5 3 108 14 F 19 2.71/61 85 DF508/Other Ad2/CFTR8 2.5 3 108 15 F 35 1.77/63 81 DF508/DF508 Ad2/CFTR8 8 3 108 16 M 38 1.70/41 81 DF508/W1282X Ad2/CFTR8 8 3 108 17 M 27 3.42/69 86 DF508/DF508 Ad2/CFTR8 8 3 108 18 M 15 3.97/85 97 DF508/DF508 Ad2/CFTR8 2.5 3 109 19 F 17 2.66/75 77 DF508/DF508 Ad2/CFTR8 2.5 3 109 20 M 24 3.35/78 93 DF508/DF508 Ad2/CFTR8 2.5 3 109 11 M/9F Average: 25.3 2.64/67.4 81.85 aFEV1 1.77 (42%) at enrollment. as well as vector type and dose for the lobar and aerosol administration groups, respectively. Login to comment
201 DAY 1 CLINICAL CHARACTERISTICS OF SUBJECTS RECEIVING AEROSOL ADMINISTRATION OF VECTOR a Age FEV1 Dose Subject Sex (years) (% pred) NIH score Genotype Vector (IU) 21 F 32 3.63/112 85 DF508/R117H Ad2/CFTR2 8 3 106 22 F 28 3.38/77 91 DF508/other Ad2/CFTR2 8 3 106 23 F 28 1.30/39b 83 DF508/other Ad2/CFTR8 2.5 3 107 24 M 18 3.51/71 96 DF508/other Ad2/CFTR8 2.5 3 107 25 F 37 1.81/61 83 DF508/DF508 Ad2/CFTR8 8 3 107 26 F 18 3.53/92 93 DF508/DF508 Ad2/CFTR8 8 3 107 27 F 27 2.24/77 81 G551D/621-1GT Ad2/CFTR8 2.5 3 108 28a M 25 4.22/93 97 G2111GT/G542X Ad2/CFTR8 2.5 3 108 29 M 15 2.01/85 90 other/other Ad2/CFTR8 8 3 108 30 M 18 4.06/109 96 DF508/3489110kbC-T Ad2/CFTR8 8 3 108 31 M 40 3.81/71 75 DF508/3849110kbC-T Ad2/CFTR8 2.5 3 109 32 F 17 2.29/75 92 DF508/G542X Ad2/CFTR8 2.5 3 109 33 F 21 2.99/89 95 DF508/DF508 Ad2/CFTR8 8 3 109 34 M 15 3.37/95 94 DF508/I507 Ad2/CFTR8 8 3 109 35a M 26 3.45/77 97 G2111GT/G542X Ad2/CFTR8 2.5 3 1010 36a F 35 2.4/74 89 DF508/other Ad2/CFTR8 2.4 3 1010 7 M/9 F 25 3.0/81.1 89.8 aPatient 10 (lobar administration) and patient 36 are one individual; patient 28 and 35 are another single individual. Login to comment

PMID: 11491164 [PubMed] Massie RJ et al: "Intron-8 polythymidine sequence in Australasian individuals with CF mutations R117H and R117C."

No. Sentence Comment

41 Infants with a positive (w60 mmol?L-1 ) or borderline (40 - 60 mmol?L-1 ) sweat chloride and in whom there is an unidentified mutation are referred for an extended mutation analysis which includes: DF508, R117H, G551D, A455E, G542X, N1303K, W1282X, 1717-1, R560T, R347P, R334W, R1162X, S549N, 621z1, 3849z10CwT, and the IVS8 polythymidine sequence. Login to comment
57 Two of the individuals had a second severe mutation (G542X/R117H and G551D/R117H), four had an unknown second mutation and one patient was homozygous for R117H. Login to comment

PMID: 11568116 [PubMed] Jenison R et al: "Silicon-based biosensors for rapid detection of protein or nucleic acid targets."

No. Sentence Comment

68 Capture sequences were as follows: For ⌬F508, the wild type was 5Ј-YAC AAC ACC AAA GAT GAT ATT TT-3Ј, and the mutant was 5Ј-YCC GAA ACA CCA ATG ATA TTT TC-3Ј For N1303K, the wild type was 5Ј-YAC GGA TCC AAG TTT TTT CTA A-3Ј, and the mutant was 5Ј-YAC GGA TCC AAC TTT TTT CTA A-3Ј For G551D, the wild type was 5Ј-YAA CTC GTT GAC CTC CAC TC-3Ј, and the mutant was 5Ј-YAA CTC GTT GAT CTC CAC TC-3Ј For G542X, the wild type was 5Ј-YAA CAC CTT CTC CAA GAA CTA TA-3Ј, and the mutant was 5Ј-XAA CAC CTT CTC AAA GAA CTA TA-3Ј antibody immobilization Capture antibodies were diluted to 2 mg/L in 0.1 mol/L sodium bicarbonate buffer, pH 9.3, and 200 nL was spotted using a Hamilton MP2200 pipetting robot equipped with a modified dispense head. Login to comment
79 Input concentrations for the probe sets was as follows: ⌬F508, 150 nmol/L for both the wild type and mutant; G542X, 75 nmol/L for the wild type and 750 nmol/L for the mutant; N1303K, 300 nmol/L for both the wild type and mutant; G551D, 150 nmol/L for both the wild type and mutant. Login to comment
119 One mutation, ⌬F508, is a 3-bp deletion, whereas the other three, G542X, G551D, and N1303K, are SNPs. Login to comment
144 Detection of SNPs in the CFTR gene. A locator for the capture probes specific for the four interrogated mutations is shown. CCD images from experiments using human DNA of defined genotype, subjected to multiplex PCR, as input to the assay as follows: (A), wild type/wild type; (B), ⌬F508/⌬F508; (C), G542X/wild type; (D), G542X/G542X; (E), G551D/ wild type; (F), G551D/G551D. multiplex array format. Login to comment

PMID: 11569691 [PubMed] Truninger K et al: "Mutations of the cystic fibrosis gene in patients with chronic pancreatitis."

No. Sentence Comment

56 Using multiplex PCR, 15 genomic fragments were amplified which contain the following mutations: ⌬F508, ⌬I507, Q493X, V520F, 1717-1G3A, G542X, G551D, R553X, R560T, S549R, S549N, 3849 ϩ 10kbC3T, 3849 ϩ 4A3G, R1162X, 3659delC, W1282X, 3905insT, N1303K, G85E, 621 ϩ 1G3T, R117H, Y122X, 711 ϩ 1G3T; 1078delT, R347P, R347H, R334W, A455E, 1898 ϩ 1G3A, 2183AA3G, 2789 ϩ 5G3A. Login to comment

PMID: 11574497 [PubMed] Josserand RN et al: "Cystic fibrosis phenotype evaluation and paternity outcome in 50 males with congenital bilateral absence of vas deferens."

No. Sentence Comment

30 Leukocytes samples were analysed for a series of 22 CF mutations including the five most frequently encountered in our region (The CF Genotype Consortium, 1994): ∆F508, G542X, N1303K, 1717-G-A, 885E; and 17 others: R117H, R334W, R347H, R347P, 556delA, S549N, S549I, S549R, G551D, R553X, R560T, G1244E, S1255X, W1282X, R1283K, 3898ins C, D1270N. Login to comment
40 sCFTR mutation was detected in 56 alleles of the 50 patients: ∆F508 in 30 alleles, R117H in six, D1270N in two, G542X in one, 1717ϩG-A in one, 2789ϩ5G-A in one, R347H in one and the 5T allele in 14. Login to comment
45 Description of the 50 men with CBAVD:CF genotype and phenotype Number age CF SCC CF-related (years) genotype (mmol/l) symptoms 1 29 ∆F508/R117H 59 2 35 ∆F508/R117H 54 3 24 ∆F508/R117H 43 4 33 ∆F508/R117H 39 5 26 ∆F508/5T 90 S/B 6 27 ∆F508/5T 67 S 7 32 ∆F508/5T 55 8 30 ∆F508/5T 51 9 31 ∆F508/5T 44 10 44 ∆F508/5T 38 S 11 36 ∆F508/5T 36 S 12 54 ∆F508/5T 21 S 13 31 R117H/R347H 79 S 14 36 1717G-A/5T 50 S 15 32 5T/5T 77 P/DM 16 27 ∆F508/- 94 S 17 41 ∆F508/- 90 S/B 18 30 ∆F508/- 88 19 30 ∆F508/- 82 S 20 32 ∆F508/- 81 21 25 ∆F508/- 79 22 31 ∆F508/- 79 23 27 ∆F508/- 75 S 24 43 ∆F508/- 70 25 38 ∆F508/- 65 26 34 ∆F508/- 52 S 27 31 ∆F508/- 47 S 28 35 ∆F508/- 40 S 29 26 ∆F508/- 39 S 30 25 ∆F508/- 36 31 33 ∆F508/- 33 32 37 ∆F508/- 28 S 33 36 ∆F508/- 18 S 34 33 G542X/- 45 S 35 37 D1270N/- 116 36 34 D1270N/- 103 S/P 37 46 R117H/- 95 39 37 2789ϩ5G-A/- 100 S 40 27 5T/- 90 S 38 30 5T/- 51 44 38 5T/- 45 41 30 -/- 57 S 42 35 -/- 52 S 43 36 -/- 46 B (tobacco) 45 33 -/- 40 S 46 31 -/- 36 S/asthma 47 32 -/- 28 B (tobacco) 48 28 -/- 28 49 30 -/- 26 50 35 -/- 20 S SCC ϭ sweat chloride concentration. Login to comment
49 Results of assisted reproduction procedures Number CF genotype CF mutation in Assisted reproduction procedure women ICSI IVFSD AID adoption 1 ∆F508/R117H 0 failure success 2 ∆F508/R117H failure 3 ∆F508/R117H failure 4 ∆F508/R117H 0 5 ∆F508/5T 0 6 ∆F508/5T success 7 ∆F508/5T ∆F508/- failure 1 8 ∆F508/5T success 9 ∆F508/5T failure 1 10 ∆F508/5T 0 1 11 ∆F508/5T 0 12 ∆F508/5T failure failure 13 R117H/R347H failure failure 14 1717G-A/5T failure 15 5T/5T 0 16 ∆F508/- ∆F508/- 0 success 17 ∆F508/- 0 1 18 ∆F508/- 0 19 ∆F508/- failure 20 ∆F508/- ∆F508/- 0 success 21 ∆F508/- success 22 ∆F508/- failure 23 ∆F508/- failure 24 ∆F508/- in process 25 ∆F508/- 0 1 26 ∆F508/- failure 27 ∆F508/- failure 28 ∆F508/- success 29 ∆F508/- 0 success 30 ∆F508/- failure success 31 ∆F508/- 0 1 32 ∆F508/- 0 33 ∆F508/- success 34 G542X/- failure failure 35 D1270N/- success 36 D1270N/- 0 37 R117H/- failure 39 2789ϩ5G-A/- in process 40 5T/- ∆F508/- 0 38 5T/- failure 44 5T/- 0 success 41 -/- success 42 -/- failure 43 -/- 0 45 -/- in process 46 -/- 0 47 -/- 0 success 48 -/- failure 49 -/- failure 50 -/- success IVFSD ϭ IVF with sperm donor; AID ϭ artificial insemination by donor. Login to comment

PMID: 11589722 [PubMed] Walkowiak J et al: "Analysis of exocrine pancreatic function in cystic fibrosis: one mild CFTR mutation does not exclude pancreatic insufficiency."

No. Sentence Comment

5 Results Severe pancreatic insufficiency was associated with the presence of two CFTR gene mutations (DF508, N1303K, CFTR dele 2,3 (21kb), G542X, 1717±1G-A, R533X, W1282X, 621GT, 2183AAG, R560T, 2184insA and DI507, G551D, 895T) and mild insufficiency with the presence of at least one mutation (R117H, 3171insC, A155P2, 138insL, 296 1 1G-A, E92GK, E217G, 2789 1 5G-A. Login to comment
51 Results Among 394 genotyped CF patients, the following mutations on alleles were found (n): DF508 (464), 3849 1 10kbC-T (30), CFTR dele2,3(21 kB) (21), N1303K (15), G542X (12), 1717±1G-A (9), R533X (6), W1282X (6), 621 1 G-T (3), R117H (2), 3171insC (2), A155P2 (2), 2183AAG (2), R334W (2), 895T (2), 296 1 1G-A (2), E92GK (2), 138insL (1), E217G (1), 2789 1 5G-A (1), R347P (1), R560T (1), 2184insA (1), I507 (1), G551D (1). Login to comment
57 CFTR gene mutations were classified as `severe' (E1 , 96 mg g21 ) ± severely affecting pancreatic function (DF508, N1303K, CFTR dele 2,3 (21kb), G542X, 1717±1G-A, R533X, W1282X, 621 1 1G-T, 2183AAG, 895T, R560T, 2184insA, DI507, G551D) and `mild' (E1 . Login to comment
81 500 DF508/3849 1 10kbC-T (17) 1 4 1 6 5 DF508/CFTR dele2,3(21kb) (15) 9 4 2 DF508/N1303K (10) 7 3 DF508/1717±1G-A (7) 5 2 DF508/G542X (7) 4 2 1 DF508/W1282X (5) 4 1 DF508/R553X (3) 3 DF508/R334W (2) 1 1 DF508/2183AAG (2) 2 DF508/R117H (1) 1 DF508/621GT (1) 1 DF508/R347P (1) 1 DF508/2184insA (1) 1 DF508/DI507 (1) 1 3849 1 10kbC-T/3849 1 10kbC-T (3) 3 N1303K/CFTR dele2,3(21kb) (2) 1 1 1717±1G-A/3849 1 10kbC-T (2) 1 1 3171insC/A155P2 (2) 1 1 296 1 1G-A/E92GK (2) 2 R117H/138insL (1) 1 W1282X/3849 1 10kbC-T (1) 1 N1303K/3849 1 10kbC-T (1) 1 CFTR dele2,3(21kb)/3849 1 10kbC-T (1) 1 R553X/G542X (1) 1 621 1 1G-T/621 1 1G-T (1) 1 G542X/M (4) 2 2 CFTR dele 2,3(21kb)/M (1) 1 2 3849 1 10kbC-T/M (2) 1 1 R533X/M (2) 2 N1303K/M (2) 2 895T/M (2) 1 1 E217G/M (1) 1 G551D/M (1) 1 R560T/M (1) 1 2789 1 5G-A/M (1) 1 Total (109) 44 21 10 4 12 18 M, unidentified mutation. Login to comment
86 Kristidis et al. [10] reported that pancreatic insufficiency strongly correlates also with two alleles of DI507, Q493X, G542X, R553X, W1282X, 621 1 1G-T, 1717±1G-A, 556delA, 3659delC, I148T, G480C, V520F and R560T while one or two mutations such as R117H, R334W, A455E, and P574H were correlated with a pancreatic sufficient phenotype. Login to comment
88 An international Cystic Fibrosis Genotype-Phenotype Consortium [25] evaluated DF508 homozygotes and seven of the most common DF508 compound heterozygotes (G542X, R553X, N1303K, W1282X, 1717±1G-A, 621 1 1GT, R117H). Login to comment

PMID: 11668613 [PubMed] Wong LJ et al: "Improved detection of CFTR mutations in Southern California Hispanic CF patients."

No. Sentence Comment

94 The next most common mutations were G542X and 3849+10kbC>T, each found in five unrelated patients (4%). Login to comment
95 These frequencies are much higher than those found in Europe and North America where G542X and 3849+10kbC>T mutations account for 2.4 and 0.2% of their patients, respectively. Login to comment
117 Summary of Mutations Found in This Group of Hispanic Patients Exon or Number of Mutation intron chromosomes Frequency % Mutations detected before full gene analysis 91 73.38% 1 F508 10 64 51.6 2 G542X 11 5 4 3 3849+10kb C>T Intron 19 5 4 4 S549N 11 3 2.4 5 I148T 4 2 1.6 6 3120+1G>A 16 2 1.6 7 R334W 7 2 1.6 8 G551D 11 1 0.8 9 N1303K 21 1 0.8 10 W1282X 20 1 0.8 11 R1162X 19 1 0.8 12 G85E 3 1 0.8 13 W1089X 17b 1 0.8 14 Y1092X 17b 1 0.8 15 P205S 6a 1 0.8 Mutations detected by full gene screening 26 20.97% 16 R1066Ca 17b 2 1.6 17 1949del84 13 1 0.8 18 2184delA 13 1 0.8 19 Q98R 4 1 0.8 20 R75X 3 1 0.8 21 G1244E 20 1 0.8 22 3876delA 20 7 5.65 23 935delA 6b 2 1.6 24 406-1G>A Intron 2 2 1.6 25 3271delGG 17a 1 0.8 26 2105-2117del13insAGAAA 13 1 0.8 27 663delT 5 1 0.8 28 3171delC 17a 1 0.8 29 2108delA 13 1 0.8 30 Q179K 5 1 0.8 31 3199del6 17a 1 0.8 32 3500-2 A->T Intron 17b 1 0.8 Total identified 117 (177)b 94.35 (97.5)b Unidentified 7 (3)b 5.65 (2.5)b Total 124 (120)b 100 (100)b a This mutation was also detected by SSCP. Login to comment

PMID: 11701644 [PubMed] Scriver CR et al: "Human genetics: lessons from Quebec populations."

No. Sentence Comment

236 The L206W allele (with a mild phenotypic effect) reflects a particular French Canadian heritage (142), whereas W1282X and G542X are prominent in Ashkenazi Jews (2, 145), which reflects corresponding twentieth century immigrations into Quebec. Login to comment

PMID: 11756355 [PubMed] Dohle GR et al: "Genetic risk factors in infertile men with severe oligozoospermia and azoospermia."

No. Sentence Comment

29 Twelve common mutations of the CFTR gene were tested (∆F508, A445E, G542X, 1717-1G→A, R553X, R117H, R1162X, N1303K, W1282X, 3659delC, E60X and S1251N). Login to comment

PMID: 11781704 [PubMed] Larriba S et al: "ATB(0)/SLC1A5 gene. Fine localisation and exclusion of association with the intestinal phenotype of cystic fibrosis."

No. Sentence Comment

151 Statistical analysis showed that the higher incidence for P17A and the lower incidence for V512L observed in the general population Table 3 CFTR mutations of the CF patients under study with and without meconium ileus (MI) CF-non MI CF-MI CFTR mutations n CFTR mutations n F508del/R117H 2 F508del/F508del 7 F508del/R334W 3 F508del/L365P 1 F508del/R347P 1 F508del/G542X 1 F508del/621+1G4Ta 1 F508del/621+IG4Ta 1 F508del/M1101K 1 F508del/R1066C 1 F508del/1609delCAa 1 F508del/W1089X 1 F508del/2789+5G4Aa 3 F508del/R1162X 1 F508del/3849+10kbC4T 1 F508del/1609delCAa 1 G542X/G85E 1 F508del/Q1281X 1 G542X/V232D 1 F508del/1811+1.6kbA4G 1 G542X/1811+1.6kb A4Ga 1 F508del/2789+5G4Aa 1 G542X/2789+5G4A 1 F508del/2869insG 1 Q890X/L206W 1 F508del/unknown 1 1811+1.6kbA4G/P205S 1 I507del/I507del 1 R1162X/3272-26A4G 1 G542X/1078delT 1 N1303K/R347H 1 G542X/1811+1.6kbA4Ga 1 N1303K/A1006E+5T 1 S549R/CFTR50kbdel 1 2789+5G4A/405+1G4A 1 R1066C/R1066C 1 W1282X/712-1G4T 1 a CF patient with a sibling presenting identical CFTR genotype and discordance of intestinal phenotype. Login to comment

PMID: 11786964 [PubMed] Zsembery A et al: "Correction of CFTR malfunction and stimulation of Ca-activated Cl channels restore HCO3- secretion in cystic fibrosis bile ductular cells."

No. Sentence Comment

1 Human cholangiocytes were isolated from control livers and from 1 patient with CF (⌬F508/G542X mutations). Login to comment
7 Consistent with reports that premature stop codon mutations (class I; e.g., G542X) can be read over by treatment with aminoglycoside antibiotics, exposure of CF cholangiocytes to gentamicin restored activation by cAMP of Cl- current and HCO3 - secretion. Login to comment
26 In addition, the CF cells available to us were heterozygous at the CFTR locus, carrying the ⌬F508 trafficking mutation (class II23) on one allele and the G542X premature stop codon mutation (class I23) on the other. Login to comment
139 Note: (1) Absence of effect of raising intracellular cAMP (column 2) and of the continuous presence of extracellular ATP (column 3); (2) large activation of HCO3 - extrusion by raising intracellular Ca2ϩ concentration with ionomycin (column 4); and (3) unveiling of cAMP-stimulated HCO3 - secretion by restoring translation of CFTR-G542X with gentamycin (column 5). Login to comment
155 This current stimulation was transient and current returned towards control values within 1 minute (data not shown).22,39 Correction of Cl- and HCO3 - Secretory Defect in CFhBDC by Gentamicin Class I mutations of CFTR, which result in premature stop codons (e.g., G542X) can be corrected with certain aminoglycoside antibiotics.24-26 We pretreated CFhBDC with 200 ␮g/mL gentamicin for 18 hours and measured HCO3 - extrusion in the presence of cAMPmix. Login to comment
173 Thus, activation by cAMP of Cl- currents and HCO3 - secretion could both be restored in CF cholangiocytes carrying the premature stop codon mutation (G542X). Login to comment
215 The CFTR-deficient cells used in this study were heterozygous exhibiting the ⌬F508/G542X alleles, mutations belonging to class II and class I groups, respectively. Login to comment
219 We had previously shown that chaperoning with glycerol leads to proper surface membrane targeting of CFTR-⌬F508, which restored cAMP-dependent HCO3 - transport in CF pancreatic ductular cells.9 Unfortunately, no more ⌬F508/G542X cholangiocytes were available and analogous experiments to restore CFTR function in bile ductular cells could not be performed. Login to comment

PMID: 11788089 [PubMed] Bombieri C et al: "Cystic fibrosis mutation testing in Italy."

No. Sentence Comment

35 CF MUTATIONS IDENTIFIED IN TWO ITALIAN REGIONS (VENETO AND TRENTINO ALTO ADIGE) Number of alleles Frequency Cumulative Mutation with mutation (%) frequency (%) DF508 107 47.6 47.56 R1162X 22 9.8 57.33 2183 AA ® G 21 9.3 66.67 N1303K 9 4.0 70.67 G542X 6 2.7 73.33 711 1 5 G ® A 6 2.7 76.00 1717-1 G ® A 5 2.2 78.22 G85E 3 1.3 79.56 R553X 3 1.3 80.89 2789 1 5 G ® A 3 1.3 82.22 Q552X 3 1.3 83.56 621 1 1 G ® T 2 0.9 84.44 W1282X 2 0.9 85.33 R347P 1 0.4 85.77 G551D 1 0.4 86.21 3849 1 10 Kb C ® T 1 0.4 86.67a 3132 del TG 2 0.9 87.54 2790-2 A ® G 2 0.9 88.43 457 TAT ® G 1 0.4 88.87 1717-8 G ® A 1 0.4 89.31 R709X 1 0.4 89.75 1898 1 3 A ® G 1 0.4 90.22 Total 203 90.22 Numbers refer to CFTR gene alleles carrying the specified mutation, over total tested alleles (n 5 225) from the affected subjects CF cohort, as indicated in the text (from Bonizzato et al., 1995). Login to comment
38 CF MUTATION PANEL (VENETO AND TRENTINO ALTO ADIGE ITALIAN REGIONS) DF508 R1162X 2183 AA ® G N1303K G542X 711 1 5 G ® A 1717-1 G ® A G85E R553X 2789 1 5 G ® A Q552X 621 1 1 G ® T W1282X R347P G551D 3849 1 10 Kb C ® T Note: Contrary to what is suggested for the U.S. population (Grody et al., 2001), R117H mutation (and its reflex IVS8-5T test) is not included in the panel because it is not commonly found in the Italian CF population (Bonizzato et al., 1995; Estivill et al., 1997; Rendine et al., 1997). Login to comment
44 CF GENE MUTATIONS IN ITALY Number of alleles Frequency Cumulative Mutation screened (%) frequency (%) DF508 3442 51.07 51.07 N1303K 3056 4.84 55.91 G542X 3082 4.83 60.75 2183 AA ® G 2596 2.66 63.41 R1162X 2580 2.42 65.83 1717-1 G ® A 2892 2.11 67.94 W1282X 2600 1.23 69.17 R553X 2882 1.15 70.31 T338I 2306 0.69 71.01 R347P 2642 0.61 71.61 711 1 5 G ® A 2454 0.57 72.18 G85E 1980 0.40 72.59 621 1 1 G ® T 2594 0.39 72.97 R334W 2366 0.30 73.27 R352Q 2112 0.24 73.50 S549N 2118 0.24 73.74 R347H 2184 0.18 73.92 L1077P 1840 0.16 74.09 R1158X 1878 0.16 74.25 541del C 1884 0.16 74.40 R1066H 1918 0.16 74.56 E585X 1922 0.16 74.72 Q552X 2172 0.14 74.86 D1152H 1824 0.11 74.97 2790-2 A ® G 1862 0.11 75.07 3132 del TG 1862 0.11 75.18 3667ins 4 1876 0.11 75.29 DI507 1914 0.10 75.39 1898 1 3 A ® G 1920 0.10 75.50 G1244E 1960 0.10 75.60 1784 del G 2052 0.10 75.69 From Rendine et al. (1997). Login to comment

PMID: 11796434 [PubMed] Loubieres Y et al: "Association between genetically determined pancreatic status and lung disease in adult cystic fibrosis patients."

No. Sentence Comment

31 The most frequent CF mutations usually found in the French population (⌬F508, ⌬I507, 1717-1G3A, G542X, G551D, R553X, W1282X, N1303K) were analyzed by polymerase chain reaction and allele-specific oligonucleotide with the INNO-LIPA CF2 kit (Innogenetics; Zwijnaarde, Belgium). Login to comment

PMID: 11804840 [PubMed] Mall M et al: "Activation of ion secretion via proteinase-activated receptor-2 in human colon."

No. Sentence Comment

50 Testing of an additional panel of the 19 most prevalent CFTR mutations among the Caucasian population in Europe, including G542X, N1303K, 1717-1 GϾT, W1282X, G551D, R553X, R1162X, R334W, R117H, 621ϩ1GϾT, 3849ϩ10kbCϾT, 3659delC, 1078delT, R347P, A445E, S1251N, ⌬I507, 2183AAϾG, and E60X (ELUCIGENE CF20; AstraZeneca Diagnostics) failed to identify the second disease causing mutation in six CF patients. Login to comment

PMID: 11824793 [PubMed] Teich N et al: "Genetic risk factors in chronic pancreatitis."

No. Sentence Comment

70 Approximately 72% of patients with cystic fibrosis are homozygous or compound heterozygous for eight mutations of the CFTR gene on chromosome 7: delta F508, G542X, R553X, W1282X, N1303K, 621 ϩ 1GÆT, 1717-1GÆA, and R117H; whereas the deletion delta F508 alone accounts for about 66% of mutant cystic fibrosis alleles. Login to comment

PMID: 11866018 [PubMed] Spitzer E et al: "Identification of a new cystic fibrosis transmembrane regulator mutation in a severely affected patient."

No. Sentence Comment

31 Discussion Studies carried out in southern European populations, including the former Yugoslavia, identified DF508, G542X, G551D, 621z1GwT, W1282X and N1303K as the most common CF mutations [6, 7]. Login to comment

PMID: 11883825 [PubMed] Padoan R et al: "Genetic and clinical features of false-negative infants in a neonatal screening programme for cystic fibrosis."

No. Sentence Comment

8 The cystic brosis transmembrane regulator (CFTR) gene mutations identi ed were delF508, D1152H, R1066C, R334W, G542X, N1303K, F1052V, A120T, 3849 ‡ 10kbC ® T, 2789 ‡ 5G ® A, 5T-12TG and the novel mutation D110E. Login to comment
34 It was initially performed by polyacrylamide gel electrophoretic (PAGE) analysis for the delF508 mutation, and later by polymerase chain reaction (PCR) and oligonucleotide ligation assay (OLA) (31 mutations: G85E, 621 ‡ 1G ® T, R117H, Y122X, 711 ‡ 1G ® T, 1078delT, R347P, R347H, R334W, A455E, 1898 ‡ 1G ® A, 2183-AA ® G, 2789 ‡ 5G ® A, DelF508, I507del, Q493X, V520F, 1717-1G ® A, G542X, G551D, R553X, R560T, S549R, S549N, 3849 ‡ 10kbC ® T, 3849 ‡ 4A ® G, R1162X, 3659delC, W1282X, 3905insT, N1303K) (14). Login to comment
40 Mutation Frequency (%) DelF508 54 N1303K 8 G542X 6.25 1717-1G ® A 2.50 R334W 1.75 2183AA ® G 1.50 R117H, L1077P, W1282X 1.25 D110E, R347P, E585X, 2789 ‡ 5G ® A 0.75 R352Q, R553X, R1066H, D1152H, R1158X, 1782delA, 1898 ‡ 1G ® A, 3659delC 0.50 G85E, R117L, G178R, D579G, H609R, Y1032C, V1153E, R1162X, 621 ‡ 1G ® T, 711 ‡ 1G ® T, 1845delAG o 1846delGA, 2143delT 0.25 Table2.Differencesinthethreestrategiesofneonatalscreening(audit1990-1999). Login to comment
70 Year of birth Patient Sex Age at diagnosis Genotype Sweat test (chloride mEq l¡1 ) 1990 1 BA F 8 mo DF508/2789 ‡ 5G ® A 74, 79 2 LG M 4 y ¡/¡ 84, 83 1991 3 BV F 6 y ¡/¡ a 61, 85, 70 4 CA F 8 y R1066C/D1152H 58, 59 5 CA F 8 y DF508/5T-TG12 65, 67 6 PS M 5 y N1303K/-a 41, 43, 55, 63, 85, 89 1992 7 AE F 1 y R334W/-a 57, 42, 78, 82 8 DA M 4 mo ¡/¡ 85, 101, 143, 9 FA M 1 y ¡/¡ a 70, 75, 98, 114 1993 10 CA F 7 y DF508/5T-TG12 45, 50 1995 11 BM M 3 y DF508/DF508 117, 123 1997 12 DG M 6 mo G542X/D110E 59, 88, 80, 70 13 DE F 2 y D1152H/3849 ‡ 10kbC ® T 31, 35 14 TL M 2 y ¡/¡ a 115, 136 1998 15 CM M 5 mo F1052V/A120T 20, 25 F: female; M: male. Login to comment
80 The CFTR alterations identi ed were D1152H, R1066C, R334W, G542X, N1303K, F1052V, A120T, 3849 ‡ 10kbC ® T, 2789 ‡ 5G ® A, 5T-12TG and the new mutation D110E (19). Login to comment

PMID: 11897641 [PubMed] Selvadurai HC et al: "The relationship between genotype and exercise tolerance in children with cystic fibrosis."

No. Sentence Comment

14 Examples of class I mutations are G542X and W1282X. Login to comment

PMID: 11933191 [PubMed] Ravnik-Glavac M et al: "DHPLC screening of cystic fibrosis gene mutations."

No. Sentence Comment

42 The following mutations have been studied: exon 3: W57G, R74W, R75Q, G85E, 394delTT, 405+ 1G>A; exon 4: E92X, P99L, 441delA, 444delA, 457TAT>G, D110H, R117C, R117H, A120T, 541delC, 544delCA, Q151X, 621+1G>T, 662- 2A>C; exon 7: 1078delT, F331L, R334W, I336K, R347C, R347P, A349V, R352Q, 1221delCT; exon 10: S492F, Q493X, 1609delCA, deltaI507, deltaF508; exon 11: G542X, S549N, G551D, R553X, A559T, R560K, R560T; exon 13: K716X, Q685X, G628R, L719X; exon 17b: H1054D, G1061R, 3320ins5, R1066H, R1066L, R1070Q, 3359delCT, L1077P, H1085R, Y1092X; exon 19: R1162X, 3659delC, 3662delA, 3667del4, 3737delA, I1234V, S1235R, 3849G>A; exon 20: 3860ins31,S1255X,3898insC,3905insT,D1270N, W1282X, Q1291R; and exon 21: N1303H, N1303K, W1316X. Login to comment

PMID: 11938439 [PubMed] Audrezet MP et al: "Determination of the relative contribution of three genes-the cystic fibrosis transmembrane conductance regulator gene, the cationic trypsinogen gene, and the pancreatic secretory trypsin inhibitor gene-to the etiology of idiopathic chronic pancreatitis."

No. Sentence Comment

56 `Gain-of-function' PRSS1 mutations are rare in ICP While PRSS1 mutations are often found in patients with hereditary pancreatitis, they can also be identified in subjects with ICP, albeit with an exceptionally low Table 1 Sequence variations identified in the PRSS1, PSTI, and CFTR genes in 39 patients with ICP CFTR Patient PRSS1 PSTI Mutant PolyT 1 ± a ± ± 7T/7T 2 ± ± F508del/R352Q 9T/7T 3 ± ± F508del/P5L 9T/7T 4 ± ± c.4575+2G4A 9T/7T 5 ± ± ± 7T/7T 6 ± N34Sb ± 7T/7T 7 ± ± ± 7T/5T 8 ± ± F508del/Q1476X 9T/7T 9 ± ± ± 7T/7T 10 ± ± ± 7T/7T 11 ± ± ± 7T/7T 12 ± ± ± 7T/7T 13 ± ± V562I 7T/5T 14 ± ± 2C4A W1282X 7T/5T 15 ± ± IVS3-6T4C 7T/7T 16 R122H ± ± 7T/7T 17 ± ± ± 9T/7T 18 ± ± ± 7T/5T 19 ± ± ± 7T/7T 20 ± N34S/N34S ± 7T/7T 21 ± ± ± 9T/5T 22 ± ± ± 7T/7T 23 ± ± E217G/A1136T 9T/7T 24 ± ± ± 7T/7T 25 ± ± ± NDc 26 ± ± ± ND 27 ± N34S IVS18 ± 20T4C 9T/7T 28 ± ± F508del 9T/7T 29 ± ± ± 7T/7T 30 ± ± N1303K ND 31 ± ± G542X 9T/7T 32 ± ± ± 7T/5T 33 ± ± F508del 9T/7T 34 ± ± 41G4Ad ± 7T/7T 35 ± ± ± 9T/7T 36 ± ± ± 9T/7T 37 ± ± ± 7T/7T 38 ± N34S L967S 7T/7T 39 ± ± ± 7T/5T a Indicates two wild alleles. Login to comment

PMID: 11966405 [PubMed] Sangiuolo F et al: "Towards the pharmacogenomics of cystic fibrosis."

No. Sentence Comment

107 G542X 621 + 1 G→→→→T 3905insT W1282X R553X 1717 - 1 G→→→→A PI Lack of CFTR biosynthesis or defective biosynthesis producing abnormal protein variants. Login to comment
156 G542X, 621+1 G→T, W1282X and R553X belong to the class I group of mutations. Login to comment

PMID: 11994102 [PubMed] Eaton TE et al: "Cystic fibrosis transmembrane conductance regulator gene mutations: do they play a role in the aetiology of allergic bronchopulmonary aspergillosis?"

No. Sentence Comment

53 Cystic ®brosis mutation analysis Genomic DNA samples were screened for 16 CF mutations utilizing allelic-speci®c oligonucleotide (ASO) hybridization; ÁF508, ÁI507, R117H, W1282X, 621 IG3T, R334W, R347P, A455E, 1717-IG3A, G542X, 5549N, G551D, R553X, R560T, N1303K and 3849 10KC3T. Login to comment

PMID: 12000363 [PubMed] Visich A et al: "Complete screening of the CFTR gene in Argentine cystic fibrosis patients."

No. Sentence Comment

35 Screening for DF508 and 12 other known mutations DF508 and 11 other frequent mutations (i.e. DI507, G551D, R553X, S549N, S549I, R1162X, 1811π1.6KbA»T, G542X, 1717-1G»A, 208 W1282X and N1303K) were detected as previously described (5). Login to comment
56 Frequency of cystic fibrosis transmembrane regulator mutations in the Argentine population: 440 chromosomes analysed Mutation Localization Chromosome Number Percentage DF508 Exon 10 258 58.64 G542X Exon 11 18 4.10 W1282X Exon 20 12 2.73 N1303K Exon 21 12 2.73 R334W Exon 7 5 1.14 1717-1G»A Intron 10 5 1.14 3849π10KbC»T Intron 19 4 0.91 1811π1.6KbA»G Intron 11 4 0.91 IVS8-5T Intron 8 4 0.91 G85E Exon 3 3 0.68 621π1G»T Intron 4 3 0.68 2789π5G»A Intron 14b 3 0.68 DI507 Exon 10 3 0.68 2184delA Exon 13 2 0.45 2566insT Exon 13 2 0.45 2686insT Exon 14a 2 0.45 3659delC Exon 19 2 0.45 R1162X Exon 19 2 0.45 4016insT Exon 21 2 0.45 2789π2insA Intron 14b 2 0.45 L6V Exon 1 1 0.23 297π2A»G Intron 2 1 0.23 W57X Exon 3 1 0.23 R75Q Exon 3 1 0.23 Q220X Exon 6a 1 0.23 Y362X Exon 7 1 0.23 D426C Exon 9 1 0.23 1460delAT Exon 9 1 0.23 1353insT Exon 9 1 0.23 1782delA Exon 11 1 0.23 R553X Exon 11 1 0.23 S549R Exon 11 1 0.23 1898π3A»G Intron 12 1 0.23 2594delGT Exon 13 1 0.23 2183AA»G Exon 13 1 0.23 I1027T Exon 17a 1 0.23 R1066C Exon 17b 1 0.23 G1061R Exon 17b 1 0.23 4005-1G»A Intron 20 1 0.23 Total 367 83.45 209 nificant differences were observed among the compared populations (Table2). Login to comment
83 Only five other mutations (i.e. G542X, W1282X, N1303K, 1717-1G»A and R334W) showed frequencies higher than 1%, while approximately half the mutations (49%) were rare since they were found in only one CF family. Login to comment
99 They have established the group of CF mutations (i.e. DF508, G542X, W1282X, N1303K, 1717-1G»A and R334W) that should be considered in screening programmes based on both IRT and DNA analysis to obtain at least 70% sensitivity. Login to comment

PMID: 12007216 [PubMed] Bobadilla JL et al: "Cystic fibrosis: a worldwide analysis of CFTR mutations--correlation with incidence data and application to screening."

No. Sentence Comment

75 This includes the analyses of Lac St. Jean-Quebec-Toronto,∆F508 in South America, and G542X in Brittany and Southern France. Login to comment
101 Mutations that fall into this category include: 1) G542X, of single origin, associated with the ancient Phoenicians [Loirat et al., 1997], 2) N1303K, also of single origin, and linked to ancient Mediterranean populations, and 3) G551D, also of single origin [Cashman et al., 1995], having been associated with the ancient Celtic tribes [Macek et al., 1991]. Login to comment
109 Mutational Arrays, Detection Rates and Methods by Region* Estimated Projected detection of Number of Number of Country/ allele two CFTR mutations chromosomes Region Mutation array detectiona mutationsb includedc (max/min)d Reference Europe Albania ∆F508 (72.4%) C276X (0.7%) 74.5 55.5 4 270/146 CFGAC [1994]; Macek et al. G85E (0.7%) R1070Q (0.7%) [2002] Austria ∆F508 (62.9%) 457TAT→G (1.2%) 76.6 58.7 11 1516/580 Estiville et al. [1997]; Dörk et al. (total) G542X (3.3%) 2183AA→G (0.7%) [2000]; Macek et al. [2002] CFTRdele2,3 (2.1%) N1303K (0.6%) R1162X (1.9%) I148T (0.5%) R553X (1.7%) R117H (0.5%) G551D (1.2%) Austria ∆F508 (74.6%) 2183AA→G (2.4%) 95.3 90.8 8 126 Stuhrmann et al. [1997] (tyrol) R1162X (8.7%) G551D (1.6%) G542X (2.4%) R347P (1.6%) 2789+5G→A (2.4%) Q39X (1.6%) Belarus ∆F508 (61.2%) R553X (0.5%) 75.2 56.6 9 278/188 Dörk et al. [2000]; Macek et al. G542X (4.5%) R334W (0.5%) [2002] CFTRdele2,3 (3.3%) R347P (0.5%) N1303K (3.2%) S549N (0.5%) W1282X (1.0%) Belgium ∆F508 (75.1%) 622-1A→C (0.5%) 100.0 100.0 27 1504/522 Cuppens et al. [1993]; Mercier et G542X (3.5%) G458V (0.5%) al. [1993]; CFGAC [1994]; N1303K (2.7%) 1898+G→C (0.5%) Estivill et al.[1997] R553X (1.7%) G970R (0.5%) 1717-1G→A (1.6%) 4218insT (0.5%) E60X (1.6%) 394delTT (0.5%) W1282X (1.4%) K830X (0.5%) 2183A→G+2184delA (1.2%) E822K (0.5%) W401X (1.0%) 3272-1G→A (0.5%) A455E (1.0%) S1161R (0.5%) 3272-26A→G (1.0%) R1162X (0.5%) S1251N (1.0%) 3750delAG (0.5%) S1235R (0.8%) S1255P (0.5%) ∆I507 (0.6%) Bulgaria ∆F508 (63.6%) R75Q (1.0%) 93.0 86.5 21 948/432 Angelicheva et al. [1997]; (total) N1303K (5.6%) 2183AA→G (0.9%) Estivill et al. [1997]; Macek G542X (3.9%) G1244V+S912L (0.9%) et al. [2002] R347P (2.2%) G85E (0.9%) 1677delTA (2.1%) 2184insA (0.9%) R1070Q (1.8%) L88X+G1069R (0.8%) Q220X (1.2%) 2789+5G→A (0.8%) 3849+10KbC→T (1.1%) G1244E (0.8%) W1282X (1.0%) 1717-1G→A (0.8%) 2176insC (1.0%) Y919C (0.7%) G1069R (1.0%) WORLDWIDEANALYSISOFCFTRMUTATIONS581 Bulgaria 1) DF508 4) 1677delTA - - 6 13 Angelicheva et al. [1997] (ethnic 2) R347P 5) Q493R Turks) 3) G542X 6) L571S - - 1 30 Angelicheva et al. [1997] Bulgaria 1) DF508 (100.0%) (Gypsy) Croatia ∆F508 (64.5%) G551D (1.1%) 72.5 52.6 5 276 Macek et al. [2002] G542X (3.3%) 3849+10KbC→T (0.7%) N1303K (2.9%) Czech ∆F508 (70.0%) 1898+1G→T (2.0%) 89.6 80.3 10 2196/628 CFGAC [1994]; Estiville et al. Republic CFTRdele2,3 (5.5%) 2143delT (1.2%) [1997]; Dörk et al. [2000]; G551D (3.8%) R347P (0.8%) Macek et al. [2002] N1303K (2.9%) 3849+10KbC→T (0.6%) G542X (2.2%) W1282X (0.6%) Denmark ∆F508 (87.5%) G542X (0.7%) 92.3 85.2 6 1888/678 CFGAC [1994]; Schwartz et al. (excluding 394delTT (1.8%) 621+1G→T (0.6%) [1994]; Estiville et al. [1997] Faroe) N1303K (1.1%) 3659delC (0.6%) Estonia ∆F508 (51.7%) R117C (1.7%) 80.2 64.3 10 165/80 Estivill et al. [1997]; Klaassen et 394delTT (13.3%) E217G (1.7%) al. [1998]; Macek et al. S1235R (3.3%) R1066H (1.7%) [2002] 359insT (1.7%) 3659delC (1.7%) I1005R (1.7%) S1169X (1.7%) Finland ∆F508 (46.2%) G542X (1.9%) 78.8 62.1 4 132/52 CFGAC [1994]; Kere et al. 394delTT (28.8%) 3372delA (1.9%) [1994]; Estivill et al. [1997] France ∆F508 (67.7%) 2789+5G→T (0.79%) 79.7 63.6 12 17854/7420 Chevalier-Porst et al. [1994]; (total) G542X (2.94%) 2184delA+2183A→G (0.77%) Estivill et al. [1997]; Claustres et al. [2000]; Guilloud-Bataille N1303K (1.83%) G551D (0.74%) et al. [2000] 1717-1G→A (1.35%) 1078delT (0.63%) W1282X (0.91%) ∆I507 (0.62%) R553X (0.86%) Y122K (0.59%) France ∆F508 (75.8%) R297Q (0.8%) 98.7 97.4 18 599/365 Férec et al. [1992]; Scotet et al. (Brittany) 1078delT (4.0%) R347H (0.8%) [2000] G551D (3.6%) I1234V (0.8%) N1303K (3.0%) R553X (0.8%) R117H (1.7%) 2789+5G→A (0.8%) 3272-26A→G (1.3%) 4005+1G→A (0.7%) G542X (1.1%) 621+1G→T (0.6%) 1717-1G→A (1.0%) ∆I507 (0.6%) G1249R (0.8%) W846X (0.5%) France ∆F508 (70.0%) N1303K (0.8%) 90.4 81.7 16 250 Claustres et al. [1993] (southern) G542X (6.4%) 3737delA (0.8%) 1717-1G→A (1.6%) R1162X (0.8%) L206W (1.2%) Y1092X (0.8%) R334W (1.2%) S945L (0.8%) ∆I507 (1.2%) K710X (0.8%) 2184delA (1.2%) 1078delT (0.8%) R1158X (1.2%) Y122X (0.8%) (Continued) BOBADILLAETAL. Login to comment
110 Germany ∆F508 (71.8%) 1789+5G→A (0.9%) 87.6 76.7 17 5662/1316 Dörk et al. [1992]; Dörk et al. R553X (2.0%) 3272-26A→G (0.9%) [1994]; Tümmler et al. [1996]; N1303K (1.8%) W1282X (0.7%) Estivill et al. [1997]; Dörk et G542X (1.2%) 2143delT (0.7%) al. [2000] R347P (1.2%) 1078delT (0.6%) CFTRdele2,3 (1.2%) 2183AA→G (0.6%) 3849+10KbC→T (1.0%) 2184insA (0.6%) G551D (0.9% 3659delC (0.6%) 1717-1G→A (0.9%) Greece ∆F508 (52.9%) 3272-26A→G (0.8%) 82.2 67.6 22 2097/718 Kanavakis et al. [1995]; Estivill 621+1G→T (5.0%) R1070Q (0.8%) et al. [1997]; Tzetis et al. G542X (4.1%) W496X (0.7%) [1997]; Macek et al. [2002] N1303K (3.3%) 621+3A→G (0.7%) 2183AA→G (1.8%) ∆I507 (0.7%) 2789+5G→A (1.7%) W1282X (0.7%) E822X (1.6%) 574delA (0.7%) R117H (1.2%) 1677delTA (0.7%) R334W (1.1%) A46D (0.6%) R1158X (1.0%) 3120+1G→A (0.6%) G85E (1.0%) G551D (0.5%) Hungary ∆F508 (54.9%) W1282X (1.8%) 68.3 46.6 9 1133/976 CFGAC [1994]; Estivill et al. 1717-1G→A (1.9%) G542X (1.7%) [1997]; Macek et al. [2002] R553X (2.1%) N1303K (1.3%) Y1092X (1.8%) G551D (1.0%) S1196X (1.8%) Ireland ∆F508 (70.4%) G542X (1.0%) 82.1 67.4 7 801/509 CFGAC [1994]; Estivill et al. G551D (5.7%) 621+1G→T (0.8%) [1994] R117H (2.4%) 1717-1G→A (0.6%) R560T (1.2%) Italy ∆F508 (50.9%) ∆I507 (0.65%) 60.3 36.4 9 3524 Estivill et al. [1997] (total) G542X (3.1%) W1282X (0.62%) 1717-1G→A (1.6%) Y122K (0.59%) N1303K (1.4%) G551D (0.53%) R553X (0.94%) Italy ∆F508 (47.6%) R553X (1.3%) 87.1 75.9 15 225 Bonizzato et al. [1995] (Northeast) R1162X (9.8%) 2789+G→A (1.3%) 2183AA→G (9.3%) Q552X (1.3%) N1303K (4.0%) 621+1G→T (0.9%) G542X (2.7%) W1282X (0.9%) 711+5G→A (2.7%) 3132delTG (0.9%) 1717-1G→A (2.2%) 2790-2A→G (0.9%) G85E (1.3%) TABLE 1. Continued. Estimated Projected detection of Number of Number of Country/ allele two CFTR mutations chromosomes Region Mutation array detectiona mutationsb includedc (max/min)d Reference WORLDWIDEANALYSISOFCFTRMUTATIONS583 Italy ∆F508 (56.4%) 711+1G→T (1.3%) 85.7 73.4 13 660/396 Castaldo et al. [1996]; Castaldo (southern) N1303K (6.8%) G1244E (1.3%) et al. [1999] G542X (5.7%) R1185X (1.3%) W1282X (3.8%) L1065P (1.3%) 1717-1G→A (2.3%) R553X (1.1%) 2183AA→G (1.9%) I148T (0.7%) 4016insT (1.8%) Latvia 1) DF508 (58.3%) 4) CFTRdele2,3 (2.8%) - - 6 36 Dörk et al. [2000]; Macek et al. 2) 3849+10KbC®T (8.3%) 5) W1282X (2.8%) [2002] 3) N1303K (5.6%) 6) 394delTT (2.8%) Lithuania ∆F508 (31.0%) N1303K (2.0%) 39.0 15.2 4 94 Dörk et al. [2000]; Macek et al. R553X (4.0%) CFTRdele2,3 (2.0%) [2002] Macedonia ∆F508 (54.3%) 711+3A→G (1.0%) 69.2 47.9 12 559/226 Petreska et al. [1998]; Dörk et G542X (4.2%) 3849G→A (1.0%) al. [2000]; Macek et al. N1303K (2.0%) 2184insA (0.9%) [2002] CFTRdele2,3 (1.3%) 457TAT→G (0.7%) 621+1G→T (1.3%) V139E (0.7%) 611-1G→T (1.2%) 1811+1G→C (0.6%) Netherlands ∆F508 (74.2%) R1162X (0.9%) 86.8 75.3 9 3167/1442 Gan et al. [1995]; Estiville et al. A455E (4.7%) S1251N (0.9%) [1997]; Collee et al. [1998] G542X (1.8%) N1303K (0.9%) 1717-1G→A (1.5%) W1282X (0.7%) R553X (1.2%) Norway ∆F508 (60.2%) G551D (1.2%) 69.8 48.7 6 410/242 Schwartz et al. [1994]; Estivill 394delTT (4.2%) G542X (0.6%) et al. [1997] R117H (3.0%) N1303K (0.6%) Poland ∆F508 (57.1%) CFTRdele2,3 (1.8%) 73.5 54.0 11 4046/1726 CFGAC [1994]; Estivill et al. 3849+10Kb C→T (2.7%) R560T (1.5%) [1997]; Dörk et al [2000]; G542X (2.6%) W1282X (0.7%) Macek et al. [2002] 1717-1G→A (2.4%) ∆I507 (0.5%) R553X (1.9%) G551D (0.5%) N1303K (1.8%) Portugal ∆F508 (44.7%) R334W (0.7%) 49.7 24.7 5 739/454 CFGAC [1994]; Estivill et al. G542X (1.6%) N1303K (0.7%) [1997] R1066C (2.0%) Romania ∆F508 (36.6%) G542X (1.4%) 51.5 26.5 11 224/74 CFGAC [1994]; Estivill et al. 2043delG (2.0%) R553X (1.4%) [1997]; Popa et al. [1997]; W1282X (1.7%) G576X (1.4%) Macek et al. [2002] 1717-2A→G (1.4%) 1898+1G→A (1.4%) I148T (1.4%) 2183AA→G (1.4%) 621+1G→T (1.4%) Russia ∆F508 (54.4%) 552insA (0.9%) 70.7 50.0 12 5073/2562 CFGAC [1994]; Estivill et al. CFTRdele2,3 (5.0%) G542X (0.9%) [1997]; Dörk et al. [2000]; R553X (3.5%) R334W (0.9%) Macek et al. [2002] 2183AA→G (1.3%) 1677delTA (0.8%) W1282X (1.0%) Y122X (0.5%) 394delTT (1.0%) 1367del5 (0.5%) (Continued) BOBADILLAETAL. Login to comment
111 Slovakia ∆F508 (57.3%) CFTRdele2,3 (1.2%) 82.7 68.4 14 908/254 CFGAC [1994]; Estivill et al. G542X (6.8%) 3849+10KbC→T (1.0%) [1997]; Dörk et al. [2000]; R553X (4.0%) S42F (0.9%) Macek et al. [2002] N1303K (3.4%) R75X (0.9%) 2143delT (1.8%) G85E (0.9%) R347P (1.4%) 605insT (0.9%) W1282X (1.3%) 1898+1G→A (0.9%) Slovenia ∆F508 (57.8%) R347P (1.1%) 79.7 63.5 16 455/132 CFGAC [1994]; Dörk et al. 2789+5G→A (4.1%) S4X (0.8%) [2000]; Macek et al. [2002] R1162X (3.2%) 457TAT→G (0.8%) G542X (1.9%) D192G (0.8%) Q552X (1.5%) R553X (0.8%) Q685X (1.5%) A559T (0.8%) 3905insT (1.5%) 2907delTT (0.8%) CFTRdele2,3 (1.5%) 3667ins4 (0.8%) Spain ∆F508 (52.7%) G85E (0.8%) 80.2 64.3 21 3608/1356 Chillón et al. [1994]; Casals et G542X (8.0%) R1066C (0.8%) al. [1997]; Estivill et al. [1997] N1303K (2.5%) 2789+5G→A (0.7%) 3601-111G→C (2.0%) 2869insG (0.7%) 1811+1.6Kb A→G (1.7%) ∆I507 (0.6%) R1162X (1.6%) W1282X (0.6%) 711+1G→T (1.3%) L206W (0.5%) R334W (1.2%) R709X (0.5%) Q890X (1.0%) K710X (0.5%) 1609delCA (1.0%) 3272-26A→G (0.5%) 712-1G→T (1.0%) Sweden ∆F508 (66.6%) E60X (0.6%) 85.9 73.8 10 1357/662 Schwartz et al. [1994]; Estivill et 394delTT (7.3%) Y109C (0.6%) al. [1997]; Schaedel et al. 3659delC (5.4%) R117H (0.6%) [1999] 175insT (2.4%) R117C (0.6%) T338I (1.2%) G542X (0.6%) Switzerland ∆F508 (57.2%) K1200E (2.1%) 91.3 83.4 9 1268/1173 Estivill et al. [1997]; R553X (14.0%) N1303K (1.2%) Hergersberg et al. [1997] 3905insT (9.8%) W1282X (1.1%) 1717-1G→A (2.7%) R347P (0.6%) G542X (2.6%) Ukraine ∆F508 (65.2%) CFTRdele2,3 (1.1%) 74.6 55.7 6 1055/580 Estivill et al. [1997]; Dörk et al. R553X (3.6%) G551D (1.8%) [2000]; Macek et al. [2002] N1303K (2.4%) W1282X (0.5%) United ∆F508 (75.3%) 621+1G→T (0.93%) 81.6 66.6 5 19622/9815 Schwartz et al. [1995b]; Kingdom G551D (3.1%) 1717-1G→A (0.57%) Estivill et al. [1997] (total) G542X (1.7%) TABLE 1. Continued. Estimated Projected detection of Number of Number of Country/ allele two CFTR mutations chromosomes Region Mutation array detectiona mutationsb includedc (max/min)d Reference WORLDWIDEANALYSISOFCFTRMUTATIONS585 United ∆F508 (56.6%) 621+1G→T (1.8%) 69.1 47.7 7 456 CFGAC [1994] Kingdom G551D (3.7%) R117H (1.5%) (N. Ireland) R560T (2.6%) ∆I507 (0.9%) G542X (2.0%) United ∆F508 (19.2%) 621+2T→C (3.8%) 84.4 71.2 11 52 Malone et al. [1998] Kingdom Y569D (15.4%) 2184insA (3.8%) (Pakistani) Q98X (11.5%) R560S (1.9%) 1525-1G→A (9.6%) 1898+1G→T (1.9%) 296+12T→C (7.7%) R709X (1.9%) 1161delC (7.7%) United ∆F508 (71.3%) 1717-1G→A (1.0%) 86.4 74.6 9 1236/730 Shrimpton et al. [1991]; Kingdom G551D (5.5%) 621+1G→T (0.6%) Gilfillan et al. [1998] (Scotland) G542X (4.0%) ∆I507 (0.6%) R117H (1.4%) R560T (0.6%) P67L (1.4%) United ∆F508 (71.6%) 1717-1G→A (1.1%) 98.7 97.4 17 183 Cheadle et al. [1993] Kingdom 621+1G→T (6.6%) 3659delC (0.5%) (Wales) 1898+1G→A (5.5%) R117H (0.5%) G542X (2.2%) N1303K (0.5%) G551D (2.2%) E60X (0.5%) 1078delT (2.2%) S549N (0.5%) R1283M (1.6%) 3849+10KbC→T (0.5%) R553X (1.1%) 4016insT (0.5%) ∆I507 (1.1%) Yugoslavia ∆F508 (68.9%) 3849G→A (1.0%) 82.2 67.6 11 709/398 Dabovic et al. [1992]; Estivill et G542X (4.0%) N1303K (0.8%) al. [1997]; Macek et al. R1162C (3.0%) 525delT (0.5%) (submitted for publication) 457TAT→G (1.0%) 621+1G→T (0.5%) I148T (1.0%) G551D (0.5%) Q552X (1.0%) Middle East/Africa Algeria 1) DF508 (20.0%) 4) 1812-1G®A (5.0%) - - 5 20 Loumi et al. [1999] 2) N1303K (20.0%) 5) V754M (5.0%) 3) 711+1G®T (10.0%) Jewish W1282X (48.0%) 3849+10KbC→T (6.0%) 95.0 90.3 6 261 Kerem et al. [1995] (Ashkenazi) ∆F508 (28.0%) N1303K (3.0%) G542X (9.0%) 1717-1G→A (1.0%) Jewish 1) N1303K - - 1 6 Kerem et al. [1995] (Egypt) Jewish 1) Q359K/T360K - - 1 8 Kerem et al. [1995] (Georgia) Jewish 1) DF508 2) 405+1G®A - - 2 11 Kerem et al. [1995] (Libya) Jewish 1) DF508 (72.0%) 3) D1152H (6.0%) - - 3 33 Kerem et al. [1995] (Morocco) 2) S549R (6.0%) Jewish ∆F508 (35.0%) W1282X (2.0%) 43.0 18.5 4 51 Shoshani et al. [1992] (Sepharadim) G542X (4.0%) S549I (2.0%) (Continued) BOBADILLAETAL. Login to comment
112 Jewish 1) 405+1G®A (48.0%) 3) W1282X (17.0%) - - 4 23 Kerem et al. [1995] (Tunisia) 2) DF508 (31.0%) 4) 3849+10KbC®T (4.0%) Jewish 1) G85E 4) G542X - - 6 10 Kerem et al. [1995] (Turkey) 2) DF508 5) 3849+10KbC®T 3) W1282X 6) W1089X Jewish (Yemen) None - - 0 5 Kerem et al. [1995] Lebanon 1) DF508 (35.0%) 6) 4096-28G®A (2.5%) - - 9 40 Desgeorges et al. [1997] 2) W1282X (20.0%) 7) 2789+5G®A (2.5%) 3) 4010del4 (10.0%) 8) M952I (2.5%) 4) N1303K (10.0%) 9) E672del (2.5%) 5) S4X (5.0%) Reunion ∆F508 (52.0%) 1717-1G→A (0.7%) 90.4 81.7 9 138 Cartault et al. [1996] Island Y122X (24.0%) G542X (0.7%) 3120+1G→A (8.0%) A309G (0.7%) A455E (2.2%) 2789+5G→A (0.7%) G551D (1.4%) Saudi North: 3) H139L - - North 1 49 families El-Harith et al. [1997]; Arabia 1) 1548delG 4) L1177X Central 3 Kambouris et al. [1997]; Central: 5) DF508 South 4 Banjar et al. [1999] 1)I1234V 6) 3120+1G®A West 9 2)1548delG 7) 425del42 East 6 3)DF508 8) R553X South: 9) N1303K 1) I1234V East: 2) 1548delG 1) 3120+1G®A 3) 711+1G®T 2) H139L 4) 3120+1G®A 3) 1548delG West: 4) DF508 1) I1234V 5) S549R 2) G115X 6) N1303K Tunisia ∆F508 (17.6%) G85E (2.6%) 58.7 34.5 11 78 Messaoud et al. [1996] G542X (8.9%) W1282X (2.6%) 711+1G→T (7.7%) Y122X (1.3%) N1303K (6.4%) T665S (1.3%) 2766del8NT (6.4%) R47W+D1270N (1.3%) R1066C (2.6%) Turkeye ∆F508 (24.5%) 1066L (1.3%) 80.6 65.0 36 1067/670 Yilmaz et al. [1995]; Estivill et al. 1677delTA (4.1%) E822X (1.3%) [1997]; Onay et al. [1998]; 2789+5G→A (3.9%) 2183+5G→A+2184insA (1.3%) Macek et al. [2002] 2181delA (3.8%) D110H (0.8%) R347H (3.6%) P1013L (0.8%) N1303K (2.9%) 3172delAC (0.8%) 621+1G→T (2.6%) 1259insA (0.8%) G542X (2.6%) M1028I (0.8%) TABLE 1. Continued. Estimated Projected detection of Number of Number of Country/ allele two CFTR mutations chromosomes Region Mutation array detectiona mutationsb includedc (max/min)d Reference WORLDWIDEANALYSISOFCFTRMUTATIONS587 E92K (2.6%) 4005+1G→A (0.7%) A96E (2.6%) W1282X (0.7%) M152V (2.6%) I148T (0.6%) 2183AA→G (2.5%) R1162X (0.6%) 296+9A→T (1.6%) D1152H (0.6%) 2043delG (1.4%) W1098X (0.6%) E92X (1.4%) E831X (0.6%) K68N (1.4%) W496X (0.6%) G85E (1.3%) F1052V (0.5%) R1158X (1.3%) L571S (0.5%) United Arab S549R (61.5%) ∆F508 (26.9%) 88.4 78.1 2 86/52 Frossard et al. [1988]; Emirates Frossard et al. [1999] North/Central/South Americas Argentina ∆F508 (58.6%) N1303K (1.8%) 69.1 47.7 5 326/228 CFGAC [1994]; Chertkoff et al. W1282X (3.9%) 1717-1G→A (0.9%) [1997] G542X (3.9%) Brazilf ∆F508 (47.7%) W1282X (1.3%) 66.8 44.6 10 820/500 CFGAC [1994]; Cabello et al. (total) G542X (7.2%) G85E (1.3%) [1999]; Raskin et al. [1999]; R1162X (2.5%) R553X (0.7%) Bernardino et al. [2000] R334W (2.5%) L206W (0.6%) N1303K (2.4%) 2347delG (0.6%) South East: >∆F508, G542X South: >N1303K Brazil ∆F508 (31.7%) N1303K (2.5%) 42.5 18.1 3 120 Parizotto and Bertuzzo [1997] (Sao Paulo) G542X (8.3%) Canada ∆F508 (59.0%) G542X (0.5%) 98.5 97.0 13 381/200 Rozen et al. [1992]; (Lac St. Jean) 621+1G→T (24.3%) N1303K (0.5%) De Braekeleer et al. [1998] A445E (8.2%) Q890X (0.5%) Y1092X (1.2%) S489X (0.5) 711+1G→T (1.0%) R117C (0.5%) I148T (1.0%) R1158 (0.5%) G85E (0.8%) Canada ∆F508 (71.4%) ∆I507 (1.3%) 90.9 82.6 7 77 Rozen et al. [1992] (Quebec City) 711+1G→T (9.1%) Y1092X (1.3%) 621+1G→T (5.2%) N1303K (1.3%) A455E (1.3%) Canada ∆F508 (70.9%) W1282X (0.9%) 82.0 67.2 10 632 Kristidis et al. [1992] (Toronto) G551D (3.1%) R117H (0.9%) G542X (2.2%) 1717-1G→A (0.6%) 621+1G→T (1.3%) R560T (0.6%) N1303K (0.9%) ∆I507 (0.6%) Chile ∆F508 (29.2%) R553X (4.2%) 33.4 11.2 2 72 Rios et al. [1994] Columbia 1) DF508 (35.4%) 3) N1303K (2.1%) - - 4 48 Restrepo et al. [2000] 2) G542X (6.3%) 4) W1282X (2.1%) Ecuador 1) DF508 (25%) - - 1 20 Paz-y-Mino et al. [1999] (Continued) BOBADILLAETAL. Login to comment
113 Mexico ∆F508 (41.6%) G551S (0.5%) 75.5 57.0 35 374/194 Orozco et al.[1993]; Villalobos- G542X (5.6%) 1078delT (0.5%) Torres et al. [1997]; Liang et al. ∆I507 (2.5%) Y1092X (0.5%) [1998]; Orozco et al. [2000] S549N (1.9%) R117H (0.5%) N1303K (1.7%) G85E (0.5%) R75X (1.5%) 1716G→A (0.5%) 406-1G→A (1.5%) W1204X (0.5%) I148T (1.5%) W1098C (0.5%) 3849+10KbC→T (1.5%) 846delT (0.5%) 621+1G→T (1.2%) P750L (0.5%) 2055del9→A (1.0%) V754M (0.5%) 935delA (1.0%) R75Q (0.5%) I506T (1.0) W1096X (0.5%) 3199del6 (1.0%) L558S (0.5%) 2183AA→G (1.0%) 4160insGGGG (0.5%) G551D (0.5%) 297-1G→A (0.5%) R553X (0.5%) H199Y (0.5%) 1924del7 (0.5%) United States ∆F508 (68.6%) R553X (0.9%) 79.7 63.5 10 25048 Cystic Fibrosis Foundation (total) G542X (2.4%) 621+1G→T (0.9%) [1998] G551D (2.1%) 1717-1G→A (0.7%) W1282X (1.4%) 3849+10KbC→T (0.7%) N1303K (1.3%) R117H (0.7%) United States ∆F508 (48.0%) S1255X (1.4%) 77.3 59.8 16 160/148 Carles et al. [1996]; Macek et al. (African 3120+1G→A (12.2%) 444delA (0.7%) [1997]; Dörk et al. [1998]; American) 2307insA (2.0%) R334W (0.7%) Friedman et al. [1998] A559T (2.0%) ∆I507 (0.7%) R553X (2.0%) 1717-1G→A (0.7%) ∆F311 (2.0%) G542X (0.7%) G480C (1.4%) S549N (0.7%) 405+3A→C (1.4%) G551D (0.7%) United States 1) L1093P - - 1 2 Yee et al. [2000] (Cherokee) United States Non-French: French: Non- Non- Non- Non- Bayleran et al. [1996] (Maine) ∆F508 (82.0%) ∆F508 (58%) French: French: French: French: G542X (2.6%) 711+1G→T (8.3%) 95.3 90.8 11 191 G551D (2.6%) I148T (4.2%) French: French: French: French: N1303K (2.1%) A455E (4.2%) 80.3 64.5 8 72 R560T (1.0%) 1717-1G→A (1.4%) Total: 621+1G→T (1.0%) G85E (1.4%) 263 711+1G→T (1.0%) 621+1G→T (1.4%) R117H (1.0%) Y1092X (1.4%) 1717-1G→A (1.0%) G85E (0.5%) W1282X (0.5%) TABLE 1. Continued. Estimated Projected detection of Number of Number of Country/ allele two CFTR mutations chromosomes Region Mutation array detectiona mutationsb includedc (max/min)d Reference WORLDWIDEANALYSISOFCFTRMUTATIONS589 United States ∆F508 (46.0%) R334W (1.6%) 58.5 34.2 7 129 Grebe et al. [1994] (SW Hispanic) G542X (5.4%) W1282X (0.8%) 3849+10KbC→T (2.3%) R553X (0.8%) R1162X (1.6%) United States 1) R1162X - - 3 17 Mercier et al. [1992] (SW Native 2) D648V American) 3) G542X United States 1) R1162X 3) G542X - - 4 16 Mercier et al. [1994] (Zuni Pueblo) 2) 3849+10KbC®T 4) D648V Venezuela ∆F508 (29.6%) G542X (3.7%) 33.3 11.1 2 54 Restrepo et al. [2000] Other Regions Australia ∆F508 (76.9%) 621+1G→T (1.1%) 88.7 78.7 8 761/464 CFGAC [1994] G551D (4.5%) N1303K (0.9%) G542X (2.8%) W1282X (0.6%) R553X (1.3%) R117H (0.6%) East Asia 1) 1898+1G®T 2) 1898+5G®T - - 2 28 Suwanjutha et al. [1998] Hutterite 1) M1101K (69.0%) 2) DF508 (31.0%) - - 2 32 Zielenski et al. [1993] Brethren New Zealand ∆F508 (78.0%) N1303K (1.9%) 87.4 76.4 5 636 CFGAC [1994] G551D (4.4%) 621+1G→T (1.1%) G542X (2.0%) *This table presents the mutation panels for all regions investigated in this study. Login to comment
155 G542X is most common in the Mediterranean regions of Europe and Africa. Login to comment
159 This gradient of decreasing G542X prevalence can be seen on both the international and intranational levels as the distance from the Mediterranean Sea increases. Login to comment
163 G542X has been implicated as a mutation that was introduced into the Mediterranean region by the migration of Phoenicians [Loirat et al., 1997]. Login to comment
164 Across Europe, G542X is found in significantly higher proportions in countries, and in regions of countries, which border the Mediterranean Sea (Table 1). Login to comment
165 Not surprisingly, G542X has its highest rates of prevalence in the south of Spain and in the north of Africa (South Spain, 14.4%; Tunisia, 8.9%). Login to comment
168 When one studies CF chromosomes in those populations of the New World that were heavily influenced by such countries as Spain and Italy, the G542X mutation frequencies are virtually identical. Login to comment
169 The mutation N1303K is another CFTR allele that has a similar distribution patterns as G542X, and may also have been introduced via the Mediterranean route (Table 1). Login to comment
193 The top 10 list for the United States (Table 1) includes five CFTR alleles found in populations with distinct ethnic ancestries, i.e., G542X, G551D, W1282X, N1303K, and 3849+10KbC→T. Login to comment
213 Ideal Recommended CFTR Mutation Screening Panel for 2001 Neonatal Screening in the USA* Location Estimated Mutation in CFTRa percentageb Reason for inclusion DF508 Exon 10 68.6% CFF registry, >1%, Pan-European G542X Exon 11 2.4% CFF registry, >1%, Mediterranean G551D Exon 11 2.1% CFF registry, >1%, Celtic W1282X Exon 20 1.4% CFF registry, >1%, Ashkenazi Jew N1303K Exon 21 1.3% CFF registry, >1%, Mediterranean R553X Exon 11 0.9% CFF registry, >0.5%, Hispanic 621+1G®T Intron 4 0.9% CFF registry, >0.5%, multi-ethnic 1717-1G®A Intron 10 0.7% CFF registry, >0.5%, Italian 3849+10KbC®T Intron 19 0.7% CFF registry, >0.5%, Hispanic R117Hc Exon 4 0.7% CFF registry, >0.5% 1898+1G→T Intron 12 0.4% CFF registry, >0.1%, East Asian DI507 Exon 10 0.3% CFF registry, >0.1%, Hispanic 2789+5G®A Intron 14b 0.3% CFF registry, >0.1% G85E Exon 3 0.3% CFF registry, >0.1% R347P Exon 7 0.2% CFF registry, >0.1% R334W Exon 7 0.2% CFF registry, >0.1%, multi-ethnic R1162X Exon 19 0.2% CFF registry, >0.1%, multi-ethnic R560T Exon 11 0.2% CFF registry, >0.1% 3659delC Exon 19 0.2% CFF registry, >0.1% A455E Exon 9 0.2% CFF registry, >0.1% 2184delA Exon 13 0.1% CFF registry, >0.1% S549N Exon 11 0.1% CFF registry, >0.1%, multi-ethnic 711+1G®T Intron 5 0.1% CFF registry, >0.1% R75X Exon 3 0.2% Hispanic 406-1G→A Intron 3 0.2% Hispanic I148T Exon 4 0.2% Hispanic, French 2055del9→A Exon 13 0.1% Hispanic 935delA Exon 6b 0.1% Hispanic I506T Exon 10 0.1% Hispanic 3199del6 Exon 17a 0.1% Hispanic 2183AA→G Exon 13 0.1% Hispanic 3120+1G®A Intron 16 1.5% African American, Arabian 2307insA Exon 13 0.2% African American A559T Exon 11 0.2% African American ∆F311 Exon 7 0.2% African American G480C Exon 10 0.2% African American 405+3A→C Intron 3 0.2% African American S1255X Exon 20 0.2% African American L1093P Exon 17b Undetermined Native American D648V Exon 13 Undetermined Native American I1234V Exon 19 Undetermined Arabian linkage S549R Exon 11 Undetermined Arabian linkage 1898+5G→T Intron 12 Undetermined East Asian linkage CFTRdele2,3 Exons 2,3 Undetermined Eastern European linkage (Slavic) Y1092X Exon 17b Undetermined French linkage 394delTT Exon 3 Undetermined Nordic linkage Y569D Exon 12 Undetermined Pakistani linkage 3905insT Exon 20 Undetermined Swiss linkage (also: Amish, Acadian, Mennonite) 1898+1G®A Intron 12 Undetermined Welsh linkage M1101k Exon 17b Undetermined Hutterite ancestry *This table presents the top 50 mutations in the USA based on the Cystic Fibrosis Foundation CF Registry data from 1997 [Cystic Fibrosis Foundation, 1998], and data generated during our investigation. Login to comment

PMID: 12070257 [PubMed] Scotet V et al: "Prenatal detection of cystic fibrosis by ultrasonography: a retrospective study of more than 346 000 pregnancies."

No. Sentence Comment

196 The heterozygous fetuses carried a severe molecular abnormality (∆F508 (n=9) or G542X (n=1)), except one who carried a mild mutation (R347H). Login to comment
202 Therefore, the second mutation Table 1 Incidence of cystic fibrosis and CF heterozygosity among fetuses with echogenic bowel in Brittany, France (1991-2000) Fetuses with echogenic bowel 142 Affected fetuses Number 14 Incidence 1/10 Genotypes ∆F508/∆F508 9 ∆F508/4005+1G→A 1 ∆F508/3129del4 1 ∆F508/Q220X 1 ∆F508/W1282X 1 ∆F508/1717-1G→A 1 CF incidence in the general population during the present study 1/2987 Risk of CF: echogenic bowel fetuses/general population 294 Heterozygous fetuses Number 11 Incidence 1/13 Mutations ∆F508 9 G542X 1 R347H 1 CF heterozygosity in the general population during the present study 1/28 Risk of CF heterozygosity: echogenic bowel fetuses/general population 2.2 Letter www.jmedgenet.com will be identified in 88.5% of the 22.6% of fetuses for which the first analysis identified only one mutation (that is, in 20.0% of all CF fetuses). Login to comment
241 However, they based their comparison on an expected carrier rate in the general population which appears to be overestimated.1 The CFTR mutations identified in fetuses with echogenic bowel that have been reported so far are associated with pancreatic insufficiency (for example, ∆F508, G542X, G551D, Table 2 Ability of the ultrasound examination to detect cystic fibrosis Cystic fibrosis TotalYes No Utrasound examination Abnormal 14 128 142 Normal 112 346 300 346 412 Total 126 346 428 346 554 2183AA→G, ∆F311).9 13 27 43 To our knowledge, only one mutation associated with a mild phenotype (R117H)13 and one mild complex CFTR allele (D443Y-G576A-R668C)44 have been identified in two of the CF affected fetuses. Login to comment

PMID: 12089190 [PubMed] Wang X et al: "Development and evaluation of a PCR-based, line probe assay for the detection of 58 alleles in the cystic fibrosis transmembrane conductance regulator (CFTR) gene."

No. Sentence Comment

68 Amplicon Size, bp Mutations (polymorphisms) Exon 13 598 2307 insA Intron 8, exon 09 548 A455E, 5T (7/9 T polymorphism) Exon 10 482 G480C, ⌬I507, ⌬F508 (F508C, I507V, I506V polymorphisms) Intron 10, exon 11 433 1717-1G3A, G542X, G551D, R553X, A559T, R560T Exon 19 420 R1162X, 3659delC Exon 21 397 N1303K Exon 20 359 S1255X, W1282X Exon 07 328 1078delT, R334W, R347P Exon 04, intron 4 288 R117H, 621ϩ1G3T Intron 14b 248 2789ϩ5G3A Intron 19 237 3849ϩ10kbC3T Exon 03 210 G85E, 405ϩ3A3C Intron 5 166 711ϩ1G3T Intron 16 139 3120ϩ1G3A Clinical Chemistry 48, No. Login to comment
88 The genotypes of each sample are as follows: lane 1, ϩ/ϩ (ϩ is the wild type); lane 2, 5T, R117H/3659delC; lane 3, G542X/ϩ; lane 4, I506V/ϩ; lane 5, I507V/ϩ; lane 6, F508C/⌬F508; lane 7, G85E/⌬F508; lane 8, 405ϩ3A3C/3120ϩ1G3C; lane 9, R117H/ϩ; lane 10, 621ϩ1G3T/⌬F508; lane 11, 711ϩ1G3T/⌬F508; lane 12, 1078delT/ϩ; lane 13, R334W/⌬F508; lane 14, R347P/⌬F508; lane 15, A455E/ϩ; lane 16, G480C/⌬F508; lane 17, ⌬I507/ϩ; lane 18, ⌬F508/ϩ; lane 19, 1717-1G3A/ϩ; lane 20, G542X/ϩ; lane 21, G551D/⌬F508; lane 22, R553X/ϩ; lane 23, R560T/⌬F508; lane 24, G551D/A559T; lane 25, 2307insA/ϩ; lane 26, 2789ϩ5G3A/⌬F508; lane 27, 3120ϩ1G3A/⌬F508; lane 28, R1162X/R1162X; lane 29, 3659delC/⌬F508; lane 30, 3849ϩ10kbC3T/⌬F508; lane 31, S1255X/⌬F508; lane 32, W1282X/G542X; lane 33, N1303K/ϩ. Login to comment

PMID: 12116247 [PubMed] Muller F et al: "Predicting the risk of cystic fibrosis with abnormal ultrasound signs of fetal bowel: results of a French molecular collaborative study based on 641 prospective cases."

No. Sentence Comment

46 Depending on the laboratory, the methods most frequently used were reverse dot blot with the Inno-Lipa CF2 kit (Murex) (eight mutations detected: DF508, DI507, G542X, G551D, R553X, 1717-1G ! Login to comment
48 A, G542X, G551D, R553X, R560T, S549R, S549N, 3849 þ 10kbC ! Login to comment
64 Of them, 14 were homozygous for DF508 and three were compound heterozygous for DF508 and another mutation (W1282X, G542X, 1078delT). Login to comment
73 Fetuses Carrying Two CFTR Mutations Cases CFTR Gene Mutations Ultrasound Findings Outcome 1-9 DF508/DF508 Hyperechogenic bowel TOP 10,11 DF508/DF508 Hyperechogenic bowel þ dilated loop TOP 12 DF508/DF508 Hyperechogenic bowel þ dilated loop þ gall bladder not seen TOP 13 DF508/DF508 Hyperechogenic bowel þ gall bladder not seen TOP 14 DF508/DF508 Intestinal dilated loops (absent at 22 wks) Birth, CF-affected, meconium ileus at birth 15 DF508/W1282X Hyperechogenic bowel (absent at 22 wks) TOP 16 DF508/G542X Hyperechogenic bowel þ dilated loop TOP 17 DF508/1078delT Hyperechogenic bowel þ dilated loop (absent at 22 wks) Birth, CF-affected,* meconium ileus at birth 18 DF508/O220X Hyperechogenic bowel þ dilated loop (present at 33 wks) Birth, CF-affected,* meconium ileus at birth 19 1078delT/394delTT Hyperechogenic bowel TOP 20** CFTRdele19/CFTRdele19 Hyperechogenic bowel (present at 33 wks) Birth, CF-affected, absence of meconium ileus at birth 21 W846X/G576A-R668C Hyperechogenic bowel Birth, potential absence of vas deferens TOP ¼ termination of pregnancy; Wks ¼ weeks of amenorrhea. Login to comment
103 Heterozygous Cystic Fibrosis Cases With Abnormal Fetal Bowel at Ultrasound Examination Cases CFTR Gene mutations Ultrasound findings Outcome 22-27 DF508/X Hyperechogenic bowel Birth, thriving 28-29 DF508/X Hyperechogenic bowel Premature birth (32 wks), thriving 30 DF508/X Hyperechogenic bowel TOP cardiomegaly þ pulmonary hypoplasia 31 DF508/X Hyperechogenic bowel Lost to follow-up 32 DF508/X Hyperechogenic bowel þ short femur Died day 2 after birth, fetal distress 33 DF508/X Intestinal dilated loops Birth, thriving 34 DF508/X Hyperechogenic bowel þ fetal hydrops Birth, parvovirus-affected, thriving 35 DF508/X Intra-abdominal calcifications Birth, thriving 36 G542X/X Hyperechogenic bowel þ polyhydramnios Birth, thriving 37 R117H/X Hyperechogenic bowel Birth, thriving 38 A534E/X Hyperechogenic bowel Birth, thriving 39 D836Y/X Dilated loop (small bowel) þ polyhydramnios Birth, small bowel atresia, operated, not CF-affected In the present study, most CF cases with intestinal anomalies (15/20) were observed during the second trimester of pregnancy, because in France all pregnant women undergo ultrasound examinations at 11, 22, and 33 weeks. Login to comment
110 It has also been demonstrated that the risk of meconium ileus is higher among children with the G542X mutation [Hamosh et al., 1992] and one of the 20 CF cases was a DF508/G542X compound heterozygote. Login to comment

PMID: 12124706 [PubMed] Orgad S et al: "Hyperechogenic bowel loops and meconium ileus in a fetus carrying the D1152H and G542X cystic fibrosis CFTR mutations."

No. Sentence Comment

20 Hyperechogenic bowel loops and meconium ileus in a fetus carrying the D1152H and G542X cystic fibrosis CFTR mutations In the Jewish cystic fibrosis (CF) patient population, 12 mutations account for more than 91% of the CF chromosomes. Login to comment
21 Ashkenazi Jews were tested in the past only for F508del, W1282X, G542X, N1303K and 3849+10KbC>T of the cystic fibrosis transmembrane conductance regulator (CFTR) gene (Kerem et al., 1995, 1997; Abeliovich et al., 1992, 1996). Login to comment
32 Since the US finding was compatible with CF, DNA from the woman was analysed and was found to carry the G542X CFTR mutation. Login to comment

PMID: 12124743 [PubMed] Salvatore F et al: "Genotype-phenotype correlation in cystic fibrosis: the role of modifier genes."

No. Sentence Comment

25 Several mutations of this group have a frequency of > 2% among CF chromosomes within most populations studied, e.g., W1282X [Shoshani et al., 1992], R553X, and G542X [Casals et al., 1993]. Login to comment
65 Secondly, pulmonary expression was heterogeneous in CF patient homozygotes for nonsense mutations, although CFTR mRNA was not detected at the pulmonary level in these patients [Hamosh et al., 1991]; for example, a mild pulmonary expression has been reported in several patient homozygotes for nonsense mutations [Cutting et al., 1990b; Cuppens et al., 1990], such as R553X [Castaldo et al., 1996] and G542X [Castaldo et al., 1997]. Login to comment
87 Similarly, we described a CF patient homozygous for the G542X mutation who had a very severe liver phenotype, unlike the six previously reported cases with this CFTR genotype, who were free of liver involvement [Castaldo et al., 1997]. Login to comment

PMID: 12133923 [PubMed] Corbetta C et al: "Screening for cystic fibrosis in newborn infants: results of a pilot programme based on a two tier protocol (IRT/DNA/IRT) in the Italian population."

No. Sentence Comment

266 Mutations identified by the assay are G85E, 621+1G→T, R117H, Y122X, 711+1G→T, 1078delT, R347P, R347H, R334W, A455E, 1898+1G→A, 2183-AA→G, 2789+5G→A, delF508, I507del, Q493X, V520F, 1717-1G→A, G542X, G551D, R553X, R560T, S549R, S549N, 3849+10kbC→T, 3849+4A→G, R1162X, 3659delC, W1282X, 3905insT, and N1303K. Login to comment
280 Genotypes are shown in table 1: 18% of our patients were delF508 homozygotes, 15% were homozygotes for other CFTR alleles (N1303K, 2183AA→G, 1717-1G→A, R334W, G542X), 21% were compound heterozygotes, and a further 43% were heterozygotes. Login to comment
285 The CFTR mutations identified and their frequencies among carriers were as follows: delF508 (72 chromosomes, 64.2%), N1303K (12, 10.7%), R117H (9, 8%), G542X (7, 6.25%), R347H, R1162X, 2789+5G→A (2 alleles each, 1.8%), 1898+1G→A, 1717-1G→A, W1282X, 2183-AA→G, 621+1G→T, and 3849+10kbC→T (1, 0.9%). Login to comment
310 Since 1998, in our CF centre, an expanded DNA CFTR gene analysis and repeat sweat test after 6-12 months of life have been performed in hypertrypsinaemic Table 1 Genotypes of 33 patients with CF identified in the 15 month period Two CFTR mutations identified (18 patients) by PCR/OLA: ∆F508/∆F508 6 N1303K/N1303K 2 ∆F508/N1303K 3 R334W/R334W 1 ∆F508/G542X 2 G542X/G542X 1 ∆F508/3659delC 1 2183AA→G/ 2183AA→G 1 ∆F508/R1162X 1 One CFTR mutation identified (13 patients) by PCR/OLA: ∆F508/D1152H* 1 ∆F508/Y1032C* 1 ∆F508/R1066H* 1 ∆F508/UN 6 ∆F508/R1066C* 1 W1282X/L1077P* 1 ∆F508/D579G* 1 G85E/UN 1 No CFTR mutation identified (two patients) by PCR/OLA: 711+3A→G*/UN 1 D110E*/D110E* 1 *CFTR alleles identified by analysis by denaturing gradient gel electrophoresis and sequencing. Login to comment

PMID: 12138064 [PubMed] Blau H et al: "Urogenital abnormalities in male children with cystic fibrosis."

No. Sentence Comment

264 Seven of these were homozygous or compound heterozygotes for the genotypes ∆F508, W1282X, G542X, S549R, and 405+1G→A. Login to comment
294 The vas deferens appeared similar to Table 1 Genotype and clinical features in pancreatic insufficient boys Pt no. Age (y) Sweat chloride CFTR mutations FEV1 Wt Ht Sh. score 1 2 69 W1282X/405+1G→A - 3 3 77 2 3 100 W1282X/W1282X 98% 50 75 92 3 5 78 Unknown 94% 50 10 92 4 6 75 Unknown 86% 50 25 85 5 7 76 W1282X/G542X 105% 95 40 90 6 8 99 W1282X/∆F508 112% 85 50 98 7 9 90 S549R/S549R 77% 25 10 70 8 10 84 W1282X/∆F508 102% 25 20 89 9 10 97 W1282X/∆F508 87% 50 50 98 FEV1, forced expiratory volume in 1 second; Wt , weight, percentile for age; Ht, height, percentile for age; Sh. score, Shwachman score. Login to comment

PMID: 12151438 [PubMed] Wang Z et al: "Analysis by mass spectrometry of 100 cystic fibrosis gene mutations in 92 patients with congenital bilateral absence of the vas deferens."

No. Sentence Comment

20 Given the frequency of CF mutations, especially in the Caucasian population ( in 25), and the common request by CBAVD men to sire their own offspring by using surgical Table I. The 100 most common cystic fibrosis mutations listed by exon Mutationa Exonb Frequency (%)c G85E 3 0.1 394delTT 3 Swedish E60X 3 Belgium R75X 3 405ϩ1G→A Int 3 R117H 4 0.30 Y122X 4 French 457TAT→G 4 Austria I148T 4 Canada (French Canadian) 574delA 4 444delA 4 R117L 4 621ϩ1G→T Int 4 0.72 711ϩ1G→T Int 5 Ͼ0.1 712-1G→T Int 5 711ϩ5G→A Int 5 Italy (Caucasian) L206W 6a R347P 7 0.24 1078delT 7 Ͼ0.1 R334W 7 Ͼ0.1 1154InsTC 7 T338I 7 Italy R347H 7 Turkey Q359K/T360K 7 Israel (Georgian Jews) I336K 7 R352Q 7 G330X 7 S364P 7 A455E 9 0.20 I507 10 0.21 F508 10 66.02 1609delCA 10 Spain (Caucasian) V520F 10 Q493X 10 C524X 10 G480C 10 Q493R 10 1717-1G→A Int 10 0.58 R553X 11 0.73 G551D 11 1.64 G542X 11 2.42 R560T 11 Ͼ0.1 S549N 11 Q552X 11 Italy S549I 11 Israel (Arabs) A559T 11 African American R553G 11 R560K 11 1812-1G→A Int 11 A561E 12 E585X 12 Y563D 12 Y563N 12 1898ϩ1G→A Int 12 0.22 1898ϩ1G→C Int 12 2183AA→G 13 Italian 2184delA 13 Ͻ0.1 K710X 13 2143delT 13 Moscow (Russian) 2184InsA 13 1949del84 13 Spain (Spanish) 2176InsC 13 2043delG 13 2307insA 13 2789ϩ5G→A Int 14b Ͼ0.1 2869insG 15 S945L 15 Q890X 15 3120G→A 16 2067 Table I. continued Mutationa Exonb Frequency (%)c 3120ϩ1G→A Int 16 African American 3272-26A→G Int 17a R1066C 17b Portugal (Portugese) L1077P 17b R1070Q 17b Bulgarian W1089X 17b M1101K 17b Canada (Hutterite) R1070P 17b R1162X 19 0.29 3659delC 19 Ͼ0.1 3849G→A 19 3662delA 19 3791delC 19 3821delT 19 Russian Q1238X 19 S1235R 19 France, South S1196X 19 K1177R 19 3849ϩ10kbC→T Int 19 0.24 3849ϩ4A→G Int 19 W1282X 20 1.22 S1251N 20 Dutch, Belgian 3905insT 20 Swiss, Acadian, Amish G1244E 20 R1283M 20 Welsh W1282R 20 D1270N 20 S1255X 20 African American 4005ϩ1G→A Int 20 N1303K 21 1.34 W1316X 21 aMutations were chosen according to their frequencies (Cystic Fibrosis Genetic Analysis Consortium, 1994; Zielenski and Tsui, 1995; Estivill et al., 1997). Login to comment
34 The mutations in the 25 mutation panel were: ∆F508, G542X, N1303K, G551D, W1282X, 1717-1G→A, R553X, 621ϩ1G→T, R1162X, 2183AA→G, R117H, ∆I507, R560T, 3849ϩ10kbC→T, S549N, S549I, S549R, R1283M, R1283K, R553G, R560K, R117L, 1774delCT, 1811ϩ1G→C, and 4006-61del14. Login to comment
35 ACMG 25 mutation panel (ACMG25): The following mutations are the recommended core mutations for general population CF carrier screening by American College of Medical Genetics (ACMG) (Grody, et al 2001): ∆F508, G542X, N1303K, G551D, W1282X, 1717-1G→A, R553X, 621ϩ1G→T, R1162X, R117H, ∆I507, 1898ϩ1G→A, G85E, R347P, A455E, R560T, R334W, 3849ϩ10kbC→T, 3659delC, 1078delT, 2789ϩ5G→A, 711ϩ1G→T, 2184delA, 3120ϩ1G→A and I148T. Login to comment
86 CFTR mutations in 92 men with congenital bilateral absence of vas deferens Mutations CFTR mutation panels CF25 CF25 ϩ 5T ACMG25 ACMG25 ϩ 5T CF100 Mutations detected in ∆F508 39 39 39 39 39 CF25 mutation panel R117H 4 4 4 4 4 W1282X 4 4 4 4 4 G551D 3 3 3 3 3 G542X 1 1 1 1 1 N1303K 1 1 1 1 1 IVS8-polyT IVS8-5T 33 33 33 Additional mutations L206W 3 detected not in CF25 D1270N 2 mutation panel 1154InsTC 1 3272-26A→G 1 A455E 1 1 1 R334W 1 1 1 Q890X 1 Total 14 52 85 54 87 95 respectively, in the total number of patients with at least one mutation. Login to comment
91 CFTR genotypes in 92 men with congenital bilateral absence of vas deferens Genotypesa CFTR mutation panelsb CF25 CF25 ϩ 5T ACMG25 ACMG25 ϩ 5T CF100 Two mutations ∆F508/5T 16 16 16 W1282X/5T 4 4 4 ∆F508/R117Hc 3 3 3 3 3 G542X/5T 1 1 1 G551D/5T 1 1 1 ∆F508/L206W 2 ∆F508/A455E 1 1 1 ∆F508/3272-26A→G 1 Q890X/5T 1 L206W/5T 1 D1270N/D1270N 1 5T/5T 1 1 1 Sub-total 3 26 4 27 33 One mutation ∆F508/ϩ 36 20 35 19 16 5T/ϩ 9 9 7 G551D/ϩ 3 2 3 2 2 G542X/ϩ 1 1 R117H/ϩ 1 1 1 1 1 N1303K/ϩ 1 1 1 1 1 W1282X/ϩ 4 4 R334W/ϩ 1 1 1 1154InsTC/ϩ 1 Sub-total 46 33 46 33 29 Total (%) 49 (53.3) 59 (64.1) 50 (54.3) 60 (65.2) 62 (67.4) No mutation (%) 43 (46.7) 33 (35.9) 42 (45.7) 32 (34.8) 30 (32.6) aMutations L206W, 3272-26A→G, Q890X, D1270N, 1154InsTC and 5T are not in either CF25 and ACMG25 panels, while A455E and R334W are not in CF25, but are part of ACMG25 panel. Login to comment
93 bThe increase in the number of patients with two mutations under CF25ϩ5T, ACMG25ϩ5T and CF100, compared with CF25 and ACMG25, was due to identification of a second mutation and reflected by the reduction of the number of patients with one mutation (e.g. ∆F508/ϩ, G551D/ϩ, G542X/ϩ, W1282X/ϩ). Login to comment

PMID: 12162817 [PubMed] Wagner JA et al: "A phase II, double-blind, randomized, placebo-controlled clinical trial of tgAAVCF using maxillary sinus delivery in patients with cystic fibrosis with antrostomies."

No. Sentence Comment

157 Of the 23 treated patients, 11 were homozygous for DF508, 3 were DF508 heterozygouswith an unidentifiedallele, 2 were DF508 heterozygous with G542X, 6 were DF508 heterozygous with another allele (one each of 3849110KB, 3905 insert T, 62111, G85E, R334W, and W1282X) and 1 patient was G542X heterozygous with an unidentified allele. Login to comment

PMID: 12167682 [PubMed] Groman JD et al: "Variant cystic fibrosis phenotypes in the absence of CFTR mutations."

No. Sentence Comment

71 MUTATION IDENTIFIED BY SCREENING FOR COMMON MUTATIONS MUTATION IDENTIFIED BY DNA SEQUENCING NO. OF PATIENTS ∆F508 5T* 3 ∆F508 D1152H 2 ∆F508 2789+2insA 2 ∆F508 R117C 2 ∆F508 D110H 1 ∆F508 2789+5G→A 1 ∆F508 P205S 1 ∆F508 L967S 1 ∆F508 I1027T 1 ∆F508 L206W 1 ∆F508 T1053I and 5T 1 ∆F508 V920M and 5T 1 ∆F508 R1070W 1 ∆F508 D579G 1 ∆F508 P67L 1 ∆F508 2811G→T†‡ 1 G85E F191V† 1 R117H G103X and 5T 1 I148T I556V 1 G542X R1162L 1 W1282X D1152H 1 None L138ins and 3272-26 A→G 1 None G463D† and 5T 1 None F693L and 5T 1 ∆F508 None 6 G551D None 1 W1282X None 1 None 5T 4 None 2307insA 1 None L997F 1 None V520I 1 None None 30 in Subject II-2 in Family 1. Login to comment

PMID: 12215837 [PubMed] Scotet V et al: "Spatial and temporal distribution of cystic fibrosis and of its mutations in Brittany, France: a retrospective study from 1960."

No. Sentence Comment

118 His genotype was ∆F508/∆F508 Mutation Exon Basse-Bretagne Haute-Bretagne Brittanya ∆F508 10 446 75.6% 224 73.7% 672 75.0% 1078delT 7 31 5.3% 3 1.0% 34 3.8% G551D 11 21 3.6% 12 3.9% 33 3.7% N1303K 21 3 0.5% 9 3.0% 12 1.3% W846X 14a 9 1.5% 1 0.3% 10 1.1% 2789+5G→A 14b 3 0.5% 6 2.0% 9 1.0% 1717-1G→A 11 5 0.8% 3 1.0% 8 0.9% Y1092X 17b 1 0.2% 6 2.0% 7 0.8% 4005+1G→A 20 6 1.0% 1 0.3% 7 0.8% E60X 3 3 0.5% 3 1.0% 6 0.7% 621+1G→T 4 3 0.5% 3 1.0% 6 0.7% R347H 7 6 1.0% 0 0.0% 6 0.7% S492F 10 2 0.3% 3 1.0% 5 0.6% G542X 11 4 0.7% 1 0.3% 5 0.6% 3272-26A→G 17b 2 0.3% 3 1.0% 5 0.6% R117H 4 3 0.5% 1 0.3% 4 0.4% G91R 3 3 0.5% 0 0.0% 3 0.3% ∆I507 10 1 0.2% 2 0.7% 3 0.3% R553X 11 3 0.5% 0 0.0% 3 0.3% W1282X 20 2 0.3% 1 0.3% 3 0.3% A72D 3 0 0.0% 2 0.7% 2 0.2% G85E 3 0 0.0% 2 0.7% 2 0.2% F311L 7 0 0.0% 2 0.7% 2 0.2% 1221delCT 7 2 0.3% 0 0.0% 2 0.2% R560K 11 0 0.0% 2 0.7% 2 0.2% 2622+1G→A 13 2 0.3% 0 0.0% 2 0.2% S945L 15 0 0.0% 2 0.7% 2 0.2% I1234V 19 2 0.3% 0 0.0% 2 0.2% G1249R 20 2 0.3% 0 0.0% 2 0.2% 3905insT 20 2 0.3% 0 0.0% 2 0.2% Unidentified - 3 0.5% 0 0.0% 3 0.3% Total - 590 65.7% 304 34.3% 896 100% IVS17bTA, IVS17bCA) of Irish, Scottish, English, Breton and Czech subjects who were carriers of this mutation, and showed that all these alleles carried a unique haplotype (16-7-17), testifying to the Celtic origin of this mutation (Cashman et al. 1995). Login to comment
161 The G542X mutation, which is the most frequent in France after the ∆F508 deletion (2.9%), is solely present on 0.6% of the mutated alleles in the population studied here. Login to comment

PMID: 12226741 [PubMed] Du M et al: "Aminoglycoside suppression of a premature stop mutation in a Cftr-/- mouse carrying a human CFTR-G542X transgene."

No. Sentence Comment

1 M. Du · J. Lanier · K.M. Keeling · D.M. Bedwell (✉) Department of Microbiology, 1530 Third Avenue, South, The University of Alabama at Birmingham, Birmingham, AL 35294-2170, USA e-mail: dbedwell@uab.edu Tel.: +1-205-9346593, Fax: +1-205-9755482 J.R. Jones · D.M. Bedwell Department of Human Genetics, University of Alabama at Birmingham, Birmingham, Alabama, USA J.R. Lindsey Department of Genomics and Pathobiology, University of Alabama at Birmingham, Birmingham, Alabama, USA Z. Bebök · E.J. Sorscher Department of Physiology and Biophysics, University of Alabama at Birmingham, Birmingham, Alabama, USA M. Du · J.R. Jones · J. Lanier · K.M. Keeling · J.R. Lindsey A. Tousson · Z. Bebök · E.J. Sorscher · D.M. Bedwell Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama at Birmingham, Birmingham, Alabama, USA J.A. Whitsett · C.R. Dey Division of Pulmonary Biology, Children`s Hospital Medical Center, Cincinnati, Ohio, USA W.H. Colledge Department of Physiology, University of Cambridge, Cambridge, UK M.J. Evans Cardiff School of Biosciences, Cardiff University, Cardiff, UK Present address: J.R. Jones, Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee, USA J Mol Med (2002) 80:595-604 DOI 10.1007/s00109-002-0363-1 O R I G I N A L A RT I C L E Ming Du · Julie R. Jones · Jessica Lanier Kim M. Keeling · J. Russell Lindsey Albert Tousson · Zsuzsa Bebök · Jeffrey A. Whitsett Chitta R. Dey · William H. Colledge Martin J. Evans · Eric J. Sorscher · David M. Bedwell Aminoglycoside suppression of a premature stop mutation in a Cftr-/- mouse carrying a human CFTR-G542X transgene Received: 1 February 2002 / Accepted: 17 May 2002 / Published online: 3 July 2002 (c) Springer-Verlag 2002 MING DU received her Ph.D. degree in Biochemistry at Chiba University, Japan. Login to comment
11 To address whether aminoglycosides can suppress a CFTR premature stop mutation in an animal model, we constructed a transgenic mouse with a null mutation in the endogenous CFTR locus (Cftr-/-) that also expressed a human CFTR-G542X cDNA under control of the intestinal fatty acid binding protein promoter. Login to comment
13 Immunofluorescence staining of intestinal tissues from Cftr-/- hCFTR-G542X mice revealed that gentamicin treatment resulted in the appearance of hCFTR protein at the apical surface of the glands of treated mice. Login to comment
16 When taken together, these results indicate that gentamicin, and to a lesser extent tobramycin, can restore the synthesis of functional hCFTR protein by suppressing the hCFTR-G542X premature stop mutation in vivo. Login to comment
17 Keywords Aminoglycoside · Cystic fibrosis · CFTR-G542X transgene · Premature stop mutation Introduction Cystic fibrosis (CF) is the most prevalent autosomal recessive disorder in the Caucasian population, affecting 1 in 2,500 newborns. Login to comment
32 To do this, a transgenic mouse expressing a hCFTR cDNA containing the G542X stop mutation under control of the rat intestinal fatty-acid binding protein (FABP) promoter was constructed. Login to comment
33 We then examined the ability of aminoglycosides to induce hCFTR expression in Cftr-/- hCFTR-G542X mice. Login to comment
35 These results provide evidence that gentamicin (and to a lesser extent, tobramycin) can suppress the hCFTR-G542X mutation in vivo. Login to comment
36 Materials and methods Plasmid construction The plasmid containing hCFTR-G542X under control of the rat FABP promoter was derived from a FABP-hCFTR-WT plasmid [14]. Login to comment
37 The G542X premature stop mutation was introduced by the direct exchange of a 3043 bp BspE1/NcoI fragment from pDB436, yielding the FABP-CFTR-G542X plasmid pDB488. Login to comment
38 In addition to the G542X mutation, this plasmid contains an additional SalI restriction site that was introduced at codon 764 of the CFTR cDNA. Login to comment
40 Generation of transgenic mice A 1.2 kb DNA fragment containing the rat intestinal fatty-acid binding protein (FABP) promoter (kindly provided by Jeffrey Gordon, Washington University, St. Louis) was used to direct expression of the human CFTR cDNA containing the G542X mutation to the intestinal epithelial cells of mice using methods previously described [14]. Login to comment
41 The chimeric FABP-hCFTR-G542X gene construct was microinjected into fertilized oocytes. Login to comment
43 The FABP-hCFTR-G542X transgene was detected by Southern analysis in founder mice using a 2.54 kb BamHI fragment from the hCFTR gene as a probe. Login to comment
45 Animals that expressed the FABP-hCFTR-G542X transgene were then bred with heterozygous Cftr+/Cftrtm1Cam mice (hereafter referred to as Cftr+/- mice). Login to comment
48 Animals that contained single copies of both the Cftrtm1Cam allele and the FABP-hCFTR-G542X transgene were interbred until the NeoR marker was eliminated and the progeny were homozygous for the FABP-hCFTR-G542X transgene. Login to comment
49 Cftr+/- mice that were homozygous for the FABP-hCFTR-G542X transgene were then intercrossed to generate the desired Cftr-/- progeny carrying the transgene. Login to comment
53 Amplification of the FABP-hCFTR-G542X transgene DNA was carried out using the primers DB985 (5'-CAAGATAGAA AGAGGACAGT TGTT-3') and DB986 (5'-TTGAGGGTTG ACATAGGTGC TTGAA-3'). Login to comment
54 This primer pair generated a 1557 bp fragment containing both the G542X mutation and the new SalI site. Login to comment
57 mRNA expression in intestinal tissue To determine whether the FABP-CFTR-G542X transgene was expressed, mRNA was isolated from intestinal tissues of FABP-hCFTR-G542X or FABP-hCFTR-WT transgenic mice. Login to comment
59 The hCFTR-G542X PCR product was digested with the restriction enzyme SalI to demonstrate that the predicted 954 and 603 bp fragments were produced. Login to comment
63 Aminoglycoside treatment Aminoglycoside treatment of homozygous Cftr-/- mice carrying the FABP-hCFTR-G542X transgene was initiated 16 days after birth (1 week before weaning). Login to comment
78 In control experiments, glibenclamide was found to block the forskolin-activated Isc in Cftr+/- mice carrying the hCFTR-G542X transgene. Login to comment
93 In vitro transcription/translation A modified form of a readthrough reporter system previously used to monitor the suppression of stop mutations by aminoglycosides [10] was used to determine whether the aminoglycosides gentamicin and tobramycin could suppress the CFTR-G542X mutation in an in vitro rabbit reticulocyte lysate translation system (Promega TNT system). Login to comment
96 In this study, the readthrough cassette contained the CFTR-G542X premature stop mutation and six upstream and downstream codons from the hCFTR gene. Login to comment
100 Efficient translation termination at the G542X stop mutation produced a 25 kDa protein, while suppression of the stop codon resulted in the synthesis of a 35 kDa protein. Login to comment
102 Suppression of the G542X mutation was expressed as percent readthrough, which was calculated as the [35 kDa protein / (25 kDa + 35 kDa proteins)] × 100. Login to comment
103 Results Genetic characterization of a Cftr-/- mouse expressing the hCFTR-G542X transgene The objective of this study was to determine whether the aminoglycosides gentamicin or tobramycin can suppress a hCFTR premature stop mutation in an animal model. Login to comment
105 As a result, we bred FABP-hCFTR-G542X mice with Cftr+/- mice that carried the HPRT gene inserted in exon 10 of the mouse Cftr gene [4, 15]. Login to comment
106 Male and female Cftr+/- mice that were homozygous for the FABP-hCFTR-G542X transgene were produced and used as breeders for all subsequent experiments. Login to comment
107 From these breeder pairs, offspring homozygous for both the Cftrtm1Cam allele and the FABP-hCFTR-G542X transgene were obtained at a frequency of 25%. Login to comment
108 To confirm the presence of the FABP-hCFTR-G542X transgene in these animals, a PCR reaction with hCFTR-specific primers was carried out using genomic DNA isolated from both the FABP-hCFTR-G542X and FABP-hCFTR-WT transgenic mice. Login to comment
110 As a unique indentifier, the hCFTR-G542X transgene also contained a new SalI restriction site polymorphism that does not alter the amino acid sequence of the hCFTR protein. Login to comment
111 Digestion of the PCR products with SalI produced the expected restriction fragments of 954 and 603 bp from the PCR product from the hCFTR-G542X mouse, but not from the hCFTR-WT mouse. Login to comment
112 This result confirmed the presence of the FABP-hCFTR-G542X transgene. Login to comment
113 We next analyzed the expression of the FABP-hCFTR-G542X transgene. Login to comment
114 Since the FABP promoter is expressed predominantly in intestine [14], mRNA was isolated from intestinal tissues from either hCFTR-G542X or hCFTR-WT transgenic mice. Login to comment
116 As can be seen in Fig. 1, a 1,557 bp fragment could be detected in both the hCFTR-G542X and hCFTR-WT transgenic mice. Login to comment
117 In addition, digestion of the cDNA fragment generated by RT-PCR with SalI site again confirmed that a SalI site was present exclusively in the mouse line carrying the hCFTR-G542X transgene. Login to comment
118 These results confirmed that the FABP-hCFTR-G542X construct is expressed in intestinal tissue from the FABP-hCFTR-G542X mice. Login to comment
119 Pathologic characterization of Cftr-/- mice expressing the hCFTR-G542X transgene Mice homozygous for both the Cftr-/- allele and the FABP-hCFTR-G542X transgene were generally smaller than their heterozygous littermates, as observed in various Cftr-/- mouse models [19]. Login to comment
121 While the survival of the Cftr-/- hCFTR-G542X mice was generally high during the first few weeks after birth, we found that most of these animals died in the days following weaning. Login to comment
123 To determine the primary cause of death of the Cftr-/- hCFTR-G542X mice, a comprehensive histopathologic examination was carried out on several animals. Login to comment
124 In particular, our attention focused on comparing healthy and sick Cftr-/- hCFTR-G542X mice in the days following weaning. Login to comment
127 Some of these findings are il- 598 Fig. 1A, B Generation of Cftr-/- FABP-hCFTR-G542X mice. Login to comment
128 A Schematic diagram of the FABP-hCFTR-G542X construct. Login to comment
129 B PCR from genomic DNA showing the presence of the hCFTR-G542X transgene (left) and an RT-PCR showing that the hCFTR-G542X transgene is expressed in intestinal tissues (right). Login to comment
131 A similar analysis of Cftr+/+ FABP-hCFTR-G542X littermates found that all tissues were normal. Login to comment
132 These results confirmed that the cftr-/- FABP-hCFTR-G542X mice, like other Cftr-/-mouse models, frequently experience intestinal blockage. Login to comment
133 However, little or no intestinal pathology was observed in Cftr-/- hCFTR-G542X mice that were not ill, other than a minimal retention of mucus in the crypts of the small and large intestine (data not shown). Login to comment
135 In preliminary experiments, we found that the subcutaneous administration of gentamicin at a similar dose was well tolerated in the FABP-hCFTR-G542X mice. Login to comment
139 Effect of aminoglycoside treatment on the survival of Cftr-/- hCFTR-G542X mice We first asked whether the subcutaneous administration of the aminoglycosides increased the survival of Cftr-/- mice carrying the hCFTR-G542X transgene. Login to comment
141 As a control for any change in survival of these animals caused by antibacterial effects rather than suppression of the hCFTR-G542X stop mutation, we also treated a control group of mice 599 Fig. 2 Histopathology observed in the jejunum of: A a Cftr+/+ mouse carrying the hCFTR-G542X transgene, and B an ill Cftr-/- mouse carrying the hCFTR-G542X transgene. Login to comment
146 Groups of both treated and untreated Cftr-/- hCFTR-G542X mice had a high rate of survival up to 20 days after birth (Fig. 4). Login to comment
154 hCFTR activity is detected in Cftr-/- hCFTR-G542X mice following aminoglycoside treatment The CFTR protein is a cAMP-activated chloride channel that facilitates transepithelial chloride conductance following its activation by cAMP agonists. Login to comment
156 In intestinal tissue from untreated Cftr+/- hCFTR-G542X mice, we observed a strong increase in transepithelial chloride current that ranged from 6.2 to 26.6 µA/cm2 following forskolin addition, demonstrating the presence of endogenous CFTR activity in these heterozygous animals. Login to comment
157 When in600 Fig. 4 Survival of homozygous Cftr-/- hCFTR-G542X mice. Login to comment
160 A Tracing from the ileum of a heterozygous Cftr +/- mouse carrying the hCFTR-G542X (without aminoglycoside treatment). Login to comment
161 B Tracing from the ileum of a homozygous Cftr-/- hCFTR-G542X mouse (without aminoglycoside treatment). Login to comment
162 C Tracing from the ileum of a homozygous Cftr-/- hCFTR-G542X (following gentamicin treatment). Login to comment
163 D Tracing from the ileum of a homozygous Cftr-/- hCFTR-G542X (following tobramycin treatment). Login to comment
167 The "n" value represents the total number of samples assayed under each condition testinal tissue from untreated Cftr-/- hCFTR-G542X mice was examined following forskolin treatment, no change in the transepithelial chloride current was detected in 13 independent sample s (Figs. Login to comment
171 In Cftr-/- hCFTR-G542X mice treated with gentamicin, we observed a modest increase in Isc upon forskolin addition in 6 of 15 samples. Login to comment
174 In cftr-/- hCFTR-G542X mice treated with tobramycin, we observed an Isc increase in 3 of 11 samples following forskolin addition, which approached statistical significance (P=0.052). Login to comment
176 These results suggest that both gentamicin and tobramycin can restore a low level of hCFTR activity in Cftr-/- hCFTR-G542X mice. Login to comment
177 hCFTR protein can be detected in intestinal glands following aminoglycoside treatment Since our functional analysis detected the presence of cAMP-activated Isc currents in intestinal tissues of Cftr-/- hCFTR-G542X mice following aminoglycoside treatment, we next asked whether the hCFTR protein could be detected. Login to comment
179 In gentamicin-treated Cftr -/- hCFTR-G542X 601 Fig. 7 CFTR immunofluorescence in intestinal tissues. Login to comment
180 Samples from the duodenum of homozygous Cftr-/- hCFTR-G542X mice (harvested from untreated, gentamicin-treated, or tobramycin-treated animals) were incubated with either preimmune serum or CFTR-NBD1 serum. Login to comment
181 Similar samples from heterozygous Cftr+/- animals that lacked the hCFTR-G542X transgene were also examined following gentamicin treatment. Login to comment
186 Furthermore, a positive signal was not observed in tissues from gentamicin-treated Cftr -/- hCFTR-G542X mice when a pre-immune serum was used, or when the hCFTR-specific antiserum was used on samples from mice that had not been treated with gentamicin. Login to comment
187 We also confirmed that a specific signal was not observed in Cftr+/- mice that did not carry the hCFTR-G542X transgene following gentamicin treatment. Login to comment
189 When taken together with the functional data presented above, these results indicate that treatment of Cftr-/- hCFTR-G542X mice with either gentamicin or tobramycin can promote the synthesis of full-length, functional CFTR that localizes to the apical epithelium of the submucosal and mucosal glands of this transgenic mouse. Login to comment
193 To more directly determine the ability of gentamicin and tobramycin to suppress the hCFTR-G542X mutation, we constructed a readthrough reporter construct for use in an in vitro translation system that contains the hCFTR-G542X stop mutation and six flanking codons upstream and downstream of the premature stop mutation (Fig. 8). Login to comment
205 B Example of gentamicin- and tobramycin-mediated suppression of the hCFTR-G542X stop mutation. Login to comment
206 C Quantitation of data shown in B full-length CFTR from a transgene containing the hCFTR-G542X premature stop mutation in vivo. Login to comment
208 To optimize our chance of detecting the appearance of hCFTR protein produced by suppression of the hCFTR-G542X mutation, we administered 34 µg/g gentamicin by subcutaneous injection a once daily. Login to comment
214 Our results also demonstrate for the first time that tobramycin is capable of weakly suppressing the hCFTR-G542X stop mutation in vivo. Login to comment
215 The hCFTR-G542X stop mutation is a UGAG tetranucleotide termination signal. Login to comment
219 Both gentamicin and tobramycin were found to suppress the hCFTR-G542X stop mutation, although gentamicin appeared to mediate this effect much more efficiently than tobramycin. Login to comment
237 In the present study, we used a similar FABP-hCFTR construct to show that aminoglycosides can suppress the hCFTR-G542X mutation. Login to comment
238 Significantly, we found that gentamicin treatment of the FABP-hCFTR-G542X mouse resulted in the appearance of CFTR in the mucosal and submucosal glands, but not in the crypts of Lieberkuhn or the intestinal villi. Login to comment

PMID: 12357328 [PubMed] McCormick J et al: "Demographics of the UK cystic fibrosis population: implications for neonatal screening."

No. Sentence Comment

79 It is envisaged that the proposed screening programme will be based on a three-stage protocol.6 In Table 3 Genotypes of the UK CF Caucasian and ISC populations Percentage of Percentage of genotyped UK CF genotyped UK CF Caucasian population ISC population Genotype n=4753 (%) n=78 (%) DF508/DF508 57.5 24.7 DF508/Unknown 11.5 3.5 DF508/G551D 5.1 0.0 DF508/G542X 2.8 0.0 Unknown/Unknown 2.7 27.1 DF508/621+1G?T 2.0 1.2 DF508/R117H 2.0 0.0 DF508/1898+1G?A 1.0 0.0 DF508/1717-G?A 0.9 0.0 DF508/N1303K 0.8 0.0 DF508 DI507 0.8 0.0 DF508/R553X 0.6 0.0 DF508/R560T 0.6 0.0 DF508/Q493X 0.5 0.0 G551D/Unknown 0.4 0.0 Other/Other 2.8 15.3* DF508/Other 6.7 0.0 Y569D/Y569D 0.0 8.2 L218X/L218X 0.0 3.5 1161delC/1161delC 0.0 3.5 R709X/V456A 0.0 2.4 G542X/G542X 0.4 2.4 Other/Unknown 1.0 3.5 The shaded areas represent the commonest genotypes in the ISC population. Login to comment
85 Table 4 The commonest CFTR mutations in the UK Genotypes UK CF population Genotyped UK Caucasian CF Genotyped UK CF ISC (n=9866 chromosomes) population (n=9506 chromosomes) population (n=156 chromosomes) CFTR mutation gene frequency per 1000 genes gene frequency per 1000 genes gene frequency per 1000 genes DF508 741.0 752.0 294.9 G551D 33.7 34.3 12.8 G542X 18.5 18.4 25.6 R117H 12.5 12.7 0.0 621+1G?T 12.7 12.7 6.4 1717-1G?A 5.8 5.8 0.0 1898+1G?A 5.7 5.9 0.0 N1303K 5.6 5.4 0.0 DI507 4.8 5.0 0.0 R560T 4.2 4.3 0.0 R553X 3.3 3.4 0.0 1154insTC 3.2 3.3 0.0 Q493X 2.8 2.9 0.0 3659delC 2.8 2.9 0.0 E60X 2.4 2.4 0.0 W1282X 2.7 2.7 0.0 P67L 2.1 2.1 0.0 G85E 2.1 2.0 0.0 V520F 1.6 1.7 0.0 1078delT 1.3 1.4 0.0 Y569D 1.5 0.0 96.2 L218X 0.6 0.0 38.5 1161delC 0.7 0.1 38.5 R1162X 0.9 0.6 19.2 R709X 0.4 0.2 12.8 3849+10kbC?T 1.2 0.8 19.2 S549R* 0.6 0.0 0.0 *S549R mutations appear in the non-Caucasian but not the ISC subgroup. Login to comment
96 There are similar frequencies for the more common mutations between our UK Caucasian CF data (Table 4) and the Schwarz data (respectively, G551D 3.43% and 3.08%; G542X 1.84% and 1.68%; 621+1G?A 1.27% and 0.93%; 1717-1G?A 0.58% and 0.57%). Login to comment
97 In North America, DF508 accounts for 71.2%, with G542X (2.4%), G551D (2.4%), W1282X (1.4%), N1303K (1.3%) and R553X (0.9%).8 Genotype frequencies in CF have previously been shown to fit a Hardy - Weinberg model in a smaller regional UK study.9 In the current study, we find that the genotype frequencies only satisfy the Hardy-Weinberg equilibrium provided we exclude those without an identified CFTR mutation in the Other/Other category. Login to comment
101 When compared with a European CFTR geographic distribution,10 the UK CF patients possess a greater proportion of DF508, G551D and 621+1G?T mutations, and a smaller proportion of G542X, N1303K, W1282X and R1162X mutations. Login to comment
102 In France, the five most common genotypes were DF508/DF508 (47.8%), DF508 /G542X (3.4%), DF508/N1303K (2.7%), DF508 /1717-1G?A (2.1%) and DF508/2789+5G?A (1.5%) (Desgeorges M, personal communication) which is different to the commonest genotypes found in the UK population (Table 3). Login to comment
103 N1303K and G542X occur at a frequency of around 5% in Italy.11 In Germany, a study of 658 CF families revealed mutation frequencies of R553X (1.8%), N1303K (1.3%), G542X (1.1%), G551D (0.8%) and R347P (0.8%).12 The frequency of CFTR mutations recorded for just over 1000 patients for the Irish CF Database include G551D in 7%, R117H in 2% and DF508 in 72% of patients.13 In the white South African population, a paper based on 192 patients found that DF508 accounts for 76% of the mutations with 3272-26A?G (4%), 394delTT (3.6%) and G542X (1.3%) the other most common mutations.14 It is suggested that the 3272-26A?G and 394delTT mutations are more common due to a founder effect in white South Africans of European descent. Login to comment

PMID: 12359632 [PubMed] Zegarra-Moran O et al: "Correction of G551D-CFTR transport defect in epithelial monolayers by genistein but not by CPX or MPB-07."

No. Sentence Comment

70 The second mutation is presently unknown, but is not one of the 15 most frequent mutations found in the CF patients of Northeast Italy, namely F508del, I507del, R1162X, 2183AA4G, N1303K, 3849+10KbC4T, G542X, 1717-1G4A, R553X, Q552X, G85E, 711+5G4A, 3132delTG, 2789+5G4A, W1282X. Login to comment

PMID: 12394352 [PubMed] Richards CS et al: "Standards and guidelines for CFTR mutation testing."

No. Sentence Comment

50 Depending upon the ethnic group, these mutation frequencies may be difficult to obtain (Table 1).5-7 CF 2.8.1 The most common mutations in the Ashkenazi Jewish population have been described.8-10 These include W1282X, ⌬F508, G542X, N1303K, and 3849 ϩ 10 kbCϾT. Login to comment
307 ⌬F508 R553X R1162X 2184delA 3120ϩ1GϾA ⌬I507 G542X G551D W1282X N1303K 621ϩ1GϾT R117H 1717-1GϾA A455E R560T G85E R334W R347P 711ϩ1GϾT 1898ϩ1GϾA 1078delT 3849ϩ10kbCϾT 2789ϩ5GϾA 3659delC I148T CF 3.3.2 Inclusion of the common R117H mutation in the test panel screens for CBAVD as well as for CF: The phenotypic consequences of the R117H mutation are modulated in cis by the 5/7/9T polypyrimidine tract in intron 8 such that R117H/7T is associated with CBAVD and R117H/5T is associated with CF.34 Moreover, the 5T allele is associated as a trans mutation in CBAVD.35 It is recommended that the 5/7/9T variant be excluded from the routine carrier screen but tested as a reflex for carriers shown to be heterozygous for the R117H mutation. Login to comment

PMID: 12414835 [PubMed] Reboul MP et al: "Splice mutation 1811+1.6kbA>G causes severe cystic fibrosis with pancreatic insufficiency: report of 11 compound heterozygous and two homozygous patients."

No. Sentence Comment

127 Genotype-phenotype data are available especially for common genotypes,2 but information remains scarce or lacking for genotypes of compound heterozygotes with a rare mutation and homozygotes for a rare mutation.3 Among rare CFTR gene mutations, 1811+1.6kbA>G is practically absent in CF patients from other parts of France, but it is not rare in patients genotyped in the south west of France, occurring in fourth place after F508del, G542X, and N1303K. Login to comment
140 RESULTS The results of genotyping the 13 CF patients carrying the mutation 1811+1.6kbA>G were: two homozygotes for 1811+1.6kbA>G/1811+1.6kbA>G and 11 compound heterozygotes for 1811+1.6kbA>G and for another CFTR mutation, that is, F508del (n=6), N1303K (n=2), G542X (n=1), 2183 AA>G (n=1), and W1063X (n=1). Login to comment
148 Key points • The splice mutation 1811+1.6kbA>G of the CFTR gene is the fourth most frequent mutation (after F508del, G542X, and N1303K) in CF patients from the south west of France. Login to comment
157 This is the case for nonsense and frameshift mutations always associated with severe CF with PI: they come into class I (for instance, G542X) when they lead to an absence of functional CFTR and into the "new" class V (for instance, Q1412X) when they cause the presence of a functional but unstable CFTR at the apical membrane. Login to comment

PMID: 12415481 [PubMed] Rakheja D et al: "Cystic fibrosis and Chiari type I malformation: autopsy study of two infants with a rare association."

No. Sentence Comment

101 In two patients, the second mutations could not be identified, while the remaining two patients showed G542X and W1282X as their second mutation, respectively. Login to comment

PMID: 12437773 [PubMed] Huber K et al: "Survey of CF mutations in the clinical laboratory."

No. Sentence Comment

8 The only other CF-alleles that we found with these tests were the G542X allele (3 persons), the G551D allele (3 persons), the 3849+10kb C-T allele (2 persons) the R117H allele (2 persons) and the 621+1G-T allele (1 person). Login to comment
36 F508C, I507V, I506V polymorphism exon 11 1717-1G → A, G542X, S549N, G551D, R553X, R560T exon 20 W1282X exon 21 N1303K intron 19 3849+10kb C → T Innogenetics assay: exon 3 394delTT, G85E, E60X exon/intron 4 621+1G-T, R117H exon 7 1078delT, R347P, R334W exon 13 2143delT, 2183AA-G, 2184delA exon 19 R1162X, 3659delC intron 5 711+5G-A intron8/exon 9 A455E,, 5T,7T,9T intron 14b 2789+5G-A intron 19 3849+10kb C-T Table 2: Genotypes of patients with mutations, final results Group 1) (patients with symptoms typical for/indicative of CF) No. Login to comment
38 IRT, normal sweat test f 0 7T/9T DF508/3849+10kb C-T x 2 CF, substantiation f 0 9T/9T 621+1G-T/621+1G-T 3 CF, substantiation f 1 9T/9T DF508/DF508 x 4 CF, substantiation f 5 9T/9T DF508/DF508 x x x 5 CF, substantiation f 7 9T/9T DF508/G542X x x 6 CF, substantiation, rec. diarrhoe, pancreas insufficiency, pos. sweat test f 8 9T/9T DF508/DF508 x 7 CF, substantiation f 12 9T/9T DF508/DF508 x 8 CF, substantiation f 13 9T/9T DF508/DF508 x 9 f 13 7T/9T DF508/WT 10 CF, substantiation f 16 9T/9T DF508/G542X 11 indicative linkage analysis f 22 7T/9T DF508/WT x 12 f 24 7T/9T DF508/WT x 13 bronchiectasis, bronchopulmonal infections since infancy f 28 7T/9T DF508/3849+10kbC-T x 14 pos. sweat test f 28 9T/9T DF508/WT x 15 typical clinic, pos. sweat test f 31 7T/9T DF508/WT x x 16 f 32 7T/7T 3849+10kb C-T/WT 17 pulmonal course typical of CF f 32 7T/9T DF508/WT x x x 18 f 34 7T/7T G551D/WT x x 19 f 41 7T/7T DF508/WT 20 CF, substantiation f 56 7T/9T DF508/3849+10kb C-T x 21 22 CF, substantiation m 0 9T/9T DF508/DF508 x 23 m 1 7T/9T DF508/WT x 24 impaired lung function, intestinal complications m 3 7T/9T DF508/WT x x 25 CF, substantiation m 5 9T/9T DF508/DF508 26 m 12 7T/7T G551D/WT x x 27 CF, substantiation m 17 9T/9T DF508/DF508 28 m 18 7T/7T R117H/WT&1466delAATT/1466delAATT 1466delAATT x 29 pos sweat test m 20 7T/9T DF508/WT 30 CF, substantiation m 25 9T/9T DF508/DF508 31 . Login to comment
40 infect., azoospermia, pancreatitis m 31 9T/9T DF508/WT 35 CF, substantiation m 33 9T/9T DF508/DF508 x 36 m 33 7T/9T DF508/WT 37 m 33 7T/9T DF508/WT 38 m 38 7T/9T R117H/G542X Group 2a) (Patients from IVF clinics) No. Login to comment
41 : Diagnosis Sex Age Intron 8 16 mut. 29 mut.b seq.c DGGEd 39 m 24 7T/9T WT 40 m 25 9T/9T WT 41 m 28 5T/9T DF508/WT x 42 m 28 5T/9T DF508/WT 43 m 29 5T/9T DF508/WT x x x 44 m 30 7T/7T WT x 45 m 31 5T/9T DF508/WT x x x 46 m 31 7T/7T WT x 47 m 31 7T/9T WT x 48 m 33 7T/9T DF508/WT x 49 m 34 7T/7T WT x 50 m 34 9T/9T DF508/WT x 51 m 35 7T/9T G542X/WT 52 m 36 5T/9T DF508/WT ents, respectively) had given informed consent for genetic analysis as required by the Austrian law. Login to comment
50 : Diagnosis Sex Age Intron 8 16 mut. 29 mut.b seq.c DGGEd 59 f 42 7T/7T 3849+10kb C-T/WT x 60 f 15 7T/9T DF508/WT x 61 f 20 7T/9T DF508/WT x 62 f 23 7T/9T DF508/WT x 63 f 25 7T/9T DF508/WT x x x 64 f 26 7T/9T DF508/WT 65 f 32 7T/9T DF508/WT x 66 f 40 7T/9T DF508/WT x x 67 f 65 9T/9T DF508/WT 68 f 30 7T/9T DF508/WT x 69 m 14 9T/9T DF508/WT x 70 m 16 7T/9T DF508/WT 71 m 25 7T/9T DF508/WT x x x 72 m 28 5T/9T DF508/WT x 73 m 32 7T/9T DF508/WT x x 74 m 45 7T/9T DF508/WT x x 75 m 48 7T/9T DF508/WT x 76 m 69 7T/9T DF508/WT 77 m 30 7T/9T G542X/WT x x 78 m 15 7T/7T G551D/WT x Details for diagnoses, number of mutations analysed, methods used, and other specifics for individuals with found mutations within the three groups are shown. Login to comment
95 Among 114 children < 18 yrs in group 1), we found 9 patients to be homozygote for ∆F508, two compound heterozygote for ∆F508/G542X, one compound heterozygote for ∆F508/3849+10kbC-T, five heterozygote for ∆F508, one G551D/WT, one R117H/WT, one homozygote for 621+1G-T, and one girl with 5T/7T alleles in intron 8 (total of 18% with mutations). Login to comment
96 Twenty-two percent of the adults in group 1) had CFTR mutations, namely two ∆F508/∆F508, thirteen ∆F508/ WT, one compound for R117H/WT and 1466delAATT (frameshift mutation in exon 9), one R117H/G542X, one G551D/WT, one 3849+10kb C-T/WT, one compound heterozygote for ∆F508/1248+1 A → G (splice mutation in intron 7), and two individuals with ∆F508/3849+10kb C-T. Login to comment
102 Nine of these men (45%) had normal alleles (and a benign thymidine polymorphism in intron 8) at the loci analysed, seven men had a genotype of 5T/9T with ∆F508/WT, one showed 7T/9T with ∆F508/ WT, one had 9T/9T with ∆F508/WT, and one had 7T/9T with G542X/WT. Login to comment
106 Of 54 individuals in group 3, tested because their partners or relatives had CFTR mutations, 37% had mutated alleles: seventeen persons had the genotype ∆F508/WT, one had G551D/WT, one had 3849+10kb C-T, and one person had G542X/WT (table 2). Login to comment
116 In comparison to CF mutation-frequencies in some European countries, the CF alleles we found (>2%) with our tests show the following distribution in our cohort: ∆F508: 83% (Romania:27%, Switzerland: 43%, Denmark: 87,2% [19]); G542X: 4,4% (France: 3,1%, Italy: 4,8%, Spain: 7,7%); G551D: 4,4% (UK: 3,1%, Czechia: 4,0%, Ireland: 6,9%), 3849+10kbC-T: 2,9% (Germany: 1,2%, Poland: 2,6%, Latvia: 12,5%), R117H: 2,9% (Greece: 1,2%, Ireland: 2,0%, Norway: 3,0%) Because we participate in the European Quality assessment trial for Cystic Fibrosis, we could evaluate the quality of the Roche Amplicor CF test in this regard as well. Login to comment

PMID: 12439892 [PubMed] Kilinc MO et al: "Highest heterogeneity for cystic fibrosis: 36 mutations account for 75% of all CF chromosomes in Turkish patients."

No. Sentence Comment

80 Haplotypes Associated With the Mutations Identified in 83 Turkish CF Patients* Mutation Total number of alleles Number of alleles Number of patients Haplotypes Homo Hetero DF508 39 (23.5) 6 7 23 M 28 13 1 0 1 6 7 23 M 30 13 1 0 1 6 9 23 M 31 13 1 0 1 6 7 23 M 31 13 11 4 3 6 7 23 M 7 17 2 0 2 6 7 16 M 31 13 3 1 1 6 7 17 M 31 13 17 5 7 6 7 17 M 32 13 3 1 1 1677delTA 12 (7.2) 7 7 16 V 30 13 12 5 2 2183AA > G 7 (4.2) 7 7 16 M 30 13 1 0 1 7 9 16 M 31 13 4 2 0 7 7 16 M 32 13 2 1 0 G542X 6 (3.6) 6 7 23 M 32 13 6 3 0 F1052V 5 (3.0) 6 7 17 M 7 13 4 1 2 7 5 17 M 7 17 1 0 1 W1282X 5 (3.0) 7 7 17 M 7 17 4 1 2 7 7 17 M 7 18 1 0 1 E92K 4 (2.4) 7 7 16 V 46 13 3 1 1 7 7 17 V 46 13 1 0 1 1525 À 1G > A 4 (2.4) 7 7 17 M 7 17 4 2 0 2789 þ 5G > A 4 (2.4) 7 9 17 M 7 17 3 1 1 7 5 17 M 7 17 1 0 1 N1303K 4 (2.4) 7 7 23 M 31 13 2 0 2 6 7 22 M 30 13 1 0 1 6 7 23 M 30 13 1 0 1 A46D 3 (1.8) 6 9 23 M 31 13 1 0 1 6 7 23 M 31 13 2 1 0 2184insA 3 (1.8) 7 5 17 V 30 13 1 0 1 7 7 16 V 30 13 2 0 2 R1070Q 3 (1.8) 7 7 16 M 31 13 1 0 1 7 7 17 M 31 13 2 0 2 Q493Pa 2 (1.2) 6/7 5 16 M 46 13 2 1 0 3849 þ 5G > Aa 2 (1.2) 7 7 16 M 31 13 2 1 0 CFTRdele17b,18a 2 (1.2) 6 9 16 V - - 2 1 0 K68Ea 1 (0.6) 6 9 17 M 7 13 1 0 1 R74W 1 (0.6) 6 7 16 M 32 16 1 0 1 306delTAGA 1 (0.6) 7 7 16 M 7 17 1 0 1 D110H 1 (0.6) 7 9 16 V 30 13 1 0 1 I125T 1 (0.6) 6 7 23 V 7 16 1 0 1 406 À 3T > Ca 1 (0.6) 7 7 16 V 33 17 1 0 1 I148T 1 (0.6) 6/7 7 16/17 M 7 17/23 1 0 1 621 þ 1G > T 1 (0.6) 6 7 21 V 31 13 1 0 1 R347P 1 (0.6) 7 9 17 V 30 13 1 0 1 S466X 1 (0.6) 7 7 23 M 33 13 1 0 1 L571S 1 (0.6) 7 7 16 V 29 13 1 0 1 1717 À 1G > A 1 (0.6) 7 9 17 M 7 16 1 0 1 E608Ga 1 (0.6) 7 9 16 M/V 29/31 13 1 0 1 2043delG 1 (0.6) 7 9 17 M 7 17 1 0 1 P1013L 1 (0.6) 6 5 16 M 21 18 1 0 1 R1066L 1 (0.6) 7 7 17 M 7 13 1 0 1 3129del4 1 (0.6) 7 7 16 V 29 13 1 0 1 V1147Ia 1 (0.6) 6 7 17 M 33 17 1 0 1 S1235R 1 (0.6) 6 7 17 M 39 13 1 0 1 CFTRdele2,3 1 (0.6) 7 7 16 V 33 13 1 0 1 Total 125 (75) 125 32 61 *The order of the polymorphisms is IVS6GATT, Tn, IVS8CA, M470V, IVS17BTA and IVS17BCA. Login to comment
159 All of the mutations that are also frequent in other populations, with the exception of G542X and 1525 À 1G > A, were found to be associated with more than one haplotype, indicating that these mutations have persisted for a long time in our population. Login to comment

PMID: 12483292 [PubMed] Mekus F et al: "Genes in the vicinity of CFTR modulate the cystic fibrosis phenotype in highly concordant or discordant F508del homozygous sib pairs."

No. Sentence Comment

11 The frequent CFTR mutations, F508del, N1303K, and G542X, are associated with several intragenic STRP haplotypes, but occur on the same flanking SNP haplotype (Dörk et al. 1992; Sereth et al. 1993; Morral et al. 1993; Cuppens et al. 1994; Morral et al. 1996). Login to comment

PMID: 12503104 [PubMed] Kulczycki LL et al: "A clinical perspective of cystic fibrosis and new genetic findings: relationship of CFTR mutations to genotype-phenotype manifestations."

No. Sentence Comment

12 The frequency of other mutations, for example R553X, G542X, and 1717-1(G-A), is estimated to range from 1-3% [Cystic Fibrosis Genetic Analysis Consortium, 1990, 1994]. Login to comment
84 At the age of 60, genetic testing indicated two mutations H1282X (severe) and A 445E (mild), confirming the CF diagnosis as a compound heterzygote with normal alleles for D F508, -G551D, -R553X, -G542X, and N1303K [Kulczycki et al., 1998]. Login to comment

PMID: 12521276 [PubMed] Eskandarani HA et al: "Cystic fibrosis transmembrane regulator gene mutations in Bahrain."

No. Sentence Comment

25 Isolation and PCR amplification of genomic DNA Genomic DNA was extracted from leucocytes according to standard procedures.10 PCR amplification of DNA was performed by preparation of a 50-µl reaction mixture that contained appropriate primers using standard protocols.4 Mutation analysis All patients were screened for 15 common mutations amongst Arabs by restriction enzyme digestion analysis with appropriate enzymes according to specific protocols4,5 and/or using the amplification refractory mutation system (ARMS-PCR) technique.11 These mutations were: 406-2A→G (intron 3), 425del42 (exon 4), 475G→T (exon 4), 548A→T (exon 4), 1161delC (exon 7), 1548delG (exon10), F508 (exon 10), G542X (exon 11), 2043delG (exon 13), 3120+1G→A (intron 16), 3661A→T (exon 19), 3849+10KbC→T (intron 19), I1234V (exon 19), W1282X (exon 20), and N1303K (exon 21). Login to comment

PMID: 12544470 [PubMed] Strom CM et al: "Extensive sequencing of the cystic fibrosis transmembrane regulator gene: assay validation and unexpected benefits of developing a comprehensive test."

No. Sentence Comment

54 Table 2 Mutant samples used for validation of sequencing assay Mutation expected wt/wt (3 patients) delta F508/wt (2 patients) R117H/wt (3 patients) 2789 ϩ 5 G 3 A/2789 ϩ 5 G 3 A (both parents confirmed carriers) R117H/delta F508 (2 patients) delta F508/I148T delta F508/R1066C delta F508/3848 ϩ 10 kb C 3 T delta F508/G542X R117H/I148T (2 patients) 2307 delA/N1303K deltaF 508/711 ϩ 1 G 3 T deltaF 508/1898 ϩ 1 G 3 A G551D/N1303K 2789 ϩ 5G3A. Login to comment

PMID: 12592165 [PubMed] Navarro J et al: "[National program for neonatal screening for cystic fibrosis: implementation and preliminary results]."

No. Sentence Comment

46 3 Les mutations étudiées sont : 1717-1G > A - G542X - W 1282 X - N 1303 K - DF 508 (M) - 3849 + 10kbC > T - 621+1 G > T - R553X - G 551D, R117H, R1162X - R 334W - A455E - 2183 AA > G - 3659delC-- 1078 delT - D1507 - R347P - S 1251N, E60X, 2789+5G > A - 394del T - G 85 E - 1811+1.6 - Y122X - 711+1G > T - W 846 X - Y 1092 - 3272-26A > G. Login to comment

PMID: 12612194 [PubMed] Mall M et al: "Modulation of Ca2+-activated Cl- secretion by basolateral K+ channels in human normal and cystic fibrosis airway epithelia."

No. Sentence Comment

32 CF patients were genotyped for the following common CFTR mutations: ⌬F508, R553X, N1303 K, G542X, G551D, and R347P. Login to comment
33 The following genotypes were identified: ⌬F508/ ⌬F508 (n ϭ 15); ⌬F508/G542X (n ϭ 1); ⌬F508/G551D (n ϭ 1); ⌬F508/- (n ϭ 2); -/- (n ϭ 8) (- ϭ mutation not identified). Login to comment

PMID: 12630958 [PubMed] Devaney J et al: "Cystic fibrosis mutation frequencies in an Irish population."

No. Sentence Comment

17 Eight common mutations were screened using polymerase chain reaction-restriction enzyme analysis (PCR-REA): R117H, 1717±1G > A, DI507, DF508, G542X, G551D, R553X and R560T. Login to comment
26 PCR-REA An in-house PCR-REA procedure was used to screen for the eight common mutations (R117H, 1717±1G > A, DI507, DF508, G542X, G551D, R553X and R560T). Login to comment
65 Frequency of common CF mutations Mutation Numberof chromosomes Frequency (%) R117H 25 2.70 1717^1G >A 20 2.16 DI507 4 0.43 DF508 658 70.97 G542X 4 0.43 G551D 70 7.55 R553X 2 0.22 R560T 4 0.43 Total 788 85 Frequencypercentages areadjustedtorepresent 85%. Login to comment
74 The G542X mutation (0.43%) was found at a lower frequency than the UK (15) (1.68%), Ireland (11) (1%) and Northern Ireland (13) (2.2%). Login to comment

PMID: 12658038 [PubMed] Walkowiak J et al: "Longitudinal follow-up of exocrine pancreatic function in pancreatic sufficient cystic fibrosis patients using the fecal elastase-1 test."

No. Sentence Comment

51 RESULTS Among the patients studied, the following mutations of the CFTR gene were present (n): ⌬F508 (223), 621+G-T (10), N1303K (9), 3849+10kbC-T (6), G542X (5), CFTRdele2,3(21kB) (4), E822X (4), 1717-1G-A (3), E836X (3), G1069-L88X (2), R533X (1), G85E (1), 1677delTA (1), G1069R (1), 1525-1G-A (1), and 2789+5G-A (1). Login to comment

PMID: 12680831 [PubMed] Cimmino M et al: "Clinical characteristics and genotype analysis of patients with cystic fibrosis and nasal polyposis."

No. Sentence Comment

47 Analysis of mutations in the CFTR gene as tested by the multiplex polymerase chain reaction (PCR), followed by the reverse dot-blot technique, which searches for 29 of the most frequent mutations (DF508, N1303K, G542X, W1282X, 1717±1 G-A, R553X, 2183 AA-G, DI507, G551D, R560T, 3849 10kbC > T, R1162X, 3659delC, 3905insT, G85E, 621 1GT, R117H, R347P, R334W, A455E, 2789 5GA, Q552X, S1251N, 3905insT, 394delTT, E60X, 2143delT, 2184delA, 711 5G > A), and by ASO dot-blot for the following mutations: I148T, R1158X, 4016 1T, G1244E G >A.26 Statistical analysis was performed using multivariate analysis, by forward stepwise comparison; it was done to ®nd out which of the examined characteristics could be associated (P < 0.01) to nasal polyposis. Login to comment
91 Frequency (percentage) of compound heterozygous genotypes by nasal polyposis status in patients with cystic fibrosis Group with nasal polyposis (n 15) Comparison group (n 20) DF508/G542X 2 (13.33) 2 (10) DF508/N1303K 2 (13.33) 4 (20) DF508/AA2183G 1 (6.67) 0 DF508/IG1717 1 (6.67) 1 (5) DF508/W1282X 1 (6.67) 1 (5) DF508/unspecified 8 (53.33) 12 (60) their study group included patients with nasal polyposis that required surgery. Login to comment
117 Several authors9,16,17 reported that certain CFTR mutations (i.e. G551D, G542X, W1282X) are associated with severe phenotypes, particularly pancreatic insuf®ciency. Login to comment

PMID: 12734544 [PubMed] Lao O et al: "Spatial patterns of cystic fibrosis mutation spectra in European populations."

No. Sentence Comment

52 As for the direction of the clines, F508del peaks in NW Europe and declines towards SE Europe, G542X declines from SW to NE Europe, G551D is almost restricted to NW Europe, and N1303 K and W1282X show gradients from SW Asia and SE Europe towards NW Europe. Login to comment
66 The correlations with Y-chromosome-based Table 1 94 middle Eastern, North African and European populations used in the analysis Population 2N F508del G542X G551D N1303K W1282X Rare Other Unknown Hmax Ymax Incidence Referencesa Austria 592 0.660 0.022 0.012 0.005 0.002 0.064 0.019 0.216 0.562 0.96 49 Belgium 646 0.752 0.025 0.002 0.028 0.012 0.053 0.046 0.082 0.430 0.56 50 Bulgaria 208 0.654 0.034 0.000 0.067 0.000 0.096 0.067 0.082 0.563 0.97 51 Crete 26 0.462 0.077 0.000 0.038 0.000 0.231 0.038 0.154 0.785 2.87 Czech Republic 584 0.697 0.021 0.034 0.026 0.005 0.051 0.021 0.146 0.512 0.78 Denmark 678 0.872 0.006 0.001 0.010 0.001 0.034 0.035 0.040 0.239 0.23 0.000210 Great Britain 0.000414b North England 4111 0.772 0.008 0.023 0.005 0.001 0.032 0.011 0.148 0.403 0.50 Scotland 1167 0.751 0.033 0.061 0.003 0.003 0.033 0.023 0.093 0.430 0.56 0.000504 South England 3679 0.769 0.020 0.029 0.005 0.002 0.032 0.009 0.133 0.407 0.51 Wales 372 0.659 0.024 0.030 0.005 0.000 0.134 0.065 0.083 0.557 0.94 Estonia 25 0.640 0.000 0.000 0.000 0.000 0.160 0.080 0.120 0.577 1.02 Former Yugoslavia 203 0.700 0.030 0.000 0.010 0.005 0.039 0.069 0.148 0.506 0.76 Finland 52 0.462 0.019 0.000 0.000 0.000 0.288 0.019 0.212 0.713 1.90 France 0.000232 Alsace 126 0.595 0.024 0.000 0.016 0.008 0.040 0.008 0.310 0.646 1.38 Aquitaine 116 0.612 0.034 0.000 0.017 0.000 0.043 0.009 0.284 0.626 1.26 Auvergne 102 0.725 0.039 0.000 0.029 0.010 0.020 0.000 0.176 0.474 0.67 Burgundy 168 0.702 0.024 0.000 0.006 0.000 0.060 0.006 0.202 0.507 0.77 Brittany 582 0.744 0.009 0.024 0.017 0.003 0.064 0.002 0.137 0.444 0.60 0.000343 Centre 218 0.716 0.050 0.000 0.023 0.000 0.023 0.000 0.188 0.486 0.71 Champagne 182 0.665 0.049 0.000 0.016 0.000 0.055 0.005 0.209 0.556 0.94 Franche-Comt ´ e 118 0.746 0.085 0.000 0.085 0.025 0.059 0.000 0.000 0.431 0.56 Languedoc 90 0.700 0.022 0.011 0.033 0.000 0.044 0.000 0.189 0.511 0.78 Llimousin 44 0.545 0.023 0.000 0.068 0.000 0.023 0.023 0.318 0.705 1.83 Loire Valley 308 0.737 0.006 0.019 0.013 0.003 0.032 0.000 0.188 0.457 0.63 Lorraine 286 0.717 0.031 0.000 0.000 0.000 0.042 0.000 0.210 0.486 0.70 Lower Normandie 174 0.644 0.017 0.023 0.017 0.000 0.069 0.000 0.230 0.585 1.06 Midi-Pyr ´ en ´ ees 114 0.649 0.035 0.000 0.018 0.009 0.018 0.000 0.272 0.580 1.03 Nord 468 0.660 0.019 0.004 0.015 0.002 0.053 0.006 0.239 0.563 0.97 Paris Region 830 0.643 0.027 0.007 0.010 0.012 0.035 0.000 0.266 0.585 1.06 Picardie 200 0.650 0.040 0.000 0.040 0.010 0.080 0.000 0.180 0.574 1.01 Poitou 100 0.770 0.030 0.000 0.020 0.000 0.020 0.000 0.160 0.408 0.51 Provence- Cote d`Azur 178 0.674 0.028 0.000 0.051 0.017 0.028 0.006 0.197 0.544 0.89 Rhone-Alpes 668 0.668 0.036 0.001 0.027 0.009 0.018 0.009 0.232 0.552 0.92 Upper Normandie 248 0.645 0.020 0.008 0.012 0.004 0.048 0.004 0.258 0.584 1.05 Germany Baden-W ¨ urttemberg 59 0.763 0.000 0.000 0.034 0.000 0.051 0.102 0.051 0.412 0.52 Bavaria 177 0.740 0.017 0.017 0.000 0.000 0.040 0.011 0.175 0.453 0.62 Berlinc 132 0.773 0.015 0.000 0.023 0.000 0.038 0.015 0.136 0.403 0.50 Bremend 74 0.689 0.014 0.014 0.000 0.000 0.054 0.014 0.216 0.528 0.84 Lower Saxony 198 0.803 0.005 0.005 0.015 0.000 0.015 0.030 0.126 0.355 0.41 North-Rhine/ Westphalia 174 0.736 0.006 0.006 0.000 0.006 0.069 0.034 0.144 0.458 0.63 Saxonye 83 0.639 0.012 0.012 0.024 0.000 0.036 0.036 0.241 0.594 1.10 Rhineland-Palatinaf 59 0.525 0.017 0.000 0.051 0.000 0.085 0.068 0.254 0.721 1.99 Greece Ipiros/Ionian Islands 46 0.609 0.000 0.000 0.043 0.000 0.087 0.043 0.217 0.632 1.30 Peloponese/Attica 89 0.573 0.000 0.022 0.045 0.000 0.146 0.045 0.169 0.667 1.52 Thesalia/Macedonia/ Thrace 61 0.672 0.066 0.000 0.033 0.000 0.033 0.082 0.115 0.543 0.89 Hungary 57 0.439 0.018 0.000 0.018 0.018 0.070 0.018 0.421 0.811 3.43 Italy Abruzzo 66 0.500 0.061 0.000 0.091 0.076 0.030 0.000 0.242 0.739 2.19 Basilicata 75 0.467 0.107 0.000 0.067 0.027 0.067 0.013 0.253 0.769 2.61 Calabria 149 0.430 0.034 0.000 0.047 0.020 0.054 0.034 0.383 0.813 3.46 distances were similar (r ¼ 0.147, P ¼ 0.116 and after controlling for geographical distance r ¼ 0.054, P ¼ 0.296). Login to comment
68 Table 1 (continued) Population 2N F508del G542X G551D N1303K W1282X Rare Other Unknown Hmax Ymax Incidence Referencesa Campania 223 0.610 0.040 0.000 0.067 0.018 0.040 0.004 0.220 0.623 1.25 Emilia-Romagna 242 0.541 0.058 0.000 0.025 0.008 0.050 0.000 0.318 0.704 1.82 0.000170 Friuli 24 0.375 0.125 0.000 0.042 0.042 0.083 0.083 0.250 0.855 4.85 Lazio 236 0.462 0.030 0.000 0.093 0.013 0.034 0.013 0.356 0.778 2.75 Liguria 44 0.591 0.114 0.000 0.023 0.000 0.045 0.000 0.227 0.646 1.38 Lombardia 399 0.499 0.038 0.000 0.038 0.010 0.090 0.050 0.276 0.743 2.24 Marche 144 0.389 0.056 0.000 0.083 0.014 0.063 0.007 0.389 0.841 4.29 Molise 27 0.481 0.037 0.000 0.074 0.000 0.037 0.000 0.370 0.775 2.70 Piemonte 117 0.675 0.034 0.000 0.000 0.000 0.043 0.017 0.231 0.544 0.89 Puglia 245 0.543 0.053 0.000 0.073 0.000 0.041 0.012 0.278 0.698 1.77 Sardegna 141 0.582 0.057 0.000 0.028 0.000 0.028 0.142 0.163 0.641 1.35 Sicilia 387 0.525 0.062 0.000 0.034 0.023 0.067 0.021 0.269 0.719 1.97 Toscana 191 0.508 0.042 0.000 0.037 0.010 0.031 0.005 0.366 0.740 2.21 Trentino 113 0.513 0.027 0.009 0.009 0.009 0.204 0.053 0.177 0.718 1.96 Umbria 37 0.676 0.081 0.000 0.027 0.000 0.027 0.000 0.189 0.545 0.90 Veneto 552 0.449 0.014 0.000 0.031 0.000 0.188 0.033 0.284 0.785 2.87 0.000370 Ireland Republic of Ireland 509 0.727 0.010 0.069 0.004 0.000 0.037 0.014 0.139 0.467 0.65 0.000684 Northern Ireland 876 0.619 0.021 0.045 0.001 0.000 0.063 0.047 0.205 0.612 1.19 0.000553 52 Israel 367 0.322 0.054 0.000 0.030 0.362 0.065 0.082 0.084 0.754 2.39 0.000304 Lebanon 40 0.350 0.000 0.000 0.100 0.200 0.025 0.225 0.100 0.794 3.04 0.000390 53 Netherlands 1442 0.744 0.013 0.001 0.009 0.007 0.072 0.019 0.135 0.444 0.60 0.000252 Norway 168 0.667 0.006 0.012 0.006 0.000 0.071 0.000 0.238 0.555 0.93 0.000152 Poland 444 0.662 0.023 0.007 0.020 0.002 0.043 0.020 0.223 0.560 0.96 Portugal Faro/Beja 25 0.680 0.000 0.000 0.000 0.000 0.040 0.000 0.280 0.547 0.90 Lisboag 100 0.480 0.030 0.000 0.000 0.000 0.080 0.060 0.350 0.767 2.57 Setubal/Evora 33 0.485 0.000 0.000 0.000 0.000 0.121 0.091 0.303 0.767 2.57 Russia 445 0.618 0.007 0.002 0.004 0.004 0.031 0.031 0.301 0.617 1.22 0.000051 Slovakia 254 0.559 0.075 0.000 0.035 0.016 0.075 0.016 0.224 0.680 1.62 Spain Andalucı´a 314 0.538 0.086 0.013 0.013 0.013 0.083 0.096 0.159 0.694 1.73 Arago´n 65 0.523 0.031 0.000 0.015 0.000 0.123 0.138 0.169 0.708 1.86 Castilla la Mancha 69 0.478 0.058 0.000 0.043 0.000 0.014 0.029 0.377 0.771 2.63 Paı´s Valencia` 125 0.464 0.104 0.000 0.056 0.000 0.096 0.040 0.240 0.771 2.63 Castilla Leo´n/ La Rioja 187 0.604 0.048 0.000 0.011 0.000 0.102 0.107 0.128 0.623 1.24 54 Catalonia 109 0.642 0.055 0.000 0.037 0.009 0.083 0.064 0.110 0.582 1.05 0.000187 Extremadura 63 0.460 0.048 0.000 0.016 0.000 0.079 0.127 0.270 0.776 2.72 Galicia 93 0.624 0.097 0.000 0.011 0.000 0.161 0.075 0.032 0.596 1.11 Madrid 51 0.510 0.059 0.020 0.039 0.000 0.059 0.020 0.294 0.742 2.23 Murcia 40 0.250 0.125 0.000 0.025 0.025 0.175 0.200 0.200 0.889 6.74 Basque Country 31 0.710 0.000 0.000 0.000 0.000 0.065 0.097 0.129 0.497 0.74 Sweden 165 0.733 0.006 0.000 0.000 0.000 0.103 0.085 0.073 0.448 0.60 0.000130 Switzerland 95 0.432 0.032 0.000 0.011 0.000 0.263 0.168 0.095 0.732 2.11 Tunisia 78 0.179 0.090 0.000 0.064 0.026 0.128 0.115 0.397 0.941 14.51 55 Turkey 263 0.274 0.038 0.000 0.042 0.004 0.087 0.114 0.441 0.907 8.44 56 Ukraine 396 0.543 0.000 0.005 0.000 0.000 0.018 0.000 0.434 0.706 1.84 57 Total 29131 0.674 0.025 0.015 0.017 0.009 0.053 0.024 0.182 0.586 1.06 N, sample size (in number of CF chromosomes); F508del, G542X, G551D, 1303K, and W1282X, relative frequencies of the main mutations; rare, relative frequency of mutations not listed in Table 2 of reference 58; other, relative frequency of mutations listed in Table 2 of reference 58. unknown, fraction of chromosomes asociated to disease bearing unidentified mutations. Login to comment
86 However, the effects of the two parameters are not equivalent: Figure 1 Geographical distribution (a) and spatial autocorrelogram (b) of F508del mutation in 94 middle Eastern, North African, and European populations. The X-axis represents geographic distance between samples; the Y-axis represents Moran`s index; a single asterisk (n) denotes Po0.05; double asterisks (nn) denote Po0.01. Figure 2 Geographical distribution (a) and spatial autocorrelogram (b) of the G542X mutation in 94 middle Eastern, North African, and European populations. The X-axis represents geographic distance between samples; the Y-axis represents Moran`s index; a single asterisk (n) denotes Po0.05; double asterisks (nn) denote Po0.01. for any Ne, doubling it would double y; for a typical CF allele frequency f0 ¼ 0.02, doubling it would mean just a 2% reduction in y. Login to comment

PMID: 12794695 [PubMed] Timmreck LS et al: "Analysis of cystic fibrosis transmembrane conductance regulator gene mutations in patients with congenital absence of the uterus and vagina."

No. Sentence Comment

82 CFTR Gene Mutations Tested DF508 R334W Y1092X 5T variant Y122X R347H G542X S549R 3,849 þ 4 G551D 3,849 þ 10 kb 2,789 þ 5 W1282X R553X 711 þ 1 3,905 þ T 621 þ 1 1,898 þ 1 N1303K 1,717À1 R1162X R117H 1078dT A455E D1507 Q493X 218dA R347P V520F G85E R560T S549N 3659dC Wolffian duct must occur at a time when the Mu¨llerian duct is no longer dependent on the Wolffian duct for development. Login to comment

PMID: 12815607 [PubMed] Scotet V et al: "Comparison of the CFTR mutation spectrum in three cohorts of patients of Celtic origin from Brittany (France) and Ireland."

No. Sentence Comment

19 This spectrum is noteworthy because it includes a main mutation, accounting for 70% of the mutated alleles world-wide (the deletion F508del), four other mutations observed with a frequency over 1% (G542X: 2.4%, G551D: 1.6%, N1303K: 1.3%, W1282X: 1.2%) and a multitude of private abnormalities (Tsui, 2003). Login to comment
44 Firstly, the National Centre for Medical Genetics, Dublin performed an analysis of the most common CFTR mutations, using the ARMS test (Ferrie et al., 1992), which enables the detection of the following mutations: F508del, R117H, I507del, G542X, G551D, R560T, N1303K, R352Q, 1717-1G>A and 621+1G>T. Login to comment
64 Spectrum of the CFTR Mutations Identified in the Cohorts from Brittany, Dublin Centre, and Cork Area Nucleotide Amino acid change * change Exon Number Frequency Number Frequency Number Frequency 211delG 2 1 0.1% 310G>T E60X 3 5 0.6% 4 0.3% 347C>A A72D 3 1 0.1% 368G>A W79X 3 1 0.1% 386G>A G85E 3 2 0.3% 3 0.2% 403G>A G91R 3 2 0.3% 482G>A R117H 4 4 0.5% 38 3.0% 4 1.4% 498T>A Y122X 4 1 0.1% 574delA 4 1 0.1% 577G>A G149R 4 1 0.1% 621+1G>T int 4 5 0.6% 21 1.7% 790C>T Q220X 6a 1 0.1% 875+1G>C int 6a 1 0.4% 905delG 6b 1 0.1% 1065C>G F311L 7 2 0.3% 1078delT 7 28 3.6% 1132C>T R334W 7 1 0.1% 1172G>A R347H 7 5 0.6% 1172G>T R347L 7 1 0.1% 1172G>C R347P 7 1 0.1% 1187G>A R352Q 7 3 0.2% 2 0.7% 1208A>G Q359R 7 1 0.1% 1154insTC 7 2 0.2% 1221delCT 7 2 0.3% 1248+1G>A int 7 1 0.1% 1249-27delTA int 7 1 0.4% 1334G>A W401X 8 1 0.1% 1461ins4 9 5 0.4% 1471delA 9 2 0.2% 1607C>T S492F 10 2 0.3% 1609C>T Q493X 10 1 0.1% 1648_1653delATC I507del 10 3 0.4% 10 0.8% 1 0.4% 1652_1655del 3 bp F508del 10 582 74.8% 966 76.5% 226 81.3% 1690G>T V520F 10 4 0.3% 1717-1G>A int 10 8 1.0% 9 0.7% 1756G>T G542X 11 5 0.6% 8 0.6% 1779T>G S549R 11 1 0.1% 1784G>A G551D 11 29 3.7% 82 6.5% 27 9.7% 1789C>G R553G 11 1 0.1% 1789C>T R553X 11 3 0.4% 1 0.1% 1806delA 11 1 0.1% 1811G>A R560K 11 2 0.3% 1811G>C R560T 11 30 2.4% 2 0.7% 1819T>A Y563N 12 1 0.1% 1853C>A P574H 12 1 0.1% 1898+1G>A int 12 1 0.1% 2184delA 13 1 0.1% 1 0.1% 2184insA 13 1 0.1% 2622+1G>A int 13 1 0.1% 2 0.2% 2622+1G>T int 13 1 0.1% 2623-2A>G ** int 13 1 0.1% 2670G>A W846X2 14a 8 1.0% 2752-1G>T int 14a 1 0.1% 2752-26A>G int 14a 2 0.2% 2789+5G>A int 14b 6 0.8% 2966C>T S945L 15 2 0.3% 3007delG 15 4 0.3% 3040G>C G970R 15 1 0.1% 3062C>T S977F 16 1 0.1% 3120+1G>A int 16 1 0.1% 3272-26A>G int 17a 4 0.5% 2 0.2% 2 0.7% 3320dupli(CTATG) 17b 1 0.1% 3329G>A R1066H 17b 1 0.1% 3340C>T R1070W 17b 1 0.1% 3408C>A Y1092X 17b 7 0.9% 3442G>T E1104X 17b 1 0.1% 3446T>G ** M1105R 17b 1 0.1% 3586G>C D1152H 18 1 0.1% 3601-17T>C + 1367delC int 18 + 9 1 0.1% 3616C>T R1162X 19 1 0.1% 2 0.2% 3659delC 19 2 0.2% 3832A>G I1234V 19 2 0.3% 3849+4A>G int 19 1 0.1% 3849+10kbC>T int 19 3 0.2% 3877G>A G1249R 20 1 0.1% 3884G>A S1251N 20 1 0.1% 3898insC 20 1 0.1% 3905insT 20 2 0.3% 3978G>A W1282X 20 3 0.4% 4005+1G>A int 20 6 0.8% 4016insT 21 1 0.1% 4041C>G N1303K 21 11 1.4% 5 0.4% 4136T>C L1335P 22 1 0.1% 1 0.4% 4279insA 23 1 0.1% Unidentified Unidentified - 3 0.4% 41 3.2% 11 4.0% Total 778 100.0% 1262 100.0% 278 100.0% * All nucleotide changes correspond to cDNA numbering. Login to comment
76 Number Frequency Number Frequency 1652_1655del 3 bp F508del 384 75.6% 196 73.1% 582 74.8% 1784G>A G551D 17 3.3% 12 4.5% 29 3.7% 1078delT 25 4.9% 3 1.1% 28 3.6% 4041C>G N1303K 3 0.6% 8 3.0% 11 1.4% 2670G>A W846X2 7 1.4% 1 0.4% 8 1.0% 1717-1G>A 5 1.0% 3 1.1% 8 1.0% 3408C>A Y1092X 1 0.2% 6 2.2% 7 0.9% 2789+5G>A 2 0.4% 4 1.5% 6 0.8% 4005+1G>A 5 1.0% 1 0.4% 6 0.8% 310G>T E60X 3 0.6% 2 0.7% 5 0.6% 621+1G>T 2 0.4% 3 1.1% 5 0.6% 1172G>A R347H 5 1.0% 5 0.6% 1756G>T G542X 4 0.8% 1 0.4% 5 0.6% 482G>A R117H 3 0.6% 1 0.4% 4 0.5% 3272-26A>G 2 0.4% 2 0.7% 4 0.5% 1648_1653delATC I507del 1 0.2% 2 0.7% 3 0.4% 1789C>T R553X 3 0.6% 3 0.4% 3978G>A W1282X 2 0.4% 1 0.4% 3 0.4% Unidentified Unidentified 3 0.6% 3 0.4% Total Total 508 100.0% 268 100.0% 778 100.0% Basse-Bretagne Haute-Bretagne Brittany * Amino acid change Nucleotide change Table 3: Distribution of the Main CFTR Nutations Observed in the Irish Cohorts (Dublin and Cork) The 62 mutations detected in Brittany combined to give 81 different genotypes in CF patients. Login to comment
98 Number Frequency Number Frequency 1652_1655del 3 bp F508del 966 76.5% 226 81.3% 1192 77.4% 1784G>A G551D 82 6.5% 27 9.7% 109 7.1% 482G>A R117H 38 3.0% 4 1.4% 42 2.7% 1811G>C R560T 30 2.4% 2 0.7% 32 2.1% 621+1G>T 21 1.7% 21 1.4% 1648_1653delATC I507del 10 0.8% 1 0.4% 11 0.7% 1717-1G>A 9 0.7% 9 0.6% 1756G>T G542X 8 0.6% 8 0.5% 1187G>A R352Q 3 0.2% 2 0.7% 5 0.3% 1461ins4 5 0.4% 5 0.3% 4041C>G N1303K 5 0.4% 5 0.3% 310G>T E60X 4 0.3% 4 0.3% 1690G>T V520F 4 0.3% 4 0.3% 3007delG 4 0.3% 4 0.3% 3272-26A>G 2 0.2% 2 0.7% 4 0.3% 386G>A G85E 3 0.2% 3 0.2% 3849+10kbC>T 3 0.2% 3 0.2% Unidentified Unidentified 41 3.2% 11 4.0% 52 3.4% Total Total 1262 100.0% 278 100.0% 1540 100.0% Dublin cohort Cork cohort Ireland Amino acid change Nucleotide change We noted similar high frequencies of the F508del and G551D mutations in the three cohorts studied. Login to comment

PMID: 12840066 [PubMed] Russo MA et al: "Abnormal passive chloride absorption in cystic fibrosis jejunum functionally opposes the classic chloride secretory defect."

No. Sentence Comment

58 The Journal of Clinical Investigation | July 2003 | Volume 112 | Number 1 119 Table 1 Demographics and CFTR mutation analysis Patient Sex, age CFTR mutation analysis Meconium BMIA FVC FEV1 Work/school Number of Experiments ileus (% pred) (% pred) statusB hospital admissionsC conductedD 1 F, 33 ∆F508/1898 + 1G-A No 23 112 106 1 1 b, c, d, e 2 M, 28 ∆F508/∆F508 Yes 18 35 23 2 2 b, c, d, e 3 F, 21 W1282X/W1282X Yes 22 77 76 1 1 a, b, d 4 M, 26 G551D/G542X No 23 68 65 1 1 b 5 M, 20 ∆F508/∆F508 Yes 19 106 99 1 1 b 6 M, 24 ∆F508/∆F508 Yes 18 69 58 1 1 b 7 M, 34 ∆F508/∆F508 No 22 64 45 1 0 a, b, d 8 F, 20 ∆F508/∆F508 No 21 81 91 1 2 a, c, d, e 9 M, 28 ∆F508/∆F508 No 18 83 67 1 1 a, d 10 F, 38 ∆F508/∆F508 No 22 58 39 3 4E a 11 M, 28 ∆F508/∆F508 Yes 18 55 44 1 1 c, e 12 M, 27 NegativeF/∆F508 No 22 48 44 2 2 c, e AHealthy adult body mass index: 18.5-24.9 kg/m2. Login to comment

PMID: 12865275 [PubMed] Ahmed N et al: "Molecular consequences of cystic fibrosis transmembrane regulator (CFTR) gene mutations in the exocrine pancreas."

No. Sentence Comment

130 The most common mutation was ∆F508 (71.3%) followed by G551D (2.9%), G542X (2.3%), 621+1G→T (1.2%), and W1282X (1.2%). Login to comment
279 For example, a patient carrying a class I mutation (for example, G542X) in combination with ∆F508 (class II) was classified as class I although the genotype is in fact a compound heterozygote of class I/II. Login to comment
293 The most common mutations were: ∆F508 (in 943 chromosomes, 71.2%), G551D (39, 2.9%), G542X (31, 2.3%), 621+1G→T, W1282X (16, 1.2%), and R117H (11, 0.8%). Login to comment
309 Table 2 Genotype classification according to the functional consequences of CFTR gene mutations Pancreatic status Class I Class II Class III Class IV Class V PS F1 , 875+1G→C(2) F, F (1) F, G551D (1) F, R117H (11) F,3849+10kbC→T (5) F, G85E2 (1) F, R347H (3) F,3272-26A→G (4) F, S1251N (2) F,A445E (3) F, D614G (1) F,P574H (2) F, R347P (1) F,3120G>A (1) R117H,R117H (1) F, 5T (8) F, L1335P (1) F,2789+5G→A (1) F,P67L (1) F,R347P/R347H (1) F,V232D(2) R334W, R334W(1) PS→PI F,3659delC (1) F,F (15) F,G551D (1) F, I1234V (1) F,2184insA (1) F,R560T (1) PI F, G542X (27) F,F (365) F, G551D (28) F, 621+1G→T (13) F, R560T (7) F,R553X (7) F, N1303K (9) F, R1162X (6) F,L1077P (2) F, 3659delC (5) F, I48T (1) F, 1717-1G→A (5) F,A559T (1) F, W1282X (5) F, G85E2 (2) F, 711+1G→T (5) G551D,G551D(1) F,2184delA(4) F,H199R (1) W1282X,W1282X (4) F,I1072T(1) F,Y1092X (3) F,S549 (R75Q) (1) F,556delA (3) F, Q493X (3) F,4016InsT (3) F, 3120+1G→A (2) F, G551D/R553X (2) F,Q814X(2) F,1154insTC (2) F,441delA (1) F, 4326delTC (1) F,Q552X(1) F,3007delG (1) F,2184insA (1) F, 4010del4 (1) F,3905insT (1) F,1078delT(1) F,E1104X (1) F,3876delA (1) F,4374+1G→T (1) F,E585X (1) F, E60X (1) CFTR, cystic fibrosis transmembrane regulator; PI, pancreatic insufficiency; PS, pancreatic sufficiency. Login to comment
322 The four next most common mutations reported in this study (G551D, G542X, 621+1G→T, and W1282X) each accounted for Table 3 Pancreatic ductular and acinar secretion classified according to the functional consequences of CFTR gene mutations Functional class n Ductular function Acinar function Fluid† (ml/kg/h) Bicarbonate‡ (mmol/kg/h) Chloride‡ (mmol/kg/h) Trypsin* (U/kg/h) Colipase* (U/kg/h) Total lipase* (U/kg/h) Class I 7 2.3 (1.5) 0.03 (0.02) 0.15 (0.14) 19 (42) 142 (201) 290 (388) Class II 33 2.9 (2.4) 0.04 (0.04) 0.21 (0.33) 31 (63) 111 (197) 202 (276) Class III 6 1.1 (0.87) 0.02 (0.02) 0.12 (0.07) 109 (256) 235 (483) 608 (1280) Class IV 14 4.0 (2.8) 0.19 (0.2) 0.32 (0.12) 1032 (768) 9840 (10698) 12563 (10461) Class V 10 4.8 (3.2) 0.12 (0.07) 0.36 (0.23) 1535 (1406) 12161 (13550) 16449 (15482) Control 21 10.0 (3.9) 0.57 (0.22) 0.62 (0.3) 2291 (836) 13036 (5958) 19767 (8623) Values are mean (SD). Login to comment

PMID: 12881448 [PubMed] Malehorn DE et al: "Detection of cystic fibrosis mutations by peptide mass signature genotyping."

No. Sentence Comment

133 In the case of exon 11, a second analyte (exon 11.2) was designed in an alternative forward reading frame to detect the 1717-1 GϾA mutation, but it also scanned the remainder of the exon and registered its own characteristic mass shifts resulting from G542X and R553X mutations. Login to comment
138 ⌬b 3 R Y 9863.78 G85E SerϾPhe 9923.90 Y 60.12 4.1 R N 7047.69 R117H AlaϾVal 7075.76 N 28.07 4.2 R Y 11161.32 lI48T AsnϾSer 11134.32 Y -27.00 621ϩ1 GϾT TyrϾTAA 6513.09 N -4648.23 5 R Y 11081.45 711ϩ1 GϾT ThrϾAsn 11094.48 Y 13.03 7.1 R N 7383.08 1078⌬T frameshift 9201.10 Y 1818.02 7 R Y 12233.9 R334W ArgϾGln 12205.87 Y -28.03 R347P ArgϾGly 12134.79 Y -99.11 9 F Y 14049.68 A455E AlaϾGlu 14107.74 Y 58.06 10.2 R Y 10525.57 ⌬I507 ⌬ Asp 10410.50 Y -115.07 ⌬F508 ⌬ Asp & LysϾAsn 10396.43 Y -129.14 11.2 F Y 11173.32 1717-1 GϾA GlyϾArg 11272.46 Y 99.14 G542X TrpϾLeu 11100.27 Y -73.05 G551D no change 11173.32 Y 0.00 R553X ThrϾMet 11203.42 Y 30.10 R560T no change 11173.32 Y 0.00 11 F N 8465.27 1717-1 GϾA no change 8465.27 N 0.00 G542X GlyϾTGA 6584.17 N -1881.10 G551D GlyϾAsp 8523.33 N 58.06 R553X ArgϾTGA 7541.18 N -924.09 R560T ArgϾThr 8410.21 N -55.06 12 F Y 10372.51 1898ϩ1 GϾA GlyϾAsp 10430.57 Y 58.06 13.2A R Y 10103.23 2184⌬A frameshift 8726.91 N -1376.32 14B R Y 9291.17 2789ϩ5 GϾA LeuϾPhe 9325.21 Y 34.04 16 F N 9398.67 3120ϩ1 GϾA ValϾIle 9412.72 N 14.05 19 F Y 17455.96 R1162X ArgϾTGA 6280.13 N -11175.83 3659⌬C frameshift 9650.06 N -7805.90 19i F Y 9699.9 3849ϩ10kB CϾT ArgϾTGA 7131.04 N -2568.86 20 F N 11125.48 W1282X TrpϾTGA 9370.40 N -1755.08 21 F Y 11183.44 N1303K AsnϾLys 11197.54 Y 14.10 a Denotes the directionality of exonic sequence when expressed as peptide. Login to comment
181 The heterozygous mutations depicted are as follows: (A), exon 3 wt/G85E; (B), exon 4.1 wt/R117H; (C), exon 4.2 wt/I148T; (D), exon 4.2 wt/621 ؉ 1G>T; (E), exon 5 wt/711 ؉ 1G>T; (F), exon 7.1 wt/1078⌬T; (G), exon 7 wt/R334W; (H), exon 7 wt/R347P; (I), exon 9 wt/A455E; (J), exon 10.2 wt/⌬I507; (K), exon 10.2 wt/⌬F508; (L), exon 11.2 wt/1717-1G>A; (M), exon 11 wt/G542X; (N), exon 11 wt/G551D; (O), exon 11 wt/R553X; (P), exon 11 wt/R560T; (Q), exon 12 wt/1898 ؉ 1G>A; (R), exon 13.2A wt/2184⌬A; (S), exon 14B wt/2789 ؉ 5G>A; (T), exon 16 wt/3120 ؉ 1G>A; (U), exon 19 wt/R1162X; (V), exon 19 wt/3659⌬C; (W), intron 19 wt/3849 ؉ 10kbC>T; (X), exon 20 wt/W1282X; (Y), exon 21 wt/N1303K. typical yield of purified protein was 1-30 ␮g/test well, depending on the analyte species. Login to comment
227 The remaining two compound heterozygotes (P175 and P176) had both mutations in exon 11; the detection of apparently wild-type analyte in these samples is attributable to translational suppression of the G542X mutation. Login to comment
228 The G542X and R553X mutations registered as mass shifts in both the exon 11 and exon 11.2 analytes, as predicted. Login to comment
229 Mutations predicted on the basis of their peptide mass Table 2. Summary of PMSG screening of putative compound heterozygous patient samples.a Exon Sample P154 P156 P158 P164 P165 P166 P168 P169 P175 P176 3.1 9871 9868 9872 9867 9863 9861 9866 9867 9861 9868 4.1 7054 7052 7057 7049 7048 7039 7048 7044 7047 7046 4.2 11172 11164 11175 11164 11157 11166 11159 11158 11163 11156 5 11096 11084 11098 11088 11088 11071 11084 11079 11076 11085 7.1 7386 7392 7382 7390 7382 7383 7379 7380 7387 7386 7 12232 12229 12234 12231 12237 12238 12239 12239 12240 12238 9 14064 14060 14065 14056 14062 14045 14050 14049 NAb 14051 10.2 10534 10531 10542 10533 No peakc 10525 10528 10527 10527 10524 Mutant 10404 10399 10409 10401 10400 10396 10398 10397 11.2 11186 11180 11182 11182 11179 11168 11175 11178 11075 11179 Mutant 11112 11205 11209 11105 11106 11 8477 8470 8477 8469 8467 8459 8468 8465 8465 ‫؍‬ supd 8459 ‫؍‬ supd Mutant 6591 8420 8427 7541 7539 8409 & 6581 8403 & 6576 12 10382 10376 10394 10379 10385 10365 10370 10370 10378 10366 13.2A 10103 10104 10103 10104 10105 10099 10099 10100 10098 10100 Mutant 8723 14B 9299 9294 9306 9300 9293 9283 9289 9291 9295 9294 16 9414 9403 9408 9402 9409 9391 9400 9396 9398 9396 19 17486 17476 17478 17481 17452 17447 17472 17453 17461 17448 Intron 19 9712 9709 9708 9709 9714 9696 9697 9704 9702 9700 20 11138 11128 11138 11135 11131 11117 NA 11122 11120 11116 Mutant 9372 21 11191 11189 11190 11187 11185 11181 11183 11185 11187 11183 Sequence result ⌬F508 ⌬F508 ⌬F508 ⌬F508 ⌬F508 ⌬F508 ⌬F508 ⌬F508 G542X G542X G542X W1282X R560T G551D ⌬F508 2183AAϾG R553X R553X R560T R560T a Shaded boxes highlight test analytes revealing evidence of mutation. Login to comment
234 d sup, slight wild-type mass analyte attributable to translational suppression of G542X mutation. Login to comment

PMID: 12885340 [PubMed] Devaney J et al: "HFE alleles in an Irish cystic fibrosis population."

No. Sentence Comment

57 Our non-DF508 CF patients were screened for the R117H, 1717-1G R A, DI507, G542X, G551D, R553X, R560K, and R560T CFTR mutations prior to inclusion in this study; it is interesting to note that the G542X and G551D alleles have positive and negative associations, respectively, with MI development (Schwarz et al., 1995; Feingold and Gailloud-Bataille, 1999). Login to comment

PMID: 12939655 [PubMed] Perri F et al: "Mutation analysis of the cystic fibrosis transmembrane conductance regulator (CFTR) gene, the cationic trypsinogen (PRSS1) gene, and the serine protease inhibitor, Kazal type 1 (SPINK1) gene in patients with alcoholic chronic pancreatitis."

No. Sentence Comment

33 Mutation screening of the CFTR gene The 31 most frequent mutations (F508del, I507del, G551D, G542X, N1303K, 1717-1G4A, W1282X, R553X, R347P, R347H, R334W, 3849+10kb C4T, R117H, 621+1G4T, A455E, S549N, R560T, S549R, V520F, Q493X, 3849+ 4A4G, 1078delT, R1162X, 3659delC, 3905insT, Y122X, 2183delAA4G, 2789+5G4A, 1898+1G4A, 711+1G4T, and G85E) were examined with the polymerase chain reaction (PCR) followed by an oligonucleotide ligation assay (OLA, Applied Biosystems, Foster City, CA, USA) and finally a sequence-coded separation. Login to comment
67 Our working hypothesis was that the pancreatic damage due to high alcohol intake could be due to either an abnormal allele in one of the three genes or a combination of multiple mutations occurring in the two alleles of the same gene (compound heterozygote) or different genes (trans- Table 1 Demographic and clinical data ACP All CFTR Mut SPINK1 Mut Mut negative N 45 4 3 38 Sex (M/F) 44/1 4/0 3/0 37/1 Age (years) 3875 3673 3774 3875 Age at onset (years) 3075 2976 3075 3276 Symptoms` duration (years) 872 773 773 673 Alcohol (g/day) 160743 130720 133723 166744 Smokers 26 3 2 21 ALD N 34 1 3 30 Sex (M/F) 28/6 1/0 3/0 24/6 Age (years) 4476 46 3977 4476 Age at onset (years) 3677 35 33711 3776 Symptoms` duration (years) 873 11 774 673 Alcohol (g/day) 140741 140 133723 140743 Smokers 19 1 1 17 Table 2 Sequence variations identified in the PRSS1, CFTR, and SPINK1 genes in 45 ACP patients CFTR Patients n PRSS1 Mutant Poly T SPINK1 1 1 Fa F508del NDb F 2 1 F G542X 7/9 F 3 1 F 711+1G>T 7/7 F 4 1 F 711+1G>T 7/7 F 5 1 F F 7/7 P55S 6 1 F F 5/7 IVS2-23A>T 7 1 F F 7/9 N34S 8 1 F F 7/7 ND 9-10 2 F F 5/7 F 11-37 27 F F 7/7 F 38-45 8 F F 7/9 F a indicates two wild alleles. Login to comment

PMID: 12940920 [PubMed] Rowntree RK et al: "The phenotypic consequences of CFTR mutations."

No. Sentence Comment

31 The majority of the other CFTR mutations are very rare with only four other mutations (G542X, N1303K, G551D and W1282X) having overall frequencies above 1%. Login to comment
47 These mutations, the most common being G542X, prevent the synthesis of a stable protein or result in the production of a truncated protein due to the creation of a premature termination codon. Login to comment
56 Alternatively, recent studies showed that premature stop codons, such as G542X and R553X, were suppressed by the addition of aminoglycoside antibiotics (e.g. gentamicin or G418) that are known to stimulate the suppression of stop codons in various organisms by near-cognate mis-pairing of an aminoacyl-tRNA with the premature stop codon (Howard et al. 1996). Login to comment

PMID: 12952861 [PubMed] Lee JH et al: "A haplotype-based molecular analysis of CFTR mutations associated with respiratory and pancreatic diseases."

No. Sentence Comment

15 Several mutations of CFTR, such as F508del, G542X and N1303K, are associated with severe CF phenotypes and display high disease penetrance. Login to comment
74 CFTR genetic variants analyzed in this study Variations found by TDGS Most common worldwide disease-causing mutations Reported disease-associated microsatellite À8G/C (50 UTR)a R117H (exon 4) T5-7,9 (IVS 8) (16) I125T (exon 4)b 621 þ 1G > T (intron 4) E217G (exon 6a)b F508del (exon 10) 1059C > T (exon 7, A309)a 1717-1G > A (intron 10) M470V (exon 10)b G542X (exon 11) I556V (exon 11)b G551D (exon 11) 2694T/G (exon 14a, T854)b R553X (exon 11) Q1352H (exon 22)b R1162X (exon 19) R1453W (exon 24)b W1282X (exon 20) N1303K (exon 21) Mutation names and nucleotide numbers are presented according to the Cystic Fibrosis Genetic Analysis Consortium (CFGAC; www.genet.sickkids.on.ca/). Login to comment
160 However, over 95% of the three most common CF-causing mutations, F508del, G542X and N1303K, arise from this haplotype. Login to comment

PMID: 12955726 [PubMed] Feldmann D et al: "CFTR genotypes in patients with normal or borderline sweat chloride levels."

No. Sentence Comment

44 Table 1 : Genotypes and Phenotypes of Patients with Normal or BordIerline Sweat Tests Patient Age at diagnosis (years) CFTR GENOTYPE* Allele 1 Allele 2 SWEAT CL- MEAN (MMOL/L) PHENOTYPE 1 0.2 F508del G149R 38 P+PI, neonatal hypertrypsinemia, 2 0.3 G551D R117H-7T 31 neonatal hypertrypsinemia 3 0.4 F508del R1070W 30.5 neonatal hypertrypsinemia 4 0.4 F508del R117H-7T 52 P 5 0.6 F508del 3849+10kbC>T 48 P 6 0.11 F508del S945L 58 P+PI 7 1 F508del 5T 40 P+CBAVD 8 2 F508del L206W 53 P 9 2 W1282X 5T 42.5 P 10 5 F508del 3849+10kbC>T 55.5 P 11 5 F508del L206W 55 P 12 5 G91R 5T 47.5 P 13 6 G551D S1235R+5T 49.5 P, neonatal hypertrypsinemia 14 7 F508del 3849+10kb 50 P, nasal popyposis 15 13 F508del R117H-7T 58 P, nasal polyposis 16 18 F508del 5T 60.5 P 17 20 G542X 3849+10kbC>T 52 P+PI 18 21 I507del 3849+10kbC>T 54 P, bronchiectasis 19 30 R347P 3849+10kbC>T 43 P, Pseudomonas colonisation 20 30 I507del L206W 57.5 CBAVD, chronic cough 21 31 F508del R117H-7T 60 CBAVD 22 32 G542X 3849+10kbC>T 30 P, Pseudomonas colonisation 23 34 F508del 3272-26A>G 64 P, CBAVD 24 37 R1070Q D1152H 56 CBAVD, bronchectasis 25 46 F508del D1152H 43 P 26 55 F508del D1152H 48 P, Pseudomonas colonisation 27 56 I507del S1235R 53 P 28 >18 F508del D1152H 60 P+PI 29 >20 F508del 3849+10kbC>T 18 P, bronchiectasis 30 >20 F508del 3272-26A>G 61 P *All mutations are named in accordance with the numbering used in the CFTR Mutation Database: http://www.genet.sickkids.on.ca/cftr/. Login to comment

PMID: 14501614 [PubMed] Efrati O et al: "Liver cirrhosis and portal hypertension in cystic fibrosis."

No. Sentence Comment

92 Unauthorized reproduction of this article is prohibited. Table 2 Details of the 10 cystic fibrosis patients with portal hypertension Pulmonary function test Symptoms Liver Patient of portal synthetic Procedures number Sex Mutation FEV1 FVC hypertension function (year) 1 M W1282X/W1282X 50% 55% H,V Abnormal Splenectomy & splenorenal shunt (`63) 2 F A¨ F508/G542X 75% 90% H,V Abnormal Portacaval end to side shunt (`77) 3 M G542X/W1282X 82% 92% H,V Abnormal Liver transplantation (`90) 4 M A¨ F508/W1282X 65% 80% H,V,A Abnormal Sclerotherapy & portacaval shunt (`98) 5 M G542X/W1282X 30% 40% H,V,A Abnormal Sclerotherapy & TIPSS (x2): right hepatic to left portal shunt (`99) 6 M A¨ F508/G542X 70% 80% H,V Abnormal Sclerotherapy & portosystemic shunt: superior mesenteric vein to left renal vein (`99) 7 M A¨ F508/A¨ F508 22% 25% H,V,A Abnormal Recurrent sclerotherapy (x5) & TIPSS 8 F W1282X/N1303K 75% 85% H,V,A Abnormal Sclerotherapy 9 M G542X/G542X 65% 70% H,V,A Abnormal Sclerotherapy 10 M A¨ F508/A¨ F508 55% 85% H,V Borderline Sclerotherapy M, male; F, female; FEV1, forced expiratory volume in 1s; FVC, forced vital capacity; H, hypersplenism; V, varices; A, ascites; TIPSS, transjugular intrahepatic portosystemic shunt. Login to comment

PMID: 14534336 [PubMed] Wilschanski M et al: "Gentamicin-induced correction of CFTR function in patients with cystic fibrosis and CFTR stop mutations."

No. Sentence Comment

15 Howardetal.demonstratedthattwoCFTR-associated stop mutations could be suppressed by treating cells with low doses of an aminoglycoside antibiotic.12 Bedwell et al. demonstrated that after incubation of bronchial epithelial cell line IB3-1, whichcarriesaW1282XmutationofCFTR,withami- noglycosides, cyclic AMP (cAMP)-activated chloride conductance and the expression of functional CFTR were restored to the apical membrane.13 Recently, Zsembery et al. isolated cholangiocytes from the liver of a patient carrying the G542X mutation of CFTR and incubated them with gentamicin, resulting in the expression of cAMP-activated chloride transport.14 Thus, in vitro, gentamicin obviated the effect of stop-codon mutations on the transcription and translation of CFTR. This effect has subsequently been demonstrated in a number of models of other diseases caused by stop mutations,includingmusculardystrophy,15 Hurler`ssyndrome,16 cystinosis,17 late infantile neuronal ceroid lipofuscinosis,18 and disorders involving the p53 gene.19 In a previous open pilot study, we found that topical application of gentamicin drops to the nose augmented chloride transport in epithelial cells of nine patients with cystic fibrosis who had at least one W1282X allele.20 Subsequently, Clancy et al.,21 in an open study, administered gentamicin intravenously to five patients who were heterozygous for stop mutations and found that four of the patients had hyperpolarization of the nasal potential differ- enceaftertheadministrationofisoproterenol,indicating that chloride transport was induced across the apical surface. Login to comment
62 Of the 24 study patients,11carriedtwostopmutations:6werehomo- zygous for W1282X, 3 were compound heterozygous for W1282X/G542X, and 2 were compound heterozygous for W1282X/3849+10KbC˚T. Login to comment
129 In vitro studies using quantitative immunohistochemistry have shown that after incubation with an aminoglycoside, cells from patients with cystic fibrosis have as much as 25 percent (in those with the R553X mutation) to 35 percent (in those with the G542X mutation) of the concentration of full-length CFTR observed in cells transfected with a wild-type CFTR complementary DNA.12,13 This in- creaseinfunctionalCFTRmightexceedthethresh- old required for normally functioning respiratory epithelial cells and might thus have corrected cell-membrane function in our patients. Login to comment

PMID: 14555458 [PubMed] Gibson RL et al: "Pathophysiology and management of pulmonary infections in cystic fibrosis."

No. Sentence Comment

77 Class 1 mutations, exemplified by G542X, contain premature stop mutations that create truncated mRNA. Login to comment

PMID: 14576497 [PubMed] Pezzilli R et al: "Mutations of the CFTR gene in pancreatic disease."

No. Sentence Comment

59 The 29 Mutations and the Tn Polymorphism Which Can Be Detected by INNO-LiPA Assays Mutation Exon/Intron (i) E60X, G85E, 394delTT 3 621 + 1G > T, R117H (i) 4, 4 711 + 5G > A (i) 5 1078delT, R347P, R334W 7 A455E, Tn (i) 8, 9 ⌬F508, ⌬I507 10 G542X, 1717-1 G > A, G551D, R553X, R560T, Q552X (i) 10, 11 2183AA > G, 2184del A, 2143delT 13 2789 + 5G > A (i) 14b R1162X, 3659delC 19 3849 + 10kbC > T (i) 19 3905insT, W1282X, S1251N 20 N1303K 21 Group 3: pancreatic cancer CFTR gene mutations were identified only in 1 of the 18 patients (5.6%) with this cancer. Login to comment

PMID: 14586256 [PubMed] Reboul MP et al: "Isolated idiopathic chronic pancreatitis associated with a compound heterozygosity for two mutations of the CFTR gene."

No. Sentence Comment

1 SUMMARY We report the case of a patient suffering from idiopathic chronic pancreatitis (ICP) and compound heterozygous for mutations G542X and S1235R of the cystic fibrosis transmembrane regulator (CFTR) gene. Login to comment
3 G542X is a severe mutation, which is usually found in classical cystic fibrosis when associated with other severe mutations. Login to comment
6 The history and the clinical features of our patient indicate an unambiguous isolated ICP in which the presence of the S1235R mutation - in trans with regard to G542X - is likely responsible for the ICP phenotype. Login to comment
8 RE´SUME´ Pancréatite chronique idiopathique isolée associée à une hétérozygotie composite pour deux mutations du gène CFTR Marie-Pierre REBOUL, David LAHARIE, Michel AMOURETTI, Didier LACOMBE, Albert IRON (Gastroenterol Clin Biol 2003;27:821-824) Nous rapportons le cas d`un malade souffrant de pancréatite chronique idiopathique (PCI) hétérozygote composite pour les mutations G542X et S1235R du gène CFTR. Login to comment
10 G542X est une mutation sévère rencontrée assez fréquemment - en association avec d`autres mutations sévères - dans des formes de mucoviscidose classique. Login to comment
13 L`histoire et le tableau clinique de la maladie chez notre malade évoquent de manière complète et sans ambiguïté une PCI isolée dans laquelle la présence de la mutation S1235R - en position trans par rapport à G542X - est très vraisemblablement responsable du phénotype de pancréatite chronique idiopathique. Login to comment
23 He had an original compound heterozygosity for the severe G542X mutation and the mild S1235R mutation. Login to comment
44 This revealed the G542X mutation with a heterozygous status. Login to comment
67 In five patients (no 5, 9, 10, 11, 15) who bear a frequent mutation well known for its severity (F508del or G542X), the involvement of the ICP phenotype could lie in their "second" missense mutation, i.e. L997F in exon 17b (Patient no 5), I1027T in exon 17a (Patient no 9), D1152H in exon 18 (Patients no 10 and 11) and S1235R in exon 19 (Patient no 15); and the presence of 2 of these 4 missense mutations in patient no 7 could actually strengthen this hypothesis but to date little is known about the possible impact of his 5T allele on the phenotype (possible sterility). Login to comment
75 It is a rare moderate mutation recently studied by Cuppens`s team [16] who showed that the deleterious character Fig. 2 - Pedigree of the family (limited to the subjects investigated) with mention of the haplotypes IVS8CA-TGm-Tn-M470V-IVS17bTA-IVS17bCA and the presence or absence (-) of the 2 familial mutations G542X (exon 10) and S1235R (exon 19). Login to comment
76 ↑ proband Arbre généalogique de la famille (limité aux sujets analysés) avec mention des haplotypes IVS8CA-TGm-Tn-M470V-IVS17bTA-IVS17bCA et de la présence ou de l`absence (-) des 2 mutations familiales G542X (exon 10) et S1235R (exon 19). Login to comment
80 Patient CFTR no PolyT genotype Sex genotype Age (years) Sweat chloride (mmol/L) Anamnestic features known to be associated with atypical CF Reference 1 F508del/R117H 9T/7T M 45 29 CBAVD [4] 2 N1303K/R117H 9T/7T F n.a. 37 bronchiectasis, sinusitis, positive NPD [5] 3 R1162X/2789+5G>A 7T/7T F n.a. 108 chronic cough [5] 4 I336K/R75Q 7T/7T F 26 26 nasal polyposis [7] 5 F508del/L997F 9T/7T M 17 24 none [11] 6 3849+10kbC>T/3878delG 7T/7T M 14 n.a. none [11] 7 S1235R/L997F 5T/7T M 27 25 none [11] 8 F508del/R117H n.a. M 45 29 CBAVD, smooth P. aeruginosa [12] 9 F508del/I1027T n.a. F 32 59 none [12] 10 F508del/D1152H n.a. M 8 62 none [12] 11 F508del/D1152H n.a. F 15 32 none [12] 12 F508del/P574H n.a. F 26 81 sinus surgery, S. aureus, S. maltophilia [12] 13 F508del/3120G>A n.a. F 40 n.a. n.a. [12] 14 F508del/G1069R n.a. M 16 n.a. n.a. [12] 15 G542X/S1235R 7T/7T M 35 15 none [this study] n.a.: not available. Login to comment

PMID: 14641997 [PubMed] Raskin S et al: "High allelic heterogeneity between Afro-Brazilians and Euro-Brazilians impacts cystic fibrosis genetic testing."

No. Sentence Comment

11 Although the major mutation causing CF accounts for 66% of mutant chromosomes screened worldwide, at least 1,000 sequence alterations associated with the disease have been identified in the CFTR gene during the past years, and their frequencies vary between populations (Tsui, 1990, 1992; Cystic Fibrosis Genetic AnalysisConsortium,1994, 1999).Previously, we have shown allelic heterogeneity in Brazilian CF patients of European origin by screening for DF508 and another four common worldwide mutations (G542X, N1303K, G551D, and R553X). Login to comment
54 Only three mutations have an overall frequency higher than 4%-DF508, G542X, and R1162X-and a fourth, 312011G R A, has a frequency of 2.6% in the Afro-Brazilian group. Login to comment
61 In this study, we also found that only four among 70 CFTR mutations included in the screening panel were present in CF patients born in the three different states of Brazil and in the two population subgroups (Euro- and Afro-Brazilians) studied; that is, DF508, G542X, R1162X, and G85E. Login to comment
63 FREQUENCIES OF 70 CFTR MUTATIONS IN DIFFERENT STATES OF BRAZIL, BY CONTINENTA L GROUP CFTR mutations SC PR MG detected n n n n % n % N % DF508 53 39 54 146 47.1 8 10.5 154 39.9 G542X 6 9 8 23 7.4 1 1.3 24 6.2 R1162X 9 2 4 15 4.8 2 2.6 17 4.4 N1303K 5 5 0 10 3.2 0 0 10 2.6 R334W 5 1 4 10 3.2 0 0 10 2.6 G85E 2 2 4 8 2.6 1 1.3 9 2.3 1717-1G®A 1 3 2 6 1.9 0 0 6 1.6 W1282X 4 1 1 6 1.9 0 0 6 1.6 3849110kbC®T 1 3 1 5 1.6 0 0 5 1.3 R553X 0 2 0 2 0.7 0 0 2 0.5 1812-1G®A 0 1 3 4 1.3 1 1.3 5 1.3 2183AA®G 2 1 0 3 1.0 0 0 3 0.8 312011G®A 0 0 2 2 0.7 2 2.6 4 1.0 Y1092X 0 1 1 2 0.7 1 1.3 3 0.8 G551D 0 0 0 0 0 0 0 0 0 W1089X 0 0 1 1 0.3 0 0 1 0.3 6211G®T 0 1 0 1 0.3 0 0 1 0.3 Q1238X 0 1 0 1 0.3 0 0 1 0.3 711-1G®T 0 1 0 1 0.3 0 0 1 0.3 R347P 1 0 0 1 0.3 0 0 1 0.3 189811G®A 1 0 0 1 0.3 0 0 1 0.3 I507 0 0 1 1 0.3 0 0 1 0.3 Subtotal 91 73 86 250 80.7 16 21.1 266 68.9 Alleles with CFTR 5 27 28 60 19.4 60 79.0 120 31.1 mutations not detected Total 96 100 114 310 100.0 76 100.0 386 100.0 Detection rate (%) 94.8 73.0 75.4 250 80.7 16 21.1 266 68.9 The following 70 CFTR mutations were selected and tested on the basis of frequency in various populations, known association with CF, or predicted deleterious effect on the CFTR protein product; DF508, G542X, N1303K, G551D, R553X, DI507, A455E, A559T, C524X, D1270N, E60X, G178R, G330X, G85E, 2307insA, I148T, K710X, P574H, Q1238X, Q493X, Q890X, R1158X, R1162X, R117H, R334W, R347H, R347P 2307insA, I148T, K710X, P574H, Q1238X, Q493X, Q890X, R1158X, R1162X, R117H, R334W, R347H, R347P 2307insA, 1148T, K710X, P574H, Q1238X, Q493X, Q890X, R1158X, R1162X, R117H, R334W, R347H, R347P, R352Q, R560T, S1196X, S1255X, S364P, S549N, S549R, V520F, W1089X, W1282X, W1310X, W1316X, Y1092X, Y122X, Y563D, 1078delT,1677delTA,1717-1G-A,1812-1G-A,1898 1 1G-A, 2043delG,2183delAA-G, 2184delA, 2789 1 5G-A, 2869insG, 2909delT, 3120 1 1G-A, 3120G-A, 3358delAC, 3659delC, 3662delA, 3750delAG, 3791delC, 3821delT, 3849 1 10KbC-T, 3849 1 4A-G, 3905insT, 405 1 1G-A, 444delA, 556delA, 574delA, 621 1 1G-T, and 711 1 1G-T. aSC, Santa Catarina State; PR, Parana State; MG, Minas Gerais State; n, number of chromosomes. Login to comment
69 G542X Our data show that G542X is the second most common CF mutation in two of the three Euro-Brazilian CF states studied (PR and MG), with an overall frequencyof 6.2% (Table 1). Login to comment
70 The presence of G542X in the Afro-Brazilian group was, as for DF508, likely the result of Caucasian admixture, in agreement with North American data (Macek et al., 1997). Login to comment
101 The presence in Afro-Brazilians of at least four CF alleles that are common in Caucasians (i.e., DF508, G542X, G85E, R1162X) indicates that the incidence of CF in Afro-Brazilians is due, at least in part, to genetic admixture. Login to comment

PMID: 14662004 [PubMed] Zeitlin PL et al: "Emerging drug treatments for cystic fibrosis."

No. Sentence Comment

57 Examples in this class include G542X, W1282X, R553X and 621 + 1 G→T. Login to comment
88 Class of mutation Molecular mechanism Pancreatic status (if known) Examples 1 No CFTR protein synthesis PI W1282X, G542X, R553X, 621 + 1 G→T, 1717-1 G→A, 3905insT, 394delTT 2 Abnormal CFTR processing and trafficking PI ∆F508, N1303K, P574H 3 Defective CFTR regulation (normal trafficking) PI G551D, G551S, G1349D, S1255P 4 Decreased CFTR chloride conductance PS R117H, R334W, R347P, P547H 5 Reduced synthesis and trafficking of normal CFTR PS A455E, 3849 + 10kb C→T, (5T) 6A Reduced apical stability PI S1455X, Q1412S, 4326delTC, 4279insA 6B Defective regulation of other ion channels PI G551D Note that the G551D is placed in Class 3 for defective regulation and Class 6B for defective regulation of the outwardly rectifying chloride channel. Login to comment

PMID: 14670800 [PubMed] Becker MN et al: "Cytokine secretion by cystic fibrosis airway epithelial cells."

No. Sentence Comment

49 3 14 NTD 51 F 3 14 30 F Not genotyped 3 15 TD 48 F 3 15 22 F ⌬F508/⌬F508 3, 4 16 NTD 45 F 3 16 42 M 2789ϩ5GϾA/N1303K 4 17 NTD 28 M 4 17 32 F ⌬F508/⌬F508 4 18 NTD 46 M 4 18 27 F ⌬F508/G542X 4 19 TD 20 M 4 19 21 F ⌬F508/G85E 4 20 PF 63 M 4 20 26 F N1303K/? Login to comment

PMID: 14711349 [PubMed] Richards CS et al: "Prenatal screening for cystic fibrosis: past, present and future."

No. Sentence Comment

37 The second most common mutation in the general Caucasian population is G542X (2.4%) [5], and there are another 4-5 above the 1% level. Login to comment

PMID: 14731137 [PubMed] Gaskin KJ et al: "CFTR gene and cystic fibrosis."

No. Sentence Comment

23 Contributed by Kevin J Gaskin Department of Gastroenterology and James Fairfax Institute of Pediatric Nutrition,The Children`s Hospital,Westmead, NSW 2145, Australia Table 1 Classification of cystic fibrosis transmembrane conductance regulator (CFTR) mutations Type Description Example I CFTR mRNA or protein not formed G542X II CFTR trafficking defect, and protein fails to locate in cell membrane DF508 III Regulation defect. CFTR inserts into cell membrane but no response to cAMP G551D IV Channel defect. CFTR inserts into cell membrane but function is reduced R117H V Synthesis defect. CFTR inserts into membrane and functions normally, but the amount of CFTR synthesized is reduced from normal Login to comment

PMID: 14739679 [PubMed] Farriaux JP et al: "Neonatal screening for cystic fibrosis: France rises to the challenge."

No. Sentence Comment

114 In its present version, the kit allows screening for 20 CFTR gene mutations (F508del, G542X, N1303K, 1717-1G>A, G551D, W1282X, R553X, I507del, 1078delT, 2183AA>G, 3849 þ 10kbC>T, R1162X, 621 þ 1G>T, R334W, R347P, 3659delC, R117H, S1251N, E60X, A455E) in one workday; moreover, it does not require any speci'c equipment. Login to comment

PMID: 14963811 [PubMed] Luzardo G et al: "Cystic fibrosis in Uruguay."

No. Sentence Comment

36 The CFTR mutations were detected by using one or more of the following methods: a) Reverse hybridization technique for eight mutations frequent in Europe (∆F508, G542X, N1303K, 1717-1G→A, W1282X, G551D, R553X and ∆I507), using a commercial kit from Inno Lipa CF2, Innogenetics, Belgium. Login to comment
42 RESULTS Genetic analysis led to the detection of 15 different mutations: ∆F508, G542X, R1162X, G85E, N1303K, R334W, R75Q, R74W, D1270N, W1282X, ∆I507, 2789+5G→A, R1066C, R553X and -816C/T. Login to comment
47 Mutation Cumulative (%)%N ∆F508 G542X R1162X G85E N1303K R334W R75Q Other mutations* Unknown 42 6 3 3 3 2 2 13 30 40.4 5.7 2.9 2.9 2.9 1.9 1.9 12.5 28.9 40.4 46.1 49.0 51.9 54.9 56.7 58.6 71.1 99.9 *R74W, D1270N, W1282X, ∆I507, 2789+5G→A, R1066C, -816C/T, R553X, 5T (3 cases associated to other mutations, 2 cases without known second mutation). Login to comment
49 The most prevalent mutation, ∆F508, was found in 42/104 CF chromosomes, with the second most common allele being the G542X (6/104). Login to comment
59 Genotypes N Percent ∆F508/∆F508 ∆F508/R1162X ∆F508/G85E ∆F508/G542X ∆F508/5T ∆F508/R334W ∆F508/1303X ∆F508/R1066C ∆F508/Unknown ∆I507/2789+G-A R74W/D1270N N1303K/G542X N1303K/R553K -816C-T/5T 5T/Unknown G542X/Unknown R75Q/Unknown W1282X/Unknown Unknown/Unknown 8 3 3 3 2 2 1 1 11 1 1 1 1 1 2 2 2 1 6 15.4 5.8 5.8 5.8 3.9 3.9 1.9 1.9 21.2 1.9 1.9 1.9 1.9 1.9 3.9 3.9 3.9 1.9 11.5 All individuals had pulmonary symptoms.All those carrying the ∆F508/∆F508 genotype had pancreatic insufficiency. Login to comment
89 We have also observed differences in the distribution and frequencies of non-∆F508 mutations between Uruguayans and patients from other LatinAmerican countries, in particular compared to theArgentinean population.AmongArgentine CF patients, seven mutations (∆F508, G542X, W1282X, N1303K, 17171G→A, R553X, R1162X) constituted 67.5% of the observed alleles (Chertkoff et al., 1997), while in our population 15 mutations corresponded to a similar cumulative percentage (71%). Login to comment
90 There is an agreement between the most common Uruguayan CFTR mutations (∆F508, G542X, R1162X, N1303K, R334W, W1282X and R553X) and those reported in the geographical regions from where most Uruguayans`ancestors originated, namely, Spain, the Canary Islands, Italy and the Basque regions. Login to comment
98 In U.S. CF patients, only three mutations (∆F508, G542X, G551D) have gene frequencies higher than 2%, and altogether represent 72.5% of the CF chromosomes with a ∆F508 frequency of 68% (Cystic Fibrosis Foundation, 1997). Login to comment
99 TheArgentine study shows similar proportions, with three mutations with a gene frequency exceeding 2% and covering 64% of the total number of chromosomes (∆F508 = 57.0%, G542X = 3.94%, W1282X = 3.07%; Chertkoff et al., 1997). Login to comment

PMID: 14998948 [PubMed] Danziger KL et al: "Improved detection of cystic fibrosis mutations in infertility patients with DNA sequence analysis."

No. Sentence Comment

59 Polyacrylamide gels were analysed for the presence of mutations following staining in ethidium bromide (EtBr) and image capture under UV using the Gel Doc 1000 system Table I. List of CFTR mutations included in common mutation panels American College of Medical Genetics CF panel (25 mutations) DF508 G542X G551D R117H W1282X N1303K R1162X 3849+10kbC®T DI507 R553X 1717-1G®A 621+1G®T R560T 3659delC 3120+1G®A I148T G85E R334W A455E 1898+1G®A 2148delA 711+1G®T 2789+5G®A R347P 1078delT Six additional mutations and one polymorphism in UCSF panel (31 mutations) Y1092X R347H 3849+4 Q493X 3905insT S549N F508C (polymorphism) (BioRad). Login to comment

PMID: 15010427 [PubMed] Strom CM et al: "Direct visualization of cystic fibrosis transmembrane regulator mutations in the clinical laboratory setting."

No. Sentence Comment

178 The optimal spotting conditions for each probe are indicated by the boxes around spots in C. wild-type controls and heterozygotes for each ACMG mutation and polymorphism, DNA from 12 compound heterozygotes (⌬F508/1898 ϩ 1GϾA, 711 ϩ 1GϾT/⌬F508, G85E/621 ϩ 1GϾT, 3659delC/⌬F508, 3120 ϩ 1GϾA/ 621 ϩ 1GϾT, R347P/G551D, A455E/⌬F508, R560T/ dF508, R553X/⌬F508, 621 ϩ 1GϾT/⌬F508, 621 ϩ 1GϾT/ 711 ϩ 1GϾT, R117H/⌬F508, and I506V/⌬F508) and DNA from 4 homozygous patients (⌬F508 and 2789 ϩ 5GϾA, 3849 ϩ 10kbCϾT, and G542X) was used in validation experiments. Login to comment
199 In this series, there were 17 ⌬F508 heterozygous patient samples, 1 ⌬F508 homozygous sample, 2 R117H heterozygous samples, and 1 heterozygous patient sample each for I148T, G542X, R553X, R347P, and 2789 ϩ 5GϾA, for a total of 26 mutant alleles. Additional mutant alleles detected in the control samples included three fixed control samples (⌬F508 homozygous, 5T/WT, 3659delC/⌬F508) on every plate and two heterozygous samples (R560T and 1078delT) and one heterozygous sample each for R334W, A455E, R347P, R117H, ⌬I507, I507V, G551D, and 1717-1GϾA as rotating controls. Login to comment
203 In this comparison, there were 19 ⌬F508 heterozygous patient samples, 3 I148T heterozygous samples, 3 R117H heterozygous and 1 R117H homozygous samples, 2 W1282X heterozygous samples, and 1 heterozygous patient sample each for G551D, R553X, R1162X, and 3849 ϩ 10kBCϾT, for a total of 36 mutant alleles. Additional mutant alleles detected for this study included fixed controls ⌬F508 homozygous, 5T/WT, and a N1303K heterozygous sample on all plates, and one heterozygous sample each for R560T, G542X, R553X, W1282X, 2184delA, G85E, I148T, 621 ϩ 1GϾT, R334W, R117H, 1078delT, and 1717-1GϾA as rotating controls. Login to comment

PMID: 15044340 [PubMed] Dempsey E et al: "Detection of five common CFTR mutations by rapid-cycle real-time amplification refractory mutation system PCR."

No. Sentence Comment

4 The five mutations [and the percentages of Irish (3) and worldwide (2) cases] are F508del (77.4%, 66.0%), G551D (7.1%, 1.6%), R117H (2.7%, 0.3%), 621ϩ1 GϾT (1.4%, 0.7%), and G542X (0.5%, 2.4%). Login to comment
5 Four of these fall into the severe class of mutations in which the mRNA is incorrectly spliced (621ϩ1 GϾT), or in which the protein is not synthesized (G542X) or is blocked during processing (F508del), or its regulation is blocked (G551D). Login to comment
23 The second reaction detects the 621ϩ1 GϾT and G542X mutations (1.9% frequency in Ireland, 3.1% worldwide). Login to comment
28 The CF11ARMS-A (5Ј-TAT- GATTACATTAGAAGGAAGATGTGCCTTT-F-3Ј) and CF11ARMS-P (5Ј-LCRed705-AATTCAGATTGAGCAT- ACT-P-3Ј) hybridization probes detect both the G551D and G542X ARMS products. Login to comment

PMID: 15047968 [PubMed] King PT et al: "Role of CFTR mutations in adult bronchiectasis."

No. Sentence Comment

230 The patients were screened for the 10 most common mutations in the local population (DF508, D1507, V520F, G542X, G551D, R553X, R117H, 621+1GRT, A455E and N1303K) responsible for 82% of cases of CF and the 5T mutation by previously published methods.7 8 Ethical approval for the project was obtained from the ethics committee at MMC. Login to comment

PMID: 15084222 [PubMed] D'Apice MR et al: "Molecular analysis using DHPLC of cystic fibrosis: increase of the mutation detection rate among the affected population in Central Italy."

No. Sentence Comment

77 Finally, in a single CF patient, we detected two different mutations [G542X (1756 G to T) and S549R (1779 T to G)] in the same exon 11-derived DNA amplicon, which showed a peculiar DHPLC pattern, different from that observed when only one of these mutations was present (data not show). Login to comment
89 Table 1: Primers and DHPLC (oven temperature, gradient) analysis conditions for 6b and 9 exons of the CFTR gene exon Primer 5' → 3' Amplicon length Oven temp (°C) % B buffer start/end 6b F - CAGAGATCAGAGAGCTGGG 323 56 55/63 R - GAGGTGGAAGTCTACCATGA 9 F - GGGATTTGGGGAATTATTTG 279 55 54/62 R - TCTCCAAAAATACCTTCCAG Table 2: CF mutations identified in cohort of 290 patients from the Central Italy Mutation Nucleotide change Exon/intron N % Method delF508 1652delCTT 10 328 56.36 INNO-LiPA, DHPLC N1303K 4041 C to G 21 51 8.76 INNO-LiPA, DHPLC G542X 1756 G to T 11 42 7.21 INNO-LiPA, DHPLC W1282X 3978 G to A 20 15 2.60 INNO-LiPA, DHPLC S549R 1779 T to G 11 8 1.37 DHPLC 621+1G-T 621+1 G to T Intron 4 7 1.20 INNO-LiPA, DHPLC 1717-1G-A 1717-1 G to A Intron 10 5 0.86 INNO-LiPA, DHPLC G85E 386 G to A 3 4 0.69 INNO-LiPA, DHPLC R553X 1789 C to T 11 4 0.69 INNO-LiPA, DHPLC H139R 548 A to G 6a 3 0.51 DHPLC R347P 1172 G to C 7 3 0.51 INNO-LiPA, DHPLC L1065P 3326 T to C 17b 3 0.51 DHPLC L1077P 3362 T to C 17b 3 0.51 DHPLC S4X 143 C to A 1 2 0.34 DHPLC D110H 460 G to C 4 2 0.34 DHPLC R334W 1132 C to T 7 2 0.34 INNO-LiPA, DHPLC M348K 1175 T to A 7 2 0.34 DHPLC 1259insA 1259 ins A 8 2 0.34 DHPLC S549N 1778 G to A 11 2 0.34 DHPLC L558S 1805 T to C 11 2 0.34 DHPLC 2183+AA-G 2183 A to G and 2184 del A 13 2 0.34 INNO-LiPA, DHPLC 2789+5G-A 2789+5 G to A Intron 14b 2 0.34 INNO-LiPA, DHPLC R1066C 3328 C to T 17b 2 0.34 DHPLC 3667ins4 3667insTCAA 19 2 0.34 DHPLC S42F 257 C to T 2 2 0.34 DHPLC R117L 482 G to T 4 1 0.17 DHPLC H199R 728 A to G 6a 1 0.17 DHPLC R334L 1133 G to T 7 1 0.17 DHPLC T338I 1145 C to T 7 1 0.17 DHPLC G551D 1784 G to A 11 1 0.17 INNO-LiPA, DHPLC Q552X 1786 C to T 11 1 0.17 INNO-LiPA, DHPLC D614G 1973 A to G 13 1 0.17 DHPLC A1006E 3149 C to A 17a 1 0.17 DHPLC 4016insT 4016 ins T 21 1 0.17 DHPLC 4040delA 4040 del A 21 1 0.17 DHPLC 4167del7 4167 delCTAAGCC 22 1 0.17 DHPLC Detected 511 88.10 Unknown 69 11.90 Total 580 100.00 N = number of CF chromosomes; % = frequency. Login to comment

PMID: 15084988 [PubMed] Naruse S et al: "A finger sweat chloride test for the detection of a high-risk group of chronic pancreatitis."

No. Sentence Comment

50 The DNA samples were analyzed using an amplification refractory mutation system kit for 20 common major CFTR mutations (E60X, R117H, R334W, R347P, A455E, ⌬I507, ⌬F508, G542X, G551D, R553X, 621+1G>T, 1078delT, R1162X, S1251N, W1282X, N1303K, 1717-1G>A, 2183AA>G, 3659delC, 3849+10kbC>T) (Elucigene CF 20, AstraZeneca Diagnostics, Abingdon, UK) following the standard procedures recommended by the manufacturer. Login to comment

PMID: 15121783 [PubMed] Fujiki K et al: "Genetic evidence for CFTR dysfunction in Japanese: background for chronic pancreatitis."

No. Sentence Comment

218 The 20 most common CF mutations (E60X, R117H, R334W, R347P, A455E, DI507, DF508, G542X, G551D, R553X, 621+1GRT, 1078delT, R1162X, S1251N, W1282X, N1303K, 1717-1GRA, 2183AARG, 3659delC, and 3849+10kbCRT) were tested by an Elucigene CF20 kit (AstraZeneca Diagnostics, Abingdon, Oxfordshire, UK). Login to comment

PMID: 15121798 [PubMed] Ogino S et al: "Bayesian risk assessment for autosomal recessive diseases: fetal echogenic bowel with one or no detectable CFTR mutation."

No. Sentence Comment

185 If a relative of parent A or parent B is affected or an obligate carrier, this table can still be applied when neither that relative nor any other family member has been tested. Table 3 Summary of carrier frequencies for cystic fibrosis, overall mutation detection rates by the ACMG 25 mutation panel, and frequencies of major mutations for each major ethnic group (adapted from Richards et al. and Bobadilla et al.)4 18 Ethnic group Cystic fibrosis carrier frequency Overall mutation detection rate by ACMG CFTR 25 mutation panel (%) Frequency DF508 among all disease alleles (%) Other major mutations (%)* Non-Hispanic 1/25 90 70 G542X 2.4 Caucasian G551D 2.1 W1282X 1.4 N1303K 1.3 Ashkenazi Jewish 1/25 97 30 W1282X 48 G542X 9.0 3849+10kbCRT 6.0 N1303K 3.0 1717-1GRA 1.0 African-American 1/65 69 48 3120+1GRA 12 2307insA 2.0 A559T 2.0 R553X 2.0 DF311 2.0 G480C 1.4 405+3ARC 1.4 S1255X 1.4 Hispanic American 1/46 57 46 G542X 5.4 3849+10kbCRT 2.3 R1162X 1.6 R334W 1.6 Asian American 1/90 ? Login to comment

PMID: 15151509 [PubMed] Casals T et al: "Bronchiectasis in adult patients: an expression of heterozygosity for CFTR gene mutations?"

No. Sentence Comment

57 One stop mutation (G542X) and one splice-site mutation (2789þ 5G> A) were detected in two other patients. Login to comment
81 Table2.ClinicalfeaturesandCFTRgenotypesfoundin20adultpatientswithbronchiectasis SampleSex/age Ageonset (years) FEV1/FVC (%predicted) Bacterial colonization Sweattest (mEq/l) Lobes affected Clinical features FirstCFTR change Second CFTRchangeM470V 1M/41520/43P30a >4-F508delL997FM/V 2F/231785/89P,S46a >4SN,ABPA,PNF508del-M/M 3F/24160/74P,S49a >4SN,PNF508del-M/V 4M/55-87/84S32a 2-F508del-M/V 5c F/372991/93S41a >4PNF508del-M/V 6F/333286/84No51a 2-G542X-M/M 7F/306101/112No56a >4-2789þ5G>A5T-12TGM/V 8F/3815106/104No29a 2OtitisS1235R-M/V 9F/34Birth75/100H20a >4SNV562L5T-11TGM/V 10d F/36530/51P20a >4SN,PNG1237S-M/V 11d M/401473/92H26a 3SN,PN,OZG1237S-M/V 12F/23541/47S23a >4HemoptysisR347HR75QV/V 13F/68548/52No34a >4PNY1014C5T-12TGV/V 14M/643088/84H39a 2-R75Q-M/V 15M/40Childhood56/79No33b >4SN,asthmaV754M-M/M 16M/474594/108No19a 2SN,PNQ179K-M/V 17M/23Childhood38/34No28a 2SN,PN5T-12TG5T-11TGM/V 18F/695068/89S52a 4DiabetesG576A,R668C-M/V 19F/47Childhood16/18P64b >4-G576A,R668C-M/V 20F/38672/88No39b >4SN,ABPA,asthma1716G/A-M/M M,male;F,female;FEV1,forcedexpiratoryvolumein1s(%ofpredictedvalueforheight);FVC,forcedvitalcapacity(%ofpredictedvalueforheight);P,Pseudomonas aeruginosa;H,Haemophilusinfluenza;S,Staphylococcusaureus;SN,sinusitis;ABPA,allergicbronchopulmonaryaspergillosis;PN,pneumonia;OZ,oligozoospermia. Login to comment
94 Among the common mutations reported in Spanish CF families (19), only three were detected in the bronchiectasis group (F508del, G542X, 2789 þ 5G> A). Login to comment

PMID: 15173476 [PubMed] Comeau AM et al: "Population-based newborn screening for genetic disorders when multiple mutation DNA testing is incorporated: a cystic fibrosis newborn screening model demonstrating increased sensitivity but more carrier detections."

No. Sentence Comment

79 The 16-mutation panel included ⌬F508, R117H, G551D, G542X, W1282X, N1303K, R334W, 621 ϩ 1GϾT, R553X, ⌬I507, 1717-1GϾA, R347P, R560T, 3849 ϩ 10kbCϾT, A455E, and S549N. Login to comment
122 False-Negative Results One of the 2 infants who were not detected by the Ͼ95th daily percentile screen had an IRT value at the 93.9th percentile and meconium ileus (positive sweat test; G542X/unknown); the other infant missed by the screen had an IRT value at the 84th percentile and presented at 2 months with failure to thrive and upper respiratory tract infection (positive sweat test; ⌬F508/R117H). Login to comment
126 The 15th infant`s IRT did not prompt a DNA assay; subsequent diagnostic testing revealed no ⌬F508 mutation but detected another (G542X) that is included in our multiple-CFTR-mutation testing panel. Login to comment
159 Genotypes and Frequencies Observed in 112 CF-Affected Infants First Mutation Second Mutation N ⌬F508 ⌬F508 55 ⌬F508 R117H 7* ⌬F508 G551D 4 ⌬F508 N1303K 3 ⌬F508 W1282X 3 ⌬F508 G542X 2 ⌬F508 1898 ϩ 1 G Ͼ A 2 G85E R117C 2 ⌬F508 1717-GϾA 1 ⌬F508 3849 ϩ 10kbC Ͼ T 1 ⌬F508 R1066C 1 ⌬F508 Y1092X 1 ⌬F508 L206W 1 ⌬F508 R560T 1 ⌬F508 1152H 1 ⌬F508 621 ϩ 1G Ͼ T 1 R117H G551D 1 R117H G85E 1 G551D 2789 ϩ 5GϾA 1 G551D R117C 1 G85E 711 ϩ 1GϾT 1 W1282X 3849 ϩ 10kbCϾT 1 R553X 2183AAϾG 1 A455E S549R 1 ⌬F508 Unknown† 13 N1303K Unknown 2 G542X Unknown 1 Unknown Unknown 2 * Includes 1 of the false-negative screens. Login to comment

PMID: 15238770 [PubMed] Felley C et al: "The role of CFTR and SPINK-1 mutations in pancreatic disorders in HIV-positive patients: a case-control study."

No. Sentence Comment

42 Samples were tested: (i) for 20 common CFTR mutations (delF508, 621+1G.T, G542X, 3849+10kbC.T, N1303K, 3659delC, 1717-1G.A, 1078delT, W1282X, R347P, G551D, A455E, R553X, S1251N, R1162X, delF507, R334W, 2183AA.G, R117H, and E60X; Elucigene CF20; Orchid Biosciences, Abingdon, UK); (ii) for the CFTR IVS8 5T variant (Elucigene CF Poly-T; Orchid); and (iii) for the SPINK-1 N34S polymorphism, by poly- Copyright (c) Lippincott Williams & Wilkins. Login to comment

PMID: 15238778 [PubMed] Ockenga J et al: "The puzzle of genes and environmental risk factors for disease susceptibility: putting the pieces together."

No. Sentence Comment

11 Approximately 72% of cystic fibrosis patients are homozygous or compound heterozygous for eight mutations of the CFTR regulator gene on chromosome 7: delta F508, G542X, R553X, W1282X, N1303K, 621 + 1G!T, 1717-1G!A, R117H [3]; whereas the deletion delta F508 alone accounts for approximately 66% of mutant cystic fibrosis alleles. Login to comment

PMID: 15297887 [PubMed] Jarzabek K et al: "Cystic fibrosis as a cause of infertility."

No. Sentence Comment

58 CFTR screening includes the most frequent CFTR mutations, for example in the German population: ΔF508, R347P, G542X, S549I, N, R (A→C), G551D, R553X, N1303K, 3849+10kbC→T [11]. Login to comment

PMID: 15333598 [PubMed] Grangeia A et al: "Characterization of cystic fibrosis conductance transmembrane regulator gene mutations and IVS8 poly(T) variants in Portuguese patients with congenital absence of the vas deferens."

No. Sentence Comment

5 The most frequent mutations were F508del and R334W in CBAVD and G542X in CUAVD, with the allelic frequencies of R334W (6.5%) and G542X (25%) being particular to the Portuguese population. Login to comment
98 The association of CFTR mutations with the 5T allele also did not increase the number of patients with at least one mutation detected. Overall, in the four CUAVD patients, the 5T allele and the G542X mutation were the most frequent mutations found, which accounted for two of the eight (25%) total alleles. Login to comment
106 G/- 1 - 1 7/9 5T/5T 2 - - 5/5 (£2) 5T/- 2 - - 5/7 (£2) CUAVD F508del/- 1 - 1 7/9 G542X/- 2 - 2 5/9 (£2) OAZ F508del/- 1 - 1 7/9 5T/- 1 - - 5/7 NOAZ-HP 3659delC/- 1 - 1 7/7 F508del/- 1 - 1 5/9 5T/5T 1 - - 5/5 5T/- 4 - - 5/7 (£4) Severe mutations are in bold. Login to comment
135 This frequency was due to the allelic frequency of G542X (25%) in Portuguese CUAVD males, which is higher than in other countries where it was also found (7-17%), France (Je´ze´quel et al., 2000) and Spain (Casals et al., 2000). Login to comment
150 The increased allelic frequency of R334W in CBAVD (6.5%) and of G542X in CUAVD (25%) appears particular to the Portuguese population. Login to comment

PMID: 15334505 [PubMed] Picard E et al: "Familial concordance of phenotype and microbial variation among siblings with CF."

No. Sentence Comment

66 The following genotypes were found among the families: DF508/DF508 (7), W1282X/W1282X (4), N1303K/N1303K (3), DF508/ W1282X (3), W1282X/N1303K (2), DF508/G542X (2), DF508/3849þ10 kb C ! Login to comment
69 T (1), G542X/G542X (1), G85E/G85E (1), 3849þ10 kb C ! Login to comment
71 A (1), S549R/S549R (1), Q359K/Q360K (1), DF508/Unknown (4), W1282X/Unknown (3), G542X/Unknown (2), G85E/Unknown (1), and Q359K/ Unknown (1). Login to comment

PMID: 15354331 [PubMed] Strom CM et al: "Cystic fibrosis screening: lessons learned from the first 320,000 patients."

No. Sentence Comment

47 Frequency, all tests Frequency, CF mutations (%) delta F508 7610 1:44 75% R117H/7T or 9T 1030 1:325 NAb R117H/5T 103 1:3,254 0.51c W1282X 529 1:625 5.2 G542X 382 1:909 3.8 G551D 278 1:1,250 2.7 N1303K 201 1:1,668 2.0 3849ϩ10kb CϾT 167 1:2,007 1.6 1717-1 GϾA 102 1:3,286 1.0 R553X 102 1:3,286 1.0 621ϩ1 GϾT 98 1:3,420 0.97 2789ϩ5 GϾA 82 1:4,087 0.80 3120ϩ1 GϾA 73 1:4,591 0.72 R1162X 54 1:6,207 0.53 R334W 54 1:6,207 0.53 685E 52 1:6,446 0.51 R560T 52 1:6,446 0.51 Delta I507 51 1:6,572 0.50 711ϩ1 GϾT 40 1:8,380 0.39 1898ϩ1 GϾA 37 1:9,059 0.36 3659 del C 36 1:9,311 0.36 A455E 34 1:9,858 0.33 R347P 33 1:10,158 0.32 2184 del A 14 1:23,943 0.14 1078 del T 6 1:55,867 0.06 a I148T has been eliminated from these data. Login to comment

PMID: 15371902 [PubMed] Watson MS et al: "Cystic fibrosis population carrier screening: 2004 revision of American College of Medical Genetics mutation panel."

No. Sentence Comment

70 It has been ar- Table 1 CFTR mutation frequency among individuals with clinically diagnosed cystic fibrosis by racial/ethnic group and in a pan-ethnic U.S. population CFTR mutation Mutation frequency among individuals with clinically diagnosed cystic fibrosis (%) Non-Hispanic Caucasian Hispanic Caucasian African American Asian American Ashkenazi Jewish Pan-Ethnic Population5 delF508 72.42 54.38 44.07 38.95 31.41 66.31 G542X 2.28 5.10 1.45 0.00 7.55 2.64 W1282X 1.50 0.63 0.24 0.00 45.92 2.20 G551D 2.25 0.56 1.21 3.15 0.22 1.93 621ϩ1GϾT 1.57 0.26 1.11 0.00 0.00 1.30 N1303K 1.27 1.66 0.35 0.76 2.78 1.27 R553X 0.87 2.81 2.32 0.76 0.00 1.21 dell507 0.88 0.68 1.87 0.00 0.22 0.90 3849ϩ10kbCϾT 0.58 1.57 0.17 5.31 4.77 0.85 3120ϩ1GϾT 0.08 0.16 9.57 0.00 0.10 0.86 R117H 0.70 0.11 0.06 0.00 0.00 0.54 1717-1GϾT 0.48 0.27 0.37 0.00 0.67 0.44 2789ϩ5GϾA 0.48 0.16 0.00 0.00 0.10 0.38 R347P 0.45 0.16 0.06 0.00 0.00 0.36 711ϩ1GϾT 0.43 0.23 0.00 0.00 0.10 0.35 R334W 0.14 1.78 0.49 0.00 0.00 0.37 R560T 0.38 0.00 0.17 0.00 0.00 0.30 R1162X 0.23 0.58 0.66 0.00 0.00 0.30 3569delC 0.34 0.13 0.06 0.00 0.00 0.28 A455E 0.34 0.05 0.00 0.00 0.00 0.26 G85E 0.29 0.23 0.12 0.00 0.00 0.26 2184delA 0.17 0.16 0.05 0.00 0.10 0.15 1898ϩ1GϾA 0.16 0.05 0.06 0.00 0.10 0.13 l148T 0.09 0.09 0.05 0.00 0.10 0.08 1078delT 0.02 0.09 0.00 0.00 0.00 0.03 Total 88.40 71.90 64.51 48.93 94.14 84.00 gued that a laboratory is obligated to report any and all information that is gleaned from a test system, however, there is no regulatory requirement and practice varies. Login to comment

PMID: 15371903 [PubMed] Sugarman EA et al: "CFTR mutation distribution among U.S. Hispanic and African American individuals: evaluation in cystic fibrosis patient and carrier screening populations."

No. Sentence Comment

35 87 mutation panel The following mutations were included in the panel: ⌬F508, ⌬F311, ⌬I507, A455E, A559T, C524X, D1152H, D1270N, E60X, G178R, G330X, G480C, G542X, G551D, G85E, G91R, I148T, K710X, L206W, M1101K, N1303K, P574H, Q1238X, Q359K/T360K, Q493X, Q552X, Q890X, R1066C, R1158X, R1162X, R117C, R117H, R1283M, R334W, R347H, R347P, R352Q, R553X, R560T, S1196X, S1251N, S1255X, S364P, S549I, S549N, S549R, T338I, V520F, W1089X, W1282X, Y1092X, Y563D, 1078delT, 1161delC, 1609delCA, 1677delTA, 1717-1GϾA, 1812-1GϾA, 1898ϩ1GϾA, 1898ϩ5GϾT, 1949del84, 2043delG, 2143delT, 2183delAAϾG, 2184delA, 2307insA, 2789ϩ5GϾA, 2869insG, 3120ϩ1GϾA, 3120GϾA, 3659delC, 3662delA, 3791delC, 3821delT, 3849ϩ10kbCϾT, 3849ϩ4AϾG, 3905insT, 394delTT, 405ϩ1GϾA, 405ϩ3AϾC, 444delA, 574delA, 621ϩ1GϾT, 711ϩ1GϾT, 711ϩ5GϾA, 712-1GϾT, 3876delA CFTR mutation analysis Genomic DNA was extracted from peripheral blood lymphocytes, buccal cell swabs, or bloodspots by Qiagen QIAmp 96 DNA Blood Kit. Specimens were tested for 87 mutations by a pooled allele-specific oligonucleotide (ASO) hybridization method as previously described.16,17 Two multiplex chain reactions (PCR) were used to amplify 19 regions of the CFTR gene. Login to comment
56 Among 318 CF patient chromosomes, 30 mutations were identified with ⌬F508, G542X, R334W, 3120ϩ1GϾA, W1089X, 3876delA, and R1066C representing 52.52% of the total. Login to comment
63 The most prevalent mutations were as follows: ⌬F508, D1152H, R117H, G542X, L206W, I148T (3199del6 status unknown), ⌬I507, R1066C, R553X, 3849ϩ10kbCϾT, and R334W representing 83.72% of the total identified. Login to comment
69 With the exception of W1089X, the next 6 most frequent mutations in the patient population (G542X, R334W, 3120ϩ1GϾA, 3876delA, W1089X, and R1066C) were all seen in the carrier population at frequencies of 1.4% to 4.2%. Login to comment
86 An additional 4 mutations (G551D, 1717-1GϾA, G542X, 711ϩ5GϾA) were detected twice (0.93% each), whereas 12 other mutations were identified on one chromosome each. Login to comment
108 In the current study, 42 different mutations were identified among the Hispanic individuals (patients and carriers) tested and the most common mutations included those previously reported to be common among Hispanics, 3876delA,32 W1089X,17 as well as mutations considered frequent in African Americans (3120ϩ1GϾA)19 and panethnic (e.g., G542X, ⌬I507) populations.33 Although regional variation in overall detection rates may occur, these data provide general guidance when developing a panethnic mutation panel and information useful for genetic counseling purposes. Login to comment

PMID: 15371905 [PubMed] Palomaki GE et al: "Clinical sensitivity of prenatal screening for cystic fibrosis via CFTR carrier testing in a United States panethnic population."

No. Sentence Comment

32 Data from the International Cystic Fibrosis Consortium were taken from Table 1 of its publication.4 Data from the Cystic Fibrosis Foundation National Patient Registry were taken from the year 1999 and stratified according to whether or not the patient was seen Table 1 CFTR mutation frequencies among Hispanic Caucasians with cystic fibrosis within the recommended minimum testing panel Ordera Mutation Mutation frequency (%) CF Consortiumb CF Foundationc Average Cumulative 1 delF508 45.51 63.25 54.38 54.38 2 G542X 5.11 5.09 5.10 59.48 8 delI507 0.59 5.02 2.81 62.29 22 R334W 2.25 1.31 1.78 64.07 6 N1303K 1.65 1.67 1.66 65.73 10 3849 ϩ 10kbC Ͼ T 1.60 1.53 1.57 67.30 7 R553X 0.63 0.73 0.68 67.98 5 W1282X 0.53 0.73 0.63 68.61 19 R1162X 0.57 0.58 0.58 69.19 3 G551D 0.31 0.80 0.56 69.75 12 1717 - 1G Ͼ T 0.10 0.44 0.27 70.02 4 621 ϩ 1G Ͼ T 0.00 0.51 0.26 70.28 14 711 ϩ 1G Ͼ T 0.10 0.36 0.23 70.51 18 G85E 0.10 0.36 0.23 70.74 11 2789 ϩ 5G Ͼ A 0.10 0.22 0.16 70.90 13 R347P 0.10 0.22 0.16 71.06 20 2184delA 0.10 0.22 0.16 71.22 24 3120 ϩ 1G Ͼ T 0.10 0.22 0.16 71.38 17 3569delC 0.10 0.15 0.13 71.51 9 R117H 0.00 0.22 0.11 71.62 23 I148T 0.10 0.07 0.09 71.71 25 1078delT 0.10 0.07 0.09 71.80 16 A455E 0.10 0.00 0.05 71.85 21 1898 ϩ 1G Ͼ A 0.10 0.00 0.05 71.90 15 R560T 0.00 0.00 0.00 71.90 All 25 59.95 83.77 71.90 a The order is based on that found for non-Hispanic Caucasians.3 b Based on between 178 and 958 chromosomes (International Cystic Fibrosis Genetic Analysis Consortium.4 c Based on 1374 chromosomes from clinically diagnosed persons registered in the Cystic Fibrosis Foundation National Patient Registry. Login to comment
80 The larger data- Table 2 CFTR mutation frequencies among African American individuals with cystic fibrosis within the recommended minimum testing panel Ordera Mutation Mutation frequency (%) CF Consortiumb CF Foundationc Average Cumulative 1 delF508 35.50 52.63 44.07 44.07 24 3120 ϩ 1G Ͼ T 12.50 6.64 9.57 53.64 8 delI507 0.74 3.89 2.32 55.96 7 R553X 2.37 1.37 1.87 57.83 2 G542X 1.18 1.72 1.45 59.28 3 G551D 0.59 1.83 1.21 60.49 4 621 ϩ 1G Ͼ T 1.18 1.03 1.11 61.60 19 R1162X 0.74 0.57 0.66 62.26 22 R334W 0.74 0.23 0.49 62.75 12 1717 - 1G Ͼ T 0.74 0.00 0.37 63.12 6 N1303K 0.00 0.69 0.35 63.47 5 W1282X 0.00 0.47 0.24 63.71 10 3849 ϩ 10kbC Ͼ T 0.00 0.34 0.17 63.88 15 R560T 0.00 0.34 0.17 64.05 18 G85E 0.00 0.23 0.12 64.17 9 R117H 0.00 0.11 0.06 64.23 13 R347P 0.00 0.11 0.06 64.29 17 3569delC 0.00 0.11 0.06 64.35 21 1898 ϩ 1G Ͼ A 0.00 0.11 0.06 64.41 20 2184delA 0.10 0.00 0.05 64.46 23 I148T 0.10 0.00 0.05 64.51 11 2789 ϩ 5G Ͼ A 0.00 0.00 0.00 64.51 14 711 ϩ 1G Ͼ T 0.00 0.00 0.00 64.51 16 A455E 0.00 0.00 0.00 64.51 25 1078delT 0.00 0.00 0.00 64.51 All 25 56.46 72.42 64.51 a The order is based on that found for non-Hispanic Caucasians.3 b Based on between 79 and 169 chromosomes reported by the International Cystic Fibrosis Genetic Analysis Consortium.4 c Based on 874 chromosomes from clinically diagnosed persons registered in the Cystic Fibrosis Foundation National Patient Registry. Login to comment
107 An earlier article10 reported that 97% of mutations were identified in 90 chromosomes from Ashkenazi Jewish individ- Table 3 CFTR mutation frequencies among Ashkenazi Jewish Caucasian individuals with cystic fibrosis within the recommended minimum testing panel Ordera Mutation Mutation frequency (%) CF Consortiumb Cumulative 5 W1282X 45.92 45.92 1 delF508 31.41 77.33 2 G542X 7.55 84.88 10 3849 ϩ 10kbC Ͼ T 4.77 89.65 6 N1303K 2.78 92.43 12 1717 - 1G Ͼ T 0.67 93.10 7 R553X 0.22 93.32 3 G551D 0.22 93.54 24 3120 ϩ 1G Ͼ T 0.10 93.64 21 1898 ϩ 1G Ͼ A 0.10 93.74 20 2184delA 0.10 93.84 23 I148T 0.10 93.94 11 2789 ϩ 5G Ͼ A 0.10 94.04 14 711 ϩ 1G Ͼ T 0.10 94.14 8 delI507 0.00 94.14 19 R1162X 0.00 94.14 22 R334W 0.00 94.14 4 621 ϩ 1G Ͼ T 0.00 94.14 15 R560T 0.00 94.14 18 G85E 0.00 94.14 9 R117H 0.00 94.14 13 R347P 0.00 94.14 17 3569delC 0.00 94.14 16 A455E 0.00 94.14 25 1078delT 0.00 94.14 Sum 94.14 a The order is based on that found for non-Hispanic Caucasians.3 b Based on between 57 and 503 chromosomes reported by the International Cystic Fibrosis Genetic Analysis Consortium.4 uals with cystic fibrosis, using a panel of 11 mutations. Login to comment
115 In an- Table 4 CFTR mutation frequencies among Asian American individuals with cystic fibrosis within the recommended minimum testing panel Ordera Mutation Mutation frequency (%) Heim et al.1b CF Foundationc Average Cumulative 1 delF508 18.80 59.09 38.95 38.95 10 3849 ϩ 10kbC Ͼ T 0.00 10.61 5.31 44.26 3 G551D 6.30 0.00 3.15 47.41 6 N1303K 0.00 1.52 0.76 48.17 8 delI507 0.00 1.52 0.76 48.93 2 G542X 0.00 0.00 0.00 48.93 4 621 ϩ 1G Ͼ T 0.00 0.00 0.00 48.93 5 W1282X 0.00 0.00 0.00 48.93 7 R553X 0.00 0.00 0.00 48.93 9 R117H 0.00 0.00 0.00 48.93 11 2789 ϩ 5G Ͼ A 0.00 0.00 0.00 48.93 12 1717 - 1G Ͼ T 0.00 0.00 0.00 48.93 13 R347P 0.00 0.00 0.00 48.93 14 711 ϩ 1G Ͼ T 0.00 0.00 0.00 48.93 15 R560T 0.00 0.00 0.00 48.93 16 A455E 0.00 0.00 0.00 48.93 17 3569delC 0.00 0.00 0.00 48.93 18 G85E 0.00 0.00 0.00 48.93 19 R1162X 0.00 0.00 0.00 48.93 20 2184delA 0.00 0.00 0.00 48.93 21 1898 ϩ 1G Ͼ A 0.00 0.00 0.00 48.93 22 R334W 0.00 0.00 0.00 48.93 23 I148T 0.00 0.00 0.00 48.93 24 3120 ϩ 1G Ͼ T 0.00 0.00 0.00 48.93 25 1078delT 0.00 0.00 0.00 48.93 Sum 25.10 72.74 48.93 a The order is based on that found for non-Hispanic Caucasians.3 b Based on 20 chromosomes. Login to comment
173 For exam- Table 7 Estimated number of carriers of the 25 recommended CFTR mutations by racial/ethnic group and weighted average, representing the panethnic population in the United States for 2002 Order CFTR mutation Number of CFTR Mutation Carriers Panethnic frequency, % Non-Hispanic Caucasian Hispanic Caucasian African American Asian American Ashkenazi Jewish Total 1 delF508 64,779 8,207 4,272 886 796 78,940 66.31 2 G542X 2,039 770 141 0 191 3,141 2.64 5 W1282X 1,342 95 23 0 1,164 2,624 2.20 3 G551D 2,013 85 117 72 6 2,293 1.93 4 621 ϩ 1G Ͼ T 1,404 39 108 0 0 1,551 1.30 6 N1303K 1,136 251 34 17 70 1,508 1.27 7 R553X 778 424 225 17 0 1,444 1.21 8 delI507 787 103 181 0 6 1,077 0.90 10 3849 ϩ 10kbC Ͼ T 519 237 16 121 121 1,014 0.85 24 3120 ϩ 1G Ͼ T 72 24 928 0 3 1,027 0.86 9 R117H 626 17 6 0 0 649 0.55 12 1717 - 1G Ͼ T 429 41 36 0 17 523 0.44 11 2789 ϩ 5G Ͼ A 429 24 0 0 3 456 0.38 13 R347P 403 24 6 0 0 433 0.36 14 711 ϩ 1G Ͼ T 385 35 0 0 3 423 0.36 22 R334W 125 269 47 0 0 441 0.37 15 R560T 340 0 16 0 0 356 0.30 19 R1162X 206 88 64 0 0 358 0.30 17 3569delC 304 20 6 0 0 330 0.28 16 A455E 304 8 0 0 0 312 0.26 18 G85E 259 35 12 0 0 306 0.26 20 2184delA 152 24 5 0 3 184 0.15 21 1898 ϩ 1G Ͼ A 143 8 6 0 3 160 0.13 23 I148T 80 14 5 0 3 102 0.09 25 1078delT 18 14 0 0 0 32 0.03 All 79,072 10,856 6,193 1,113 2,389 99,684 84.00 Bolded numbers indicate mutations that are more likely to be found in a racial/ethnic group other than non-Hispanic Caucasians. Login to comment

PMID: 15371906 [PubMed] Kornreich R et al: "Premarital and prenatal screening for cystic fibrosis: experience in the Ashkenazi Jewish population."

No. Sentence Comment

14 Although the demand for screening was great, widespread population screening was not actually recommended by the American College of Obstetrics and Gynecology (ACOG) and American College of Medical Genetics (ACMG) until 2001.5 Based on a frequency of at least 0.1% of mutant alleles in a large CF patient database, a panel of 25 mutations was recommended even though the sensitivity was still below 90% in most ethnic groups.6 The results of screening with this mutation panel were reviewed in 20027 and most recently, in this issue.8 The Ashkenazi Jewish (AJ) population represents a unique group for genetic screening as common mutations occur in prevalent recessive diseases due to founder effect and/or selection.9,10 With regard to CF, five CFTR mutations (W1282X, ⌬F508, G542X, 3849ϩ10kb CϾT, N1303K) account for 97% of the mutant alleles in AJ CF patients.11 This population has a very high acceptance rate for genetic screening and has had a positive experience with carrier screening, beginning with Tay-Sachs disease in 1970.12,13 In this study, we report our experiences with CF carrier screening in the AJ population using two different approaches: premarital (Dor Yeshorim, DY) and prenatal screening (Mount Sinai School of Medicine, MSSM). Login to comment
19 DOI: 10.1097/01.GIM.0000139510.00644.F7 September/October 2004 ⅐ Vol. 6 ⅐ No. 5 a r t i c l e Genetics IN Medicine Jewish community, began premarital screening in 1983 for Tay-Sachs.14 CF was added to their premarital testing panel in 1993.15 The Genetic Testing Laboratory at MSSM has been conducting prenatal CF carrier screening since 1992 and has performed over 60,000 CF tests.16 Both programs initially screened for five, reported common AJ mutations (W1282X, ⌬F508, G542X, 3849ϩ10kb CϾT, N1303K).11 In 2000, DY observed the presence of the D1152H CF mutation in the AJ population and, therefore, added this mutation along with 1717-1 GϾA to its routine AJ screening panel. Login to comment
32 For the DY cohort, all individuals were initially tested for five mutations (W1282X, ⌬F508, G542X, 3849ϩ10kb CϾT, N1303K). Login to comment
36 At MSSM, for the period January 1997 through December 2000 for which data and ethnic information are available, five mutations (W1282X, ⌬F508, G542X, 3849ϩ10kb CϾT, N1303K) were analyzed by PCR amplification and restriction enzyme analyses. Login to comment
45 The G542X, 3849ϩ10 kb CϾT, and N1303K were tested in over 117,000 screenees and occurred at similar frequencies in both programs, with overall detection rates of 1 in 413 (0.0024), 1 in 490 (0.0020), and 1 in 633 (0.0016), respectively. Login to comment
47 For the five mutations (W1282X, ⌬F508, G542X, 3849ϩ10kb CϾT, N1303K) for which over 117,000 AJ screenees were tested, a total of 4,498 carriers were identified (1 in 26 or 0.038). Login to comment
68 Of the remaining 31 prenatal diagnoses, 24 fetuses were heterozygotes and Table 1 Carrier frequencies of seven routinely tested AJ CF mutations CF mutation No. individuals tested Frequency Combined frequency Previous studies DY MSSM DY MSSM Ref 3 n ϭ 6076 Ref 15 n ϭ 6850 W1282X 110889 6247 1 in 49.7 (0.0201) 1 in 48.8 (0.0205) 1 in 49.6 (0.0202) 1 in 48.2 (0.0207) 1 in 48.2 (0.0207) ⌬F508 110898 6247 1 in 81.7 (0.0122) 1 in 86.8 (0.0115) 1 in 82.0 (0.0122) 1 in 79.7 (0.0126) 1 in 77.9 (0.0128) D1152H 42208 2322 1 in 189.2 (0.00528) 1 in 193.5 (0.00517) 1 in 189.5 (0.00528) 1 in 113.5a (0.00881) NDb G542X 110893 6247 1 in 410.7 (0.00243) 1 in 446.2 (0.00224) 1 in 412.5 (0.00242) 1 in 338.3 (0.00296) 1 in 506.3 (0.00197) 3849ϩ10kb CϾT 110888 6247 1 in 490.7 (0.00204) 1 in 480.5 (0.00208) 1 in 490.1 (0.00204) 1 in 402.9 (0.00248) 1 in 607.6 (0.00165) N1303K 110894 6247 1 in 637.2 (0.00157) 1 in 567.9 (0.00176) 1 in 633.2 (0.00158) 1 in 913.3 (0.00109) 1 in 552.4 (0.00181) 1717-1 GϾA 57869 2322 1 in 7233.6 (0.000138) 1 in 2322 (0.000431) 1 in 6687.9 (0.000150) NDb NDb Five mutations (Without D1152H and 1717-1 GϾA) 1 in 26.1 (0.0384) 1 in 26.2 (0.0381) 1 in 26.1 (0.0384) 1 in 25.1 (0.0398) 1 in 25.7 (0.0389) Seven mutations 1 in 22.8 (0.0438) 1 in 22.9 (0.0437) 1 in 22.8 (0.0438) a n ϭ 1305. b Not determined. Login to comment
69 Table 2 Distribution of CF mutations in DY and MSSM carriers for five and seven common AJ mutations CF mutation % of AJ carriers (5 mutations) % of AJ carriers (7 mutations) DY MSSM Combined DY MSSM Combined W1282X 52.3 53.8 53.1 45.9 46.9 46.4 ⌬F508 31.9 30.2 31.0 27.9 26.3 27.1 G542X 6.3 5.9 6.1 5.5 5.1 5.3 3849ϩ10kb CϾT 5.3 5.5 5.4 4.7 4.8 4.8 N1303K 4.1 4.6 4.4 3.6 4.0 3.8 D1152H - - - 12.1 11.8 12.0 1717-1GϾA - - - 0.3 1.0 0.6 seven did not carry either parental mutation. Login to comment
83 Previous studies of AJ patients with CF indicated that screening for five mutations (W1282X, ⌬F508, G542X, 3849ϩ10kb CϾT, N1303K) would detect 97% of alleles causing CF in the AJ population.11 Based on the data presented in this study, the largest dataset on AJ carrier screening reported to date, the CF carrier frequency in the 100% AJ population is about 1 in 26 for these five mutations (Table 1). Login to comment
86 For example, W1282X was the most prevalent mutation among Ashkenazi Jews, present in 46.4% of AJ carriers, whereas it was present in only 1.5% of non-Hispanic Caucasian CF patients.8 ⌬F508, the most common mutation in non-Hispanic Caucasian CF pa- Table 3 Frequency of CFTR mutations among screenees reporting 100% AJ or Ͻ 100% AJ descent who requested carrier testing for CF and at least one other AJ recessive disease CF mutation % of mutations in carriers reporting 100% AJ descent (n ϭ 45,530-117,145) % of mutations among carriers reporting Ͻ100% AJ descent (n ϭ 7,393) % of Non-Hispanic Caucasian CF patient chromosomes8 (n ϭ 37,263) W1282X 46.4 (n ϭ 117,136) 32.3 1.5 ⌬F508 27.1 (n ϭ 117,145) 35.7 71.5 D1152H 12.0 (n ϭ 44,530) 8.7 0.03 G542X 5.3 (n ϭ 117,140) 6.1 2.3 3849ϩ10kb CϾT 4.8 (n ϭ 117,135) 4.9 0.7 N1303K 3.8 (n ϭ 117,141) 3.0 1.3 1717-1GϾA 0.6 (n ϭ 60,191) 1.9 0.7 R117H a 2.7 0.8 I148T a 2.3 0.05 R334W - 0.76 0.16 A455E - 0.76 0.19 G551D a 0.38 2.5 R553X - 0.38 1.0 a These mutations were detected when screening Ϸ2,300 100% AJ individuals with the ACMG recommended panel. Login to comment
99 However, previous reports indicate that the D1152H mutation together with a classic CF mutation results in variant CF phenotypes, including an adult (D1152H/ ⌬F508) with mild pulmonary disease.22 The D1152H/⌬F508 genotype also has been reported in four adults with mild pulmonary symptoms, two with Pseudomonas colonization, and another with pancreatic insufficiency.23,24 This mutation has also been observed in males with CBAVD.25,26 However, this mutation was present along with G542X in a fetus with hyperechogenic bowel loops and meconium ileus, suggesting a more severe course would occur in this case.27 In contrast to the limited number of CFTR mutations that were detected in screenees who reported themselves to be 100% AJ, the distribution of CFTR mutations in the over 7,000 MSSM screenees who were of Ͻ 100% AJ descent differed significantly. Login to comment
104 Based on the results of these studies, it is recommended that premarital/prenatal carrier screening for CF be performed by testing the five common AJ CFTR mutations (W1282X, DF508, G542X, 3849ϩ10kb CϾT, N1303K), along with D1152H, for individuals who report that they are 100% AJ. Login to comment

PMID: 15371907 [PubMed] Monaghan KG et al: "Genotype-phenotype correlation and frequency of the 3199del6 cystic fibrosis mutation among I148T carriers: results from a collaborative study."

No. Sentence Comment

97 3199del6 was reported to the CF Consortium in 1998 in a pancreatic insufficient CF patient with I148T and 3199del6onthesamechromosomeand⌬F508ontheotherchro- mosome.1 Another study noted a patient with severe CF and 3199del6 and I148T, though it is not noted specifically whether thesemutationsarein-cisorin-trans.16 3199del6alsooccursinthe absence of I148T, as a patient with severe CF has been reported with 3199del6 (negative for I148T) and G542X.17 Recent data suggests that 3199del6 is the deleterious mutation among I148T/3199del6 complex alleles.9 It is puzzling that early reports of patients with classic CF and I148T/⌬F508 did not identify 3199del6, despite the fact that 2 reports described performing mutation analysis of the entire CFTR coding region and splice site junctions either by a screening method (DDGE) or DNA sequencing.5,7 However, a recent report identified 3199del6 in 24 French-Canadian CF patients originally described as compound heterozygous for I148T and a severe CF mutation.11 Though there is little doubt that 3199del6 is a deleterious CF mutation, the clinical significance of I148T in the absence of 3199del6 is unclear, as we have identified this genotype in 3 males with infertility, two of the obstructive type. Login to comment

PMID: 15371908 [PubMed] Buyse IM et al: "Use of MALDI-TOF mass spectrometry in a 51-mutation test for cystic fibrosis: evidence that 3199del6 is a disease-causing mutation."

No. Sentence Comment

2 Results: CF testing was performed on over 5,000 individuals, including a 3-year-old Hispanic-American patient with a compound heterozygous G542X/3199del6 genotype. Login to comment
67 Identification of a CF patient with a G542X/3199del6 genotype In the course of clinical testing with the extended CF panel, we studied a 3-year old Hispanic-American male referred by the Baylor Cystic Fibrosis Care Center at Texas Children`s Hospital. Login to comment
77 This assay also demonstrated heterozygosity for the G542X mutation, and reflex testing for the 5T variant at CFTR intron 8 showed a genotype of 7T/9T in this patient (data not Table 3 Description of the 16 multiplex assays designed to analyze 51 CFTR mutations Multiplex Mutations Exon 1 1078delT, G314E, R352Q, G330X 7 2 R347H, R347P, R334W, 1717-1A 7, 11 3 R553X, S549N, R1162X 11, 19 4 A559T, R560T, G551D 11 5 G542X, S549R, 621ϩ1T, Y122X 4, 11 6 W1282X, 3876delA, 3905insT, D1152H 18, 20 7 3849ϩ4G, 3659delC, 1898ϩ1A 12, 19 8 405ϩ1A, 405ϩ3C, 3120A, 3120ϩ1A 3, 16 9 394delTT, E60X, G85E 3 10 A455E, ⌬F508a 9, 10 11 G480C, Q493X, V520F 10 12 711ϩ1T, G178R, 3199del6 5, 17a 13 2143delT, 2184delA, K710X, F316L 7, 13 14 I148T, R117H, R117C 4 15 N1303K, 2789ϩ5A, 3849ϩ10kbT 14b, intron19, 21 16 ⌬I507a 10 17 5Tb intron 8 a F508C and I507V, I506V, I506M variants are tested for concurrently with the ⌬F508 and ⌬I507 assays respectively. Login to comment
80 Compound heterozygosity for the 3199del6 and G542X mutations was confirmed by parental studies, which identified 3199del6 in the patient`s mother and G542X in the father. Login to comment
84 No definitive mutations were identified in addition to G542X and 3199del6. Login to comment
113 The identification of a CF patient with a compound heterozygous 3199del6/G542X genotype represents the first report of 3199del6 that is not associated with I148T on a CF chromosome. Login to comment

PMID: 15371909 [PubMed] Edelmann L et al: "Cystic fibrosis carrier screening: validation of a novel method using BeadChip technology."

No. Sentence Comment

35 Mutation controls included DNA from previously identified positive patient samples (I148T, D1152H, W1282X, R117H, G85E, A455E, delF508, N1303K) and DNA from NIGMS Human Genetic Cell Repositories (Coriell Cell Repositories) (delF508, delI507, G542X, R560T, 3849ϩ10kbCϾT, N1303K, G85E; G551D, R553X, 621ϩ1GϾT, 1717-1GϾA, A455E, R334W, R347P, R1162X, 3659delC; 711ϩ1GϾT, 2789ϩ5GϾA, 3120ϩ1GϾA). Login to comment
46 Mutant ASOs were end-labeled with ␥-32 P-ATP and pooled into three subgroups (IA-IC) for Group I and four subgroups (IIA-IID) for Group II mutations with the following breakdown of mutations: IA: delF508, delI507, W1282X, R117H; IB: G542X, R560T, 3849ϩ10kbCϾT, N1303K, G85E; IC: G551D, R553X, 621ϩ1GϾT, 1717-1GϾA, I148T; IIA: A455E, R334W, D1152H; IIB: R347P, 1078delT, R1162X, 3659delC; IIC: 711ϩ1GϾT, 1898ϩ1GϾA, 2789ϩ5GϾA, 3120ϩ1GϾA; IID: 2184delA. Login to comment
84 Certain mutations including 711ϩ1GϾA, R117H, G542X, R560T, and W1282X, required a heterozygous allelic ratio with an upper limit set at 2.50. Login to comment
160 I II III IV V VI VII VIII Totals Samples tested 87 57 69 72 66 35 72 61 519 Controls testedk 0h 17h 20 29 22 16 20 21 145 PCR Failuresi 4 4 2 1 1 2 1 3 18 (3.5%) Assay Failuresi 2 0 1 0 2 2 1 1 9 (1.7%) Positives 4a 3b 0 3c 4d 2e 2f 1g 19 (3.7%) a W1282X, delF508, D1152H, W1282X b delF508, delF508, D1152H c delF508, R117H, R117H d G542X, delF508, D1152H, N1303K (does not include proficiency samplesj ) e W1282X, delF508 f I148T, 3849ϩ10kbCϾT g I148T h Runs I and II were amplified with the same master mix and used the same control samples. Login to comment

PMID: 15379964 [PubMed] Cuppens H et al: "CFTR mutations and polymorphisms in male infertility."

No. Sentence Comment

34 Examples include the G542X, G551D, R553X, W1282X and N1303K mutations. Login to comment

PMID: 15469408 [PubMed] Sangiuolo F et al: "Toward the pharmacogenomics of cystic fibrosis--an update."

No. Sentence Comment

412 31. Hamosh A, Rosenstein BJ, Cutting GR: CFTR nonsense mutations G542X and W1282X associated with severe reduction of CFTR mRNA in nasal epithelial cells. Login to comment

PMID: 15510065 [PubMed] Kerem E et al: "Pharmacologic therapy for stop mutations: how much CFTR activity is enough?"

No. Sentence Comment

82 Howard et al. [21] demonstrated in Hela cells transfected with plasmid vector carrying the CFTR nonsense mutations G542X and R553X that aminoglycosides caused a dose-dependent increase in CFTR expression. Login to comment
86 Zsembery et al. [23] isolated cholangiocytes from the liver of a patient carrying the G542X mutation, and incubated them with gentamicin, and they exhibited cAMP activated chloride transport. Login to comment
89 Immunofluorescence staining of intestinal tissues from Cftr-/- mouse carrying a human CFTR-G542X transgene revealed that gentamicin treatment resulted in the appearance of human CFTR protein at the apical surface of the glands of treated mice. Login to comment
92 When taken together, these results indicate that gentamicin, and to a lesser extent tobramycin, can restore the synthesis of functional human CFTR protein by suppressing the human CFTR-G542X premature stop mutation in vivo. Login to comment
133 Quantification studies have shown that after aminoglycoside incubation, the amount of full-length CFTR produced is as much as 25% (in the R553X mutation) to 35% (in the G542X mutation) of that observed in cells transfected with a wild-type CFTR complementary DNA [18,22]. Login to comment

PMID: 15516474 [PubMed] Fajac I et al: "Nasal airway ion transport is linked to the cystic fibrosis phenotype in adult patients."

No. Sentence Comment

219 RESULTS Patients Four of the 79 CF patients included in the study had a normal sweat test; three were compound heterozygous for the F508D mutation and the R117H, D1152H and R347H mutations, respectively, and one patient was compound heterozygous for the G542X and 3849+10 kb (C)R (T) mutations. Login to comment

PMID: 15520400 [PubMed] Niel F et al: "Rapid detection of CFTR gene rearrangements impacts on genetic counselling in cystic fibrosis."

No. Sentence Comment

207 Gender Current age Phenotype Genotype Origin Age at diagnosis Pancr. status Lung disease Other Sweat test Allele 1 Allele 2 rearrangement involving exon(s) Parental Geographic 1 M 10 years 1 month PI Severe 114 F508del 1 Father North eastern Italy 2 M 16 years Birth PI Severe 130 A561E 2 Father Southern Italy 3 M 10 years 1 year PI Severe + R553X 17b Mother France 4 F 13 years 4 years PI Severe NP + F508del 14b-17b Father Eastern France 5 F 24 years 1 month PI Severe 100 F508del 17a-17b Mother ND 6 F 21 years Childhood PI Moderate + F508del 17a-17b Father Eastern France 7 M 35 years 1 year PI Severe CBAVD, NP 103 F508del 17a-17b Father Eastern France 8* 2 F Deceased at 2 and 6 months Birth PI Severe ND F508del 17a-17b Father Eastern France 9 F Deceased at 15 years 5 years PI Severe 300 1812- 1GRA 3-10,14b-16À Mother Kabylie (Algeria)/ Brittany (France) 10 M 37 years 37 years PS None CBAVD ND R117H(-7T) 1-24 Mother France 11 M Deceased at 31 years 3 months PI Severe DB 90 G542X 4-8 Mother Eastern France CBAVD, congenital bilateral absence of the vas deferens; DB, disseminated bronchiectasis; del, deletion; dup, duplication; F, female; M, male; NP, nasal polyposis; Pancr., pancreatic; PI, pancreatic insufficiency; PS, pancreatic sufficiency. Login to comment
237 **The linked haplotype was hypothesised, considering the most frequent haplotype IVS8(CA)23-IVS17b(TA)33-IVS17b(CA)13 linked to G542X.43 Considering the CFTR deletions already described and those we report here, it clearly appears that some CFTR sequences may be prone to rearrangements. Login to comment

PMID: 15528020 [PubMed] Cohn JA et al: "The role of cystic fibrosis gene mutations in determining susceptibility to chronic pancreatitis."

No. Sentence Comment

78 The European data Table 1 Abnormal CFTR and PSTI genotypes detected in two studies of idiopathic chronic pancreatitis* CFTR genotype category N Genotypes detected in individual subjects US study (Noone et al [47]) CFsev / CFm-v compound heterozygotes 8 DF508 / R117H-7T**; DF508 / 5T; DF508 / 5T; DF508 / D1152H; DF508 / D1152H; DF508 / P574H; DF508 / 3120G>A; 621þ1G>T/G1069R CFm-v / CFm-v compound heterozygotes 1 5T / 5T** CFsev / - (CF carriers) 1 N1303K / - CFm-v / - 7 R117H-7T / -; 5T / -**; 5T / -; 5T / -; 5T / -; 5T / -; 5T / - Normal (- / -) CFTR genotype 22 1 was homozygous for the N34S PSTI mutation; 5 were N34S carriers European study (Audrezet et al [50]) CFsev / CFm-v compound heterozygotes 4 DF508/R352Q; DF508/P5L; DF508/Q1476X; W1282X/5T*** CFm-v / CFm-v compound heterozygotes 2 V562I/5T; E217G/A1136T CFsev / - (CF carriers)**** 3 DF508 / -; DF508 / -; G542X / - CFm-v / - 9 L967S/-**; IVS18-20T>C/-**; c.4575þ2G>A/-; IVS3-6T>C; 5T/-; 5T/-; 5T/-; 5T/-; 5T/- Normal (- / -) CFTR genotype 17 1 was homozygous for the N34S PSTI mutation; 1 was a N34S carrier * CFTR mutations were classified as causing either severe (CFsev ) or mild-variable loss-of-function (CFm-v ) [18,47]; all detected CFsev mutations are CF-causing mutations according to current consensus criteria [79]. Login to comment

PMID: 15536480 [PubMed] Modiano G et al: "A large-scale study of the random variability of a coding sequence: a study on the CFTR gene."

No. Sentence Comment

33 In the Tajima`s test,19 the null hypothesis of neutrality is rejected if a statistically significant difference between p Common and rare nonsynonymous and synonymous cSNSs G Modiano et al European Journal of Human Genetics Table 1 List of the 61 cSNSsa encountered in the present survey The random samples of genes (and the technique utilized) cSNS variants found NE Italy (DGGE) Central Italy (DGGE) Southern France (DGGE) Northern France (DHPLC) Spain (SSCA) Czechia (DGGE) Hb Â 104 Exon Exon Length (bp) Ref. no. SNS SASc 1st 100d 2nd 500 1st 100d 2nde 1st 100d 2nd 500 1st 100 2nde 82d 72 Abs. Freq. Total sample size q Â 104 se Â 104 NSf Sf 1g 53 0 0 0 0 0/452 0 924 2 111 1 223C4T R31C 1 1 1/500 1 1 0 0/450 0 5 (11) 1 932 (2 432) 45.23 13.61 90 2 224G4T R31L 0 0 0/500 0 0 0 1/450 0 1 1 932 5.17 5.17 10 3 257C4T S42F 0 0 1/500 0 0 0 0/450 0 1 1 932 5.17 5.17 10 3 109 4 334A4G K68E 1 0 0 0/498 0 0 0 0/452 0 0 1 2 504 3.99 3.99 8 5 352C4T R74W 0 0 0 0/498 0 0 0 1/452 0 0 1 2 504 3.99 3.99 8 6 356G4A R75Q 1 7 1 7/498 2 9 2 9/452 0 2 40 (40) 2 504 (2 544) 157.23 24.66 310 7 386G4A G85E 0 0 1 1/498 0 0 0 0/452 0 0 2 2 504 7.99 5.65 16 4 216 8 482G4A R117H 0 0 0 0/292 0 2 0 1/456 0 0 3 2 302 13.03 7.52 26 9 528T4G I132M 0 0 0 0/292 0 0 0 1/456 0 0 1 2 302 4.34 4.34 8 10 575T4C I148T 1 2 0 1/292 0 0 0 1/456 0 1 6 2 302 26.06 10.63 52 5 90 11 640C4T R170C 0 0 0 0/6 0 0 1/448 0 1 1 436 6.96 6.96 14 12 641G4A R170H 1 1 0 0/6 0 0 2/448 0 4 (4) 1 436 (1 930) 20.73 10.35 41 6a 164 0 0 0/6 0 0 0/432 0 0 992 6b 126 0 0 0/6 0 0 0/454 0 942 7 247 0 0 0/6 0 0 0/796 0 1 284 8 93 13 1281G4A L383 0 0 0 0/6 0 0 1/456 0 0 1 1 516 6.60 6.60 13 9 183 14 1402G4A G424S 0 0 0/6 0 0 1/454 0 1 940 10.64 10.64 21 15 1459G4T D443Y 0 0 0/6 0 0 1/454 0 1 940 10.64 10.64 21 10 192 16 1540A4G M470Vh 42 197 30 37/96 39 199 (i) (i) 27 571(736) 1 484 (1 912) 3849.37 111.28 4 735 17 1598C4A S489X 0 0 0 0/96 0 0 0 1/796 0 1 2 374 4.21 4.21 8 18 1648A4G I506V 1 0 0 0/96 0 0 0 0/796 0 1 2 374 4.21 4.21 8 19 1655T4G F508C 0 1 0 0/96 0 0 0 1/796 0 2 2 038 8.42 5.96 17 20 1716G4A Q528 2 16 1 0/96 0 19 i I 5 43 (58) 1 478 (2 024) 286.56 37.08 557 11 95 21 1756G4T G542X 0 2 0 0/134 0 0 0/796 0 0 2 1 984 10.08 7.12 20 22 1764T4G G544 0 0 0 0/134 0 0 1/796 0 0 1 1 984 5.04 5.04 10 23 1784G4A G551D 0 0 0 0/134 0 0 1/796 0 0 1 1 984 5.04 5.04 10 12 87 24 1816G4A V562I 0 0 0 0 1 0 0/450 0 0 1 (1) 2 004 (2 504) 3.99 3.99 8 25 1816G4C V562L 0 0 0 1 0 0 1/450 0 0 2 (3) 2 004 (2 504) 11.98 6.91 24 26 1859G4C G576A 1 2 0 1 11 0 8/450 0 0 23 (27) 2 004 (2 538) 106.38 20.36 213 13 724j 449 27 1997G4A G622D 0 0 0/80 0/96 1 0 0 0/444 0 1 2 002 5.00 5.00 10 28 2082C4T F650 1 0 0/80 0/20 0 0 0 0/444 0 1 (1) 1 926 (2 412) 4.15 4.15 8 29 2134C4T R668C 1 2 0/80 0/96 1 11 0 12/444 0 27(32) 2 002 (2 558) 125.10 21.98 247 275 30 2377C4T L748 0 0 0/6 0 1 1 388 25.77 25.77 52 14a 129 31 2670G4A W846X 0 0 0/6 0 1 0/452 0/80 0 1 1 010 9.90 9.90 20 32 2694T4G T854 33 23 0/6 33 38 149/452 14/80 11 301 1 010 2980.20 143.92 4 184 33 2695G4A V855I 0 0 0/6 0 0 1/452 0/80 0 1 1 010 9.90 9.90 20 14b 38 0 0 0 0/520 0 0 0 0/446 0 2 448 15 251 34 2816G4C S895T 0 0 0/6 0 0 2/436 0 0 2 996 20.08 14.18 40 35 2831A4C N900T 0 0 0/6 0 0 1/436 0 0 1 996 10.04 10.04 20 36 2988G4C M952I 0 0 0/6 0 0 1/436 0 0 1 996 10.04 10.04 20 37 3030G4A T966 (2)k (1)k 0 6/436 0 6 (25)k 618 (1814)k 137.82 27.37 272 38 3032T4C L967S 0 0 0/6 0 0 1/436 0 0 1 996 10.04 10.04 20 16 80 0 0 0/498 0 0 0/450 0 0 1 502 17a 151 39 3123G4C L997F 0 2 2 1/494 0 7 1 4/454 0 0 17 2 502 67.95 16.42 135 40 3157G4A A1009T 0 2 0 0/494 0 0 0 0/454 0 0 2 2 502 7.99 5.65 16 41 3212T4C I1027T 1 0 0 0/494 0 0 0 0/454 0 0 1 2 502 4.00 4.00 8 17b 228 42 3286T4G F1052V 1 1 0 1/194 0 0 0 0/452 0 0 3 (3) 2 200 (2 240) 13.39 7.73 27 43 3337G4A G1069R 0 1 0 0/194 0 0 0 0/452 0 0 1 2 200 4.55 4.55 9 CommonandrarenonsynonymousandsynonymouscSNSs GModianoetal 186 EuropeanJournalofHumanGenetics 44 3345G4T Q1071H 0 0 0 0/194 0 1 0 0/452 0 0 1 2 200 4.55 4.55 9 45 3417A4T T1995 1 3 0 0/194 1 1 0 0/452 0 0 6 (8) 2 200 (2 506) 31.92 11.27 64 46 3419T4G L1096R 0 0 0 0/194 1 0 0 0/452 0 0 1 2 200 4.55 4.55 9 47 3477C4A T1115 0 0 0 0/194 0 0 0 1/452 0 0 1 2 200 4.55 4.55 9 18 101 48 3523A4G I1131V 0 0 1 0/10 0 0 0/448 0 0 1 (2) 1 512 (1 908) 10.48 7.07 21 49 3586G4C D1152H 0 0 0 0/10 0 0 1/448 0 0 1 1 512 6.61 6.61 13 19 249 50 3617G4T R1162L 0 0 1 1/494 0 0/260 0 0/454 0 0 2 2 262 8.84 6.25 18 51 3690A4G Q1186 0 0 0 0/494 0 0/260 0 0/454 1 0 1 2 262 4.42 4.42 9 52 3813A4G L1227 0 1 0 0/494 0 0/260 0 0/454 0 0 1 2 262 4.42 4.42 9 53 3837T4G S1235R 1 1 0 1/494 0 4/260 0 7/454 0 1 15 (15) 2 262 (2 310) 69.94 16.71 140 20 156 54 4002A4G P1290 2 3 0/6 3 5 18/454 3/80 2 36 1 012 357.73 58.22 690 21 90 55 4009G4A V1293I 0 0 0/6 0 0/300 0 1/456 0 0 1 1 316 7.60 7.60 15 56 4029A4G T1299 1 0 0/6 0 1/300 0 1/456 0 0 3 (8) 1 316 (2 330) 34.33 12.12 69 57 4041C4G N1303K 1 0 0/6 0 0/300 0 0/456 0 0 1 1 316 7.60 7.60 15 58 4085T4C V1318A 0 0 0/6 0 0/300 0 1/456 0 0 1 1 316 7.60 7.60 15 22 173 0 0 0/18 0 0 0/450 0 0 1 022 23 106 0 0 0 0/6 0 0 0/448 0 1 436 24l 198+3 59 4404C4T Y1424 1 0 0/6 1 2 5/420 0 2 11 (32) 980 (2 516) 127.19 22.34 251 60m 4521G4A Q1463 (21) (16) (3/32) (14/80) (30) (94/420) 15/76 (17) 15 (227) 76 (1052) 2142.86 131.07 3 367 61 4563T4C D1477 0 0 0/6 0 1 0/420 0 0 1 980 10.20 10.20 20 Totals 6 525 9 584 16 109 The bracketed figures include also the RFLP analysis data (see Materials and methods); the NE Italy, Central Italy, Southern and Northern France are each subdivided into two samples where the 1st is made up of 100 genes. 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PMID: 15537723 [PubMed] Jalalirad M et al: "First study of CF mutations in the CFTR gene of Iranian patients: detection of DeltaF508, G542X, W1282X, A120T, R117H, and R347H mutations."

No. Sentence Comment

12 The next most common mutations were W1282X (4 per cent) and G542X (2.7 per cent). Login to comment
15 Most of the families in whom ∆F508, W1282X, and G542X mutations BRIEF REPORTS Journal of Tropical Pediatrics Vol. 50, No. Login to comment
16 6 359 First Study of CF Mutations in the CFTR Gene of Iranian Patients: Detection of ∆F508, G542X, W1282X, A120T, R117H, and R347H Mutations by M. Jalalirad,a,b M. Houshmand,a R. Mirfakhraie,a M. H. Goharbari,a and F. Mirzajania a National Research Center for Genetic Engineering and Biotechnology (NRCGEB),Tehran, Iran b Biology Department, Gilan University, Rasht, Iran Summary Thirty-seven unrelated Iranian CF families were screened for the presence of seven common mutations (∆F508, G542X, W1282X, G551D, N1303K, 1717-1G→A, and 621-1G→T) using ARMS PCR and exons 4 and 7 of the CFTR gene by SSCP method. Login to comment
17 This study resulted in the identification of 26.8 per cent of all CF alleles: ∆F508 (16.2 per cent), W1282X (4 per cent), G542X (2.7 per cent), R117H (1.3 per cent), R347H (1.3 per cent), and A120T (1.3 per cent) mutations were detected. Login to comment
32 The next two most common mutations were W1282X (4 per cent) and G542X (2.7 per cent), which have high frequencies in Mediterranean countries.11 R347H, which has the highest incidence in Turkey,8 was detected in a Turkish child residing in north-west Iran with normal sweat chloride values. Login to comment
31 The next two most common mutations were W1282X (4 per cent) and G542X (2.7 per cent), which have high frequencies in Mediterranean countries.11 R347H, which has the highest incidence in Turkey,8 was detected in a Turkish child residing in north-west Iran with normal sweat chloride values. Login to comment

PMID: 15591474 [PubMed] Rodman DM et al: "Late diagnosis defines a unique population of long-term survivors of cystic fibrosis."

No. Sentence Comment

117 GENOTYPE DISTRIBUTION Early Diagnosis Late Diagnosis ⌬F508/⌬F508 10 1 ⌬F508/⌬I507 1 ⌬F508/G551D 1 ⌬F508/M1101K 1 ⌬F508/P67L/11027T 1 ⌬F508/3120G-A 1 ⌬F508/2789ϩ5G-A 1 2 ⌬F508/W1282X 1 ⌬F508/621ϩ1G-T 1 ⌬F508/R347P 1 ⌬F508/3849ϩ10kbC-T 1 1 ⌬F508/A455E 2 ⌬F508/R347H 2 ⌬F508/D1152H 1 ⌬508/I148T 1 ⌬F508/R117H 1 ⌬F508/Y109N 1 ⌬F508/IVS8-5T 1 ⌬F508/unknown 3 5 S1251N/D1152H 1 G542X/R117C 1 R117H/G551D 1 W1282X/D1152H 1 Unknown 4 4 Values represent number of individuals in each diagnostic group with each genotype. Login to comment

PMID: 15619635 [PubMed] Du K et al: "The DeltaF508 cystic fibrosis mutation impairs domain-domain interactions and arrests post-translational folding of CFTR."

No. Sentence Comment

362 Du, M. et al. Aminoglycoside suppression of a premature stop mutation in a CFTR-/- mouse carrying a human CFTR-G542X transgene. Login to comment

PMID: 15638824 [PubMed] Castaldo G et al: "Comprehensive cystic fibrosis mutation epidemiology and haplotype characterization in a southern Italian population."

No. Sentence Comment

33 The 13 mutations in this panel are: F508del, N1303K, G542X, W1282X, 2183AA>G, 1717-1G>A, R553X, I148T, R1158X, 711+1G>T, 4016insT, L1065P and G1244E. Login to comment
52 We also identified three homozygotes for G542X, three for 852del22, two for 2183AA>G, and one each for N1303K, 1717-1G>A, 4016insT, R553X, R1158X and L1065P. Login to comment
62 A procedure for the large-scale analysis of several mutations peculiar to southern Italy is also indicated Mutation Analytical CF alleles Campania Basilicata Puglia Total procedure n = 340 n = 52 n = 350 n = 742 DF508 55.6 55.8 46.8 51.5 N1303K 7.3 3.8 7.7 7.3 G542X 5.0 3.8 7.1 5.9 W1282X 3.5 3.8 0.6 2.2 2183 AA>G 2.3 5.8 0.8 1.9 852del22 0 5.8 3.2 1.9 3% agarose 1717-1G>A 2.3 1.9 1.1 1.8 4382delA 0 0 3.7 1.8 RE (Ear I -) 1259insA 0 0 3.1 1.5 4016insT 2.1 0 1.1 1.5 ASO R553X 1.5 0 1.7 1.5 R1158X 1.5 0 1.3 1.2 ASO or RE (Sfa N 1 -) L1077P 0.6 0 1.9 1.2 I502T 0.3 0 2.0 1.1 RE (Mse I -) 3849+10kbC>T 0 1.9 1.6 0.9 D579G 0 0 1.6 0.8 RE (Avr II +) G1244E 0.9 3.8 0.3 0.8 ASO or RE (Mbo II +) G1349D 0 0 1.7 0.8 RE (Sty I -) 2789+5 G>A 0.6 0 0.8 0.7 711+1 G>T 1.5 0 0 0.7 ASO L1065P 1.2 0 0 0.5 ASO or RE (Mnl I +) R347P 0.3 0 0.9 0.5 2522insC 0.9 0 0 0.4 E585X 0.6 0 0 0.3 G85E 0.6 0 0 0.3 G178R 0.6 0 0 0.3 D1152H 0.3 0 0.3 0.3 I148T-3195del6 0.6 0 0 0.3 I148T (alone) 0 0 0.3 0.1 R334W 0 0 0.3 0.1 DI507 0 0 0.3 0.1 I1005R 0 0 0.3 0.1 3272-26A>G 0.3 0 0 0.1 2711delT 0.3 0 0 0.1 L558S 0 1.9 0 0.1 W1063X 0 0 0.3 0.1 D110H 0.3 0 0 0.1 S549R (A>C) 0 1.9 0 0.1 2184insA 0.3 0 0 0.1 3131del22 0.3 0 0 0.1 R709N 0 0 0.3 0.1 A349V 0 0 0.3 0.1 4015insA 0 0 0.3 0.1 Y849X 0 1.9 0 0.1 Cumulative 91.6 92.1 91.7 91.5 Unknown 8.4 7.9 8.3 8.5 Total 100,0 100,0 100,0 100,0 RE: restriction enzyme (-/+: abolition or introduction of a RE site); ASO: allele specific oligonucleotide Figure 2 Multiplex denaturing gradient gel electrophoretic analysis of exons 8, 5 and 18 of the cystic fibrosis transmembrane regulator gene in a cystic fibrosis patient (case n. Login to comment

PMID: 15644056 [PubMed] Mennicke K et al: "Rational approach to genetic testing of cystic fibrosis (CF) in infertile men."

No. Sentence Comment

49 In the presence of CFTR mutations, further genetic screening for the seven most frequently identified CF mutations [G542X, N1303K, 1717-1(GoA), W1282X, G551D, R553X, DI507; The Cystic Fibrosis Analysis Consortium, 1990] was performed. Login to comment

PMID: 15672947 [PubMed] Augarten A et al: "Systemic inflammatory mediators and cystic fibrosis genotype."

No. Sentence Comment

5 Group A included 25 patients who carried two mutations associated with a pathological sweat test and pancreatic insufficiency (∆F508, W1282X, G542X, N1303K, S549R). Login to comment
28 Group A included 25 patients who carried two mutations associated with a pathological sweat test and pancreatic insufficiency (∆F508, W1282X, G542X, N1303K, S549R) [2]. Login to comment
67 : Systemic inflammatory mediators and cystic fibrosis genotype 101 Table 1 Clinical characteristics of cystic fibrosis (CF) patients Group Aa (n=25) Group Bb (n=11) P Age (years) 16.9±7.2 17.7±9.1 NS Pancreatic sufficiency 0% 0/25 36.3% 4/11 <0.01 Sweat chloride (mmol/l) 105±28 92±18.6 NS Weight percentiles 19±19.8 57.2±25.2 <0.01 Sputum Pseudomonas 88% 22/24 40% 4/10 <0.01 a Group A CF patients carrying two mutations associated with severe disease presentation (∆F508, W1282X, G542X, N1303K, S549R) b Group B CF patients carrying mutations associated with mild disease presentation (3849+10kb CǞT, 5T) Table 2 Comparison of serum chemokine levels between groups (IL-8 interleukin-8, MCPI monocyte chemoattractant protein-1) Chemokine Group Aa Group Bb P IL-8 (pg/ml) 11.4±2.1 5.0±0.9 0.01 MCP1(pg/ml) 157±16 88.8+16.4 0.01 RANTES (pg/ml) 323±48 287.5±93 NS a Group A CF patients carrying two mutations associated with severe disease presentation (∆F508, W1282X, G542X, N1303K, S549R) b Group B CF patients carrying mutations associated with mild disease presentation (3849+10kb CÞT, 5T) Fig. 1 Relationship between interleukin-8 (IL-8) levels and forced expiratory volume in 1 s (FEV1) values defective protein production; class II, defective protein processing; class III, defective chloride channel regulation; and class IV, defective chloride channel conduction. Login to comment

PMID: 15704202 [PubMed] Massie J et al: "Diagnosis of cystic fibrosis after newborn screening: the Australasian experience--twenty years and five million babies later: a consensus statement from the Australasian Paediatric Respiratory Group."

No. Sentence Comment

47 Management of infants with a borderline sweat test after NBS ABBREVIATIONS CF Cystic fibrosis CFTR Cystic fibrosis transmembrane conductance regulator Cl Chloride DNA Deoxyribonucleic acid IRT Immunoreactive trypsinogen MI Meconium ileus Na Sodium NBS Newborn screening NPD Nasal potential difference TABLE 1- Newborn Screening for CF in Australia and New Zealand1 State/country Year screening started Babies screened (to end of 2003) New South Wales 1981 1,940,000 Victoria 1989 913,181 Queensland 1983 878,905 South Australia (including Tasmania and Northern Territory) 1990 407,625 Western Australia 2001 63,000 New Zealand 1981 1,098,329 Total 5,301,040 1 Mutations screened: New South Wales, DF508; Victoria DF508; South Australia (including Tasmania and Northern Territory), DF508, DI507, G551D, G542X, and R553X; Western Australia, DF508, G551D, G542X, and 621 þ 1G ! Login to comment
48 T; Queensland, DF508, DI507, G551D, G542X, 621 þ 1G ! Login to comment
49 T, R553X, N1303K, and R117H; New Zealand, DF508, G551D, and G542X. Login to comment

PMID: 15705292 [PubMed] Claustres M et al: "Molecular pathology of the CFTR locus in male infertility."

No. Sentence Comment

159 Examples include nonsense (G542X), frameshifl (3659delC) or severe splicing (1717-lG-^A) mutations. Login to comment

PMID: 15705796 [PubMed] O'Sullivan BP et al: "Platelet activation in cystic fibrosis."

No. Sentence Comment

44 Clinical characteristics of cystic fibrosis patients Patient Age, y Vitamin E, mg/L* FEV1, % predicted† Inpatient or outpatient‡ Genotype Platelet studies§ 1 20 6.6 25 In ␦F508/unk A 2 20 3.6 70 In ␦F508/G542X A 3 11 16.8 92 Out ␦F508/dF508 A 4 16 5.4 101 Out ␦F508/G542X A 5 9 3.9 124 Out ␦F508/dF508 A,F 6 6 5.1 118 Out ␦F508/dF508 A,F 7 13 8.1 119 Out ␦F508/dF508 A,F 8 10 9.7 104 Out ␦F508/dF508 A,F 9 22 9.0 58 In ␦F508/dF508 A 10 19 8.0 57 Out ␦F508/N1303K A 11 17 7.0 24 Out ␦F508/dF508 A,D,E 12 20 3.2 55 Out ␦F508/dF508 A,D 13 15 5.8 41 In ␦F508/dF508 A,D,E 14 26 12.7 88 Out ␦F508/dF508 A,D 15 11 16.3 72 Out ␦F508/W1282X A,D 16 18 10.0 58 In ␦F508/dF508 A,D 17 22 10.5 50 Out ␦F508/dF508 A,D 18 35 8.6 87 Out ␦F508/C276X A,E 19 17 16.2 62 In ␦F508/dF508 B,E 20 14 4.1 85 In ␦F508/dF508 B 21 22 2.3 62 In ␦F508/G542X B 22 21 7.7 54 In ␦F508/N1303K B 23 19 2.4 69 In ␦F508/Y1092X B 24 19 4.6 87 In ␦F508/dF508 B, C, E 25 21 8.2 58 In R334W/unk C 26 22 5.8 85 In ␦F508/dF508 C,E 27 22 2.9 67 In unk/unk C 28 20 6.7 77 In ␦F508/dF508 E 29 18 13.3 92 In ␦F508/dF508 E 30 22 8.8 71 In ␦F508/394delTT E 31 15 13.0 68 In ␦F508/dF508 E 32 14 unk 97 Out ␦F508/dF508 E unk indicates unknown. Login to comment

PMID: 15709055 [PubMed] Sermet-Gaudelus I et al: "Chloride transport in nasal ciliated cells of cystic fibrosis heterozygotes."

No. Sentence Comment

57 Ten had class I mutations: 3659delC, 1078delT, 3791delC, 1717-1GϾA, 2183AAϾG, S466X, W1282X, R553X, or G542X (n ϭ 2). Login to comment

PMID: 15727251 [PubMed] Radivojevic D et al: "Spectrum of cystic fibrosis mutations in Serbia and Montenegro and strategy for prenatal diagnosis."

No. Sentence Comment

2 Six different mutations (F508del, G542X, 621؉1G Ǟ T, 2789؉5G Ǟ A, R1070Q, and S466X) accounted for 79.71% of CF alleles, with the F508del mutation showing a frequency of 72.28%. Login to comment
40 Six different mutations (F508del, 621ϩ1G Ǟ T, G542X, S466X, R1070Q, and 2789ϩ5G Ǟ A) accounted for 79.71% of the CF alleles in Yugoslavian population, of which the F508del mutation had a frequency of 72.28% (253/350). Login to comment
44 CFTR MUTATIONS IDENTIFIED IN 175 YUGOSLAVIAN CF PATIENTS Location Number of positive Frequency Mutation (exon/intron) CF alleles (percentage) F508del Exon 10 253 72.28 621 ϩ 1G → T Intron 4 10 2.86 G542X Exon 11 9 2.57 S466X Exon 10 3 0.86 2789 ϩ 5 G → A Intron 14b 2 0.57 R1070Q Exon 17b 2 0.57 MI1 Exon 1 1 0.28 R75X Exon 3 1 0.28 457TAT → G Exon 4 1 0.28 574delA Exon 4 1 0.28 A120T Exon 4 1 0.28 R334W Exon 7 1 0.28 1525-1 G → A Intron 9 1 0.28 I507del Exon 10 1 0.28 E585X Exon 12 1 0.28 2184insA Exon 13 1 0.28 2723delTTa Exon 14a 1 0.28 2907delTT Exon 15 1 0.28 Unknown - 61 17.43 aNew frameshift mutation. Login to comment
55 Nine different mutations were detected: F508del, 2907delTT, S466X, 457TAT Ǟ G, R75X, 2184insA, G542X, 621ϩ1G Ǟ T, and R1070Q in a total of 76 prenatal analyses (Table 2). Login to comment
63 A few studies on CF patients from the former Yugoslavian Republic have been published to date, but in only one, based on a relatively small number of CF patients, two mutations were found in affected children from Serbia and Montenegro (F508del, 70%; G542X, 4%) (Dabovic et al., 1992). Login to comment
67 Six of the molecular defects identified in Yugoslavian patients belong to the 24 most common mutations worldwide (F508del, G542X, 621ϩ1G Ǟ T, I507del, 2789ϩ5G Ǟ A, and R334W) (CFGCA, 1994) (Table 1). Login to comment
70 The third most common mutation in our population, G542X, is one of the most frequent in European populations (2.6%), is detected in 6.1% CF alleles in Mediterranean countries, and is found TABLE 2. Login to comment
71 RESULTS OF PRENATAL DIAGNOSIS OF CF IN SERBIA AND MONTENEGRO Number of prenatal Genotype Material diagnoses Outcome F508del/F508del CVS, AF, CBa 51 11 Affected, 25 carriers, 15 normal, F508del/2907delTT CVS 2 1 Affected, 1 carrier F508del/S466X CVS, AF 2 2 Carriers F508del/457TATϾG CVS 1 1 Carrier F508del/2184insA CVS 1 1 Affected F508del/621ϩ1GϾT CVS 1 1 Normal F508del/R1070Q CVS 1 1 Normal G542X/621ϩ1GϾT CVS 4 1 Affected, 2 carriers, 1 normal G542X/R7X CVS 3 2 Carriers, 1 normal F508del/? Login to comment

PMID: 15738290 [PubMed] Dugueperoux I et al: "The CFTR 3849+10kbC->T and 2789+5G->A alleles are associated with a mild CF phenotype."

No. Sentence Comment

51 Two genotypes accounted for almost 80% of the patients, 3849+10kbC-.T/DF508 (n527, 69.2%) and 3849+10kbC-.T/ G542X (n54, 10.3%), and two siblings shared the G1244E allele (5.2%). Login to comment
63 Although only borderline significant, lung function was definitely better in the 3849+10kbC-.T/DF508 group (FEV1 83.0% and FVC 91.6% pred) than in the DF508 homozygote group (FEV1 59.9% TABLE 1 Genotypes identified among cystic fibrosis patients sharing the 3849+10kbC-.T or the 2789+5G-.A mutation Genotypes 3849+10kbC-.T 2789+5G-.A DI507 2 DF508 27 61 1525-1G-.A 1 1717-1G.A 1 2183AA.G 3 3129del4 1 3659delC 1 G542X 4 6 G551D 1 G970R 2 G1244E 2 L558S 1 M1V 1 N1303K 1 R347P 1 R553X 1 1 R1066C 1 S1251N 1 Unknown 1 6 Total 39 88 I. DUGUE´PE´ROUX AND M. DE BRAEKELEER MILD PHENOTYPE ASSOCIATED WITH TWO CFTR MUTATIONS c and FVC 76.9% pred). Login to comment
71 Three genotypes accounted for almost 80% of the patients: 2789+5G-.A/DF508 (n561, 69.3%), 2789+5G-.A/G542X (n56, 6.8%) and 2789+5G- .A/2183AA-.G (n53, 3.4%). Login to comment

PMID: 15741992 [PubMed] Bombieri C et al: "Frequency of large CFTR gene rearrangements in Italian CF patients."

No. Sentence Comment

36 In all patients, the rearrangements are present in compound heterozygosity with a common CF mutation (F508del, G542X, or Q552X). Login to comment

PMID: 15749233 [PubMed] Cohn JA et al: "The impact of cystic fibrosis and PSTI/SPINK1 gene mutations on susceptibility to chronic pancreatitis."

No. Sentence Comment

90 Table 1 Abnormal CFTR and PSTI genotypes detected in two studies of idiopathic chronic pancreatitis* CFTR genotype category N Genotypes detected in individual subjects US study (Noone et al [47]) CFsev / CFm-v compound heterozygotes 8 DF508 / R117H-7T**; DF508 / 5T; DF508 / 5T; DF508 / D1152H; DF508 / D1152H; DF508 / P574H; DF508 / 3120G>A; 621þ1G>T/G1069R CFm-v / CFm-v compound heterozygotes 1 5T / 5T** CFsev / - (CF carriers) 1 N1303K / - CFm-v / - 7 R117H-7T / -; 5T / -**; 5T / -; 5T / -; 5T / -; 5T / -; 5T / - Normal (- / -) CFTR genotype 22 1 was homozygous for the N34S PSTI mutation; 5 were N34S carriers European study (Audrezet et al [50]) CFsev / CFm-v compound heterozygotes 4 DF508/R352Q; DF508/P5L; DF508/Q1476X; W1282X/5T*** CFm-v / CFm-v compound heterozygotes 2 V562I/5T; E217G/A1136T CFsev / - (CF carriers)**** 3 DF508 / -; DF508 / -; G542X / - CFm-v / - 9 L967S/-**; IVS18-20T>C/-**; c.4575þ2G>A/-; IVS3-6T>C; 5T/-; 5T/-; 5T/-; 5T/-; 5T/- Normal (- / -) CFTR genotype 17 1 was homozygous for the N34S PSTI mutation; 1 was a N34S carrier * CFTR mutations were classified as causing either severe (CFsev ) or mild-variable loss-of-function (CFm-v ) [18,47]; all detected CFsev mutations are CF-causing mutations according to current consensus criteria [79]. Login to comment

PMID: 15758663 [PubMed] Cohn JA et al: "Reduced CFTR function and the pathobiology of idiopathic pancreatitis."

No. Sentence Comment

69 Abnormal CFTR and PSTI Genotypes Detected in Two Studies of ICP CFTR Genotype Category* N Genotypes Detected in Individual Subjects U.S. study (Noone et al47 ) CFsev / CFm-v compound heterozygotes 8 DF508 / R117H-7T †; DF508 / 5T; DF508 / 5T; DF508 / D1152H; DF508 / D1152H; DF508 / P574H; DF508 / 3120G.A; 621 + 1G.T/G1069R CFm-v / CFm-v compound heterozygotes 1 5T / 5T † CFsev / 2 (CF carriers) 1 N1303K / 2 CFm-v / 2 7 R117H-7T / 2; 5T / 2 †; 5T / 2; 5T / 2; 5T / 2; 5T / 2; 5T / 2 Normal (2 / 2) CFTR genotype 22 1 was homozygous for the N34S PSTI mutation; 5 were N34S carriers French study (Audrezet et al50 ) CFsev / CFm-v compound heterozygotes 4 DF508/R352Q; DF508/P5L; DF508/Q1476X; W1282X/5T‡ CFm-v / CFm-v compound heterozygotes 2 V562I/5T; E217G/A1136T CFsev / 2 (CF carriers)§ 3 DF508 / 2; DF508 / 2; G542X / 2 CFm-v / 2 9 L967S/2 †; IVS18-20T.C/ 2†; c.4575+2G.A/2; IVS3-6T.C; 5T/2; 5 /2; 5T/ 2; 5T/2; 5T/ 2 Normal (2 / 2) CFTR genotype 17 1 was homozygous for the N34S PSTI mutation; 1 was a N34S carriers *Mutations of the cystic fibrosis (CF) gene (CFTR) were classified as causing either severe (CFsev ) or mild-variable loss-of-function (CFm-v )18,47 ; all detected CFsev mutations are CF-causing mutations according to current consensus criteria.68 In the U.S. study, most patients were tested for rare mutations by DNA sequencing47 ; in the French study, most patients were tested by dHPL.50 †These patients were also carriers for the N34S mutation of a trypsin inhibitor gene (PSTI). Login to comment

PMID: 15776432 [PubMed] Clain J et al: "Misprocessing of the CFTR protein leads to mild cystic fibrosis phenotype."

No. Sentence Comment

112 For most patients (30/36), p.L206W was combined with a severe mutation (p.F508del, p.I507del, p.G542X, p.W216X, p.R851X, and p.E60X) on the other CFTR allele. Login to comment
143 ]c 179 [p.L206W]+[p.F508del] [1540A]+[1540A] [(TG)9(T)9]+[(TG)10(T)9] [16;7;17]+[23;31;13] 422 [p.L206W]+[p.G542X] [1540A]+[1540A] [(TG)9(T)9]+[(TG)10(T)9] [16;7;17]+[23;33;13] 1720 [p.L206W]+[p.F508del] [1540A]+[1540A] [(TG)9(T)9]+[(TG)10(T)9] [16;7;17]+[17;32;13]c 1878 [p.L206W]+[p.F508del] [1540A]+[1540A] [(TG)9(T)9]+[(TG)10(T)9] [16;7;17]+[17;31;13]c 626 [p.L206W]+[p.E60X] [1540A]+[1540G] [(TG)9(T)9]+[(TG)11(T)7] [16;7;17]+[16;31;13] 1455 [p.L206W]+[1342-6(T)5]] [1540A]+[1540G] [(TG)9(T)9]+[(TG)12(T)5] [16;7;17]+[16;31;14]c 2104 [p.L206W]+[p.F508del] [1540A]+[1540A] [(TG)9(T)9]+[(TG)10(T)9] [16;7;17]+[23;31;13]c 652 [p.L206W]+[p.E216X] [1540A]+[1540A] [(TG)9(T)9]+[(TG)10(T)9] [16;7;17]+[23;32;13] 2345 [p.L206W]+[p.F508del] [1540A]+[1540A] [(TG)9(T)9]+[(TG)10(T)9] [16;7;17]+[17;32;13] a The DNA and mutation numbering follows the CFTR mutation database, (www.genet.sickkids.on.ca/cftr), the A of the ATG translation start codon being numbered +133 (GeneBank NM_000492.2).We followed the approved nomenclature format in mutation names at the protein level and in genotype writing. Login to comment
148 [1995] [p.L206W]+[p.G542X]II/I2237MCBAVDPS^c 65711(3)Desgeorgesetal. Login to comment
165 [1999] [p.L206W]+[p.W216X]II/I0.116F^PSNo75(1)Thisstudy [p.L206W]+[p.F508del]II/II0.2d 2F^PSe BronchialhyperreactivityPositiveThisstudy [p.L206W]+[p.F508del]II/II216F^PSNo54714(6)Thisstudy [p.L206W]+[p.F508del]II/II24M^PSe Bronchitis65(1)Thisstudy [p.L206W]+[p.F508del]II/II23M^PSe Bronchitis9672(2)Thisstudy [p.L206W]+[p.F508del]II/II47F^PIBronchitis5478(2)Thisstudy [p.L206W]+[p.F508del]II/I56F^PSAsthma7576(2)Thisstudy [p.L206W]+[1342-6(T)5]II/-2833MCBAVDPSBronchitis^Thisstudy [p.L206W]+[p.G542X]II/I3243MCBAVDPSNo^Thisstudy [p.L206W]+[p.F508del]II/II3740MCBAVD^^^Thisstudy [p.L206W]+[p.E60X]II/I2938MCBAVDPSNo64(1)Thisstudy [p.L206W]+[p.F508del]II/II3536MCBAVDPINo93(1)Thisstudy a Theclassi'cationofmissensemutationswasbasedonfunctionalstudies[Lietal.,1993;Chengetal.,1990;Champignyetal.,1995]. Login to comment

PMID: 15781764 [PubMed] Wang X et al: "Increased prevalence of chronic rhinosinusitis in carriers of a cystic fibrosis mutation."

No. Sentence Comment

94 Distribution of CFTR Alleles in CRS and Non-CRS Obligate CF Carriers Using a Screen for 16 CF Alleles CF Allele CRS (n = 26) Non-CRS (n = 27) Allele Frequency, % (n = 53) ⌬F508 18 20 71.7 R117H 0 1 1.9 G542X 0 1 1.9 G551D 0 2 3.8 W1282X 0 2 3.8 N1303K 1 0 1.9 3849 + 10 kb C→T 1 0 1.9 Not detected 6 1 12.8 Abbreviations: CF, cystic fibrosis; CRS, chronic rhinosinusitis; kb, kilobase. Login to comment

PMID: 15784035 [PubMed] Gallegos-Orozco JF et al: "Lack of association of common cystic fibrosis transmembrane conductance regulator gene mutations with primary sclerosing cholangitis."

No. Sentence Comment

55 CFTR Mutations and Associated Phenotype Classic Nonclassic Cystic Fibrosis Cystic Fibrosis Variant Normal 621 + 1G→T R117H G85E* 7T 711 + 1G→T R334W 5T† 9T 1078delT R347P M470V‡ F508C I507 A455E I507V F508 2789 + 5G → A I506V 1717 - 1G→A 3849 + 10kbC→T G542X G551D R553X R560T R1162X 3659delC W1282X N1303K * Classic cystic fibrosis and nonclassic cystic fibrosis. Login to comment

PMID: 15789152 [PubMed] Langfelder-Schwind E et al: "Cystic fibrosis prenatal screening in genetic counseling practice: recommendations of the National Society of Genetic Counselors."

No. Sentence Comment

155 Mutations described as "severe,"forexample, F508, I507,G542X,G551D, W1282X, N1303K, R553X, 621 + 1G>T, and 1717-1G>A, are usually categorized as Class I, II, or III, and the expected pancreatic insufficient phenotype occurs when one of these mutations is inherited in trans with a second mutation, of Class I, II, or III. Login to comment

PMID: 15832355 [PubMed] Castellani C et al: "Cystic fibrosis carriers have higher neonatal immunoreactive trypsinogen values than non-carriers."

No. Sentence Comment

40 Distribution and Classification of the Tested Mutations in the Normal IRT Heterozygote Population Under Study Mutations Type of mutation Class of mutation Number of cases F508del Severe II 161 N1303K Severe II 19 G542X Severe I 19 711 þ 5G > A - V 15 R117H Mild IV 13 R1162X Severe I 13 R553X Severe I 11 G85E - IV 8 2183AA > G Severe I 8 1717-1G > A Severe I 8 R334Q Mild - 4 Q552X Severe I 4 W1282X Severe I 3 2789 þ 5G > A Mild V 2 1898 þ 3A > G Mild V 2 T338I Mild IV 1 R709X Severe I 1 R347H Mild IV 1 3849 þ 10KbC > T Mild V 1 Total 294 Other tested mutations: 1078delTn1609delCAn1717-8g/an394delTTn457TAT> Gn541delCn621 þ 1g/tn711 þ 1g/tnA559TnDI507nG551DnR1158XnR334Wn R347PnR352QnS549InS549NnS549Ra/cn2790-2G > An1811 þ 1.2KbA > G; 711þ5G > A and G85E not categorized in type of mutation; R334Q not categorized in class of mutation. Login to comment

PMID: 15860566 [PubMed] Krafft AE et al: "Time-motion analysis of 6 cystic fibrosis mutation detection systems."

No. Sentence Comment

43 These included 58 patient DNA samples initially characterized by CF Gold 1.0, of which 28 were wild type and 30 contained 1 of the following 16 mutant alleles: F508del, R553X, 2184delA, 3120 ϩ 1GϾA, I507del, G542X, G551D, W1282X, N1303K, 621 ϩ 1GϾT, R117H, 1717-1GϾA, R560T, R334W, R347P, and I148T. Login to comment

PMID: 15868140 [PubMed] Moskowitz SM et al: "Cystic fibrosis lung disease: genetic influences, microbial interactions, and radiological assessment."

No. Sentence Comment

48 Class 1 alleles (second panel), such as one with a nonsense mutation in codon 542 that normally encodes glycine (G542X allele), contain premature stop codons that result in truncated RNA messages. Login to comment
71 Modifier genes as modulators of CF lung phenotype Some DF508 homozygous individuals develop severe obstructive lung disease during the first and second decades of life despite maximal medical therapy, while others with the same genotype have little or no obstructive lung disease despite minimal therapy during Table 2 Examples of disease-associated CFTR alleles CFTR allele Allele class Usual clinical status (when compounded with a severe CFTR allelea ) Allele frequency in Caucasiansb General populationc CF CAVD G542X (9T) 1 Pancreatic-insufficient CF 0.001 0.023 0.003 DF508 (9T) 2 Pancreatic-insufficient CF 0.012-0.016 0.694 0.20 G551D (7T) 3 Pancreatic-insufficient CF 0.001 0.022 0.01 R117H (5T) 4 Pancreatic-sufficient CF 0.0001 0.004 ND R117H (7T) 4 CAVD or carrier 0.002-0.003 0.003 0.04 A455E (9T) 5 Pancreatic-sufficient CF ND 0.001 ND 3849+10kbC fi T 5 Pancreatic-sufficient CF ND 0.007 ND WT (5T) 5 CAVD or carrier 0.042 d 0.19 Other allelese 1-5 Variable 0.002-0.006 0.247 0.55 WT (7T or 9T) Wild-type Carrier 0.935 e e a Severe CFTR allele is defined as a class 1, 2, or 3 allele. Login to comment
89 This suppression of translational termination might be of therapeutic benefit for genetic disease caused by nonsense mutations such as the CFTR Class 1 allele G542X [36-38]. Login to comment

PMID: 15870824 [PubMed] Stuppia L et al: "Screening of mutations in the CFTR gene in 1195 couples entering assisted reproduction technique programs."

No. Sentence Comment

64 of detected carriers Prevalence among detected CFTR mutations DF508 40 (3.34%) 65.58% DI507 0 0 G542X 6 (0.50%) 9.84% 1717-1G-A 1 (0.08%) 1.64% G551D 0 0 R553X 0 0 R560T 0 0 Q552X 0 0 W1282X 7 (0.58 %) 11.48% S1251N 0 0 N1303K 3 (0.20%) 4.91% 394delTT 0 0 G85E 3 (0.25%) 4.91% E60X 0 0 621+1G-T 0 0 R117H 0 0 1078delT 0 0 R347P 0 0 R334W 0 0 2143delT 0 0 2183AA-G 0 0 2184delA 0 0 711+5G-A 0 0 2789+5G-A 1 (0.08%) 1.64% R1162X 0 0 3659del5 0 0 3849+10kbC-T 0 0 A455E 0 0 5T 78 (6.52%) Table 2 Distribution of CFTR mutations and 5T allele according to phenotype for the 1195 individuals Phenotype CF/WT 5T/WT CF/5T WT/WT Infertile males (non-CBAVD), N ¼ 304 20 (6.58%) 30 (9.87%) 0 254 (83.55%) Infertile males (CBAVD), N ¼ 16 0 10 (62.50%) 6 (37.50 %) 0 Infertile females, N ¼ 93 5 (5.37%) 7 (7.53%) 0 81 (87.10%) Unexplained infertility, N ¼ 782 30 (3.84%) 31 (3.96%) 0 721 (92.20%) Total ¼ 1195 55 (4.60%) 78 (5.50%) 6 (0.50%) 1056 (88.40%) CFTR alteration was detected, including a mutation in three cases and the 5T polymorphism in the remaining six. Login to comment
85 Altogether, we detected a CFTR mutation or the 5T allele in 139 (11.6%) single partners of our couples, in agreement with the figure Table 3 Couples with both partners carriers of a CFTR mutation or a 5T allele First partner Second partner W1282X/5T 5T/wt 1717-1G4A/5T 5T/wt G542X/5T 5T/wt DF508/wt 5T/wt DF508/wt 5T/wt DF508/wt 5T/wt 5T/wt G542X/wt 5T/wt 1717-1G4A/wt 5T/wt 5T/wt Table 4 Distribution of the different TG-M470V-5T associations in relation to the phenotype for the 67 investigated males Phenotype TG12-V470 TG12-M470 TG11-V470 TG11-M470 Total Fertile men 7 0 9 8 24 CBAVD 11 0 0 2 13 Azoospermia 4 0 0 2 6 Oligozoospermia 8 2 7 7 24 Total 30 2 16 19 67 expected in the general Caucasian population. Login to comment

PMID: 15880796 [PubMed] Kerem E et al: "Pharmacological induction of CFTR function in patients with cystic fibrosis: mutation-specific therapy."

No. Sentence Comment

53 This class may include promoter mutations that reduce transcription TABLE 1- Classes of CFTR Mutations1 Class Mutations I Stop codons: W1282X, G542X, R1162X, R553X, E822X Splicing mutations that completely abolish protein synthesis: 1717 À 1G ! Login to comment
74 Howard et al. demonstrated in HeLa cells transfected with plasmid vector carrying the CFTR nonsense mutations G542X and R553X that aminoglycosides caused a dose-dependent increase in CFTR expression.14 Subsequently, the same group showed that functional CFTR was restored to the apical membrane, and the relative level of mRNA transcript increased in bronchial cell line IB3-1 expressing the W1282X mutation. Login to comment
75 Following incubation with aminoglycosides, cAMP-activated chloride conductance and the expression of functional CFTR were restored to the apical membrane.15 Zsembery et al. isolated cholangiocytes from the liver of a patient carrying the G542X mutation and incubated them with gentamicin. Login to comment
77 Du et al. daily administered the aminoglycoside antibiotics gentamicin or tobramycin.17 Immunofluorescence staining of intestinal tissues from CftrÀ/À hCFTR-G542X mice revealed that gentamicin treatment resulted in the appearance of CFTR protein at the apical surface of the glands of treated mice. Login to comment
80 When taken together, these results indicate that gentamicin, and to a lesser extent tobramycin, can restore the synthesis of functional CFTR protein by suppressing the G542X premature stop mutation in vivo. Login to comment
243 Quantification studies showed that after aminoglycoside incubation, the amount of full-length CFTR produced is as much as 25% (in the R553X mutation) to 35% (in the G542X mutation) of that observed in cells transfected with a wild-type CFTR complementary DNA (cDNA).14,15 This increase in functional CFTR might be above the threshold required for normal respiratory epithelial cell function. Login to comment

PMID: 15888700 [PubMed] Rowe SM et al: "Cystic fibrosis."

No. Sentence Comment

120 About 5 to 10 percent ofCFTR mutations are due toprematuretruncationornonsensealleles(designated by "X," such as G542X, a class I mutation). Login to comment

PMID: 15891431 [PubMed] Rubenstein RC et al: "Novel, mechanism-based therapies for cystic fibrosis."

No. Sentence Comment

23 Such mutations are relatively infrequent in the general CF population (G542X, 2.4%; R553X, 0.9%; W1282X, 1.4% of mutant alleles in the 2003 Cystic Fibrosis Foundation Patient Registry). Login to comment
25 Treatment of cells expressing these 'X` mutations with aminoglycoside antibiotics such as gentamicin or G418 (Geneticin, Life Technologies, Inc., Gaithersburg, MD, USA) causes expression of a full-length, functional CFTR protein from G542X [8], R553X [8], R1162X [9], and W1282X [9] alleles. Login to comment
27 Similar effects were noted in a murine cftr(ÿ/ÿ) knockout model where the G542X allele was expressed under control of an intestine-specific promoter. Login to comment

PMID: 15908456 [PubMed] Sanchez-Garcia JF et al: "Multiple mutation analysis of the cystic fibrosis gene in single cells."

No. Sentence Comment

38 Cell samples Isolated buccal cells were collected by mouthwashes from three normal individuals, three patients affected by mutations DF508, DF508/1078delT and DF508/3849þ10kbC.T and five heterozygous carriers for CFTR mutations DF508, N1303K, G542X, R347P and 2183AA.G. Login to comment
61 The mutations assayed are: DF508, DI507, Q493X, V520F, 1717-1G.A, G542X, G551D, R560T, S459R, S459N and R553X labelled with FAM (blue), 3849þ10kbC.T, 3849 þ 4A . Login to comment
88 A similar result was seen in heterozygous cells for G542X and 3849þ10kbC.T. Login to comment
121 250 S549 20 25 60 15 75 30 13.3 46.7 40 86.7 R553 20 15 65 20 85 30 6.7 46.7 46.7 93.3 G551 20 15 70 15 85 30 10 46.7 43.3 90 V520 20 5 40 55 95 30 0 13.3 86.7 100 I507 20 5 45 50 95 30 0 26.7 73.3 100 F508 20 10 80 10 90 30 10 50 40 90 dF508 (*) 12 25 66.7 8.3 75 19 10.5 52.6 36.8 89.5 Q493 20 10 75 15 90 30 10 56.7 33.3 90 1717-G1 20 25 60 15 75 30 6.7 46.7 46.7 93.3 G542 20 20 65 15 80 30 10 50 40 90 G542X (*) 2 50 50 0 50 7 14.3 85.7 0 85.7 R560 20 20 50 30 80 30 6.7 43.3 50 93.3 R347 20 5 70 25 95 30 0 16.7 83.3 100 R347P (*) - - - - - 3 0 33.3 66.7 100 3849 þ 4A 20 15 55 30 85 30 3.3 50 46.7 96.7 W1282 20 20 40 40 80 30 13.3 30 56.7 86.7 R334 20 10 75 15 90 30 0 13.3 86.7 100 1078 20 25 60 15 75 30 0 13.3 86.7 100 1078 del T (*) 2 0 100 0 100 - - - - - 3849 þ 10kbC 20 20 65 15 80 30 3.3 56.7 40 96.7 3849 þ 10kbC . Login to comment

PMID: 15915083 [PubMed] Ogino S et al: "Risk calculations for cystic fibrosis in neonatal screening by immunoreactive trypsinogen and CFTR mutation tests."

No. Sentence Comment

32 Table 1 Summary of CF carrier frequencies, overall mutation detection rates by the ACMG panel, and frequencies of major mutations for each major ethnic group (adapted from Watson et al.10 and Richards et al.1) Ethnic group CF carrier frequency Overall mutation detection rate by the ACMG CFTR 23-mutation panel10 Fraction of F508del among all disease alleles Other major mutations (fraction)a Non-Hispanic Caucasian 1/25 88.29% 72.42% G542X (2.28%) G551D (2.25%) 621ϩ1GϾT (1.57%) W1282X (1.50%) N1303K (1.27%) Ashkenazi Jewish 1/25 94.04% 31.41% W1282X (45.92%) G542X (7.55%) 3849ϩ10kbCϾT (4.77%) N1303K (2.78%) African American 1/65 64.46% 44.07% 3120ϩ1GϾA (9.57%) R553X (2.32%) I507del (1.87%) G542X (1.45%) G551D (1.21%) 621ϩ1GϾT (1.11%) Hispanic Caucasian 1/46 71.72% 54.38% G542X (5.10%) R553X (2.81%) R334W (1.78%) N1303K (1.66%) 3849ϩ10kbCϾT (1.57%) Asian American 1/90 48.93% 38.95% 3849ϩ10kbCϾT (5.31%) G551D (3.15%) Bayesian analysis to calculate CF risks for neonates with a positive IRT test A fraction of each major CFTR disease allele among all CFTR disease alleles and a mutation detection rate are summarized for each of five major ethnic groups (Table 1). Login to comment

PMID: 15948195 [PubMed] Quint A et al: "Mutation spectrum in Jewish cystic fibrosis patients in Israel: implication to carrier screening."

No. Sentence Comment

25 MUTATION ANALYSIS The following mutations are routinely tested in Jewish patients: the Ashkenazi founder mutations, DF508, W1282X, N1303K, G542X, 3849 þ 10 kb C!T, 1717-1G > A [Abeliovich et al., 1992], mutations commonly found in non-Ashkenazi patients, S549R (T!G), G85E, 405 þ 1G!A, W1089X, Y1092X, D1152H. Login to comment
36 The G542X, N1303K, 3849 þ 10 kb C!T, and 1717-1G!A mutations were found on 21.6% of the CF chromosomes. Login to comment
37 In this group we revealed two additional mutations L165S and A455E, each was identified on a single chromosome and one mutation remained unidentified. The relative frequencies of the Ashkenazi founder mutations in Ashkenazi patients were W1282X (43%), DF508 (33%), G542X (10%), 3849 þ 10 kb C!T (5%), N1303K (5%), and 1717 (1%). Login to comment
44 Patients from the Balkan countries, Greece and Turkey (21 alleles), had some of the Ashkenazi founder mutations (W1282X, DF508, G542X, and 3849 þ 10 kb C!T), in addition to two other mutations, G85E and W1089X that were not found in Jewish patients from other origins. Login to comment
58 Mutations in the CF Bearing Alleles in the Jewish Patients According to the Ethnic Origin Country of origin Ashkenazi Morocco Tunisia Balkan Iraq Iran/ Kurdistan Georgia Yemen Total Number of alleles (%) 193 (69.0) 34 (12.1) 12 (4.3) 21 (7.5) 8 (2.8) 3 (0.7) 8 (2.8) 2 (0.7) 281 W1282X (%) 83 (42.8) 1 (8.3) 4 (19.0) 88 (31.3) DF508 (%) 65 (33.5) 24 (70.6) 3 (25.0) 7 (33.3) 1 100 (35.6) N1303K (%) 10 (5.2) 10 (3.6) G542X (%) 19 (10.3) 4 (19.0) 24 (8.5) 3849-10 kbC!T (%) 10 (5.1) 1 (2.9) 2 (9.5) 13 (4.6) 1717-1G!A (%) 2 (1.0) 2 (0.7) D1152H (%) 1 (0.5) 1 (0.4) S549R (T!G) (%) 4 (11.8) 4 (1.4) G85E (%) 2 (9.5) 2 (0.7) 405 þ 1G!A (%) 8 (66.7) 8 (2.8) Y1092X (%) 3 (37.5) 3 (1.1) W1089X (%) 2 (9.5) 2 (0.7) Q359K/T360K (%) 8 (100) 8 (2.8) I1234V (%) 2 (100) 2 (0.7) 2751 þ 1insT (%) 2 (25.0) 2 (0.7) 3121-1G > A (%) 1 1 (0.4) M952I (%) 1 (12.5) 1 (0.4) L165S (%) 1 (0.5) 1 (0.4) A455E (%) 1 (0.5) 1 (0.4) L997F (%) 1 (2.9) 1 (0.4) G1244E (%) 1 (2.9) 1 (0.4) Unkown (%) 1 (0.5) 3 (8.8) 2 (25.0) 1 7 (2.5) Mutation Spectrum in Jewish CF Patients [Wahab, 2003]. Login to comment
69 We suggest that 15 mutations that were found on two or more CF chromosomes from unrelated patients (DF508, W1282X, N1303K, G542X, 3849 þ 10 kb C!T, 1717-1 G!A, S549R (T!G), G85E, 405 þ 1G!A, W1089X, Y1092X, 2751 þ 1insT, 3121-1G!A, Q359K/T360K, I1234V) be tested in the CF screening of all Jewish individuals regardless of their origin. Login to comment

PMID: 15952991 [PubMed] Highsmith WE Jr et al: "A CFTR mutation (D1152H) in a family with mild lung disease and normal sweat chlorides."

No. Sentence Comment

15 The three siblings with the clinical syndrome of CF were compound heterozygotes, D1152H/G542X. Login to comment
29 The lung disease attributable to the D1152H/G542X genotype in this family, even with the additional insult of prolonged smoking, is associated with survival into the seventh and eighth decade of life. Login to comment

PMID: 15970608 [PubMed] Mei-Zahav M et al: "The prevalence and clinical characteristics of cystic fibrosis in South Asian Canadian immigrants."

No. Sentence Comment

303 Table 3 CFTR gene mutations among CF patients of South Asian origin and all patients living in the same geographic region in the CF population Mutation South Asian CF population Mutation General CF population (number, % of total alleles) (number, % of total alleles) No. identified % of alleles No. identified % of alleles DF508 13 50 DF508 375 65.1 L218X 2 7.7 W1282X 16 2.8 1525-1GRA 1 3.8 G551D 15 2.6 S549N 1 3.8 G542X 10 1.7 3849+10kbCRT 1 3.8 621+1GRT 10 1.7 V392G 1 3.8 R117H 7 1.2 N1303K 7 1.2 49 others (,1%) 89 16.4 Unidentified 7 26.9 Unidentified 47 8.2 What is already known on this topic N CF is rare in populations not of European Caucasian origin N More severe disease has been reported in South Asian CF patients N DF508, the most common mutation in Caucasians, is less prevalent in South Asians What this study adds N Prevalence and clinical course of CF in children of South Asian origin is similar to that in the general Toronto population N Previous reports reflect inadequate awareness of CF in this ethnic group N The prevalence of DF508 is confirmed to be lower in South Asians than other Caucasian groups Mei-Zahav, Durie, Zielenski, et al www.archdischild.com Authors` affiliations . Login to comment

PMID: 15994263 [PubMed] de Gracia J et al: "Genotype-phenotype correlation for pulmonary function in cystic fibrosis."

No. Sentence Comment

209 To study the decline in pulmonary function between groups the ANOVA method (repeated measures) was used with baseline and current spirometric values as dependent variables, genotype groups as the independent variable, and age and evolution time as Table 1 CFTR mutation according to functional classification Class Molecular dysfunction Mutation I Defective protein production G542X, 711+1GRT, 1609delCA, R1162X, 1717-8GRA, W1282X, 1782delA, Q890X, 1898+3ARG, CFTRdele19, 936delTA II Defective protein processing F508del, N1303K, I507del, R1066C III Defective protein regulation D1270N, G551D IV Defective protein conductance L206W, R334W, R117H, R347H, D836Y, P205S V Partially defective production or processing 2789+5GRA, 1811+1.6kbARG, 3849+10kbCRT, 3272+26GRA Table 2 Groups based on genotype in CF adult patients Functional classes Genotype No of subjects I-I G542X/W1282X 1 R1162X/1898+3ARG 1 R1162X/CFTRdele19 1 I-II F508del/G542X 5 F508del/711+1GRT 2 F508del/1717-8GRA 1 F508del/936delTA 1 F508del/R1162X 1 N1303K/1609delCA 1 I-III G542X/D1270N+R74W 1 711+1G-T/G551D 1 I-IV G542X/P205S 1 Q890X/R334W 1 1609delCA/R347H 1 I-V G542X/2789+5GRT 2 G542X/1811+1.6kbARG 1 1782delA/2789+5GRA 1 1609delCA/1811+1.6kbARG 1 II-II F508del/F508del 21 F508del/N1303K 1 F508del/R1066C 1 II-III F508del/D1270N+R74W 1 I507del/D1270N+R74W 1 II-IV F508del/L206W 4 F508del/R334W 3 F508del/R117H 3 F08del/R347H 2 F508del/D836Y 1 II-V F508del/2789+5GRA 5 F508del/3849+10kbCRT 2 F508del/1811+1.6kbARG 2 F508del/3272+26GRA 1 N1303K/1811+1.6kbARG 1 N1303K/2789+5GRA 1 adjusted variables. Login to comment

PMID: 16075239 [PubMed] Kostuch M et al: "Analysis of most common CFTR mutations in patients affected by nasal polyps."

No. Sentence Comment

1 Forty-four patients affected by nasal polyps were admitted to the Department of Otolaryngology, Lublin University School of Medicine, Lublin, Poland, and screened for the most-commonly identified CFTR mutations [DF508, G542X, N1303 K, 1717-1 (G to A), W1282X, G551D, R553X and DI507] by applying the INNO-LIPA CF2 test strips. Login to comment
48 Using the INNO-LIPA CF2 test strips, it is possible to detect eight mutations simultaneously within the CFTR gene: DF508, G542X, N1303 K, 1717-1 (G to A), W1282X, G551D, R553X and DI507 [14]. Login to comment
83 Positive bands are seen for wild-types [DF508, G542X, N1303 K, 1717-1 (G to A), W1282X, G551D and R553X], but the only positive band for mutant types is DF508 this mutation reported in the control subjects (see Results). Login to comment

PMID: 16088579 [PubMed] Gallati S et al: "Genetics of cystic fibrosis."

No. Sentence Comment

43 Mutations (missense, nonsense, frameshift, splice, small and large in-frame deletions or insertions) con- Table 1 Distribution of theWorldwide 24 Most Common Cystic Fibrosis Mutationsa Exon/ Northern Southern North South Austral- Relative Mutation Intron Europe Europe America America asia Africa Asia Frequency G85E E 03 30 14 16 n.a. n.a. 0 7 0.15 R117H E 04 62 3 61 n.a. 7 0 0 0.30 621+1G→T I 04 97 37 154 n.a. 27 0 0 0.72 711+1G→T I 05 15 13 21 n.a. n.a. n.a. 0 0.11 1078delT E 07 53 2 1 n.a. 1 n.a. 0 0.13 R334W E 07 18 21 12 n.a. 2 0 0 0.12 R347P E 07 55 24 26 n.a. 1 0 0 0.24 A455E E 09 35 0 27 n.a. n.a. n.a. 0 0.14 ⌬I507 E 10 57 5 20 2 9 0 0 0.21 ⌬F508 E 10 14,866 4007 6901 342 2309 351 173 66.02 1717-1G→A I 10 160 65 44 n.a. 12 0 3 0.65 G542X E 11 439 259 234 38 56 9 27 2.42 S549N E 11 18 2 5 1 3 1 0 0.07 G551D E 11 356 37 206 1 117 0 0 1.64 R553X E 11 165 44 96 5 11 1 0 0.73 R560T E 11 40 0 24 0 3 0 0 0.15 1898+1G→A I 12 41 10 2 n.a. n.a. n.a. 0 0.12 2184delA E 13 14 7 8 n.a. n.a. n.a. 0 0.07 2789+5G→A I 14b 27 10 17 n.a. n.a. n.a. 0 0.12 R1162X E 19 36 68 19 0 2 0 0 0.28 3659delC E 19 39 1 14 n.a. n.a. n.a. 0 0.12 3849+10kbC→T I 19 23 8 57 n.a. n.a. n.a. 16 0.24 W1282X E 20 120 43 245 n.a. 6 2 120 1.22 N1303K E 21 209 179 130 11 23 8 29 1.34 Chromosomes 21,154 7281 10438 758 3095 515 608 screened Detection rate 80.2 66.7 79.9 52.8 83.7 72.2 61.7 aAccording to the Cystic Fibrosis Genetic Analysis Consortium, http://www.genet.sickkids.on.ca/cftr/. Login to comment
67 SSCP analysis is one of the most popular methods for the detection of sequence variants in polymerase chain reaction (PCR) amplified DNA fragments.29 The princi- Table 3 Cystic Fibrosis Mutations Detected by Commercial Kits INNO-LiPA Mutations CF2 ⌬F508, ⌬I507, G542X, 1717-1G→A, G551D, R553X, W1282X, N1303K CFTR12 ⌬F508, ⌬I507, G542X, 1717-1G→A, G551D, R553X, W1282X, N1303K, S1251N, R560T, 3905insT, Q552X CFTR17+Tn 394delTT, G85E, 621+1G→T, R117H, 1078delT, R347P, R334W, E60X, 2183AA→G, 2184delA, 711+5G→A, 2789+5G→A, R1162X, 3659delC, 3849+10kbC→T, 2143delT, A455E, (5T/7T/9T) Elucigene CF4 ⌬F508, G542X, G551D, 621+1G→T CF12 ⌬F508, G542X, G551D, N1303K, W1282X, 1717-1G→A, R553X, 621+1G→T, R117H, R1162X, 3849+10kbC→T, R334W CF20 1717-1G→A, G542X, W1282X, N1303K, ⌬F508, 3849+10kbC→T, 621+1G→T, R553X, G551D, R117H, R1162X, R334W, A455E, 2183AA→G, 3659delC, 1078delT, ⌬I507, R345P, S1251N, E60X CF Poly-T 5T/7T/9T OLA CF OLA assay ⌬F508, F508C, ⌬I507, Q493X, V520F, 1717-1G→A, G542X, G551D, R553X, R560T, S549R, S549N, 3849+10kbC→T, 3849+4A→G, R1162X, 3659delC, W1282X, 3905insT, N1303K, G85E, 621+1G→T, R117H, Y122X, 711+1G→T, 1078delT, R347P, R347H, R334W, A455E, 1898+1G→A, 2183AA→G, 2789+5G→A b Figure 2 Mutation screening of exon 19 of the cystic fibrosis transmembrane conductance regulator (CFTR) gene using polymerase chain reaction (PCR) followed by single-strand conformation polymorphism/heteroduplex (SSCP/HD) analysis on a silver-stained polyacrylamide gel. Login to comment

PMID: 16101453 [PubMed] Suh KS et al: "Intracellular chloride channels: critical mediators of cell viability and potential targets for cancer therapy."

No. Sentence Comment

86 A variety of other mutations have been detected in CF patients [39] leading to ablation of protein synthesis (nonsense G542X, frameshift 394delTT, or splice junction 1717 G/A), blocked protein processing (missense N1303K or AA deletion in F508), blocked protein regulation (missense at G551D), altered conductance (missense R117H or R347P), and reduced protein synthesis (missense A455E, alternative splicing 3849 + 10kbC/T) [40]. Login to comment

PMID: 16124861 [PubMed] Cutting GR et al: "Modifier genetics: cystic fibrosis."

No. Sentence Comment

133 As expected, mutations highly associated with pancreatic insufficiency, such as F508 and G542X, exist at higher frequency in patients with meconium ileus than those without meconium ileus (44, 79). Login to comment
544 Two cystic fibrosis patients with the genotype G542X/G551D. Login to comment

PMID: 16126774 [PubMed] Morea A et al: "Gender-sensitive association of CFTR gene mutations and 5T allele emerging from a large survey on infertility."

No. Sentence Comment

47 CFTR gene alterations were first scored by PCR and reverse dot blot (Chehab and Wall, 1992), targeted to the detection of the following mutations: ∆F508, G85E, 541∆C, D110H, R117H, 621+1G→T, 711+5G→A, R334W, R334Q, T338I, 1078∆T, R347H, R352Q, ∆I507, 1609∆CA, E527G, 1717-1G→A, 1717-8G→A, G542X, R347P, S549N, S549R A→C, Q552X, R553X, A559T, D579G, Y577F, E585X, 1898+3A→G, 2183AA→G, R709X, 2789+5G→A, 3132∆TG, 3272-26A→G, L1077P, L1065P, R1070Q, R1066H, M1101K, D1152H, R1158X, R1162X, 3849+10KbC→T, G1244E, W1282R, W1282X, N1303K and 4016∇T. Login to comment
77 All these rare mutations, having been sought only in one partner, and only in the appropriate cases, are not included in the data discussed in Tables I, II and IV. Finally, as regards the mutations found in women of the control group, who bore 5T and a CFTR mutation, these 15 subjects presented eight cases of ∆F508 and single instances of the following: R117H, G542X, W1282X, R1162X, N1303K, 2183 aa/g and D1152H. Login to comment
101 Mutations Women (987) Men (867) N IVS8-T genotype N IVS8-T genotype ∆F508 16 15(7/9); 1(9/9) 26 15(7/9)*; 11(5/9) N1303K 4 4(7/9) 1 7/7 3849+10KbC→T 1 5/7 1 5/7 G542X 2 7/9 1 7/9† 2183AA→G 2 7/7 4 7/7 R553X 2 7/7 0 - R1162X 2 7/7 6 5(7/7)‡; 1(7/9) D1152H 0 - 3 2(7/7); 7/9† 711+5G→A 0 - 3 7/7 1717-8G→A 0 - 1 5/7 1717-1G→A 1 7/7 0 - Y577F 0 - 1 7/7 R117H 1 7/7 1 7/9* 621+3A→G 1 7/9 0 - W1282X 1 7/7 0 - deltaI1507 1 7/7 0 - T3381 1 7/7 1 7/9 R1066H 0 - 1 7/7§ R334Q 0 - 1 7/9 2789+5G→A 1 7/7 2 7/7‡§ Total 36¶ 53¶ records, all these mutations are normally found in trans with respect of 5T. Login to comment

PMID: 16182665 [PubMed] Sarles J et al: "Combining immunoreactive trypsinogen and pancreatitis-associated protein assays, a method of newborn screening for cystic fibrosis that avoids DNA analysis."

No. Sentence Comment

44 A closer look at the results revealed that among the newborns with CF with moderately elevated IRT (50 to <100 ng/mL), 10 had genuine forms of the disease, their genotypes being DF508/DF508 (n = 6), DF508/P574H (n = 1), DF508/G542X (n = 1), DF508/G149R (n = 1), or DF508/? Login to comment

PMID: 16191501 [PubMed] Chou LS et al: "A comparison of high-resolution melting analysis with denaturing high-performance liquid chromatography for mutation scanning: cystic fibrosis transmembrane conductance regulator gene as a model."

No. Sentence Comment

6 However, when the absolute temperatures of HRMA were considered, G542X but not F508del homozygotes could be distinguished from wild type. Login to comment
18 Materials and Methods Sample Source and Study Design Eleven commercially genotyped samples were obtained from Coriell Cell Repositories, Coriell Institute for Medical Research, Camden, NJ (Y122X, R334W, R347P, A455E, I507del, F508del, F508C, G542X/G542X, R553X, R560T, and M1101K). Login to comment
31 ❚Table 1❚ Mutations Analyzed in the Study Position From 5' Exon (or Intron) Genotype* No. of Samples Nucleotide Change SNP Class† End/Amplicon Size (bp) 3 394delTT 1 Del‡ - 132/234 4 R117H 1 G→A 1 83/270 Y122X 1 T→A 4 99/270 I148T 2 T→C 1 176/270 Intron 4 621+1 2 G→T 2 233/270 7 R334W 1 C→T 1 208/345 R347P 1 G→C 3 248/345 9 A455E 2 C→A 2 155/263 10 I507del 1 Del‡ - 171/292 F508del 3 Del‡ - 174/292 F508del/F508del 1 Del - 174/292 F508C 1 T→G 2 175/292 11 G542X 1 G→T 2 90/175 G542X/G542X 1 G→T 2 90/175 G551D 1 G→A 1 118/175 R553X 2 C→T 1 123/175 R560T 1 G→C 3 145/175 13 2184delA 1 Del‡ - 356/458 17b M1101K 1 T→A 4 196/292 21 N1303K 1 C→G 3 175/250 bp, base pairs; SNP, single nucleotide polymorphism. Login to comment
32 * All genotypes were heterozygous except homozygous F508del and G542X. Login to comment
49 Of 20 heterozygous samples, all were detected by melting and 19 by dHPLC for sensitivities of 100% and 95%, respectively. Homozygous mutations F508del and G542X could not be identified by melting analysis or dHPLC when only curve shapes were compared. Login to comment
50 However, when melting curve position and shape were considered, G542X homozygotes could be identified by high-resolution melting. Login to comment
75 Additional mutations in exons 9, 10, 11, and 21 included 7 heterozygous SNPs (A455E, F508C, G542X, G551D, R553X, R560T, and N1303K) and 2 heterozygous 3-base deletions (I507del and F508del). Login to comment
78 The dHPLC traces of homozygous G542X and F508del mutations were the same as wild-type control samples (Figure 3). Login to comment
80 G542X but not F508del homozygotes could be discerned from their wild types if curve position (absolute temperature) instead of curve shape was used for comparison. Login to comment
81 Nearest-neighbor calculations predict that the ∆Tm between wild type and G542X homozygotes is Time (min) Absorbance(mV) 0 1 2 3 4 5 20 - 19 - 18 - 17 - 16 - 15 - 14 - 13 - 12 - 11 - 10 - 9 - 8 - 7 - 6 - 5 - 4 - 3 - 2 - 1 - 0 - R347P het R334W het WT Temperature (°C) Fluorescence 82 83 84 85 86 87 100 - 90 - 80 - 70 - 60 - 50 - 40 - 30 - 20 - 10 - 0 - R334W het C::A T::G R347P het C::C G::G WT G::C Temperature (°C) Fluorescence 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 100 - 90 - 80 - 70 - 60 - 50 - 40 - 30 - 20 - 10 - 0 - WT 0 50 100 150 200 250 300 350 100 90 80 70 60 50 40 30 20 10 Temperature(°C) Base Pairs Temperature (°C) Fluorescence 75 76 77 78 79 80 100 - 90 - 80 - 70 - 60 - 50 - 40 - 30 - 20 - 10 - 0 - A B C D ❚Figure 2❚ High-resolution melting and denaturing high-performance liquid chromatography (dHPLC) analysis of exon 7 of the cystic fibrosis transmembrane conductance regulator gene. Login to comment
86 Analysis of 5 different wild types and the single available G542X homozygote revealed a shifted curve position (Figure 4), suggesting that absolute temperature differences may be used to identify homozygous sequence alterations. Login to comment
98 In comparison, Ravnik-Glavac et al28 reported correct detection of heterozygous Time (min) Absorbance(mV) 0 1 2 3 20 - 19 - 18 - 17 - 16 - 15 - 14 - 13 - 12 - 11 - 10 - 9 - 8 - 7 - 6 - 5 - 4 - 3 - 2 - 1 - 0 - G542X het G542X hom WT Time (min) Absorbance(mV) 0 1 2 3 20 - 19 - 18 - 17 - 16 - 15 - 14 - 13 - 12 - 11 - 10 - 9 - 8 - 7 - 6 - 5 - 4 - 3 - 2 - 1 - 0 - F508del het F508del hom WT A B ❚Figure 3❚ Denaturing high-performance liquid chromatography analysis of mutations G542X (exon 11) and F508del (exon 10) of the cystic fibrosis transmembrane conductance regulator gene. Login to comment
99 A, Elution patterns of the wild-type (WT), heterozygous (het) G542X, and homozygous (hom) G542X samples. Login to comment
101 Temperature (°C) Fluorescence 77 78 79 80 81 82 83 84 85 86 100 - 90 - 80 - 70 - 60 - 50 - 40 - 30 - 20 - 10 - 0 - G542X het WT G542X hom ❚Figure 4❚ High-resolution melting analysis of exon 11. Login to comment
102 Melting curves shown are 5 wild-type (WT) samples, 1 G542X heterozygote (het), and 1 G542X homozygote (hom). Login to comment
131 Homozygous SNP detection has been reported in PCR products up to 544 bp.19 In the present study, dHPLC missed the G542X homozygote, but melting analysis was able to identify the homozygous change using Tm differences. Login to comment

PMID: 16202788 [PubMed] Rock MJ et al: "Newborn screening for cystic fibrosis in Wisconsin: nine-year experience with routine trypsinogen/DNA testing."

No. Sentence Comment

30 Mutations included in this assay are 2184delA, A455E, DI507, DF508, G542X, G551D, R553X, R560T, 1717-1G>A, R1162X, 3659delC, N1303K, W1282X, R334W, R347P, 1078delT, R117H, I148T, 62111G>T, 278915G>A, 3849110kbC>T, G85E, 109811G>A, 71111G>T and 312011G>A. Login to comment
64 Two alleles, with 1 being an R117H: 5 cases of DF508/R117H(7T/9T), 1 case of G542X/ R117H(7T/9T), 1 case of R117H/R117H(5T/7T), and 1 case of I148T/R117H(7T/9T). Login to comment

PMID: 16207791 [PubMed] Song Y et al: "Hyperacidity of secreted fluid from submucosal glands in early cystic fibrosis."

No. Sentence Comment

90 Clinical characteristics of study subjects CF Subjects Age, Sex Genotype FEV1 Shwachman Brasfield CF1 13, F ⌬F508 - E60X 117% 85 22 CF2 22, M G542X - unknown 58% 70 15 CF3 10, M ⌬F508 - unknown 99% 80 23 CF4 20, M ⌬F508 - ⌬F508 71% 90 23 CF5 16, F ⌬F508 - unknown 79% 65 15 CF6 16, M ⌬F508 - ⌬F508 115% 75 19 Non-CF Subjects Age, Sex Diagnosis Procedure N1 3, F OSA T & A N2 2, M OSA T & A N3 10, F Recurrent tonsillitis T & A N4 10, M Recurrent tonsillitis Tonsillectomy N5 13, M Chronic cough T & A and BAL N6 4, M OSA T & A N7 6, F Recurrent tonsillitis T & A N8 3, M OSA T & A CF, cystic fibrosis; N, non-CF; OSA, obstructive sleep apnea; T & A, tonsillectomy and adenoidectomy; BAL, bronchoalveolar lavage; FEV1, forced expiratory volume in the first second. Login to comment
124 Genotype analysis showed that all subjects carried at least one copy of the ⌬F508 gene, except for one subject, whose genotype was G542X/ unknown. Login to comment

PMID: 16227367 [PubMed] McWilliams R et al: "Cystic fibrosis transmembrane regulator gene carrier status is a risk factor for young onset pancreatic adenocarcinoma."

No. Sentence Comment

277 R McWilliams Department of Oncology and Department of Medicine, Mayo Clinic, Rochester, Minnesota, USA W E Highsmith Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA K G Rabe, M de Andrade, L A Tordsen Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA Conflict of interest: None declared. Table 1 Comparison of CFTR mutation frequencies detected in the young onset pancreatic cancer cohort versus the clinical database Young onset pancreatic cancer cases (,60 y old at diagnosis, n = 166) Mayo Clinic clinical database reference group (n = 5349) No % No % CFTR mutation non-carriers 152 91.6 5132 95.9 CFTR mutation carriers 14 8.4 217 4.1 Mutation distribution DF508 12 85.7 155 71.4 R177H 1 7.1 28 12.9 G551D 6 2.8 2789+5G.A 6 2.8 G542X 4 1.8 N1303K 1 7.1 3 1.4 1717-1G.T 2 0.9 3849+10kbC.T 2 0.9 A455E 2 0.9 R1162X 2 0.9 R347H 1 0.5 R553X 1 0.5 3905insT 1 0.5 621+1G.T 1 0.5 W1282X 1 0.5 1898+1G.A 1 0.5 R560T 1 0.5 Young onset pancreatic cancer cases were more frequent carriers of the CFTR mutations compared with patients in the control database (odds ratio 2.18 (95% confidence interval 1.24-3.29); p = 0.006). Login to comment

PMID: 16243854 [PubMed] Massie J et al: "Markedly elevated neonatal immunoreactive trypsinogen levels in the absence of cystic fibrosis gene mutations is not an indication for further testing."

No. Sentence Comment

220 Table 2 shows the relatively poor PPV of Table 1 Details of cystic fibrosis patients with IRT .99th centile but no DF508 mutation, Victoria, Australia, 1991-2003 Patient IRT (MoM) Genotype* Presentation Patient 1 2.77 R117H/2 Sibling with CF Patient 2 4.57 N1303K/2 Meconium ileus/sibling with CF Patient 3 3.28 2/2 Failure to thrive Patient 4 18.16 N1303K/N1303K Failure to thrive/recurrent cough Patient 5 2.98 V520F/2 Meconium ileus Patient 6 3.79 2/2 Meconium ileus Patient 7 6.65 G551D/3849 Failure to thrive/recurrent cough Patient 8 8.32 2/2 Failure to thrive Patient 9 6.45 2/2 Failure to thrive Patient 10 3.69 2/2 Clinical details not available Patient 11 13.81 2/2 Failure to thrive Patient 12 6.64 G542X/2 Recurrent chest infection Patient 13 5.51 2/2 Affected sibling Patient 14 3.95 G542X/2 Meconium ileus Patient 15 6.92 2/2 Recurrent chest infection Patient 16 6.82 2/2 Failure to thrive Patient 17 7.31 2/2 Failure to thrive Patient 18 7.66 2/2 Sibling with CF IRT, immunoreactive trypsinogen; MoM, multiple of median. Login to comment
222 *All patients underwent an extended CFTR mutation analysis for the following mutations in addition to DF508: G551D, R553X, G542X, R117H, N1303K, 621+1G-T, A455E, V520F, 1717-1G-A, W1282X, R1162X, 3849+10kbC-T, R347P, R334W, R560T, S549N. Login to comment

PMID: 16251901 [PubMed] Pompei F et al: "Haplotype block structure study of the CFTR gene. Most variants are associated with the M470 allele in several European populations."

No. Sentence Comment

30 The T2A rate was much lower than 1 Frequencies of the CFTR variants within the M or the V alleles exon or intron VARIANT SITES in the M genes (MM subjects) in the V genes (VV subjects) A 5' UTR 125 g/c 8/144 (0.056) 3/356 (0.008) -80 1 2 R31C 5/226 (0.004) 1/576 (0.002) -56 in M genes in V genes 6 2 R75Q 1/226 (0.004) 15/576 (0.026) -51 M V (ttga)n 0.461 0.017 7 3 G85E 0/226 (0) 1/576 (0.002) -51 2.214 0.362 (tg)n 0.616 0.114 B i 3 406-6 t/c 0/226 (0) 6/576 (0.010) -29 (t)n 0.499 0.036 8 4 R117H 2/226 (0.009) 0/576 (0) -29 10 4 I148T 3/224 (0.013) 0/576 (0) -29 C i 4 621+3 a/g 1/224 (0.004) 0/576 (0) -29 12 5 R170H 1/158 (0.006) 0/402 (0) -26 D i 6a 875+40 a/g 6/36 (0.167)c 0/118 (0)c -25 i 6b (ttga)6 13/36 (0.361) 1/118 (0.008) -23 E i 6b 1001+11 c/t 5/60 (0.083) 0/166 (0) -23 F i 8 1341+28 c/t 1/152 (0.007) 0/464 (0) -18 i 8 (tg)10 39/76 (0.513) 5/218 (0.023) -11 i 8 (tg)11 21/76 (0.276) 205/218 (0.940) -11 i 8 (tg)12 16/76 (0.211) 8/218 (0.037) -11 i 8 t5 4/76 (0.053) 2/218 (0.009) -11 i 8 t7 48/76 (0.632) 214/218 (0.982) -11 i 8 t9 24/76 (0.316) 2/218 (0.009) -11 16 10 M470V H ex 10 F508del 3/226 (0.013) 0/572 (0) 0 19 10 F508C 0/226 (0) 1/572 (0.002) 0 20 10 1716g/a 15/226 (0.066) 0/572 (0) 0 21 11 G542X 1/158 (0.006) 0/400 (0) +28 24 12 V562I 1/226 (0.004) 0/576 (0) +30 25 12 V562L 1/226 (0.004) 0/576 (0) +30 26 12 G576A 3/226 (0.013) 0/576 (0) +30 28 13 2082c/t 1/104 (0.010) 0/226 (0) +32 29 13 R668C 3/224 (0.013) 0/562 (0) +32 32 14a 2694t/g 45/70 (0.643) 9/208 (0.043) +35 I i 14a 2752-15 c/g 0/226 (0) 5/576 (0.009) +44 37 15 3030g/a 1/158 (0.006) 7/402 (0.017) +44 O i 15 3041-71 g/c 5/226 (0.022) 0/576 (0) +47 39 17a L997F 1/226 (0.004) 4/576 (0.007) +51 40 17a A1009T 0/226 (0) 1/572 (0.002) +51 42 17b F1052V 1/226 (0.004) 0/572 (0) +52 43 17b G1069R 1/226 (0.004) 0/572 (0) +52 44 17b Q1071H 1/226 (0.004) 0/572 (0) +52 45 17b 3417a/t 0/226 (0) 4/572 (0.007) +52 46 17b L1096R 1/226 (0.004) 0/572 (0) +52 52 19 3813a/g 0/118 (0) 1/484 (0.002) +68 53 19 S1235R 3/100 (0.030) 0/294 (0) +68 54 20 4002a/g 5/56 (0.089) 1/168 (0.006) +83 q in the M alleles q in the V alleles 56 21 4029a/g 0/194 (0) 3/506 (0.006) +93 57 21 N1303K 1/92 (0.011) 0/272 (0) +93 59 24 4404c/t 3/226 (0.013) 14/576 (0.024) +107 60 24 4521g/a 21/56 (0.375) 2/172 (0.012) +107 "slow evolution" markers "fast evolution" markers (i.e. STRs) H is the sum of the degrees of heterozygosity of all the markers Ref.No.a ABSOLUTE AND RELATIVE FREQUENCIES distance from the M470V siteb (Kb) H associated with the…. Login to comment

PMID: 16258369 [PubMed] Gullo L et al: "Mutations of the CFTR gene in idiopathic pancreatic hyperenzymemia."

No. Sentence Comment

52 A (i) 5 1078delT, R347P, R334W 7 A455E, Tn (i) 8, 9 DF508, DI507 10 G542X, 1717-1 G . Login to comment

PMID: 16272177 [PubMed] Tabary O et al: "Adherence of airway neutrophils and inflammatory response are increased in CF airway epithelial cell-neutrophil interactions."

No. Sentence Comment

66 Sex Age, yr CF Genotype Clinical Score FVC, % FEV1, % Pseudomonas aeruginosa Colonization 1 M 15 ⌬F508/⌬F508 30 32 21 yes 2 M 16 ⌬F508/⌬F508 60 70 43 yes 3 M 17 ⌬F508/⌬F508 30 41 23 yes 4 F 4 ⌬F508/⌬F508 80 NA NA no 5 F 16 ⌬F508/⌬F508 50 53 41 yes 6 M 15 ⌬F508/⌬F508 30 33 20 yes 7 M 13 ⌬F508/⌬F508 50 61 37 yes 8 M 15 ⌬F508/⌬F508 70 70 50 no 9 F 21 R1066C/NI 50 60 77 yes 10 F 14 2183A/2183A 50 48 39 yes 11 M 14 G542X/2176insC 30 34 25 yes 12 M 17 ⌬F508/R560C 30 47 27 yes 13 M 17 IVS8 (5T)/IVS8 (5T) NA NA NA yes 14 F 18 3906insT/1609⌬CA 40 47 30 yes 15 F 13 G551D/S1235Rϩ5T 70 84 86 no 16 F 15 N1303K/347 del70 70 44 35 yes Clinical score, Schwachman-Kulczycki score; FVC, forced vital capacity; FEV1, forced expiratory volume in 1 s; M, male; F, female; NA, not applicable. Login to comment

PMID: 16272798 [PubMed] Uzun S et al: "Cystic fibrosis transmembrane conductance regulator gene mutations in infertile males with congenital bilateral absence of the vas deferens."

No. Sentence Comment

28 Other CF mutations, G542X, G551D, D1152H, M470W, R334W, R74W, M952I, W1282X, N1303K, and G85E, are known to be involved in CBAVD etiology (Wang et al. 2002; Danziger et al. 2004). Login to comment
34 ΔF508 and G542X are known as severe alleles and R117H as a mild allele. Login to comment
63 The remaining two patients were heterozygous for the nonsense mutation G542X and missense mutation D1152H (Table 1). Login to comment
89 D1152H / -- 1725 ΔF508 mut. het ΔF508 / -- 1827 G542X Nonsense mutation, het. Login to comment
90 G542X / -- 1879 ΔF508 mut. het ΔF508 / -- 2097 ΔF508 mut. het ΔF508 / -- 2162 ΔF508 mut. het M952I Missense mutation, het. Login to comment
92 G542X Mutation. A G to T transversion at nucleotide position 1756 in exon 11 generates a nonsense mutation. Login to comment

PMID: 16361706 [PubMed] Hallows KR et al: "Up-regulation of AMP-activated kinase by dysfunctional cystic fibrosis transmembrane conductance regulator in cystic fibrosis airway epithelial cells mitigates excessive inflammation."

No. Sentence Comment

57 Six of the 10 CF HBE cell lines were from patients who were homozygous for the ⌬F508 CF mutation, and the remaining lines were from compound heterozygotes who had one ⌬F508 allele along with a Class I or III mutation in the other allele, including G542X, W1282X, and G551D (one each); one mutation was unknown. Login to comment

PMID: 16362824 [PubMed] Hantash FM et al: "Novel and recurrent rearrangements in the CFTR gene: clinical and laboratory implications for cystic fibrosis screening."

No. Sentence Comment

122 DNA from patient 5, a 4-month-old Ashkenazi Jewish infant with severe CF, harbored two point mutations: G542X (in Fig. 2 a Detection of a deletion of exons 17a-18 in a patient (b) and her father (c). Login to comment
127 The early onset of severe CF phenotype in the 4-month-old patient is likely the result of the G542X and the deletion of exons 4-6. Login to comment

PMID: 16379540 [PubMed] Stanziale P et al: "Indirect CFTR mutation identification by PCR/OLA anomalous electropherograms."

No. Sentence Comment

50 FREQUENCY DISTRIBUTION OF CFTR MUTATIONS IDENTIFIED IN 116 PATIENTS WITH CYSTIC FIBROSIS ORIGINATING FROM CENTRAL-SOUTHERN ITALY Mutations Allele frequency (%) F508del 47.41 G542X 9.48 N1303K 5.60 G85E 5.17 2789ϩ5GϾA 1.29 621ϩ1G-ϾT 1.29 R347P 1.29 R553X 1.29 S589N 1.29 W1282X 1.29 CFTRdele14b-17b 0.86 1717-1G-ϾA 0.43 2183 AA-ϾG 0.43 R1162X 0.43 R334W 0.43 711ϩ5G-ϾA 0.43 3849ϩ1OKbC-ϾT 0.43 Unidentified 21.12 A B C D GTTG-3Ј), 14bF (5Ј-GGGAGGAATAGGTGAAGAT-3Ј) and 14bR (5Ј-AATCCACTATGTTTGTATGTA-3Ј), 17bF (5Ј-AA- TGACATTTGTGATATGAT-3Ј) and 17bR (5Ј-ACTTTAG- CTAAGCATTTAAG-3Ј), respectively. Login to comment

PMID: 16384879 [PubMed] De Boeck K et al: "Cystic fibrosis: terminology and diagnostic algorithms."

No. Sentence Comment

361 Examples include the G542X, G551D, R553X, W1282X and N1303K mutations. Login to comment

PMID: 16385442 [PubMed] Hirche TO et al: "[New concepts of pathophysiology and therapy in cystic fibrosis]."

No. Sentence Comment

61 1 Verteilung und Klassifikation der 10 häufigsten CFTR Mutationen in Deutschland 2003 (modifiziert nach [2]) CFTR Mutation identifizierte Mutationen häufigste Mutationen CFTR Mutationsklassea n (%) (%) I II III IV V ˜F508 6593 65,8 88,0 X R553X 172 1,7 2,3 X G542X 160 1,6 2,1 X N1303K 154 1,5 2,0 X G551D 141 1,4 1,9 X R347P 100 1,0 1,3 X 1717 ±1G fi A 61 0,6 0,8 X 3849 + 10 Kb C fi T 49 0,5 0,7 X W1282X 35 0,4 0,5 X R117H 25 0,3 0,4 X andere 524 5,1 gesamt n = 8014 79,9% 100% 7,6%b 88,0% 1,9% 1,7% 0,8% a Zur Einteilung der CFTR Mutationsklassen vergleiche Abb. 3. b Anteil der CFTR Mutationsklasse an den 10 häufigsten Mutationen [%] teinsynthese proportional zu der Schwere der pulmonalen Erkrankung war. Login to comment

PMID: 16429424 [PubMed] Choi EH et al: "Association of common haplotypes of surfactant protein A1 and A2 (SFTPA1 and SFTPA2) genes with severity of lung disease in cystic fibrosis."

No. Sentence Comment

33 Complementary mutations were identified in 51 CF subjects: R117H (4), R347H (1), R347P (1), G542X (7), G551D (4), 1717-1G-A (2), 2789 þ 5G > A(3), 3120 þ 1G > A (2), 3659delC (3), 3849 þ 10kbC>T (6), 394delTT (1), 621 þ 1G>T (4), 711 þ 1G > T (1), G85E (1), I507 (1), N1303K (2), R352Q (1), R553X (2), R560T (1), and W1282X (4). Login to comment
35 Eleven subjects had rare mutations such as G551D/G551D, G551D/3659delC, G551D/I507, G551D/ Neg (2), E60X/Q493X, R1162X/G542X, W1282X/ W1282X (3), and 1717 À G > A/Neg. Login to comment

PMID: 16435054 [PubMed] Zilfalil BA et al: "Detection of F508del mutation in cystic fibrosis transmembrane conductance regulator gene mutation among Malays."

No. Sentence Comment

55 MUTATIONS R553X G551D 1507 del F508 del 1717-1 G>A G542X R560T R347P W1282X R334W 1078 Del T 3849 + 10KB C>T R1162X N1303K 3659 Del C A455E R117H 2183 AA>G 2789+5 G>A 1898 +1 G>A 621+1 G>T 711+1 G>T G85E S549N S549R V520F Q493X R347H 3849 +4 A>G 3905 INS T Y122X 4 software before running the gel electrophoresis in 1X TBE using ABI PRISM® 377 Genetic Analyzer (Applied Biosystems, USA) for 45 minutes. Login to comment

PMID: 16472140 [PubMed] Becq F et al: "On the discovery and development of CFTR chloride channel activators."

No. Sentence Comment

38 Corresponding proteins are degraded rapidly or alternatively no protein is produced (e.g. stop mutations: W1282X, G542X). Login to comment

PMID: 16540752 [PubMed] de Vries TW et al: "Analyzing DNA from buccal cells is a reliable method for the exclusion of cystic fibrosis. Results of a pilot study."

No. Sentence Comment

36 3 b r i e f r e p o r t Genetics IN Medicine Polymerase Chain Reaction (PCR) PCR followed by restriction-fragment length polymorphism (RFLP) was performed to analyze delta F508, G542X, G551D, R553X, N1303K, and A455E according to previously described methods on a Perkin Elmer PE 2400 thermocycler.5 As an alternative, the delta F508 mutation was also analyzed by means of amplification refraction mutation system (ARMS) using the following primer combination: common reverse primer 5=GGGTAGTGTGAAGGGTTCATATGCATAATC3=, Wildtype Forward primer 5=GCCTGGCACCATTAAAGAA- AATATCATCTT3=, and Mutant Forward primer 5=GCCTG- GCACCATTAAAGAAAATATCATTGG3=.6 After PCR was performed, amplicons were digested (in the case of RFLP) using appropriate restriction enzymes as previously described. Login to comment

PMID: 16541275 [PubMed] Du M et al: "Clinical doses of amikacin provide more effective suppression of the human CFTR-G542X stop mutation than gentamicin in a transgenic CF mouse model."

No. Sentence Comment

6 David M. Bedwell Clinical doses of amikacin provide more effective suppression of the human CFTR-G542X stop mutation than gentamicin in a transgenic CF mouse model Received: 31 October 2005 / Accepted: 9 January 2006 / Published online: 16 March 2006 # Springer-Verlag 2006 Abstract Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene cause the disease cystic fibrosis. Login to comment
7 We previously reported that gentamicin administration suppressed a CFTR premature stop mutation in a Cftr-/- mouse model carrying a human CFTR-G542X (hCFTR-G542X) transgene, resulting in the appearance of hCFTR protein and function. Login to comment
9 We then asked whether these doses could suppress the hCFTR-G542X mutation in the Cftr-/- hCFTR-G542X mouse model. Login to comment
11 However, we found that amikacin suppressed the hCFTR-G542X premature stop mutation more effectively than gentamicin when administered at these clinically relevant doses. Login to comment
42 We previously reported that the aminoglycoside gentamicin is capable of suppressing CFTR premature stop mutations in a CF transgenic mouse model, in which an hCFTR cDNA containing the G542X premature stop mutation was expressed under the control of the rat intestinal fatty acid binding protein (FABP) promoter in a Cftr-/- mouse. Login to comment
46 This hCFTR-G542X Cftr-/- mouse was used to show that once daily administration of 34 mg/kg of gentamicin or tobramycin via subcutaneous injections could suppress the G542X nonsense mutation and partially restore expression of functional hCFTR protein [20]. Login to comment
50 In a previous study, we showed that gentamicin suppressed the hCFTR-G542X nonsense mutation in vivo, although peak serum concentrations used were well above the levels allowed during the recommended clinical use of these compounds [20]. Login to comment
52 In the current study, we examined whether gentamicin and amikacin could suppress the G542X mutation when administered at doses within the recommended therapeutic range of serum peak and trough levels. Login to comment
53 We obtained evidence that both compounds could suppress the hCFTR-G542X mutation in the Cftr-/- mouse model and partially restore functional CFTR expression when administered at doses that produced serum levels in the recommended range. Login to comment
54 However, our results indicate that amikacin suppressed the hCFTR-G542X mutation in vivo much more effectively than gentamicin under these conditions, suggesting that it may represent a better choice for the suppression of the hCFTR-G542X stop mutation (and possibly other premature stop mutations that cause CF). Login to comment
55 Materials and methods Plasmid construction and generation of transgenic mice Expression of the hCFTR cDNA transgene that contained the G542X (UGA) premature stop mutation was driven by the rat FABP promoter. Login to comment
56 The plasmid construction of the FABP-hCFTR-G542X transgene and generation of the Cftr-/- hCFTR-G542X were described previously [20]. Login to comment
57 In vitro translation system A modified form of a readthrough reporter system, previously used to monitor the suppression of stop mutations by aminoglycosides [4, 5], was used to determine whether amikacin (Calbiochem) could suppress the hCFTR-G542X mutation in an in vitro rabbit reticulocyte lysate (RRL) translation system (Promega TNT system). Login to comment
60 In the present study, the readthrough cassette contained the hCFTR-G542X premature stop codon and six upstream and downstream codons from the hCFTR gene. Login to comment
64 Efficient translation termination at the G542X stop mutation produced a 25-kDa protein, while suppression of the stop codon resulted in the synthesis of a 35-kDa protein. Login to comment
66 Suppression of the G542X mutation was expressed as percent readthrough, which was calculated as the 35 kda protein= 25 kda þ 35 kda proteinsð Þ½ Â 100: Aminoglycoside treatment Aminoglycoside treatment of homozygous Cftr-/- mice carrying the FABP-hCFTR-G542X transgene was initiated 16 days after birth (1 week before weaning). Login to comment
91 Results Amikacin suppresses the hCFTR-G542X premature stop mutation in a mammalian in vitro translation system The ability of an aminoglycoside to suppress a premature stop mutation depends on several factors, including the specific features of its chemical structure, the identity of the stop codon to be suppressed, and the sequence context surrounding the stop codon in the mRNA [4, 5]. Login to comment
93 Although amikacin has been shown to suppress premature stop mutations in several mammalian mRNAs in vitro [5, 17], it has not yet been shown to suppress the CFTR-G542X mutation in vitro. Login to comment
94 We previously reported that gentamicin and tobramycin suppressed the hCFTR-G542X mutation in a mammalian RRL translation system [20]. Login to comment
96 Accordingly, we first asked whether amikacin, an aminoglycoside commonly used to treat bacterial infections, could also suppress the hCFTR-G542X mutation using the RRL translation system. Login to comment
97 Initially, we cloned the hCFTR-G542X premature stop codon and six flanking codons on either side into a readthrough reporter plasmid (Fig. 1) [20]. Login to comment
98 In this reporter system, a 25-kDa protein is produced if termination occurs at the G542X premature stop mutation, while a 35-kDa protein is produced if the G542X stop codon is suppressed. Login to comment
99 This construct was expressed in a RRL-based coupled transcription/translation system in the presence of increasing concentrations of gentamicin or amikacin, and the concentration of each aminoglycoside that induced the maximum level of readthrough of the G542X mutation (without inhibiting total protein synthesis) was determined. Login to comment
100 While both compounds were found to suppress termination at the G542X mutation, gentamicin induced readthrough at much lower concentrations than amikacin. Login to comment
101 The maximum level of G542X readthrough induced by amikacin (11%) was similar to that induced by gentamicin (14%). Login to comment
106 These results demonstrate that amikacin can effectively suppress the hCFTR-G542X mutation without inhibiting total protein synthesis as observed with gentamicin. Login to comment
112 In a previous study, we reported that the subcutaneous injection of 34 mg/kg gentamicin once daily suppressed the G542X mutation in Cftr-/- hCFTR-G542X mice and restored a significant level of functional hCFTR protein [20]. Login to comment
114 In the current study, we sought to determine whether aminoglycosides could suppress the hCFTR-G542X mutation in our mouse model when administered at concentrations that produced serum levels well below the maximum recommended for humans. To determine an acceptable dose of each aminoglycoside, mice were injected subcutaneously with various concentrations of each compound. Login to comment
118 The hCFTR-G542X UGA mutation (boxed) and surrounding context are indicated by the expanded sequence. Login to comment
119 Termination at the G542X mutation results in a 25-kDa protein, while suppression of that mutation allows continued elongation and the production of a 35-kDa protein. Login to comment
120 b Data showing suppression of the G542X mutation in an RRL in vitro translation system. Login to comment
121 c Quantitation of G542X readthrough from data shown in b samples were then collected at specified times after administration and serum concentrations were determined using FPIA (Fig. 2). Login to comment
129 A clinical dose of gentamicin suppresses the hCFTR-G542X mutation but restores only a barely detectable amount of hCFTR protein We initially used an immunofluorescence assay to ask whether a once daily, low dose of 5 mg/kg gentamicin can suppress the hCFTR-G542X mutation. Login to comment
131 A similar immunofluorescence assay was performed using intestinal tissues from untreated Cftr-/- hCFTR-G542X mice or from mice treated with either 34 mg/kg or 5 mg/kg gentamicin (Fig. 3a). Login to comment
133 In the samples treated with the hCFTR-specific antiserum, no hCFTR protein was detected in the intestinal tissue from untreated Cftr-/- hCFTR-G542X mice, while a strong hCFTR protein signal was detected at the apical surface of epithelial cells in the submucosal glands of the duodenum from mice treated with 34 mg/kg gentamicin. Login to comment
135 These results suggest that this lower, clinically relevant dose of gentamicin can suppress the G542X mutation and restore hCFTR protein in Cftr-/- hCFTR-G542X mice, although the level of hCFTR protein detected was substantially less than was observed in animals treated with the higher dose. Login to comment
136 A clinical dose of amikacin suppresses the hCFTR-G542X mutation and restores a significant amount of hCFTR protein expression We next asked whether amikacin could suppress the hCFTR-G542X mutation in the Cftr-/- hCFTR-G542X mouse. Login to comment
138 Because 34 mg/kg gentamicin was well-tolerated by Cftr-/- hCFTR-G542X mice in our previous study [20] and the doses of amikacin routinely recommended for human use are several folds higher than gentamicin [28], we initially chose to compare a high dose of 170 mg/kg amikacin and a low dose of 15 mg/kg amikacin. Login to comment
140 To determine the ability of amikacin to suppress the hCFTR-G542X mutation, the same administration protocol was used and intestinal tissues from mice were assayed by immunofluorescence using either preimmune serum or an hCFTR-specific polyclonal antiserum. Login to comment
141 No hCFTR protein was detected in samples from untreated Cftr-/- hCFTR-G542X mice using hCFTR-specific antiserum or in samples from treated mice using preimmune serum. Login to comment
144 These results indicate that amikacin can restore a significant amount of hCFTR protein in the Cftr-/- hCFTR-G542X mice when administered at either a very high dose or at a lower dose that produces a peak serum level well within the recommended clinical range. Login to comment
147 The aminoglycoside concentration in each serum sample was determined by fluorescence polarization immunoassay Analysis of hCFTR activity in Cftr-/- hCFTR-G542X mice after treatment with clinical doses of gentamicin or amikacin The hCFTR protein is a cyclic adenosine monophosphate (cAMP)-activated chloride channel that facilitates transepithelial chloride conductance upon activation by cAMP agonists such as forskolin. Login to comment
148 We previously demonstrated that cAMP-dependent transepithelial chloride conductance could be detected in intestinal tissues of Cftr-/- hCFTR-G542X mice that had been treated with 34 mg/kg gentamicin [20]. Login to comment
150 Figure 4 shows representative short-circuit current tracings obtained from Cftr-/- hCFTR-G542X mouse intestinal tissues that were harvested from untreated Cftr-/- hCFTR-G542X mice, or from Cftr-/- hCFTR-G542X mice treated once daily with either 5 mg/kg gentamicin or 15 mg/kg amikacin for 2 to 3 weeks. Login to comment
152 Table 1 provides a summary of data collected from short-circuit current tracings of intestinal tissues harvested from untreated Cftr+/+ hCFTR-G542X mice, +/+ hCFTR-G542X mice treated with low doses of gentamicin or amikacin, untreated Cftr-/- hCFTR-G542X mice, and Cftr-/- hCFTR-G542X mice treated with high or low doses of gentamicin or amikacin. Login to comment
158 a Samples from the duodenum of homozygous Cftr -/-hCFTR-G542X mice (untreated or treated with 5 or 34 mg/kg gentamicin). Login to comment
159 b Samples from the duodenum of homozygous Cftr-/-hCFTR-G542X mice (untreated or treated with 15 or 170 mg/kg amikacin). Login to comment
163 A P<0.05 value was considered as significant In untreated Cftr-/- hCFTR-G542X mice used as negative controls, we observed a cAMP-stimulated short-circuit current in only 8% of the samples (1/12), resulting in an average current of only 0.2 μA/cm2 . Login to comment
164 In our experimental samples, we found that 63% of samples (5/8) from Cftr-/- hCFTR-G542X mice treated with 34 mg/kg gentamicin yielded cAMP-activated short-circuit currents after forskolin addition, resulting in an average current of 1.67 μA/cm2 . Login to comment
165 In contrast, 35% of samples (7/20) from Cftr-/- hCFTR-G542X mice treated with 5 mg/kg of gentamicin yielded cAMP-stimulated short-circuit currents, resulting in an average current of 0.82 μA/cm2 . Login to comment
167 They also demonstrate that the administration of a clinically relevant dose of gentamicin to Cftr-/- hCFTR-G542X mice can restore a statistically significant increase (P value<0.05) in cAMP-stimulated chloride currents relative to untreated controls, consistent with a partial restoration of CFTR protein and activity. Login to comment
169 We found that treatment of Cftr-/- hCFTR-G542X mice with 170 mg/kg of amikacin once daily for 23 weeks yielded a short-circuit response in 75% of intestinal tissues assayed (9/12), resulting in an average current of 1.77 μA/cm2 . Login to comment
173 Discussion The results of this study show that amikacin, like gentamicin, can effectively suppress the hCFTR-G542X stop mutation in a transgenic CF mouse model. Login to comment
174 In fact, we found that the low dose of amikacin tested in this study appears to suppress the hCFTR-G542X mutation more effectively than the low dose of gentamicin. Login to comment
182 a Tracing from the ileum of a homozygous Cftr-/- hCFTR-G542X mouse without any prior aminoglycoside treatment. Login to comment
183 b Tracing from the ileum of a homozygous Cftr-/- hCFTR-G542X mouse after 5 mg/kg gentamicin treatment once daily for 2-3 weeks. Login to comment
184 c Tracing from the ileum of a homozygous Cftr-/- hCFTR-G542X mouse after 15 mg/kg amikacin treatment once daily for 2-3 weeks. Login to comment
210 The expression of the human CFTR-G542X cDNA in this animal will undoubtedly be different than the expression of endogenous mouse Cftr that contains a premature stop mutation. Login to comment
212 In our study, we found that the administration of amikacin at doses that produced serum levels within the clinically accepted range could suppress the hCFTR-G542X mutation and restore functional hCFTR protein. Login to comment
213 While gentamicin was also found to suppress the hCFTR-G542X mutation when administered in doses that produced serum levels in the accepted clinical range, the levels of suppression appeared to be significantly less than those observed with amikacin. Login to comment

PMID: 16617455 [PubMed] Courtney JM et al: "Association of improved pulmonary phenotype in Irish cystic fibrosis patients with a 3' enhancer polymorphism in alpha-1-antitrypsin."

No. Sentence Comment

80 T 1.2% 1.7% 1.4% Nonmild R560T 1.5% 1.3% 1.4% Nonmild G542X 0.7% 1.7% 1.1% Nonmild E60X 0.5% 0.9% 0.6% Mild R553X 0.0% 1.3% 0.5% Nonmild N103K 0.7% 0.0% 0.5% Nonmild 9DELTT 0.0% 0.9% 0.3% Mild 3849 þ 10 kb C > T 0.0% 0.9% 0.3% Mild R75Q 0.0% 0.9% 0.3% Mild 1717 þ 1 G > A/À 0.5% 0.0% 0.3% Mild D1507 0.5% 0.0% 0.3% Mild Minor alleles 9.5% 27.4% 15.9% Mild 1 Alleles listed individually occur at a frequency of !0.5% in either population. Login to comment

PMID: 16648884 [PubMed] Mishra A et al: "The relevance of sweat testing for the diagnosis of cystic fibrosis in the genomic era."

No. Sentence Comment

94 These mechanisms of CFTR dysfunction are intended to provide a framework for understanding the molecular basis of epithelial cell abnormalities in CF.71 Class 1: Defective Protein Synthesis Mutations in this class include the most severe CF phenotypes resulting in no protein being synthesised.2,59,67 The most common Class I mutation is G542X, which either prevents the synthesis of a stable protein or results in the production of a truncated protein due to the creation of a premature termination codon.67 The aminoglycoside antibiotics can suppress premature termination codons by permitting translation to continue to the normal termination of the transcript.72 This has shown to be promising in in vitro and in clinical trials but further studies need to be performed to make it a safer compound that may be administered to children with this class of mutation from the time of diagnosis.72 Class II: Defective Protein Processing Mutations in this class result in a CFTR protein that fails to traffic to the correct cellular localisation due to mis-folding of the protein. Login to comment
131 However there is a diminishing chance of detecting a mutation after ∆F508 which has an allele frequency in CF of 70%, when one considers that the next most common mutations (in Australia) are G551D (5%), G542X (2.4%), N1303K (1.3%) andmostothermutationshaveanallelefrequencysignificantly less than 0.5%. Login to comment

PMID: 16690975 [PubMed] McKone EF et al: "Variants in the glutamate-cysteine-ligase gene are associated with cystic fibrosis lung disease."

No. Sentence Comment

62 * Severe cystic fibrosis transmembrane conductance regulator (CFTR) mutations (Class I-III) ϭ G542X, R553X, W1282X, R1162X, 621-1G→T, 1717-1G→A, 1078⌬T, 3659⌬C, ⌬F508, ⌬I507, N1303K, S549N, G551D, R560T. Login to comment

PMID: 16807389 [PubMed] Elborn JS et al: "Diagnosing CF: sweat, blood and years."

No. Sentence Comment

193 Over 1000 mutations of the CFTR gene have now been described, but only a proportion are associated with disease.4 Mutations of the CFTR gene which cause disease can be classified as follows: class 1, defective protein synthesis (e.g. G542X); class 2, defective protein processing (e.g. DF508); class 3, defective protein regulation (e.g. G551D). Login to comment

PMID: 16837565 [PubMed] Cabello GM et al: "Polymorphic markers suggest a gene flow of CFTR gene from Sub-Saharan/Arabian and Mediterranean to Brazilian Population."

No. Sentence Comment

23 A previous screening of the whole coding region and flanking intronic sequences from the 23 exons of the CFTR gene in 190 chromosomes allowed us to identify 11 different mutations: DF508 (28.4%), G85E (4.7%), 3120 þ 1G / A (3.7%), R334W (2.6%), G542X (2.1%), P205S (1.0%), G551D (0.5%), R1162X (0.5%), Y1092X (0.5%), S549R (0.5%), and S4X (0.5%) (Cabello GMK, Cabello PH, Otsuki, and others 2005). Login to comment
68 The most common 9T-1-1 haplotype among Caucasians was also the most frequent haplotype linked to DF508 and G542X mutations in our patients. Login to comment
88 The 9T-1-1 haplotype was also found to be associated with G542X mutation. Login to comment

PMID: 16954950 [PubMed] Sobczynska-Tomaszewska A et al: "Analysis of CFTR, SPINK1, PRSS1 and AAT mutations in children with acute or chronic pancreatitis."

No. Sentence Comment

64 For the first 50 patients enrolled in this study, the CFTR mutations F508del, G542X, G551D, R553X, N1303K, W1282X, 1717-1G/A, I507del, S1251N, R560T, 3905insT, Q552X (INNO-LiPA CFTR12, Innogenetics, Gent, Belgium), CFTRdele2,3 (16) and polyT variant in intron 8 (IVS8-T) (17) were analyzed. Login to comment

PMID: 16959918 [PubMed] Kraemer R et al: "Effect of allergic bronchopulmonary aspergillosis on lung function in children with cystic fibrosis."

No. Sentence Comment

74 * Miscellaneous-numbers in brackets: ⌬F508 and 1717-1GϾA(3), W1282X(2), 2347delG (1), 621ϩ1GϾT(1), Q525X(2), N1303K(1), 2176insC (1), 394delTT (1), 4005ϩ1G-A(1), 420DEL9 (1), E585X(1), G126D(1), G85E(1), R347P(1); 3905insT and 1717-1GϾA(1), K710X(1), M1101K(1), Q39X(1); R553X and R553X(1), 3905insT (1); G542X and T5(3), G542X(1); Q542X and K1200E(2); N1303K and 2347delG (1), 2789ϩ5GϾA(1); 1199delG and R560S(1). Login to comment

PMID: 16980811 [PubMed] Kammesheidt A et al: "Comprehensive genetic analysis of the cystic fibrosis transmembrane conductance regulator from dried blood specimens--implications for newborn screening."

No. Sentence Comment

73 Apart from delta F508, nine other mutations were present more than once in this data set, with several mutations occurring 4-5 times (1288insTA, 2055del9insA, 406-1GϾA, G542X and H199Y). Login to comment
98 In states with single specimenmodels,originalspecimensaretestedforthepresenceof themostcommonmutation,deltaF508,and/orotherdeleterious Table 1 Genotype data from panel testing and comprehensive Ambry TestTM : CF analysis Case Ethnicity ABI-31 Mutation 1 ABI-31 Mutation 2 Genzyme-87 Mutation 1 Genzyme-87 Mutation 2 Ambry Mutation 1 Ambry Mutation 2 Ambry Mutation 3 1 Hispanic delF508a 4382delAa 2 Hispanic delF508 N/I delF508 N/I delF508a 1248ϩ1GϾAa 3 African-American N/I N/I N/I N/I M150K CFTRdele17A,17Bb 4 Hispanic G542X N/I G542X N/I G542Xa 1288insTAa 5 African-American N/I N/I 3120ϩ1GϾA N/I 3120ϩ1GϾAa Q98Xa 3849؉72G>A 6 Hispanic delF508 N/I delF508 N/I delF508a 2289del10ins5a 7c Hispanic N/I N/I N/I N/I H199Ya 406-1GϾAa 8 Hispanic delF508 N/I delF508 N/I delF508a CFTRdele2,3(21kbb 9 Hispanic delF508 N/I delF508 N/I delF508a 2105-2117del13insAGAAAa 10 Hispanic G542X N/I G542X N/I G542X M952I Y914X 11 Hispanic N/I N/I N/I N/I 663delT L558S 12 Hispanic N/I N/I delF311 N/I delF311a 406-1GϾAa 13 Hispanic N/I N/I 2055del9insAa 2055del9insAa 14 Hispanic delF508 N/I delF508 N/I delF508 2055del9insA 15 Hispanic delF508 N/I delF508 N/I delF508 E257X 16 Hispanic N/I N/I N/I N/I V232D V232D 17 Hispanic delF508 N/I delF508 N/I delF508 H199Y 18 Hispanic delF508 N/I delF508 4160insGGGG 19 Caucasian delF508 N/I delF508 297-1GϾA 20 Hispanic 2183delAAϾG N/I 2183delAAϾG N/I 2183de1AAϾG 3500-2AϾG 21 Hispanic delF508 N/I delF508 S492F 22 Hispanic delF508 N/I delF508 N/I delF508 935delA 23 Caucasian R1162X N/I R1162X N/I R1162X 3940delG 24 Hispanic 711ϩ1GϾT N/I 711ϩ1GϾT T465N 25 Hispanic delF508 N/I delF508 N/I delF508 406-1GϾA 26 Hispanic delF508 N/I delF508 2055del9insA 27 Hispanic delF508 N/I delF508 N/I delF508 V232D 28 Hispanic delF508 N/I delF508 N/I delF508 S1235R 29 Hispanic G542X N/I G542X N/I G542X 297-1GϾA 30 Hispanic delF508 N/I delF508 N/I delF508 Q1100P 31 Hispanic delF508 N/I delF508 W216X 32 Hispanic N/I N/I N/I N/I 406-1GϾA H199Y 33 Hispanic N/I N/I N/I N/I 3272-26AϾG R75X 34 Hispanic N/I N/I Q890X N/I Q890X 2055del9insA 35 Hispanic delF508 N/I delF508 N/I delF508 W216X 36 Hispanic delF508 N/I delF508 N/I delF508 H199Y 37 Hispanic delF508 N/I delF508 N/I delF508 1288insTA I1027T 38 Hispanic G542X N/I G542X N/I G542X 663delT 39 Hispanic delF508 N/I delF508 N/I delF508 1288insTA 40 Hispanic delF508 N/I delF508 1288insTA mutations using mutation panels. Login to comment
111 del) AA F 572.9 No 2 mo 99 9 y 134 27 5 Q98X 3120ϩ1GϾA 3849؉72G>A (c.3717؉72G>A) AA F 253.1 No 6 mo 143 7 y 116 20 6 delF508 2289del10ins5a (c.2158_2167delACAA ATGAATinsGTAAG; p.L719fs) H M 70.8 No 1 y 104 14 y N/A N/A 8 delF508 CFTRdele2,3 (21 kb)b H F 214.2 No 3 y 103 5 y 108 18.6 10 G542X M952I Y914X (c.2742T>A;p.Y914X) H M 250.5 No 3 mo 95 6 y 112 22.2 15 delF508 E257X (c.769G>T; p.E257X) H M 301.3 No 0 mo 89 5 y N/A N/A 23 R1162X 3940delG (c.3808delG; p.D1270fs) C F N/A No 4 mo 86 8 mo 65 5.2 24 711ϩ1GϾT T465N (c.1394C>A; p.T465N) H F N/A N/A N/A N/A Deceased N/A N/A AA, African-American; H, Hispanic; C, Caucasian; MI, meconium ileus; IRT, immunoreactive trypsinogen; N/A, not available. Login to comment

PMID: 17003641 [PubMed] Keiles S et al: "Identification of CFTR, PRSS1, and SPINK1 mutations in 381 patients with pancreatitis."

No. Sentence Comment

54 Patients With More Than 1 CFTR Mutation CFTR Mutation 1 CFTR Mutation 2 CFTR Mutation 3 No. of Patients deltaF508 5T 3 deltaF508 D1152H 1 deltaF508 deltaF508 1 deltaF508 F575Y 1 deltaF508 K598E 1 deltaF508 T164S 1 deltaF508 R74W D1270N 1 deltaF508 Q1476X 1 deltaF508 L997F 1 R553X D1152H 1 R553X G1069R 1 2789+5 G9A 2183 AA9G 1 3849+10kb C9T L1260P 1 711+3 A to G I1139V 1 1341+1 G9A G194R 5T 1 621+25 A9G 3500-19 C9T 1 R74W V855I 1 G542X R117H 1 G551D F311L 1 G576A R668C 2 K710X L997F 1 L997F L320V 1 G1069R 5T 1 1818+18 G9A 5T 1 F1074L 5T 1 F834L 5T 1 R74Q R297Q 1 R74Q R297Q 5T 1 R785Q 5T 1 R117H 5T 3 deltaF508 I1027T 1 Total patients 36 MutationsinboldfacewouldnothavebeendetectedbytheAmericanCollegeofObstetrics and Gynecology (ACOG)/American College of Medical Genetics (ACMG) mutation panel. Login to comment
71 Patients With 1 CFTR Mutation CFTR Mutation 1 No. of Patients 1717-1 G9A 1 2789+5 G9A 1 3849+10kb C9T 2 3849+45 G9A 1 621+3 A9G 2 A1364V 1 A349V 1 A455E 1 D1152H 1 D1445N 1 deltaF508 16 E217G 1 F1286C 1 F316L 1 G542X 1 G551D 1 I148T 1 I807M 1 L206W 1 L967S 2 L997F 2 P55S 1 Q179K 1 Q220X 1 R117H 3 R1453W 1 R297Q 1 R31C 1 R668C 2 S1235R 1 S573C 1 S945L 1 V562A 1 V754M 2 Y1092X 1 Total patients 58 MutationsinboldfacewouldnothavebeendetectedbytheACOG/ACMGmutationpanel. Login to comment

PMID: 17035430 [PubMed] Ziedalski TM et al: "Prospective analysis of cystic fibrosis transmembrane regulator mutations in adults with bronchiectasis or pulmonary nontuberculous mycobacterial infection."

No. Sentence Comment

11 Other known CFTR mutations identified were V456A, G542X, R668C, I1027T, D1152, R1162L, W1282X, and L183I. Login to comment
79 Other identified mutations included R75Q, G542X, V4566A, D1152H, F650L, I1027T, W1282X, and the intron 8 polymorphism IVS 8 5T. Login to comment
94 Comparison of pulmonary function test data did not demonstrate significant differences between the Table 1-Subjects With Diagnosis of CF* Patient No. Age, yr Sex Bronch NTM† Other Infection‡ CFTR Mutations M470V Alleles IVS8 PolyT§ Sweat Chloride Level, mEq/dL 1 63 F Y MAC, Mch ⌬F508, I1027T 1 7T/9T 41 2 58 F Y MAC 2 7T/7T 65 3 66 F Y MAC, Mka PA 1 7T/7T 70 4 62 F Y MAC R75Q 2 5T/7T 67 5 53 F Y MAC G542X 0 5T/7T 60 6 74 F Y MAC SA ⌬F508, D1152H 1 9T/9T 46 7 33 F Y N PA ⌬F508, V456A 1 9T/9T 74 8 49 M Y N 1 7T/7T 77 9 73 F Y N S malto W1282X 1 7T/7T 63 10 52 F N Msi 2 2 7T/7T 68 *Bronch ϭ bronchiectasis (Bronch); F ϭ female; M ϭ male; Y ϭ yes; N ϭ no. Login to comment

PMID: 17099022 [PubMed] McKone EF et al: "CFTR genotype as a predictor of prognosis in cystic fibrosis."

No. Sentence Comment

46 Alleles High-risk CFTR genotype Class I 2,131 G542X, R553X, W1282X, R1162X, 621-1G3T, 1717-1G3A, 1078⌬T, 3659⌬C Class II 11,231 ⌬F508, ⌬I507, N1303K, S549N, G85E Class III 783 G551D, R560T Low-risk CFTR genotype Class IV 391 R117H, R334W, R347P Class V 421 3849 ϩ 10KbC3T, 2789 ϩ 5G3A, A455E *Patients with both CFTR alleles in either class I, class II, or class III were grouped together as a high-risk genotype, while patients with at least one mutant allele in class IV and V were considered to have low-risk genotypes; 380 patients had both mutations in either class I, II, or III, while 314 patients had both mutations in either class IV or V (total, n ϭ 15,651). Login to comment

PMID: 17137500 [PubMed] Kraemer R et al: "Progression of pulmonary hyperinflation and trapped gas associated with genetic and environmental factors in children with cystic fibrosis."

No. Sentence Comment

99 420del9(1), E585X(1), G126D(1), G85E(1), R347P(1), 1078delT(1); Miscellaneous 43 28.3 3905insT and1717-1G>A(1),K710X(1), M1101K(1), Q39X(1), P5L(1), R553X(1); R553X andR553X(1); G542X and T5(3), G542X(1); Q542X and3732delA(2); N1303K and2347delG(1), 2789+5G>A(1); 1199delG andR560S(1). Login to comment

PMID: 17218617 [PubMed] Figueredo J et al: "Prediction of cellular immune responses against CFTR in patients with cystic fibrosis after gene therapy."

No. Sentence Comment

25 Most of the other CFTR mutations are rare, with only four mutations (G542X, N1303K, G551D, and W1282X) having overall frequencies above 1%. Login to comment

PMID: 17287432 [PubMed] Jouret F et al: "Cystic fibrosis is associated with a defect in apical receptor-mediated endocytosis in mouse and human kidney."

No. Sentence Comment

96 Genotyping identified the ⌬F508 mutation in all patients (homozygous in 25 of 30; heterozygous with N1303K, G542X, or 3849 10 kb C⌸T in three of 30; second mutation not identified in two of 30). Login to comment

PMID: 17290305 [PubMed] Linde L et al: "Nonsense-mediated mRNA decay affects nonsense transcript levels and governs response of cystic fibrosis patients to gentamicin."

No. Sentence Comment

83 It is important to note that in all previous clinical trials in CF patients, aminoglycosides (22, 23, 29) or other molecules (41-44) affected only the chloride transport Table 1 Study patients and response to gentamicin treatment Patient Genotype Basal NPD Chloride transport Response number Before treatment After gentamicin Before treatment After gentamicin 1 W1282X/ΔF508 -38 -18 -1 -6 + 2 W1282X/ΔF508 -41 -41 -3 -5 + 3 W1282X/ΔF508 -43 -30 -1 -4 + 4 W1282X/ΔF508 -40 -30 4 -4 + 5 W1282X/ΔF508 -40 -30 -2 -2 +/-A 6 W1282X/W1282X -47 -32 0 -9 + 7 W1282X/G542X -43 -45 -2 -11 + 8 W1282X/W1282X -40 -35 11 -9 + 9 W1282X/W1282X -32 -33 2 4 - 10 W1282X/3849+10 kb C→T -65 -56 3 -3 - All values are expressed as mV. Login to comment
218 Methods Patients. Five of the patients were heterozygous for the W1282X and the ΔF508 mutations (patients 1-5); 3 were homozygous for the W1282X mutation (patients 6, 8, and 9); 1 was heterozygous for the W1282X and G542X mutations (patient 7); and 1 was heterozygous for W1282X and 3849+10 kb C→T mutations (patient 10), which can lead to inclusion of an 84-bp cryptic exon harboring a PTC. Login to comment
328 Du, M., et al. 2002. Aminoglycoside suppression of a premature stop mutation in a Cftr-/- mouse carrying a human CFTR-G542X transgene. Login to comment
432 CFTR nonsense mutations G542X and W1282X associated with severe reduction of CFTR mRNA in nasal epithelial cells. Login to comment

PMID: 17347447 [PubMed] Clancy JP et al: "No detectable improvements in cystic fibrosis transmembrane conductance regulator by nasal aminoglycosides in patients with cystic fibrosis with stop mutations."

No. Sentence Comment

50 GENOTYPE AND DEMOGRAPHIC INFORMATION OF STUDY SUBJECTS Age (yr) Sex Genotype Premature stop mutation subjects 16 Male 621ϩ1G-T/E60X 16 Male ⌬F508/G542X 22 Male ⌬F508/G542X 12 Female ⌬F508/G542X 22 Female ⌬F508/G542X 11 Male ⌬F508/R553X 15 Female 621ϩ1G-T/R553X 27 Female ⌬F508/R553X 32 Female ⌬F508/Y1092X 28 Male ⌬F508/R1162X 11 Female ⌬F508/W1282X Mean yr (SD) 20.2 (8.9) M:F 5:6 (six separate stop alleles represented) Control subjects 8 Male ⌬F508/⌬F508 14 Male ⌬F508/⌬F508 16 Female ⌬F508/⌬F508 16 Female ⌬F508/⌬F508 16 Male ⌬F508/⌬F508 18 Female ⌬F508/⌬F508 18 Male ⌬F508/⌬F508 20 Male ⌬F508/⌬F508 20 Female ⌬F508/⌬F508 20 Male ⌬F508/⌬F508 24 Female ⌬F508/⌬F508 32 Female ⌬F508/⌬F508 35 Male ⌬F508/⌬F508 42 Female ⌬F508/⌬F508 29 Male ⌬F508/G551D 59 Female ⌬F508/2789ϩ5G-T 16 Male ⌬F508/3905InsT 15 Female ⌬F508/N1303K Mean yr (SD) 23.2 (12.3) M:F 9:9 ⌬F508/⌬F508: 14:18 were provided (with 25% overfill) at Days 0, 7, 42, and 49 for the premature stop group, and at Days 0 and 7 for the control group. Login to comment
165 (B) Low-power fields of nasal cells obtained from a normal subject, a patient with CF homozygous for the ⌬F508 CFTR mutation, and a subject with CF possessing a premature stop mutation (G542X/⌬F508). Login to comment
168 The final panel demonstrates minimal CFTR staining (G542X/⌬F508 subject). Login to comment
176 Figure 4 provides examples of cytoplasmic and surface CFTR staining of nasal cells brushed from normal control subjects, perinuclear CFTR staining from a ⌬F508/⌬F508 subject with CF, and sparse staining from a subject with CF heterozygous for a premature stop mutation (G542X/⌬F508; all staining shown was from cells isolated from subjects off of treatment). Login to comment
230 The four most common stop mutations (G542X, R553X, R1162X, W1282X CFTR) all contain a UGA codon, and all have been shown to be suppressed by aminoglycoside treatment in vitro using heterologous expression systems. Login to comment

PMID: 17375191 [PubMed] Daksis JI et al: "Heteropolymeric triplex-based genomic assay to detect pathogens or single-nucleotide polymorphisms in human genomic samples."

No. Sentence Comment

125 Sequence bglIR-WT25C 1 59-TATTTTGATTATAGGACATGAAGAT-39 DR01-WT15 2 59-GAGCCGAAGGGGCAG-39 CFTR delta F508-WT25C 3 59-TAGGAAACACCAAAGATGATATTTT-39 CFTR delta F508-MUT25C 4 59-ATAGGAAACACCA---ATGATATTTTCT-39 CFTR delta I507-WT25C 5 59-TAGGAAACACCAAAGATGATATTTT-39 CFTR delta I507-MUT25C 6 59-ATAGGAAACACCAAAGA---TATTTTCT-39 CFTR 3659delC-WT25C 7 59-TGGTTTGGTTGACTTGGTAGGTTTA-39 CFTR 3659delC-MUT25C 8 59-ATGGTTTGGTTGACTTG-TAGGTTTA-39 CFTR 3849+10kbCRT-WT25C 9 59-GTGTCTTACTCGCCATTTTAATACT-39 CFTR 3849+10kbCRT-MUT25C 10 59-GTGTCTTACTCACCATTTTAATACT-39 CFTR 2789+5GRA-WT25C11 59-AATAGGACATGGAATACTCACTTTC-39 CFTR 2789+5GRA-MUT25C 12 59-AATAGGACATGGAATATTCACTTTC-39 CFTR G551D-WT25C 13 59-ATTCTTGCTCGTTGACCTCCACTCA-39 CFTR G551D-MUT25C 14 59-ATTCTTGCTCGTTGATCTCCACTCA-39 CFTR 621+1GRT-WT25C 15 59-AAGTATTACCTTCTTATAAATCAAA-39 CFTR 621+1GRT-MUT25C16 59-AAGTATTAACTTCTTATAAATCAAA-39 CFTR R1162X-WT25C 17 59-AACTTAAAGACTCGGCTCACAGATC-39 CFTR R1162X-MUT25C 18 59-AACTTAAAGACTCAGCTCACAGATC-39 CFTR 1717-1GRA-WT25C 19 59-TGGAGATGTCCTATTACCAAAAATA-39 CFTR 1717-1GRA- MUT25C 20 59-TGGAGATGTCTTATTACCAAAAATA-39 CFTR A455E-WT25C 21 59-CCAGCAACCGCCAACAACTGTCCTC-39 CFTR A455E-MUT25C 22 59-CCAGCAACCTCCAACAACTGTCCTC-39 CFTR G542X-WT25C 23 59-ATTCCACCTTCTCCAAGAACTATAT-39 CFTR G542X-MUT25C 24 59-ATTCCACCTTCTCAAAGAACTATAT-39 CFTR N1303K-WT25C 25 59-TAGGGATCCAAGTTTTTTCTAAATG-39 CFTR N1303K-MUT25C 26 59-TAGGGATCCAACTTTTTTCTAAATG-39 CFTR R560T-WT25C 27 59-AGTTATTCACCTTGCTAAAGAAATT-39 CFTR R560T-MUT25C 28 59-AGTTATTCACGTTGCTAAAGAAATT-39 CFTR W1282X-WT25C 29 59-TTTCCTCCACTGTTGCAAAGTTATT-39 CFTR W1282X-MUT25C 30 59-TTTCCTTCACTGTTGCAAAGTTATT-39 MTHFR C677T-WT25C 31 59-TGATGATGAAATCGGCTCCCGCAGA-39 MTHFR C677T-MUT25C 32 59-TGATGATGAAATCGACTCCCGCAGA-39 FVL G1691A-WT25C 33 59-CCCTCTGTATTCCTCGCCTGTCCAG-39 FVL G1691A-MUT25C 34 59-CCCTCTGTATTCCTTGCCTGTCCAG-39 All 25-mer probes listed were antisense. Login to comment
704 Mutation Source Number of tests Percentage GC in probe sequence Percentage difference of mismatched TAF relative to perfect match TAF CFTR delta F508 blood 102 28% 2100% to 281% CFTR delta I507 blood 6 28% 2100% to 285% CFTR 3659delC blood 11 40% 2100% to 255% CFTR 3849+10kbCRT blood 9 36% 2100% to 282% CFTR 2789+5GRA blood 16 36% 2100% to 275% CFTR 2789+5GRA saliva 13 36% 2100% to 266% CFTR G551D blood 11 48% 2100% to 261% CFTR 621+1GRT blood 5 20% 2100% to 257% CFTR R1162X blood 6 44% 267% to 236% CFTR 1717-1GRA blood 12 32% 2100% to 258% CFTR A455E blood 9 60% 2100% to 289% CFTR G542X blood 6 36% 2100% to 260% CFTR N1303K blood 8 32% 2100% to 283% CFTR R560T blood 6 28% 2100% to 254% CFTR W1282X blood 14 36% 2100% to 274% MTHFR C677T blood 55 52% 2100% to 272% FVL G1691A blood 34 60% 2100% to 281% TAF indicates Triplex-Associated Fluorescence. doi:10.1371/journal.pone.0000305.t004 ..................................................................................... brighter when intercalated into complexes of identical short oligonucleotides, such as the probes used in our assay, than when a like number of YOYO-1 molecules were in the presence of genomic duplex DNA. Login to comment

PMID: 17394390 [PubMed] Lebo RV et al: "Testing and reporting ACMG cystic fibrosis mutation panel results."

No. Sentence Comment

141 Alternatively, when the genotype of a more closely related carrier has been reported, this information becomes the most informative (i.e., uncle is a ⌬F508 carrier rather than affected second cousin is a compound heterozygote for the ⌬F508 and the G542X mutations). Login to comment

PMID: 17394637 [PubMed] Sermet-Gaudelus I et al: "In vitro prediction of stop-codon suppression by intravenous gentamicin in patients with cystic fibrosis: a pilot study."

No. Sentence Comment

8 Results: After in vitro gentamicin incubation, the readthrough efficiency for the Y122X mutation was at least five times higher than that for G542X, R1162X, and W1282X. Login to comment
27 Methods Readthrough quantification in cell culture A dual gene reporter system was used to quantify the readthrough efficiency directed by the most frequent stop mutations in the French population (Y122X, G542X, R1162X and W1282X) [10], in the presence or absence of gentamicin. Login to comment
65 Table 1: Oligonucleotide sequences used in the dual reporter gene assay, corresponding to the Y122X, G542X, R1162X and W1292X mutations and the TQ in frame control. Login to comment
67 Readthrough level (%)* Mutation Oligonucleotides** 0 600 μg/ml gentamicin Y122X w 5' CGCTCTATCGCGTAACTAGGCATAGGC 3'; c 5' GCCTATGCCTAGTTACGCGATAGAGCG 3' 0.52 1.6 W1282X w 5` AATATAGTTCTTTGAGAAGGTGGAATC 3` c 5` GATTCCACCTTCTCAAAGAACTATATT 3` 0.115 0.35 R1162X w 5' CGATCTGTGAGCTGAGTCTTTAAGTTC 3'; c 5' GAACTTAAAGACTCAGCTCACAGATCG 3' 0.023 0.22 G542X w 5' ACTTTGCAACAGTGAAGGAAAGCCTTT 3'; c 5' AAAGGCTTCCTTCACTGTTGCAAAGT 3' 0.017 0.26 TQ: in frame control w 5' GCAGGAACACAACAGCAATTACAG 3' c 5' CTGTAATTGCTGTTGTGTTCCTGC 3' 100 100 *At least five independent experiments were performed with each construct and showed less than 20% variation. Login to comment
78 The R1162X and the G542X mutations yielded basal readthrough of less than 0.03% and increased by a factor of 10 and 15 respectively after gentamicin. Login to comment
79 The basal readthrough of W1282X was ~10 times higher than those of R1162X and G542X and tripled after gentamicin. Login to comment
80 Y122X had a basal readthrough level five times higher than that for the W1282X mutation, 22 times that for R1162X and 30 times that for G542X. Login to comment
81 After gentamicin incubation, Y122X readthrough efficiency remained at least 4.5 times higher than that for W1282X, six times that for G542X and 7.3 that for R1162X. Login to comment
85 Four had another stop mutation: one was homozygous for G542X, one for R1162X, and two were compound heterozygous for W1282X/F508del and R553X/CFTRdele17b (Group B). Login to comment
123 Genotype Sputum colonisation Age (year) Δscore FEV1var FVCvar FEF25-75var Sweat Cl- at D0 Sweat Cl- at D15 ΔCl-free-iso at D0 ΔCl-free-iso at D15 ICC Y122X+/+ SA 11 -4 24 23 31 126 91 0 0 - Y122X+/+ PA* 16 -2 -12 -6 -15 79 37 NP 0 - Y122X+/+ PA*,SA 18 -4 2 -2 -8 109 115 0 NP + Y122X+/+ PP* 15 -5 25 19 86 90 91 -0.5 0 + Y122X+/+ PP* 13 -15 18 8 96 103 46 -1.6 -3.8 + Y122X+/+ SA 22 -13 3 0 7 108 100 -3.7 -17.6 + Y122X+/+ BC* 21 -22 18 24 150 136 135 0 -4 + Y122X+/+ PA* 12 -12 3 -9 NP 119 86 0 -8.2 NP Y122X+/F508del SA* 10.5 -3 21 21 45 114 65 -1 -3.3 + R1162X +/+ SA 14 -2 0.4 0 4 116 131 0 0 - F508del/W1282X PA 13 -2 15 14 27 103 100 0 -1.3 NP G542X +/+ SA 11 -4 21 17 20 113 105 0 0 NP R553X/CFTRdele17b PA* 10 0 NP NP NP 115 NP -4 NP NP PA: Pseudomonas aeruginosa; SA: Staphylococcus aureus; PP: Pseudomonas putida; BC: Burkholderia cepacia; * bacteria resistant to gentamicin. Login to comment
172 In contrast, patients with mutations producing lower levels of translational readthrough in the cell culture assay (G542X, R1162X and W1282X) did not show significant changes in clinical status, chloride secretion in either the nasal or sweat gland epithelia after gentamicin treatment. Login to comment
192 The +4C nucleotide could account for the better response to gentamicin, because it is associated with greater readthrough efficiency, whereas the other mutations tested in our study, R1162X and G542X, imply a +4G nucleotide, which is associated with a poor readthrough [11]. Login to comment

PMID: 17413420 [PubMed] Grangeia A et al: "Molecular characterization of the cystic fibrosis transmembrane conductance regulator gene in congenital absence of the vas deferens."

No. Sentence Comment

93 DeltaF508 was the second most common mutation, representing 21 (23.3%) of total alleles, followed by R334W (6, Table 1 CFTR gene mutations and polymorphisms in patients with congenital absence of the vas deferens Mutation Location Nucleotide alteration Effect Method 1 CFTRdele2,3 Exons 2-3 Deletion of exons 2 and 3 Frameshift QFM-PCR 2 R117H Exon 4 G¡A at 482 AA substitution 31 mutation panel 3 P205S Exon 6a C¡T at 745 AA substitution DGGE/dHPLC 4 L206W Exon 6a T¡G at 749 AA substitution DGGE/dHPLC 5 R258G Exon 6b A¡G at 904 AA substitution DGGE/dHPLC 6 R334W Exon 7 C¡T at 1132 AA substitution 31 mutation panel 7 T5 allele Intron 8 Deletion of 2T at 1342-12 to -6 Aberrant splicing DGGE/DNA sequencing 8 P439S Exon 9 C¡T at 1447 AA substitution DGGE/dHPLC 9 D443Ya Exon 9 G¡T at 1459 AA substitution DGGE/dHPLC 10 I507del Exon 10 Deletion of 3 bp at 1648-1653 AA deletion 31 mutation panel 11 DeltaF508 Exon 10 Deletion of 3 bp at 1652-1655 AA deletion 31 mutation panel 12 G542X Exon 11 G¡T at 1756 Truncation 31 mutation panel 13 V562I Exon 12 G¡A at 1816 AA substitution DGGE/dHPLC 14 G576Aa Exon 12 G¡C at 1859 Aberrant splicing DGGE/dHPLC 15 D614G Exon 13 A¡G at 1973 AA substitution DGGE/dHPLC 16 R688Ca Exon 13 C¡T at 2134 AA substitution DGGE/dHPLC 17 V754M Exon 13 G¡A at 2392 AA substitution DGGE/dHPLC 18 E831X Exon 14a G¡T at 2623 Truncation DGGE/dHPLC 19 3272-26AϾG Intron 17a A¡G at 3272-26 Aberrant splicing DGGE/dHPLC 20 2789ϩ5G¡A Intron 14b G¡A at 2789ϩ5 Aberrant splicing 31 mutation panel 21 V1108L Exon 17b G¡C at 3454 AA substitution DGGE/dHPLC 22 L1227S Exon 19 T¡C at 3812 AA substitution DGGE/dHPLC 23 S1235R Exon 19 T¡G at 3837 AA substitution DGGE/dHPLC 24 P1290S Exon 20 C¡T at 4000 AA substitution DGGE/dHPLC 25 N1303K Exon 21 C¡G at 4041 AA substitution 31 mutation panel 26 E1401K Exon 23 G¡A at 4333 AA substitution DGGE/dHPLC Polymorphisms 1 TG repeats Intron 8 9-13 copies at 1342-12 to -35 Sequence variation DGGE/DNA sequencing 2 M470V Exon 10 A or G at 1540 Sequence variation DNA sequencing 3 125G/C Exon 1 G¡C at 125 Sequence variation DGGE/dHPLC 4 1001ϩ11T/C Intron 6b C¡4T at 1001ϩ11 Sequence variation DGGE/dHPLC 5 1716G/A Exon 10 G¡A at 1716 Sequence variation DGGE/dHPLC 6 1899-136T/G Intron 12 T¡G at 1899-136 Sequence variation DGGE/dHPLC 7 T854T Exon 14a T¡G at 2694 Sequence variation DGGE/dHPLC 8 3601-65C/A Intron 18 C¡A at 3601-65 Sequence variation DGGE/dHPLC 9 4521G/A Exon 24 G¡A at 4521 Sequence variation DGGE/dHPLC QFM-PCR, semiquantitative fluorescent multiplex polymerase chain reaction; bp, base pair; DGGE, denaturing gradient gel electrophoresis; dHPLC, denaturing high-performance liquid chromatography. Login to comment
97 The allelic frequency of the other mutations was 4.4% for R117H, G576A, and R668C, 3.3% for S1235R and 3272-26A¡G, and 2.2% for P205S, L206W, D443Y, G542X, D614G, and N1301K, whereas the remaining 12 mutations were present in single patients (Table 3). Login to comment
101 The missense M470V polymorphism was evaluated in all 45 pa- tientswithCAVD(Table2).TheallelicfrequencyoftheM470variant Table 2 CFTR genotypes identified in patients with congenital absence of the vas deferens CFTR mutation genotypes [(TG)mTn] genotype M470V Patients N % DeltaF508 (TG)10T9 (TG)12T5 M V 11 24.4 DeltaF508 (TG)10T9 (TG)11T5 M M 1 2.2 DeltaF508 R117H (TG)10T9 (TG)10T7 M M 2 4.4 G542X (TG)10T9 (TG)12T5 M V 2a 4.4 DeltaF508 R334W (TG)10T9 (TG)11T7 M V 1 2.2 DeltaF508 D443Y-G576A-R668C (TG)10T9 (TG)10T7 M M 1 2.2 DeltaF508 D614G (TG)10T9 (TG)11T7 M V 1 2.2 DeltaF508 E831X (TG)10T9 (TG)11T7 M V 1 2.2 DeltaF508 L1227S (TG)10T9 (TG)11T7 M M 1 2.2 DeltaF508 E1401K (TG)10T9 (TG)11T7 M V 1 2.2 I507del D614G (TG)11T7 (TG)10T7 M V 1 2.2 N1303K L206W (TG)10T9 (TG)9T9 M M 1 2.2 R117H P205S (TG)11T7 (TG)10T7 M V 1 2.2 R117H R334W (TG)10T7 (TG)11T7 M V 1 2.2 R334W P439S (TG)11T7 (TG)11T7 M V 1 2.2 R334W R334Wb (TG)11T7 (TG)11T7 V V 1 2.2 R334W V562I (TG)11T7 (TG)11T5 V M 1 2.2 D443Y-G576A-R668C 3272-26A¡G (TG)10T7 (TG)10T7 M M 1 2.2 G576A-R668C V754Mb (TG)10T7 (TG)11T7 M M 1 2.2 S1235R S1235Rb (TG)13T5 (TG)13T5 M M 1 2.2 2789ϩ5G¡A S1235Rb (TG)10T7 (TG)13T5 M M 1 2.2 3272-26A¡G P1290S (TG)11T7 (TG)10T7 M V 1 2.2 P205S (TG)11T7 (TG)12T5 V V 1 2.2 G576A-R668C b (TG)10T7 (TG)11T5 M M 1 2.2 V1108L b (TG)11T7 (TG)11T5 V M 1 2.2 N1303K (TG)10T9 (TG)12T5 M V 1 2.2 3272-26A¡G b (TG)10T7 (TG)12T5 M V 1 2.2 CFTRdele2,3 b (TG)11T7 (TG)13T5 V M 1 2.2 b (TG)11T5 (TG)12T5 M V 1 2.2 b (TG)13T5 (TG)12T5 M V 1 2.2 DeltaF508 - (TG)10T9 (TG)11T7 M V 1a 2.2 L206W -b (TG)9T9 (TG)11T7 M V 1 2.2 R258G -b (TG)11T7 (TG)11T7 V V 1 2.2 a CUAVD. Login to comment
110 Large Table 3 Allelic frequencies of CFTR mutations in patients with congenital absence of the vas deferens CBAVD CUAVD Total Patients 42 3 45 Alleles 84 6 90 Mutations N % N % N % 1 T5 allele 26a 31 2 33.3 28 31.1 2 DeltaF508 20 23.8 1 16.7 21 23.3 3 R334W 6a 7.1 0 0 6 6.7 4 R117H 4 4.8 0 0 4 4.4 5 G576A 4b 4.8 0 0 4 4.4 6 R688C 4b 4.8 0 0 4 4.4 7 S1235R 3a 3.6 0 0 3 3.3 8 3272-26A¡G 3 3.6 0 0 3 3.3 9 P205S 2 2.4 0 0 2 2.2 10 L206W 2 2.4 0 0 2 2.2 11 D443Y 2b 2.4 0 0 2 2.2 13 D614G 2 2.4 0 0 2 2.2 14 N1303K 2 2.4 0 0 2 2.2 12 G542X 0 0 2 33.3 2 2.2 15 R258G 1 1.2 0 0 1 1.1 16 P439S 1 1.2 0 0 1 1.1 17 I507del 1 1.2 0 0 1 1.1 18 V562I 1 1.2 0 0 1 1.1 19 V754M 1 1.2 0 0 1 1.1 20 E831X 1 1.2 0 0 1 1.1 21 2789ϩ5G¡A 1 1.2 0 0 1 1.1 22 V1108L 1 1.2 0 0 1 1.1 23 L1227S 1 1.2 0 0 1 1.1 24 P1290S 1 1.2 0 0 1 1.1 25 E1401K 1 1.2 0 0 1 1.1 26 CFTRdele2,3 1 1.2 0 0 1 1.1 CBAVD, congenital bilateral absence of the vas deferens; CUAVD, congenital unilateral absence of the vas deferens. Login to comment

PMID: 17471160 [PubMed] Huang CK et al: "Validation of cystic fibrosis mutation analysis using ABI 3130XL genetic analyzer."

No. Sentence Comment

58 Mutation controls: to specifically assess the detection of CF mutations, 20 cell line DNA samples with mutations of R553X, 3659delC/delF508, delF508/Q493X, 711+ 1G>T/621+1G>T, 621+1G>T/delF508, G85E/ 621+1G>T, R560T/delF508, A455E/621+1G>T, N1303K, W1282X, G551D/R553X, 2789+5G>A/ 2789+5G>A, 3849+10C>T/3849+10C>T, 1717-1G>A, delF508/delF508, R347P/G551D, R334W, V520F, R117H/delF508/5T/9T, or G542X/G542X, respectively, from the Coriell Cell Repositories were analyzed. Login to comment

PMID: 17510919 [PubMed] Ochshorn Y et al: "Clinical evaluation of isolated nonvisualized fetal gallbladder."

No. Sentence Comment

32 Mutation analysis for cystic fibrosis: The mutation panel included cystic fibrosis transmembrane conductance regulator (CFTR) mutations that are common in the Israeli population, including F508del, W1282X, N1303K, G542X, and D1152H. Login to comment

PMID: 17534127 [PubMed] Southern KW et al: "Cystic fibrosis and formes frustes of CFTR-related disease."

No. Sentence Comment

34 Interestingly, the most prevalent CFTR mutations aside from phe508del are thought to originate from ancient populations (G542X, Phoenicians [16]; G551D, Celtic [17], and 394delTT, Nordic [17]), though none approach the prevalence of phe508del. Login to comment
60 Classes of CFTR mutations, with molecular and phenotypic consequences Class Molecular consequence Example Phenotypic consequence I nonsense or frameshift mutations that result in no significant protein product G542X typical CF phenotype II protein product does not negotiate intracellular trafficking pathways phe508del R1066C A561E typical CF phenotype III protein product transported to the cell membrane but no significant ion transport function G551D typical CF phenotype IV protein product transported to cell membrane and functions at a low level R117H R334W associated with pancreatic sufficiency V reduced mRNA expression, protein product normal 5T variant of intron poly T region. Login to comment

PMID: 17541014 [PubMed] Rowe SM et al: "Restoration of W1282X CFTR activity by enhanced expression."

No. Sentence Comment

85 RESULTS Preferential Enhancement of CFTR Activity in W1282X CFTR Expressing Cells by Sodium Butyrate Previous studies have examined the function of several CFTR molecules containing clinically relevant premature stop codons in transient, high-level expression systems using nonpolarizing cell types (including G542X, R553X, R1162X, and W1282X CFTR), with variable levels of constitutive and regulated CFTR activity described (7, 8, 33). Login to comment
221 In previously published studies, our laboratory has reported that high-level expression of the two most common CFTR premature stop mutations G542X and R553X CFTR (using transient vaccinia-based expression in non-polarizing cells) led to constitutive halide transport function lacking cAMP-dependent regulation (8, 27). Login to comment

PMID: 17573513 [PubMed] Kaza V et al: "Correlation of chest radiograph pattern with genotype, age, and gender in adult cystic fibrosis: a single-center study."

No. Sentence Comment

62 Homozygous ⌬F508 38 F508/no ID 10 F508/G542X 4 F508/n3849 ϩ 10KBT 2 F508/N1303K 2 F508/G85E 2 F508/G551D 2 F508/R1179H 1 F508/3849 ϩ 10 KBC.T 1 F508/621ϩIG-T 1 F508/3659deltaC 1 F508/P67L 1 F508/2789 ϩ 5E 1 G551/LL48T 1 G551D/no ID 1 Total 68 570 our adult CF population was UL predominance; 26% of those homozygous for ⌬F508 (group I) and 30% of the other genotypes (group II) had the radiologic appearance of UL disease (Fig 2). Login to comment

PMID: 17579582 [PubMed] Limberis MP et al: "Activation of CFTR-specific T Cells in cystic fibrosis mice following gene transfer."

No. Sentence Comment

16 The first set of studies attempted to model the consequences of in vivo gene transfer in recipients void of CFTR -expression such as in those with two Class I CFTR gene -mutations, with CFTR being either deleted or substantially truncated (i.e., G542X).16 This clinical situation was modeled by delivering an adenovirus vector expressing hCFTR into mice homozygous for the germ line interruption of CFTR. Login to comment
133 The most common Class I CFTR mutation, which is also the next-to-most frequent mutation in Caucasian populations, is G542X.25 The premature stop codon in this CFTR mutation leads to the production of a truncated non-functional CFTR protein25 resulting in a significant repertoire of CFTR-specific T cells that escape central tolerance and are at risk of activation in the setting of CFTR gene therapy. Login to comment
286 CFTR nonsense mutations G542X and W1282X associated with severe reduction of CFTR mRNA in nasal epithelial cells. Login to comment

PMID: 17594398 [PubMed] Narzi L et al: "Does cystic fibrosis neonatal screening detect atypical CF forms? Extended genetic characterization and 4-year clinical follow-up."

No. Sentence Comment

48 CFTR genotypes, IRT2 and sweat test values of the 32 newborns analyzed Newborn CFTR genotype IRT2 Sweat test (mmol/l [Cl2 ]) at enrolment True heterozygous subjects 1 N1303K/1 Negative 18 2 2183AAtoG/1 Negative 11 3 G85E/1 Positive 19 4 F508del/1 Negative 21 5 F508del/1 Negative 20 6 R117H/1 Negative 6 7 1717-1GtoA/1 Positive 7 8 W1282X/1 Negative 14 9 278915GtoA/1 Negative 23 10 N1303K/1 Negative 19 11 F508del/1 Negative 14 12 G542X/1 Negative 39 % of positivity ¼ 16.7% Average Æ SD ¼ 18 Æ 9 Compound heterozygous subjects 13 F508del/D806G Positive 24 14 F508del/D836Y Negative 12 15 R347P/R1162L Negative 18 16 F508del/P5L (TG)11T5 Negative 16 17 F508del/L997F Positive 32 18 R347P/D1152H Positive 42 19 F508del/P5L Negative 42 20 278915GtoA/71113AtoG Positive 33 21 F508del/P5L Positive 39 22 F508del (TG)12T7/(TG)12T5 Negative 23 23 N1303K/S1235R (TG)12T7 Negative 30 24 F508del/L997F Positive 34 25 F508del/(TG)12T5 Negative 34 26 R117H/(TG)12T7 Positive 22 27 F508del/P1013L Positive 8 28 F508del/L997F Negative 28 29 N1303K/(TG)12T5 Positive 13 30 F508del/L997F Positive 50 31 R1162X/P5L Negative 31 32 L997F/S549R(AtoC) Positive 38 % of positivity ¼ 55.0% Average Æ SD ¼ 29 Æ 12 CFTR, cystic fibrosis transmembrane conductance regulator. Login to comment
75 Discussion The majority of the mutations found (F508del, R347P, D1152H, 2789 1 5G-.A, 711 1 3A-.G, N1303K, R117H, R1162X, S549R(A-.C), 2183AA-.G, G85E, 1717-1G-.A, G542X, and W1282X) have an established pathogenic role (26-44). Login to comment

PMID: 17627383 [PubMed] Knezevic J et al: "Analysis of cystic fibrosis gene mutations and associated haplotypes in the Croatian population."

No. Sentence Comment

2 Among 96 tested alleles, we found nine different mutations: ⌬F508, 58.33%; G542X, 3.12%; N1303K, 2.08%; R1162X; 621 ؉ 1G→T; G85E; Y569C; E585X; and S466X, 1.04%. Login to comment
5 Both of these haplotypes also carried a CFTR gene mutation (⌬F508 or G542X) on 27 out of 32 chromosomes. Among 12 (of all together 29) CF alleles on which no mutations were found, we detected 10 different haplotypes. Login to comment
11 Only four other mutations, G542X, G551D, N1303K, and W1282X, are relatively frequent in the European population (1-2.5%) (Morral et al., 1996). Login to comment
39 INNOGENETICS INNO-LIPA CFTR 12 and INNO-LIPA CFTR 7 ϩ Tn diagnostic kits were used to assess the presence of the 29 mutations in CF patients; ⌬F508, ⌬I507, G542X, N1303K, 1717-1G Ǟ A, W1282X, G551D, R553X, S1251N, R560T, 3905insT, Q552X, 394delTT, G85E, E60X, 621 ϩ 1G Ǟ T, R117H, 1078delT, R347P, R334W, 2143delT, 2183AA Ǟ G, 2184delA, 711 ϩ 5G Ǟ A, 2789 ϩ 5G Ǟ A, R1162X, 3659delC, 3849 ϩ 10kbC Ǟ T, and A455E. Login to comment
50 Nine different mutations were found: ⌬F508 (58.33%), G542X (3.12%), N1303K (2.08%), R1162X, 621 ϩ 1G Ǟ T, G85E, Y569C, E585X, and S466X (1.04%). Login to comment
76 Of three CFTR alleles with the G542X mutation, two had the 21-23-13 haplotype. Login to comment
81 MUTATIONS AND CORRESPONDING GENOTYPES OBSERVED IN A CROATION COHORT OF CF PATIENTS Number of affected Number of detected Mutation alleles (%) Genotype genotypes (%) ⌬F508 56 (58.33) ⌬F508/⌬F508 19 (39.58) G542X 3 (3.12)0 ⌬F508/Na 7 (14.58) N1303K 2 (2.08)0 ⌬F508/G542X 3 (6.25)0 R1162X 1 (1.04)0 ⌬F508/N1303K 2 (4.17)0 621ϩ1G→T 1 (1.04)0 ⌬F508/R1162X 1 (2.08)0 G85E 1 (1.04)0 ⌬F508/621ϩ1G→T 1 (2.08)0 Y569C 1 (1.04)0 ⌬F508/G85E 1 (2.08)0 E585X 1 (1.04)0 ⌬F508/Y569C 1 (2.08)0 S466X 1 (1.04)0 ⌬F508/E585X 1 (2.08)0 Na 29 (30.21) ⌬F508/S466X 1 (2.08) Na/Na 11 (22.92) Total 96b Total 48c aAlleles without mutation. Login to comment
89 The most frequent was ⌬F508 (65%), followed by G542X (5%), N1303K, and 1717-1G Ǟ A (3.3%). Login to comment
100 The two most often seen haplotypes (21-23-13 and 21-17-13) carried either ⌬F508 or G542X in 75% of tested chromosomes (27 out of 36). Login to comment
112 ASSOCIATION BETWEEN MICROSATELLITE HAPLOTYPES AND CFTR GENE MUTATIONS IN A CROATIAN COHORT OF CF PATIENTS Haplotype Number of haplotypesa (%) Mutationsb No mutationc 21-23-13 20 (40) ⌬F508 (15) 3 G542X (2) 21-17-13 12 (24) ⌬F508 (10) 2 21-25-13 3 (6)0 ⌬F508 (3) / 21-21-13 2 (4)0 ⌬F508 (1) / 621ϩ1G→T (1) / 20-23-13 2 (4)0 ⌬F508 (2) / 22-17-13 1 (2)0 ⌬F508 (1) / 22-16-13 1 (2)0 G85E (1) / 25-17-13 1 (2)0 1 25-16-14 1 (2)0 1 26-16-13 1 (2)0 1 21-16-13 2 (4)0 2 22-23-13 1 (2)0 1 23-23-13 1 (2)0 1 19-23-13 1 (2)0 1 22-16-17 1 (2)0 1 aNumber of alleles with the corresponding haplotype. Login to comment

PMID: 17700961 [PubMed] Quinton PM et al: "Too much salt, too little soda: cystic fibrosis."

No. Sentence Comment

30 Of the other mutations only a few occur with a frequency greater than 1%, including G542X (2.4%), G551D (1.6%), N1303K (1.3%), and W1282X (1.2%). Login to comment

PMID: 17718859 [PubMed] Faucz FR et al: "Cystic fibrosis in a southern Brazilian population: characteristics of 90% of the alleles."

No. Sentence Comment

20 We previously reported the mutation heterogeneity in Brazilian CF patients by direct analysis of F508del and four other common mutations (G542X, N1303K, G551D and R553X). Login to comment
55 Nine mutations showed a frequency higher than 1%, F508del (45.5%), G542X (6.3%), N1303K (4.5%), G85E, R334W and R1162X (3.6%), 2183AA.G and W1282X Table1.FrequenciesoftheCFTRmutations,theirmicrosatellitehaplotypesandIVS8-6(T)nallelesintheBrazilianCFpatientsa MutationExon/intron ChromosomesParana State/SantaCatarina State(total)%HaplotypesIVS8CA,IVS17bTA,IVS17bCA(n)(T)nlocus(n) DF508Exon1027/24(51)45.5416-7-17(1)/16-29-14(1)/16-31-13(1)/17-30-13 (1)/17-31-13(20)/17-32-13(7)23-31-13(15)/23-32-14 (1)/23-46-13(1)/25-30-13(1)/26-31-13(1)/unknown(1) 9T(44)/7T(3)unknown(4) G542XExon115/2(7)6.2523-32-13(1)/23-33-13(5)/23-34-13(1)9T(7) N1303KExon212/3(5)4.4616-30-13(1)/23-30-13(1)/23-31-13(3)9T(4)/7T(1) G85EExon32/2(4)3.5716-24-13(4)7T(4) R334WExon71/3(4)3.5716-34-13(1)/(16-48-13)(1)/17-33-13(1)/17-41-13(1)7T(3)/unknown(1) R1162XExon191/3(4)3.5717-31-13(4)7T(4) 2183AA.GExon131/2(3)2.6816-31-13(2)/16-31-14(1)7T(2)/unknown(1) W1282XExon201/2(3)2.6817-7-17(3)7T(2)/9T(1) R553XExon112/0(2)1.7817-44-11(1)/17-47-11(1)7T(1)/unknown(1) S4XExon11/0(1)0.89(16-__-13)(1)Unknown(1) 232del18Exon20/1(1)0.8921-36-13(1)Unknown(1) 62111G.TIntron41/0(1)0.89__-34-13(1)Unknown(1) 71111G.TIntron51/0(1)0.8916-25-13(1)7T(1) 71115G.AIntron51/0(1)0.89__-7-17(1)Unknown(1) R347PExon70/1(1)0.8916-32-13(1)7T(1) 1717-1G.AIntron101/0(1)0.8916-7-17(1)7T(1) 1717-8G.AIntron101/0(1)0.8916-33-13(1)9T(1) 1812-1G.AIntron111/0(1)0.8916-31-14(1)9T(1) A561EExon121/0(1)0.8916-44-13(1)7T(1) E585XExon121/0(1)0.89Unknown(1)7T(1) 189811G.AIntron120/1(1)0.8916-45-13(1)7T(1) G1069RExon17b1/0(1)0.8917-30-13(1)Unknown(1) Y1092XExon17b1/0(1)0.8916-30-137T(1) 3849110kbC.TIntron191/0(1)0.8916-7-17(1)7T(1) W1282GExon201/0(1)0.8916-32-14(1)7T(1) Unknown13/0(13)11.6016-7-17(1)/16-29-13(2)/16-30-13(1)/16-31-13 (1)/16-32-13(3)/16-33-13(1)16-34-13(1)/16-38-16 (1)/18-35-13(2) Unknown(13) Total112100 Ôn`,thetotalnumberofchromosomesbearingeachhaplotypeor(T)nlocus;Ôunknown`,usedwhenthehaplotype/(T)nlocuscannotbecharacterized;Ô_`,usedwhenaspecific alleleofthehaplotypecannotbecharacterized. Login to comment
90 Previously, such heterogeneity was indeed identified in Brazilian CF patients of European origin by the screening of five common mutations (F508del, G542X, N1303K, G551D and R553X) (13). Login to comment
96 Our mutational spectrum showed a certain similarity with that reported in the Italian population (F508del, 48.9%; G542X, 5.9%; N1303K, 5.9%; and 2183AA.G, 2.6%) (28). Login to comment
98 For example, common mutations in the Portuguese population show quite different frequencies (G542X, 1.3%; N1303K, 0.7%, and 2183AA.G, 0%) (10). Login to comment

PMID: 17850636 [PubMed] Girardet A et al: "Negative genetic neonatal screening for cystic fibrosis caused by compound heterozygosity for two large CFTR rearrangements."

No. Sentence Comment

34 If IRT at day 3 is positive (.65 ng/ml), the card is subjected to an ARMS Elucigen kit (Tepnel) testing for 30 common CF mutations (F508del, Y1092X, 1717-1G.A, G542X, W1282X, N1303K, 3849110kbC.T, 394delTT, 62111G.T, S1251N, G551D, R117H, R1162X, R334W, A455E, 2183AA.G, 3659delC, 1078delT, I507del, R347P, R553X, E60X, 1 8 1 1 11 . Login to comment

PMID: 17890437 [PubMed] Montgomery J et al: "Scanning the cystic fibrosis transmembrane conductance regulator gene using high-resolution DNA melting analysis."

No. Sentence Comment

202 With the exception of p.G551D and p.R553X, the melting profile of each genotype is distinct, including the G542X homozygote. Login to comment
9 The homozygotes p.G542X, c.2789 ؉ 5G>A, and c.3849 ؉ 10kbC>T were directly identified, but homozygous p.F508del was not. Login to comment
132 Furthermore, 3 homozygous disease-causing variants were identified in the blinded study: p.G542X, c.2789 ϩ 5GϾA, and c.3849 ϩ 10kbCϾT. Login to comment

PMID: 17901983 [PubMed] Gallego Romero I et al: "CFTR mutations and reproductive outcomes in a population isolate."

No. Sentence Comment

15 F508 accounts for up to 83% of CF mutations in northern European populations, and 66% of mutations worldwide, well above the 2.4% worldwide frequency of the second most common mutation, G542X, in CF patients (Zielenski and Tsui 1995). Login to comment

PMID: 17913891 [PubMed] Scott-Ward TS et al: "Chimeric constructs endow the human CFTR Cl- channel with the gating behavior of murine CFTR."

No. Sentence Comment

241 For example, gentamicin improves the survival of G542X CF mice (27) and rescues CFTR function in CF patients bearing stop codon mutations (28). Login to comment

PMID: 17914215 [PubMed] Van Biervliet S et al: "Serum zinc concentrations in cystic fibrosis patients aged above 4 years: a cross-sectional evaluation."

No. Sentence Comment

73 Table 1 Genotype of the 101 CF Patients: Details of the CF Mutations and Classification into Two Groups Genotype Groups Genotype No of Patients A ΔF508/ΔF508 47 ΔF508/E60X 1 ΔF508/G542X 7 ΔF508/N1303K 3 ΔF508/Q493X 1 ΔF508/1717-1G→A 1 ΔF508/Y1092X 1 ΔF508/394delTT 1 ΔF508/R785X 1 ΔF508/R553X 1 ΔF508/ΔI507 1 394delTT/394delTT 1 N1303K/N1303K 2 B ΔF508/3849+10kbC-T 1 ΔF508/306ΔTAGA 1 ΔF508/S1251N 8 ΔF508/L927P 1 G458V/1717-1G→A 1 ΔF508/I336K 2 G542X/622-2 A→C 1 ΔF508/G970R 3 ΔF508/3272-26A→G 2 ΔF508/R117H 2 ΔF508/2789+5G→A 2 1717-1G->A/S1251N 1 G542X/G970R 1 394delTT/Y913C 1 N1303K/deletion exon 19 1 Unidentified/unidentified 2 3600+2insTA/2005 del T 1 ΔF508/1898+1G→A 1 Deletion exon 2/del exon 2 1 There was no difference according to gender or age. Login to comment

PMID: 17949287 [PubMed] Lebo RV et al: "One multiplex control for 29 cystic fibrosis mutations."

No. Sentence Comment

103 For example, the Intron 10/Exon 11 fragment spans 5 common mutation sites: 1717-1G Ǟ A, G542X, G551D, R553X, and R560T, while the ⌬I507 and ⌬F508 mutations in Exon 10 overlap by one basepair and each delete three basepairs. Login to comment
105 Because the G551D and R553X mutations are within four basepairs, these mutations were also synthesized on independently cloned Intron 10/Exon 11 fragments, both of which carried three other mutations: 1717-1G Ǟ A, G542X, and R560T (Fig. 2, fragments 1 and 3). Login to comment
165 As part of this validation, two different Intron10/Exon11 fragments were sequenced and tested: both contain the 1717-1G Ǟ A, G542X, and R560T mutations, and the first also contains the G551D mutation (Fig. 2, clone 1; Fig. 3, f1), while the second also contains the R553X mutation (Fig. 2, clone 3; Fig. 3, f3). Login to comment
166 When tested individually, clone 1 hybridized uniquely to the G551D mutant allelic site as well as to the other three mutations (1717-1G Ǟ A, G542X, and R560T), but not to the wild-type (normal) R553 allelic site because the G551D mutation sequence interferes with the binding to the wild type R553 probe on the strip (Fig. 3, f1, left strip). Login to comment

PMID: 18272502 [PubMed] Du M et al: "PTC124 is an orally bioavailable compound that promotes suppression of the human CFTR-G542X nonsense allele in a CF mouse model."

No. Sentence Comment

2 Using a mouse model for cystic fibrosis (CF), we show that s.c. injection or oral administration of PTC124 to Cftr-/- mice expressing a human CFTR-G542X transgene suppressed the G542X nonsense mutation and restored a significant amount of human (h)CFTR protein and function. Login to comment
4 First, immunofluorescence staining showed that PTC124 treatment resulted in the appearance of hCFTR protein at the apical surface of intestinal glands in Cftr-/- hCFTR-G542X mice. Login to comment
6 These results indicate that PTC124 can effectively suppress the hCFTR-G542X nonsense mutation in vivo. Login to comment
12 Of these mutations, CFTR-G542X is the most common. Login to comment
24 Accordingly, in the present work we show that subcutaneous (s.c.) or oral administration of PTC124 suppressed the G542X mutation in a CF mouse model that expressed a human CFTR-G542X transgene in a Cftr-/- background, leading to a significant restoration of CFTR expression and function. Login to comment
26 Results Subcutaneous Injection of PTC124 Suppresses Nonsense Mutations and Induces hCFTR Expression in Cftr-/- hCFTR-G542X Mice. Login to comment
27 We constructed a CF transgenic mouse model that expressed a human CFTR (hCFTR) cDNA containing the G542X premature stop mutation in a mouse line that carried a knockout of the endogenous Cftr locus (referred to hereafter as the Cftr-/- hCFTR-G542X mouse line) (8). Login to comment
38 Because of these differences, we used the compact, intestine-specific rat fatty acid-binding protein (FABP) promoter to drive expression of the CFTR-G542X transgene. Login to comment
39 This Cftr-/- hCFTR-G542X mouse model was used to show that both gentamicin and amikacin could suppress the hCFTR-G542X mutation and partially restore CFTR protein expression and function (7, 8). Login to comment
40 To examine the ability of PTC124 to suppress the hCFTR-G542X mutation in vivo, once daily s.c. injections of PTC124 were administered to Cftr-/- hCFTR-G542X mice at dosages of 60, 30, or 15 mg/kg body weight for 14-21 days. Login to comment
45 Similarly, no hCFTR protein was detected in intestinal tissues from untreated Cftr-/- hCFTR-G542X mice with hCFTR-specific antiserum. Login to comment
46 However, strong hCFTR staining was observed at the apical surface of epithelial cells in submucosal glands from Cftr-/- hCFTR-G542X mice treated with 60 mg/kg PTC124 and, as observed, in tissues from mice treated with 34 mg/kg gentamicin. Login to comment
48 These results indicate that PTC124 can suppress the G542X mutation and partially restore hCFTR protein expression in Cftr-/- hCFTR-G542X mice. Login to comment
49 Subcutaneous Injection of PTC124 Partially Restores cAMP-Stimulated Chloride Channel Activity in Cftr-/- hCFTR-G542X Mice. Login to comment
51 We reported that cAMP-dependent transepithelial chloride conductance appeared in intestinal tissues of Cftr-/- hCFTR-G542X mice after treatment with 34 mg/kg gentamicin (7, 8). Login to comment
53 Supporting information (SI) Fig. 7 shows representative short-circuit current tracings obtained from Cftrϩ/ϩ mice, untreated Cftr-/- hCFTR-G542X mice, and Cftr-/- hCFTR-G542X mice treated with once daily s.c. injections of either 60 mg/kg PTC124 or 34 mg/kg gentamicin. Login to comment
54 The intestinal tissues harvested from untreated Cftr-/- hCFTR-G542X mice showed no change in short-circuit currents after the addition of forskolin, a cAMP agonist. Login to comment
55 In contrast, forskolin addition frequently induced an increase in short-circuit current in intestinal tissues from Cftr-/- hCFTR-G542X mice injected with 60 mg/kg PTC124 or 34 mg/kg gentamicin once a day for 14-21 days. Login to comment
56 Fig. 2 summarizes the data collected from short-circuit current measurements from intestinal tissues harvested from untreated Cftr-/- hCFTR-G542X mice, Cftr-/- hCFTR-G542X mice treated with three different dosages of PTC124 for 14-21 days, or Cftr-/- hCFTR-G542X mice treated with 34 mg/kg gentamicin for 14-21 days. Login to comment
58 In untreated Cftr-/- hCFTR-G542X mice, we detected cAMP-stimulated short-circuit currents in only 8% of samples (1 of 12), resulting in an average current of 0.20 ␮A/cm2 . Login to comment
59 In the Cftr-/- hCFTR-G542X mice treated with 60 mg/kg PTC124, 47% of samples (8 of 17) showed a positive reaction after the addition of forskolin, resulting in an average current of 1.66 ␮A/cm2 . Login to comment
60 Similarly, Cftr-/- hCFTR-G542X mice treated with 34 mg/kg gentamicin manifested cAMP-stimulated short-circuit currents in 63% of samples (5 of 8), resulting in an average current of 1.67 ␮A/cm2 . Login to comment
62 Samples were prepared from the duodenum of untreated Cftr-/- hCFTR-G542X mice and Cftr-/- hCFTR-G542X mice treated with 15, 30, or 60 mg/kg PTC124. Login to comment
63 Intestinal tissues from Cftr-/- hCFTR-G542X mice treated with 34 mg/kg gentamicin by the same administration protocol were also examined as a positive control. Login to comment
67 PTC124 to Cftr-/- hCFTR-G542X mice once daily by s.c. injection produced a statistically significant increase (P Ͻ 0.05) in cAMP-stimulated transepithelial chloride currents in intestinal tissues relative to untreated controls, resulting in 29% of the mean cAMP-stimulated short currents measured in wild-type mice. Login to comment
69 The s.c. administration of PTC124 at 30 or 15 mg/kg once daily did not show a significant increase in cAMP-stimulated short currents after forskolin addition relative to untreated Cftr-/- hCFTR-G542X mice, indicating that 60 mg/kg PTC124 is the minimal effective dose with this administration protocol. Login to comment
73 Oral Administration of PTC124 Partially Restores hCFTR Protein Expression and cAMP-Stimulated Chloride Channel Activity in Cftr-/- hCFTR-G542X Mice. Login to comment
74 The results above indicated that once daily s.c. injection of 60 mg/kg PTC124 suppressed the G542X mutation in Cftr-/- hCFTR-G542X mice and restored the expression of functional hCFTR protein. Login to comment
75 To determine serum levels resulting from this administration protocol, age-matched Cftrϩ/- hCFTR-G542X mice were injected with 60 mg/kg PTC124, and orbital blood was collected at various times after injection (Fig. 3A). Login to comment
78 Because of the potential for intestinal blockage in Cftr-/- hCFTR-G542X mice, these animals are routinely fed a liquid complete diet (Peptamen Complete Elemental Diet; Nestle´) upon weaning to promote survival. Login to comment
79 To identify an oral dose of PTC124 that might provide a therapeutic benefit, the compound was dissolved in the liquid diet at two concentrations (0.3 and 0.9 mg/ml) and given to Cftrϩ/- hCFTR-G542X mice as the sole source of food and water for 2-6 days. Login to comment
83 Because the average serum levels obtained by oral administration with these doses of PTC124 effectively bracketed the peak serum levels obtained immediately after s.c. injection and the optimal dosing established in the mdx studies, Cftr-/- hCFTR-G542X mice were fed the Peptamen liquid diet containing 0.3 or 0.9 mg/ml PTC124 for 14-21 days to determine whether this dosing protocol could lead to effective suppression of the G542X mutation. Login to comment
86 In mice maintained on Cftr-/- hCFTR-G542X Cftr+/+ UnTreated Gent 34mg/kg PTC124 60mg/kg PTC124 30mg/kg PTC124 15mg/kg UnTreated PTC124 60mg/kg Positive/Total Reactions 1/12 5/8 8/17 2/16 2/13 12/12 10/10 100% 5.78 0.48 101% Positive Reactions (%) 8% 63% 47% 13% 15% 100% Mean Current (µA/cm2 ) 0.20 1.67 1.66 0.29 0.12 5.72 P value - 0.023 0.034 0.36 0.36 - % WT Current 3.5% 29% 29% 5.1% 2.1% 100% ShortCircuitCurrent(µA/cm2 ) 0 2 4 6 8 10 12 14 Fig. 2. Login to comment
87 Effect of PTC124 s.c. injection on cAMP-stimulated transepithelial chloride currents in intestinal tissues from Cftr-/- hCFTR-G542X and Cftrϩ/ϩ mice. Login to comment
93 No hCFTR protein was detected in the intestines of treated Cftr-/- hCFTR-G542X mice with preimmune serum. Login to comment
95 These results indicated that oral administration of PTC124 could partially restore hCFTR protein expression in Cftr-/- hCFTR-G542X mice. Login to comment
97 We found that intestinal tissues harvested from Cftr-/- hCFTR-G542X mice fed the liquid diet with 0.3 mg/ml PTC124 yielded cAMP-stimulated short-circuit currents in 29% of intestinal tissues assayed (7 of 24), resulting in an average currents of 0.91 ␮A/cm2 . Login to comment
100 The mean cAMP-stimulated short-circuit currents observed in Cftr-/- hCFTR-G542X mice fed the liquid diet with 0.9 mg/ml PTC124 was 24% of the average cAMP-stimulated currents measured in wild-type mice. Login to comment
104 Finally, cAMP-stimulated short-circuit currents were not observed in Cftr-/- knockout mice that lacked the hCFTR-G542X transgene, regardless of whether they were untreated or treated with 0.9 mg/ml PTC124. Login to comment
105 This result confirmed that the CFTR function observed after PTC124 treatment depends on the presence of the hCFTR-G542X transgene, consistent with a role for PTC124 in inducing readthrough of premature translation termination codons. Login to comment
108 Hence, although PTC124 is thought to have a direct effect on nonsense codon readthrough (14), it is formally possible that the ability of the drug to suppress the hCFTR-G542X mutation is attributable to an effect on mRNA stability. Login to comment
109 However, RT-PCR analysis demonstrated that there were comparable levels of mRNA from the hCFTR-G542X transgene in untreated mice and in mice treated with 0.9 mg/ml PTC124 in the liquid diet (Fig. 6). Login to comment
118 (A) Blood was taken from different age-matched Cftrϩ/- hCFTR-G542X mice at the indicated times after s.c. injection of 60 mg/kg PTC124. Login to comment
119 (B) Blood samples were taken after feeding Cftrϩ/- hCFTR-G542X mice a liquid diet containing 0.3 or 0.9 mg/ml PTC124 for 2-6 days or Cftr-/- hCFTR-G542X mice a liquid diet containing 0.3 or 0.9 mg/ml PTC124 for 14-21 days. Login to comment
123 Samples were from the duodenum of Cftr-/- hCFTR-G542X mice treated with 0.3 or 0.9 mg/ml PTC124 in the Peptamen liquid diet. Login to comment
126 to Cftr-/- hCFTR-G542X mice by s.c. injection restored 29% of the normal intestinal transepithelial cAMP-stimulated short-circuit currents observed in Cftrϩ/ϩ mice. Login to comment
129 Our data indicate that the human CFTR protein produced by suppression of the nonsense mutation in Cftr-/- hCFTR-G542X mice is located primarily at the epithelial surface of the submucosal glands in the duodenum. Login to comment
131 To determine whether the suppressed level of CFTR expression can prevent the frequent intestinal blockage associated with the lack of functional CFTR protein, we are currently making a knockin Cftr-G542X mouse that will have a normal distribution of CFTR expression. Login to comment
132 We observed an occasional weak cAMP-stimulated current in intestinal tissues from Cftr-/- hCFTR-G542X mice in the absence of any treatment but not in Cftr-/- knockout mice that lacked the transgene (see Fig. 5). Login to comment
133 These data suggest that there may be a low level of endogenous readthrough of the premature stop codon in Cftr-/- hCFTR-G542X mice that we occasionally detect because such residual activity would not be observed in Cftr-/- knockout mice that lack the hCFTR-G542X transgene. Login to comment
134 Previous studies have shown that some nonsense codons (particularly UGA codons like that encoded by the G542X mutation) have a higher basal level of readthrough and are more susceptible to readthrough induced by aminoglycosides than other stop codons (19-21). Login to comment
140 In conclusion, our results demonstrate that PTC124 induces readthrough of the premature translation termination codon encoded by the hCFTR-G542X nonsense mutation, resulting in the partial restoration of CFTR protein and cAMP-activated chloride currents in the intestines of Cftr-/- hCFTR-G542X transgenic mice. Login to comment
142 Cftr-/- hCFTR-G542X Cftr+/+ Cftr-/- UnTreated PTC124 0.3mg/ml PTC124 0.9mg/ml UnTreated PTC124 0.9mg/ml UnTreated PTC124 0.9mg/ml 0/8 0/8 0% 0.00 - 0% 0% 0.00 - Positive/Total Reactions 2/16 7/24 5/11 12/12 0% 13/13 100% 6.15 0.35 108% Positive Reactions (%) 13% 29% 45% 100% Mean Current (µA/cm2) 0.20 0.91 1.35 5.72 P value - 0.021 0.027 - % WT Current 3.5% 16% 24% 100% ShortCircuitCurrent(µA/cm2 ) 0 4 8 12 16 ++++++++ 2 6 10 14 Fig. 5. Login to comment
143 Effect of PTC124 oral administration on cAMP-stimulated transepithelial chloride currents in intestinal tissues from Cftr-/- hCFTR-G542X, Cftrϩ/ϩ, and Cftr-/- mice. Login to comment
147 RT-PCR detection of hCFTR mRNA in untreated Cftr-/- hCFTR-G542X mice and Cftr-/- hCFTR-G542X mice treated with an oral dose of 0.9 mg/ml PTC124. Login to comment
149 The rat FABP promoter was used to drive expression of the hCFTR transgene that contained the G542X (UGA) premature stop mutation. Login to comment
150 The plasmid construction of the FABP-hCFTR-G542X transgene and generation of the Cftr-/- hCFTR-G542X mouse were described in refs. 7 and 8. Login to comment
153 Subcutaneous injections with the indicated doses of PTC124 or gentamicin were made in the hind limb of age-matched Cftr-/- hCFTR-G542X mice. Login to comment
156 Because of the potential for intestinal blockage in Cftr-/- hCFTR-G542X mice, they were maintained on a liquid diet (Peptamen) after weaning, and other food and water were withheld. Login to comment
190 To monitor expression of the hCFTR-G542X transgene, mRNA was isolated from intestinal tissues of untreated Cftr-/- hCFTR-G542X mice and Cftr-/- hCFTR-G542X mice treated with 0.9 mg/ml PTC124 in the liquid diet for 17 days. Login to comment
191 RT-PCR analysis of hCFTR-G542X mRNA was done by using a SuperScript III one-step RT-PCR system with platinum Taq polymerase (Invitrogen). Login to comment
193 The primers used to amplify a 1,557-bp fragment from the hCFTR-G542X mRNA were DB985 (5Ј-CAAGATAGAA AGAGGACAGT TGTT-3Ј) and DB986 (5Ј-TTGAGGGTTG ACATAGGTGC TTGAA-3Ј). Login to comment
217 Du M, et al. (2006) Clinical doses of amikacin provide more effective suppression of the human CFTR-G542X stop mutation than gentamicin in a transgenic CF mouse model. Login to comment
220 Du M, et al. (2002) Aminoglycoside suppression of a premature stop mutation in a Cftr-/- mouse carrying a human CFTR-G542X transgene. Login to comment

PMID: 18301294 [PubMed] Augarten A et al: "The changing face of the exocrine pancreas in cystic fibrosis: the correlation between pancreatic status, pancreatitis and cystic fibrosis genotype."

No. Sentence Comment

23 The mutations DF508, W1282X, G542X, S549R, Q359K/T360K, 405 + 1G, 1717, and N1303K were defined as severe and the mutations 3849 + 10 kb, D1152H, G85E, I1234V, R334W, and 5T were defined as mild/variable. Login to comment

PMID: 18304229 [PubMed] Sakamoto H et al: "Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutation associated with a congenital bilateral absence of vas deferens."

No. Sentence Comment

29 In our case, we analyzed exons 10 and 11 in the CFTR gene to evaluate the possibility of transmission of CF to newborn because common mutations such as D508, DI507, 551D, G542X, and R553X associated with CF in Caucasians was frequently identified in these exons.1 I556V found in the present case is a mutation initially reported in a French male who had asthma-like bronchopathy and chronic diarrhea, which was recently identified in 10% to 15% of Asians irrespective of chronic respiratory diseases.7 CBAVD is suggested based on the identification of azoospermia with either normal-sized or slightly smaller testes, a non-palpable vas deferens, characteristic imaging findings and the physical and biological properties of the ejaculate: small volume (<2 mL), low pH (<7), and low fructose concentration.1 Most CBAVD patients have defects in the derivatives of the wolffian duct system presenting as an absence of the distal portion of the epididymides, seminal vesicle atrophy or absence, and the absence of the vas deferens by scrotal and transrectal ultrasonography.4,5,9 However, not all men with CBAVD have extensive abnormalities of the derivatives of the wolffian duct system.5,9 Previous studies showed that seminal vesicle anomalies with either agenesis, hypoplasia, or cystic dysplasia occur in 36% to 92% of men with CBAVD.4-6,9 Jarvi et al. showed that all CBAVD patients with at least one CFTR gene mutation had abnormalities of both the seminal vesicles and ampulla of the vas deferens and that 50% of CBAVD patients with no detectable CFTR gene mutation had a normal ampulla of the vas deferens and seminal vesicles.5 Therefore, the frequency and severity of the wolffian duct malformations in the CBAVD patients may be related directly to the CFTR genotype.5 Moreover, previous studies report that 11% to 21% of CBAVD patients had renal agenesis.6,9 Renal agenesis has been reported to occur predominately in men with a congenital absence of vas deferens (CAVD) without CFTR gene mutations.9 However, Casales et al. showed CFTR gene mutations in five of 16 CAVD patients (bilateral absence in six, and unilateral absence in 10) with renal agenesis.6 In addition, CAVD may also be associated with cryptorchidism and inguinal hernia.6 The prevalence of the CFTR gene mutation carrier in the Japanese population may be approximate to that of the Caucasian.1,2 Moreover, infertile patients with CBAVD can now be treated by assisted reproduction technology.1 Genetic counseling may be recommended for any couple attempting assisted reproduction technology when the man has defects of the vas deferens.1-3,8 References 1 Jarzabek K, Zbucka M, Pepiñski W et al. Cystic fibrosis as a cause of infertility. Login to comment

PMID: 18306312 [PubMed] Gene GG et al: "N-terminal CFTR missense variants severely affect the behavior of the CFTR chloride channel."

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133 Genotype^Phenotype Correlation in the N-Terminal CFTR MissenseVariants Under StudyÃ Missense varianta Phenotype Second allele (number of patients)b p.P5L CF p.F508del (1), p.P205S (1) p.S50P CBAVD p.F508del (1), p.E115del (1) p.E60K CF p.G542X (1), p.I507del (1) p.R75Q HT p.F508del (3), p.E725K (1) B p.R347H (1), p.R75Q (1), n.i. (4) Br c.1584G4A (2), c.1210-7_1210-6delTT (1), n.i.(3) NT p.F508del (1) CP c.1584G4A (1), n.i. (3) MI n.i. (1) CUAVD n.i. (2) OZ n.i. (2) Normal p.R75Q (1), c.2052_2053insA (1), n.i. (1) p.G85E CF p.F508del (8), p.G542X (2), p.I507del (1), c.580-1G4T (1), p.G85E (1), c.1477_ 1478delCA (1) CBAVD p.G576A (1) HT p.L997F (1),WT (1) p.G85V CF p.F508del (2), p.G542X (2), p.Y1092X (1), c.265715G4A (1), p.A1006E, c.1210-7_1210- 6delTT (1), n.i. (1) p.Y89C CF n.i. (1)c p.E92K CF p.F508del (2), p.Q890X (1), p.L206W (1) CBAVD c.1210-7_1210-6delTT (1) ÃThe recommendations for mutation nomenclature (www.hgvs.org/mutnomen/) were used to name CFTR gene sequence variations at both the nucleotide level and the protein level. Login to comment

PMID: 18344710 [PubMed] Madore AM et al: "Distribution of CFTR mutations in Saguenay- Lac-Saint-Jean: proposal of a panel of mutations for population screening."

No. Sentence Comment

48 Altogether, the six mutations represent 95.89% of the CFTR allele of CF patients in the SLSJ population, whereas the proportions are 86.85, 85.27, and Table 2 Cystic fibrosis mutations present in the four populations studied Mutationa Allelic frequency (number of alleles [%]) Populationb 1 2 3 4 „F508 106 (62.35) 55 (72.37) 398 (72.36) 67 (57.78) 621 ؉ 1G>T 42 (24.71) 6 (7.89) 30 (5.45) 1 (0.85) A455E 12 (7.06) 2 (2.63) 14 (2.55) 1 (0.85) 3199del6 1 (0.59) 1 (1.32) 7 (1.27) 1 (0.85) 711 ؉ 1G>T 1 (0.59) 1 (1.32) 15 (2.73) 1 (0.85) Y1092X 1 (0.59) 1 (1.32) 5 (0.91) 0 R117C 2 (1.18) 0 0 0 ‚I507 1 (0.59) 2 (2.63) 10 (1.82) 0 L206W 1 (0.59) 1 (1.32) 9 (1.64) 0 R1158X 1 (0.59) 0 0 0 S489X 1 (0.59) 0 1 (0.18) 0 R553X 0 2 (2.63) 2 (0.36) 0 R334W 0 1 (1.32) 2 (0.36) 0 G542X 0 0 10 (1.82) 0 G85E 0 0 6 (1.09) 5 (4.24) N1303K 0 0 5 (0.91) 1 (0.85) IVS8-5T 0 0 4 (0.73) 0 W1282X 0 0 3 (0.55) 7 (5.93) R347P 0 0 1 (0.18) 2 (1.69) V520F 0 0 1 (0.18) 0 I1027T 0 0 1 (0.18) 0 R1066C/IVS 0 0 1 (0.18) 0 Q1313X 0 0 1 (0.18) 0 1898ϩ3GϾA 0 0 1 (0.18) 0 2183AAϾG 0 0 1 (0.18) 0 2951insA 0 0 1 (0.18) 0 G551D 0 0 0 2 (1.69) 1525-iG-A 0 0 0 2 (1.69) Y109C 0 0 0 1 (0.85) S549N 0 0 0 1 (0.85) 3154del1G 0 0 0 1 (0.85) UNKNOWN 1 (0.59) 4 (5.26) 20 (3.82) 25 (21.19) Number of alleles genotypedc 170 (100) 76 (100) 550 (100) 118 (100) a The six mutations included in the panels proposed are in bold. Login to comment

PMID: 18350634 [PubMed] Huang Q et al: "Comparative analysis of common CFTR polymorphisms poly-T, TG-repeats and M470V in a healthy Chinese population."

No. Sentence Comment

9 However, in Asians, the prevalence of CF is very low, with an incidence of approximately 1 in 100 000, and in particular, the severe mutations, such as ∆F508, G542X and N1303K, are rarely found in Asians. Login to comment

PMID: 18373402 [PubMed] Lakeman P et al: "CFTR mutations in Turkish and North African cystic fibrosis patients in Europe: implications for screening."

No. Sentence Comment

113 Identity and Frequency of CFTR Mutations on Unrelated Turkish (Tr) and North African (NA) CF alleles Total number of allelesa Number of CF patients with this mutationb Mutation Exon All Tr NA Homozygote Compound heterozygote: two mutations found Compound heterozygote: one mutation found F508delc 10 73 33 40 27 11 6 N1303K 21 22 12 10 10 5 2 711 þ 1G > T Intron 5 14 - 14 7 2 0 G542X 11 14 6 8 7 1 0 R1162X 19 11 - 11 1 5 2 2183AA > G 13 9 9 - 3 3 1 W1282X 20 7 3 4 2 3 1 2789 þ 5G > A Intron 14b 6 3 3 1 4 1 L227R 6a 4 - 4 3 1 0 1677delTA 10 4 4 - 2 1 1 2184insA 13 4 4 - 1 2 0 R334W 7 4 4 - 1 1 1 G85E 3 4 3 1 1 2 0 R709X 13 3 - 3 2 0 0 L732X 13 3 3 - 2 0 0 2184delA 13 3 3 - 0 3 0 del exon 1-4d 1-4 3 3 - 1 1 0 del exon 19 19 2 2 - 2 0 0 3849 þ 10kbC > T Intron 19 2 - 2 1 0 0 S549N 11 2 1 1 0 1 1 3120 þ G > A Intron 16 2 2 - 1 0 0 3601-2A > G Intron 18 2 2 - 1 0 0 D1152H 18 2 2 - 1 0 0 E1104X 17b 2 - 2 1 0 0 S1159F 19 2 2 - 1 0 0 S977F 16 2 - 2 0 1 0 2347delG 13 2 - 2 1 0 0 4096-3C > G Intron 21 1 1 - 1 0 0 E831X 14a 1 1 - 1 0 0 L619S 13 1 1 - 1 0 0 1525-1G > Ac Intron 9 1 1 - 1 0 0 F1052V 17b 1 1 - 1 0 0 3130delA 17a 1 1 - 1 0 0 R352Q 7 1 - 1 0 1 0 1812-1G > A Intron 11 1 - 1 0 1 0 R553X 11 1 - 1 0 0 1 IVS8-5T Intron 8 1 1 - 0 1 0 R1066C 17b 1 - 1 0 1 0 3129del4 17a 1 - 1 0 1 0 D110H 4 1 1 - 0 1 0 R117H 4 1 - 1 0 1 0 S945L 15 1 - 1 0 1 0 1716G=A 10 1 - 1 0 0 1 711 þ 3A > G Intron 5 1 1 - 0 1 0 R75X 3 1 1 - 0 1 0 R764X 13 1 - 1 0 1 0 S1196X 19 1 1 - 0 1 0 S492F 10 1 - 1 0 1 0 G551D 11 1 - 1 1 0 0 del exon 2 2 1 1 - 1 0 0 Subtotal 231 113 118 - No mutation 80 63 17 - Total 311 176 135 88 60 18 a n ¼ 311 alleles, based on 166 CF patients (332 alleles) with both parents and 22 CF patients (22 alleles) with one parent from Turkey or North Africa, minus 43 alleles of homozygous CF patients with consanguineous parents of whom only one allele was taken into account. Login to comment

PMID: 18470946 [PubMed] Berwouts S et al: "Evaluation and use of a synthetic quality control material, included in the European external quality assessment scheme for cystic fibrosis."

No. Sentence Comment

143 Two of the laboratories that saw this weak signal for wild-type R553X (c.1657C4T, p.Arg553X) also reported weak mutant signals for Q552X (c.1654C4T, p.Gln552X) or G542X (c.1624G4T, p.Gly542X), possibly indicating DNA overload. Login to comment
153 These very faint signals for wild-type R553X (c.1657C4T, p.Arg553X), wild-type R117H (c.350G4A, p.Arg117His), mutant G542X (c.1624G4T, p.Gly542X), and mutant A455E (c.1364C4A, p.Ala455Glu) signal were often not visible to the assessors on the copies of the raw data. Login to comment
157 ErrorTypes for the QCS in More Detail, for the LaboratoriesThat Used Only One Detection AssayÃ Genotype error Genotype Detection assay Number of labs Expected Reported Comment OLA-CFASR v2.0 1 R117 H hom ^ Correct on raw data INNO-LiPA CFTR36 1 R117 H hom R117 H het No signal for wt R117 H visible on copy of the raw data, could be very weak on original raw data INNO-LiPA CFTR36 1 R553X hom R553X het No signal for wt R553X visible on copy of the raw data, could be very weak on original raw dataI507del hom I507del/F508del Sequencing 2 R347 H hom ^ No complete raw data received Sequencing 1 I507del hom ^ No raw data received Additional mutation(s) reported Detection assay Number of labs Additional mutation(s) Comment OLA-CFASR v3.0 US 1 2184delAa hom Software called it INNO-LiPA CFTR36 3 A455E het (3labs), F508del (1lab) No signal for mut A455E visible on copy of the raw data, could be very weak on original raw data ARMS-ElucigeneTM CF29 3 2184delAa (3labs), R347P (3labs), 1717-1G4A (3labs), 3849110kbC4T (2labs) Cross reaction with 2183AA4Gb and R347 H and no full compatibility of MMQCI-CF-P1and ARMS method: no control bands visible ARMS-ElucigeneTM CF29 1CF-HT 1 2184delAa , R347P Cross reaction with 2183AA4Gb and R347H Sequencing 1 W1282X het, N1303 K het No raw data received ASPE-CFTR 4014 Tag-It 1 71111G4T het No raw data received Genotype error 1 additional mutation(s) reported Genotype Detection assay Number of labs Expected Reported Comment Additional mutation(s) Comment OLA-CFASR v3.0 EU 1 R117 H hom ^ No raw data received; probably 2183AA4Gb missed, but 2184delAa reported due to cross reaction 2184delAa hom No raw data received, probably due to cross-reaction with 2183AA4Gb 394delTTc hom 394delTTc het 2183AA4Gb hom ^ INNO-LiPA CFTR36 1 R553X hom I507del hom R553X het I507del/ F508del No signal for wt R553X visible on copy of the raw data, could be very weak on original raw data G542X het A455E het No signal for mut G542X and mut A455E visible on copy of the raw data, could be very weak on original raw data INNO-LiPA CFTR36 1 Italian regional 1 R553X hom R553X het No signal for wt R553X visible on copy of the raw data, could be very weak on original raw data Q552X het Misinterpretation: wt and mut signal for Q552X not visible, but this is a normal reaction pattern when R553X is hom present; the lab reported R553X het ARMS-ElucigeneTM CF29 1 I507del hom ^ No full compatibility of MMQCI- CF-P1 and ARMS method: no control bands R347P Cross-reaction with R347H2183AA4Gb hom ^ ÃIf the zygosity is not mentioned in the table, the laboratory did not report it. Login to comment
191 For example, reporting the weak bands for wild-type R553X (c.1657C4T, p.Arg553X) and R117 H (c.350G4A, p.Arg117His), mutant G542X (c.1624G4T, p.Gly542X) and A455E (c.1364C4A, p.Ala455Glu) seen by some of the laboratories using the INNO-LiPA assay could be explained in this respect. Login to comment

PMID: 18490773 [PubMed] Maiuri L et al: "Tissue transglutaminase activation modulates inflammation in cystic fibrosis via PPARgamma down-regulation."

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35 Materials and Methods Human airway biopsies and ex vivo cultures Nasal polyp explants from 10 CF patients carrying the common CFTR mutations (⌬F508/⌬F508, ⌬F508/W1282X, ⌬F508/N1303K, or ⌬F508/G542X) and 10 non-CF patients with nonallergic idiopathic polyposis were cultured, for 4-24 h (9), with or without specific TG2 inhibitors 1,3-dymethyl-2-[(2-oxopropyl) thio] imidazolium (R283) (250 ␮M) (12) or halo-dihydroisox- azole-derivate transglutaminase inhibitor KCC009 (250 ␮M), reactive oxygen species (ROS) scavenger EUK 134 (50 ␮g/ml; Alexis Biochemical), N-acetylcysteine (NAC, 10 mM; Alexis Biochemical), PPAR␥ antagonist GW9662 (1 ␮M; Alexis Biochemical), or R283 for 24 h, followed by GW9662 (1 ␮M) for 4 h. Informed consent was obtained from all subjects, and the ethical committee of Regione Campania Health Authority approved the study. Login to comment
36 Cell lines and cultures IB3-1 (human CF bronchial epithelial cell line with the common ⌬F508/ W1282X CFTR mutation) and C38 (isogenic stably rescued with functional CFTR) cell lines (LGC Promochem) (2, 7, 10) were stimulated for 6 h with R283 (250 ␮M) or KCC009 (250 ␮M), ionomycin (1 ␮M; Calbiochem), BAPTA-AM (5 ␮M, Calbiochem), EUK 134 (50 ␮g/ml), rosiglitazone (10 ␮␮), NAC (10 mM), proteasome inhibitor MG132 (50 ␮M for 6 h; Calbiochem), or R283 for 24 h, followed by 6-h rosiglitazone. Login to comment

PMID: 18506640 [PubMed] Voter KZ et al: "Diagnosis of cystic fibrosis."

No. Sentence Comment

114 Figure reproduced from Ref. [6], with permission Table 7 Classes of CFTR gene mutations associated with CF disease Mutation class Mechanism of action Examples I Absence of protein synthesis because of a stop codon in the gene G542X II Improper folding and processing ΔF508 III Reduced response to regulatory molecules G551D IV Reduce ion conductance R117H V Decreased protein production due to splice defects or promoter mutations 3,849+10 kb C→T VI Decreased protein stability Q1412X 104 measurement of transepithelial ion flow in the nasal mucosa [28-30]. Login to comment

PMID: 18535191 [PubMed] Adler AI et al: "Genetic determinants and epidemiology of cystic fibrosis-related diabetes: results from a British cohort of children and adults."

No. Sentence Comment

54 Genotypes associated with cystic fibrosis were coded into five established classes reflecting CFTR function of defective production, processing, regulation, conductance, and quantity of CFTR protein (12) as follows: I: G542X, R553X, W1282X, R1162X, 621-1G3T, 1717- 1G3 A, 1078⌬T, and 3659⌬C; II: ⌬F508, ⌬I507, N1303K, and S549N; III: G551Dand R560T; IV: R117H, R334W, G85E, and R347P; V: 3849ϩ5G3A, and A455E; and unknown: 711ϩIG3 T, 2184DA, and 1898ϩIG3 A. Login to comment

PMID: 18567645 [PubMed] Radpour R et al: "Genetic investigations of CFTR mutations in congenital absence of vas deferens, uterus, and vagina as a cause of infertility."

No. Sentence Comment

36 Examples include the G542X, G551D, R553X, W1282X, and N1303K mutations. Login to comment

PMID: 18616886 [PubMed] Tamburino L et al: "Molecular analysis of mutations and polymorphisms in the CFTR gene in male infertility."

No. Sentence Comment

136 Cystic fibrosis transmembrane regulator (CFTR) and IV.S8-Poly T genotypes according to semen parameters. Semen analysis Group 1 Total Group !l Total Group m TutuI Group IV Total CFTR genotype AF508/- AF508/- 2789+5G_^A/- N13O3K/- G542X/- - / - - / - - / - AF508/- AF508/R1I7H» NI3Ü3K/- 3849+ 10kbC_T/3849+1 O k b C ^ P - / - -/_ - / - AF5O8/- N1303K/- 3849+!0kbC-+T/- - / - - / - - / - - / - - / - - / - AF508/- N1303K/- 3849+10kbC->T/- I148T/- WI282X/- - / - - / - _/_ - / - - / - -/_ genotype 5T/9T 7T/9T 7T/7T 5T/9T 5T/9T 5T/7T 5T/9T 7T/7T 7T/9T 7T/9T 7T/9T 7T/7T 5T/7T 7T/7T 7T/9T 5T/9T 7r/7T 7T/9T 5T/5T 5T/7T 5T/9T 7T/7T 7T/9T 9T/9T 7T/9T 7T/9T 7T/7T 7T/9T 7T/7T 5T/5T 5T/7r 5T/9T 7T/7T 7T/9T 9T/9T No. Login to comment

PMID: 18639722 [PubMed] Farrell PM et al: "Guidelines for diagnosis of cystic fibrosis in newborns through older adults: Cystic Fibrosis Foundation consensus report."

No. Sentence Comment

142 Recommended panel of CF-causing mutations Missense, deletion, stop mutations Splicing, frameshift mutations G85E I507del R560T 621ϩ1GϾT 2789ϩ5GϾA R117H F508del R1162X 711ϩ1GϾT 3120ϩ1GϾA R334W G542X W1282X 1717-1GϾA 3659delC R347P G551D N1303K 1898ϩ1GϾA 3849ϩ10kbCϾT A455E R553X 2184delA Revised from the mutation panel for population screening for CF developed by the ACMG.77 Additional or alternative mutations present at significant frequencies in an ethnic population served by an NBS program may be added. Login to comment

PMID: 18647844 [PubMed] Webb EM et al: "Colonic wall redundancy at CT in patients with cystic fibrosis."

No. Sentence Comment

86 In particular, the G542X mutation was seen exclusively in patients with colonic wall redundancy (three [30%] of 10 patients, P ϭ .06). Login to comment
96 * Non-⌬F508 gene mutations include G542X, 3905insT, R347P, 711ϩ1GϾT, 3120ϩ1GϾA, W1282X, and 1161delC. Login to comment
126 The next most common mutation, G542X, accounts for only 2.4% of mutations (13). Login to comment

PMID: 18685558 [PubMed] Dequeker E et al: "Best practice guidelines for molecular genetic diagnosis of cystic fibrosis and CFTR-related disorders--updated European recommendations."

No. Sentence Comment

144 A (T)5 variant can either be associated with (TG)11, (TG)12, (TG)13, and rarely (TG)15 repeats.74 When (T)5 is found in diagnostic testing, for example, for CBAVD or atypical presentation, determination of Table 4 Classification of CFTR mutations with regard to their potential for causing disease Mutation group Examples CF-causing F508del Mainly nonsense, frameshift, splicing (invariant dinucleotide): G542X, R553X, W1282X, 2183AA4G, 3659delC, 1717-1G4A, 3120+1G4A Missense that severely affects CFTR synthesis or function: G551D, N1303K, R347P 2789+5G4A, 3849+10kbC4T, 3272-26A4G, L206Wa , D1152Ha , (TG)13(T)5a CFTR-related disorders associated L206Wa , D1152Ha , (TG)13(T)5a [R117H;(T)7], (TG)12(T)5, L997F, V562I, [R668C;G576A;D443Y], [R74W;D1270N] (TG)11(T)5b , S1235Rb No clinical consequences 875+40A4G, M470V (1540A4G), I506V (1648A4G), F508C (1655T4G), 1716G4A, 2694T4G, 4002A4G, 2752-15G4C (TG)11(T)5b , S1235Rb Unproven or uncertain clinical relevance Mainly missense mutations G622D, R170H, V938G, I125T Putative splice mutations: 406-6T4C, 2752-26A4G, 3601-17T4C Only a fraction of mutations and patients have been characterized in detail and, with the exception of frequent mutations, only small numbers of patients have been available for the study of most mutations. Login to comment

PMID: 18782298 [PubMed] Sharma N et al: "Identification and characterization of CFTR gene mutations in Indian CF patients."

No. Sentence Comment

41 Seven other mutations were searched for by either single ARMS PCR (R117H, N1303K, and R553X) or by multiplex ARMS PCR (621 + 1G-T, G542X, G551D, W1282X). Login to comment

PMID: 18782827 [PubMed] Kukavica-Ibrulj I et al: "Animal models of chronic lung infection with Pseudomonas aeruginosa: useful tools for cystic fibrosis studies."

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167 Finally, a transgenic KO model expressing a human CFTR with the G542X mutation under the control of the intestinal fatty-acid-binding protein (FABP) gene promoter has been generated and used to study the effect of aminoglycosides on suppression of this CFTR premature stop mutation (Du et al. 2002). Login to comment
170 Table 2 Cystic fibrosis (CF) mouse models CF mice Mutation/molecular strategy Phenotype/limitation CFTR KO CFTRtm1Unc (Snouwaert et al. 1992) Exon 10 replacement, null mutation, inframe stop Severe intestinal phenotype and high mortality; no lung disease CFTRtm1Hgu (Dorin et al. 1992) Exon 10 insertional mutagenesis Intestinal blockage; minor pathology in lungs of one mouse CFTRtm1Cam (Ratcliff et al. 1993) Exon 10 replacement, null mutation Severe intestinal phenotype and high mortality; pathology in lacrimal gland and pancreas of some mice; no lung disease CFTRtm1Bay (O`Neal et al. 1993) Exon 3 insertional duplication, null mutation Severe intestinal phenotype and high mortality; no lung disease CFTRtm1Hsc (Rozmahel et al. 1996) Exon 1 replacement, null mutation Severe intestinal phenotype and high mortality; no lung disease Other mutations CFTRtm1Kth (Zeiher et al. 1995) DF508 by exon 10 replacement High mortality and reduction in size, variable pathology of the gastrointestinal tract, normal lung, pancreas, gallbladder, male reproductive tract, lacrimal gland and submandibular glands CFTRtm1Eur (van Doorninck et al. 1995, French et al. 1996) DF508 by exon 10 'hit and run` Normal survival, growth retarded but no abnormalities or stasis of inspissated mucus in lungs, pancreas, liver bile ducts, vas deferens and salivary glands CFTRtm1G551D (Delaney et al. 1996) G551D by exon 11 replacement Moderate phenotype with reduced incidence of intestinal blockage and 67% survival; no lung disease CFTRtm2Hgu (Dickinson et al. 2000) G480C by exon 10 'hit and run` Normal survival, no reduction in body weight, preserved cAMP-mediated Cl2 response, decreased Ca2þ -related Cl2 response CFTR2/2hCFTR-G542X (Du et al. 2002) CFTR2/2 null mutation that also express a human CFTR-G542X stop mutation under control of the intestinal FABP promoter Suppression of the hCFTR-G542X mutation in vivo by aminoglycosides CFTRtm1Unc -TgN(FABPCFTR) (Zhou et al. 1994) Stop codon in the murine CFTR gene (S489X) but also express human CFTR in the gut epithelium (transgenic introduction of CFTR under FABP promoter) Functional correction of ileal goblet cell and crypt cell hyperplasia and cyclic adenosine monophosphate-stimulated chloride secretion, improved survival Congenic C57BL/6J CFTR2/2 (Durie et al. 2004) Long-lived congenic C57BL/6J CFTR2/2 All organs pathologically affected by the human form of CF Scnn1a-, Scnn1b- and Scnn1c-transgenic mice (Mall et al. 2004) Transgenic mice overexpressing airway-specific ENaC to increase Naþ absorption CF-like lung disease FABP: fatty acid-binding protein, ENaC: epithelial Naþ channels. Login to comment

PMID: 18810634 [PubMed] Sharma N et al: "Implication of the cystic fibrosis transmembrane conductance regulator gene in infertile family members of Indian CF patients."

No. Sentence Comment

40 1G-T, G542X, G551D, and W1282X by multiplex ARMS PCR (Ferrie et al. 1992). Login to comment

PMID: 18951463 [PubMed] Krasnov KV et al: "Localization studies of rare missense mutations in cystic fibrosis transmembrane conductance regulator (CFTR) facilitate interpretation of genotype-phenotype relationships."

No. Sentence Comment

140 As for the remaining R1070W patients (8/24 with detailed clinical information), five individuals carried a CFTR mutation associated with pancreatic insufficiency (2869insG (c.2737insG, p.Tyr913fs); G542X (c.1624G4 T, p.Gly542X); R668C-K710X (c. Login to comment

PMID: 18953248 [PubMed] Frulloni L et al: "Clinical and radiological outcome of patients suffering from chronic pancreatitis associated with gene mutations."

No. Sentence Comment

31 All patients were tested for 25 CFTR gene mutations ($F508, $I507, R117H, R1162X, 2183AAYG, N1303K, 3849 + 10KbCYT, G542X, G551D, 1717-1GYA, R347P, R352Q, R553X, Q552X, G85E, 711 + 5GYA, W1282X, 3272-26AYG, 3132delTG, R334W, I148T, 3659del_C, 3120 + 1GYA, 1898 + 1GYA, and 2789 + 5GYA), which cover approximately 72% of the cystic fibrosis mutations in the Italian population. Login to comment

PMID: 19014821 [PubMed] Soultan ZN et al: "Sweat chloride testing in infants identified as heterozygote carriers by newborn screening."

No. Sentence Comment

54 Sweat [Cl- ] and the results of genetic screening of 11 patients with [Cl- ] > 24 mmol/L Patients Sweat [Cl- ] mmol/L Mutations Poly T-TG Repeats 1 89 91 R347P CFTRdel 17a-18 7T/9T 2 85 82 ⌬F508 2622ϩ1 GϾT 9T/9T 3 71 - G542X Y1014del 7T/9T 4 69 65 ⌬F508 c.759AϾG 9T/7T 5 58 49 ⌬F508 L206W 9T/9T 6 44 27 ⌬F508 R352W, P750L - 7 38 41 ⌬F508 - 9T-TG10 5T-TG12 8 24 - ⌬F508 - 9T-TG10 5T-TG12 9 25 27 ⌬F508 - 9T-TG10 5T-TG12 10 24 25 ⌬F508 - 9T-TG12 5T-TG12 11 35 26 ⌬F508 - 9T 9T Soultan et al The Journal of Pediatrics • December 2008 should be followed. Login to comment

PMID: 19092437 [PubMed] Moskowitz SM et al: "Clinical practice and genetic counseling for cystic fibrosis and CFTR-related disorders."

No. Sentence Comment

31 Pulmonary disease is the major cause of morbidity and Table 1 Classification scheme for CFTR mutations112 Mutation class Effect on CFTR protein Mechanisms I Reduced or absent synthesis Nonsense, frameshift, or splice junction mutations II Block in protein processing Missense mutations or amino acid deletions III Block in regulation of CFTR chloride channel Missense mutations IV Altered conductance of CFTR chloride channel Missense mutations V Reduced amounts of functioning CFTR protein Missense or splice junction mutations Table 2 Phenotypes of 10 most common CFTR alleles in whites with CF41 Mutation Relative frequency (%)a Functional classb Phenotypec ⌬F508 66.0 II Classic G542X 2.4 I Classic G551D 1.6 III Classic N1303K 1.3 II Classic W1282X 1.2 I Classic R553X 0.7 I Classic 621ϩ1GϾT 0.7 I Classic 1717-1GϾA 0.6 I Classic R117H 0.3 IV Nonclassic R1162X 0.3 Not cleard Classic a Calculated using total CFTR alleles as the denominator. Login to comment
56 Liver disease is second to pulmonary disease (plus organ transplantation complications) as a cause of mortality in CF (1.7% of deaths).26 Table 3 Core mutation panel carrier recommended by the ACMG for routine CF diagnostic testing and carrier screening of the general population7 Intronic mutations Exonic mutations Missense Nonsense In-Frame Deletion 621ϩ1GϾT G85E G542X ⌬I507 711ϩ1GϾT R117H R553X ⌬F508 1717-1GϾA R334W R1162X 1898ϩ1GϾA R347P W1282X 2184delA A455E 2789ϩ5GϾA G551D 3120ϩ1GϾA R560T 3659delC N1303K 3849ϩ10kbCϾT Endocrine manifestations of CF CF-related diabetes mellitus (CFRDM) may present in adolescence. Login to comment

PMID: 19136563 [PubMed] Du M et al: "Poly-L-aspartic acid enhances and prolongs gentamicin-mediated suppression of the CFTR-G542X mutation in a cystic fibrosis mouse model."

No. Sentence Comment

35 Printed in the U.S.A. MARCH 13, 2009•VOLUME 284•NUMBER 11 JOURNAL OF BIOLOGICAL CHEMISTRY 6885 an increased and prolonged level of suppression of the CFTR-G542X nonsense mutation in a CF mouse model. Login to comment
55 Mice and Treatment Protocols-The CFTR-G542X mice used in this study contained the Cftrtm1Cam knock-out (20) and expressed a human CFTR transgene with the G542X premature stop mutation (3, 4, 21) (referred to as Cftr-/- hCFTR-G542X mice). Login to comment
57 Transcription of the hCFTR-G542X transgene was driven by the rat intestinal fatty acid-binding protein promoter. Login to comment
114 PAA Enhances Gentamicin-induced Readthrough in Cftr-/- hCFTR-G542X Mice-We previously reported that once daily subcutaneous injections of 5 mg/kg gentamicin or 15 mg/kg amikacin resulted in suppression of the hCFTR-G542X mutation and a partial restoration of CFTR protein and function in Cftr-/- hCFTR-G542X mice (4). Login to comment
117 Because our in vitro results indicated that the co-administration of gentamicin plus PAA enhanced suppression, we next investigated whether PAA could enhance the readthrough of a nonsense mutation by a low dose of gentamicin in Cftr-/- hCFTR-G542X mice. Login to comment
121 To systematically examine the effect of PAA on readthrough of the hCFTR-G542X nonsense mutation, Cftr-/- hCFTR-G542X mice were included in six different treatment groups as shown in Fig. 4A. Treatments consisted of subcutaneous injections of 5 mg/kg gentamicin alone or 5 mg/kg gentamicin plus 70 mg/kg PAA delivered once daily in a hind limb. Login to comment
122 Groups 1-3 contained Cftr-/- hCFTR-G542X mice that were treated as indicated for 14 days. Group 1 contained control mice that were left untreated for 14 days. Group 2 contained mice treated with gentamicin alone for 14 days, whereas group 3 contained Cftr-/- hCFTR-G542X mice that were administered gentamicin plus PAA for 14 days. Login to comment
124 Groups 4-6 contained Cftr-/- hCFTR-G542X mice that were again treated for 14 days as described above, followed by a 4-day chase period before assays were performed. Login to comment
134 PAA Enhances CFTR Nonsense Codon Readthrough 6888 JOURNAL OF BIOLOGICAL CHEMISTRY VOLUME 284•NUMBER 11•MARCH As controls, both wild type mice (Cftrϩ/ϩ , group 8) and Cftr knock-out mice without the hCFTR-G542X transgene (Cftr-/- , group 10) were treated with gentamicin plus PAA for 14 days with continuing administration of PAA for another 4 days. Login to comment
136 The results of short circuit current measurements from the 10 different treatment groups of Cftr-/- hCFTR-G542X, wild type mice, and Cftr-/- mice are shown in Fig. 4B. A summary and statistical analysis of short circuit currents from the 10 different treatment groups are shown in Table 2. Login to comment
137 The results from group 1 (untreated Cftr-/- hCFTR-G542X mice) revealed that 11% of samples (3/28) exhibited cAMP-stimulated short circuit currents, resulting in an average current of only 0.2 ␮A/cm2 . Login to comment
138 The infrequent response observed in untreated Cftr-/- hCFTR-G542X mice may be attributable to a low baseline level of endogenous readthrough of the hCFTR-G542X transgene, because these currents are not observed in Cftr-/- mice that do not carry the transgene, as shown below and discussed in a previous report (21). Login to comment
151 Effect of gentamicin treatment (؎PAA) on cAMP-activated transepithelialchloridecurrentsinintestinaltissuesfromCftr-/- hCFTR-G542X. Login to comment
152 A, diagram of different treatment groups of Cftr-/- hCFTR-G542X mice, as well as wild type (Cftrϩ/ϩ ) and Cftr-/- controls. Login to comment
157 Cftr-/- hCFTR-G542X Cftr؉/؉ Cftr-/- Group 1 Group 2 Group 3 Group 4 Group 5 Group 6 Group 7 Group 8 Group 9 Group 10 Treatment (14 days) None Gent Gent PAA Gent Gent PAA Gent PAA None Gent PAA None Gent PAA Chase (4 days) No No No Yes Yes Yes ϩPAA No Yes ϩPAA No Yes ϩPAA Positives/total 3/28 9/26 8/18 1/12 6/17 9/18 14/15 13/14 0/8 0/8 Positives (%) 11 35 44 8 35 50 93 93 0 0 Mean current (␮A/cm2 ) 0.2 0.7 1.1 0.13 1.2 2.1 5.0 5.9 0 0 p value (relative to group 1)a Ͻ0.05 Ͻ0.05 0.35 Ͻ0.05 Ͻ0.01 p value (relative to group 4)b Ͻ0.05 Ͻ0.05 Wild type current (%) 4 14 22 3 24 42 100 118 0 0 a p values of mean currents measured in groups 2-6 are relative to the mean current measured in group 1. b p values of mean currents measured in groups 5 and 6 are relative to the mean current measured in group 4. Login to comment
161 When considered together, these results indicate that the co-administration of PAA significantly increases the average cAMP-stimulated short circuit current induced by gentamicin in hCFTR-G542X mice. Login to comment
168 Together, these results confirmed that the CFTR activity that appears following gentamicin (or gentamicin plus PAA) treatment is dependent upon the presence of the hCFTR-G542X transgene. Login to comment
187 Samples from the duodenum of Cftr-/- hCFTR-G542X mice were incubated with either preimmuneserumorCFTR-NBD1serum.Afterincubationofthesamplewithafluorescentsecondaryantibody, the samples were visualized by fluorescence microscopy. Login to comment
197 Our results with Cftr-/- hCFTR-G542X mice suggest that the higher level of accumulated intracellular gentamicin also remains accessible for ribosome binding in vivo, because the co-administration of gentamicin with PAA had a stimulatory effect on readthrough of the hCFTR-G542X mutation. Login to comment
200 These results are consistent with our in vitro readthrough results and strongly suggest that PAA co-administration increases the intracellular aminoglycoside concentration accessible to ribosomes in the intestinal tissues of Cftr-/- hCFTR-G542X mice. Login to comment
202 When Cftr-/- hCFTR-G542X mice were administered gentamicin for 14 days and then left for 4 days without treatment, we found that the CFTR protein and activity was reduced to a negligible level (3% of the mean wild type cAMP-activated short circuit current). Login to comment
204 Because readthrough of the CFTR-G542X mutation probably ceases shortly after the gentamicin treatment is terminated, this loss of CFTR activity probably reflects the turnover of the hCFTR protein synthesized during the treatment period. Login to comment
208 These results demonstrate that the co-administration of gentamicin with PAA not only enhances the suppression of the hCFTR-G542X nonsense mutation in Cftr-/- hCFTR-G542X mice but also extends the time period during which hCFTR activity and protein can be detected following the termination of gentamicin treatment. Login to comment

PMID: 19181743 [PubMed] Sharma N et al: "Heterogenous spectrum of CFTR gene mutations in Indian patients with congenital absence of vas deferens."

No. Sentence Comment

55 We next screened R117H, N1303K and R553X each by single ARMS PCR and 621 þ 1G-T, G542X, G551D and W1282X by multiplex ARMS PCR. Login to comment

PMID: 19277125 [PubMed] Scambi C et al: "Preliminary evidence for cell membrane amelioration in children with cystic fibrosis by 5-MTHF and vitamin B12 supplementation: a single arm trial."

No. Sentence Comment

73 Patient Gender Age (yr) CFTR mutations BMI (kg/m2) FEV1 (%) Pancreatic sufficiency M.o. in sputum Antibiotic treatment 1 M 8 DF508/DF508 17,29 81 no no no 2 F 7 DF508/DF508 21,7 101 no P. aeruginosa C azithromycin p.o. tobramycin neb. 3 F 6 DI507/711+5G A 22,5 91 no no no 4 F 5 DF508/not identified 15,2 NA no no no 5 M 8 DF508/DF508 15,4 92 no no no 6 M 7 N1303K/2789+5G A 19,2 73 no no no 7 F 7 DF508/621+1G T 15,1 82 no S. aureus no 8 F 8 DF508/1717-1G T 18,3 91 no S. aureus no 9 F 8 DF508/not identified 21,2 95 yes no no 10 F 7 DF508/2789+5G A 14,4 93 no no no 11 M 8 DF508/2789+5G A 15,9 106 yes no no 12 F 7 R1162X/R1162X 17,15 78 no S. aureus no 13 M 8 DF508/not identified 15,2 63 no no no 14 M 6 DF508/DF508 17,1 115 no P. aeruginosa I ciprofloxacin p.o. tobramycin neb. 15 F 8 DF508/R1162X 14 49 no P. aeruginosa C azithromycin p.o. tobramycin neb. 16 M 5 G542/1717-1G A 16,5 NA no no No 17 F 5 DF508/not identified 13,3 NA no P. aeruginosa I ciprofloxacin p.o. tobramycin neb. 18 M 4 DF508/G542X 15,7 NA no no no 19 F 7 DI507/R1162X 16,5 94 no no no 20 F 4 DF508/Q552X 13,5 NA no no no 21 M 8 DF508/R1162X 13,8 78 no no no 22 F 6 2183AA G/N1303K 16,8 102 no no no P.: Pseudomonas; S.: Staphylococcus; H.: Haemophilus; C: chronic colonization; I: intermittent colonization; NA: not applicable; p.o.: per os; neb.: nebulized. Login to comment

PMID: 19372188 [PubMed] Bickmann JK et al: "A novel approach to CFTR mutation testing by pyrosequencing-based assay panels adapted to ethnicities."

No. Sentence Comment

62 We had initially focused on CF mutations potentially prevalent in our local, ethnically mixed, but mainly German population: F508del, I507del, 1677delTA, R347P, G542X, G551D, R553X, N1303K, 1717-1GϾA, 3849ϩ10kb CϾT, CFTRdele2,3 (21 kb), R117H, 1342-6 (T)n (5T/7T/9T) (reported by our laboratory only if a R117H allele was present, unless genetic analysis served to investigate a case of CBAVD or atypical mild CF), and the (TG)n region starting at base position 1342-12 of IVS 8 (exclusively tested in the case of a 5T allele) (Fig. 1, boldface text), with an expected sensitivity of 85% among German patients. Login to comment
100 Diagnostic evaluation of the PSQ-based first-level testing of a predominantly German CF population.a Panethnic population Clinical diagnosis All patients Sweat test-confirmed CF Suspected atypical CF Carrier screening Chromosomes, n 310 184 96 30 PSQ screen 168 (54.2%) 158 (85.9%) 5 (5.2%) 5 (33.3%) Conventional sequencing 25 (8.1%) 25 (13.6%) 0 (0%) 0 (0%) Total detected alleles 193 (62.3%) 183 (99.5%) 5 (5.2%) 5 (33.3%) German ethnicity Other ethnicities Clinical diagnosis Sweat test-confirmed CF Sweat test-confirmed CF Chromosomes, n 146 38 PSQ screen F508del 106 (72.6%) 14 (36.8%) I507del 1 (0.7%) 1 (2.6%) 1677delTA 0 (0%) 2 (5.3%) G551D 6 (4.1%) 0 (0%) R553X 2 (1.4%) 0 (0%) Q552X 1 (0.7%) 0 (0%) G542X 2 (1.4%) 1 (2.6%) S549N 0 (0%) 2 (5.3%) W1282X 1 (0.7%) 3 (7.9%) R117H 1 (0.7%) 0 (0%) 1342-12 (TG)11-5T 0 (0%) 0 (0%) R347P 2 (1.4%) 1 (2.6%) 3849ϩ10kb CϾT 2 (1.4%) 0 (0%) N1303K 3 (2.1%) 3 (7.9%) 1717-1 GϾA 1 (0.7%) 0 (0%) CFTRdele2,3 (21 kb) 2 (1.4%) 1 (2.6%) Sum 130 (89.0%) 28 (73.7%) Conventional sequencing 16 (11.0%) 9 (23.7%) Total detected alleles 146 (100%) 37 (97.4%) a Data are presented as the number of chromosomes (percent). Login to comment
118 An example of the integration of a mutation that was not primarily targeted (S549N) into a PSQ assay for G542X. Login to comment
119 The G542X (1756 GϾT) assay had originally been designed to include adjacent but rare mutations G544S (1762 GϾA) and G544V (1763 GϾT), with the sequence to analyze reaching as far as base 1783. Login to comment
123 See Fig. 1 in the online Data Supplement for example pyrograms of a wild-type sample and heterozygous samples for G542X and S549N. Login to comment
153 The fact that simultaneously detecting some mutations (e.g.: F508del, 1677delTA, and I507del; G542X and S549N; or G551D, R553X, and Q552X) within a single assay improves the sensitivity of each PSQ run underlines even further the advantages that arise from detecting neighboring mutations as well as the target mutation within one assay (Table 2). Login to comment

PMID: 19381016 [PubMed] Choi JY et al: "Substance P stimulates human airway submucosal gland secretion mainly via a CFTR-dependent process."

No. Sentence Comment

279 Genotypes were available for 8 of the CF subjects; 5 were ΔF508 homozygous, with 1 of each of the following: ΔF508/N1303K, G542X/W1282X, and 406-1 G->A/H119Y. Login to comment

PMID: 19431193 [PubMed] Levy H et al: "IL1B polymorphisms modulate cystic fibrosis lung disease."

No. Sentence Comment

111 The other 12% of the CFTR mutations included G551D, G542X, G85E, W1282X, and N1303K. Login to comment

PMID: 19443567 [PubMed] Elce A et al: "Three novel CFTR polymorphic repeats improve segregation analysis for cystic fibrosis."

No. Sentence Comment

105 The 98 chromosomes from non-CF individuals were associated with 59 differ- enthaplotypes.Similarly,mostfrequentCFTRmutations are associated with more haplotypes (26 different haplotypes for the 90 chromosomes bearing the F508del mutation, 13 alleles for the 20 chromosomes bearing the N1303K mutation, and 7 haplotypes for the 10 chromosomes bearing the G542X mutation). Login to comment

PMID: 19625650 [PubMed] Luciani A et al: "SUMOylation of tissue transglutaminase as link between oxidative stress and inflammation."

No. Sentence Comment

77 Patients and ex vivo cultures of nasal polyp mucosal biopsies Seven consecutive CF patients carrying the common CFTR mutations (F508del/F508del, F508del/W1282X, F508del/N1303K, or F508del/ G542X) (mean age, 19 years; range, 13-29 years) with chronic sinusitis and nasal polyposis and seven consecutive non-CF patients (mean age, 21 years; range, 16-32 years) with idiopathic polyposis underwent surgical treatment. Login to comment
78 Patients and ex vivo cultures of nasal polyp mucosal biopsies Seven consecutive CF patients carrying the common CFTR mutations (F508del/F508del, F508del/W1282X, F508del/N1303K, or F508del/ G542X) (mean age, 19 years; range, 13-29 years) with chronic sinusitis and nasal polyposis and seven consecutive non-CF patients (mean age, 21 years; range, 16-32 years) with idiopathic polyposis underwent surgical treatment. Login to comment

PMID: 19648261 [PubMed] Montgomery GS et al: "Cystic fibrosis."

No. Sentence Comment

31 Twelve of the most common mutations account for 85% of CF genotypes in North American patients and include deltaF508, G542X, G551D, W1282X, W1303K, and R553X. Login to comment

PMID: 19734129 [PubMed] Gonska T et al: "Sweat gland bioelectrics differ in cystic fibrosis: a new concept for potential diagnosis and assessment of CFTR function in cystic fibrosis."

No. Sentence Comment

68 Table 1 Summary of study subjects ID Category Sex Age Genotype ID Category Sex Age Genotype 1 HC F 49 +/+ 21 CFPS M 46 deltaF508/P67L 2 HC F 39 +/+ 22 CFPS F 41 deltaF508/R117C 3 HC M 32 +/+ 23 CFPS F 57 G542X/D1152H 4 HC M 23 +/+ 24 CFPS M 34 deltaF508/M1101K 5 HC F 28 +/+ 25 CFPS F 29 deltaF508/L1335P 6 HC M 26 +/+ 26 CFPS F 48 deltaF508/+ 7 HC M 26 R75Q/+ 27 CFPS M 26 deltaF508/R117H 8 HC M 30 +/+ 28 CFPS M 44 deltaF508/3272_26A.G 9 HC M 22 +/+ 29 CFPS M 46 deltaF508/R117H 5T 10 HC M 22 +/+ 30 CFPS M 48 R347P/2753-2A.G 11 Hz F 26 deltaF508/+ 31 CFPI M 29 deltaF508/deltaF508 12 Hz F 54 deltaF508/+ 32 CFPI M 29 deltaF508/2194inA 13 Hz F 24 deltaF508/+ 33 CFPI F 40 G551D/621+1 G.T 14 Hz F 33 deltaF508/+ 34 CFPI M 33 deltaF508/deltaF508 15 Hz M 25 deltaF508/+ 35 CFPI M 27 deltaF508/deltaF508 16 Hz F 37 deltaF508/+ 36 CFPI M 25 deltaF508/deltaF508 17 Hz F 49 deltaF508/+ 37 CFPI M 27 deltaF508/deltaF508 18 Hz M 49 deltaF508/+ 38 CFPI M 29 deltaF508/deltaF508 19 Hz F 55 deltaF508/+ 20 Hz M 61 deltaF508/+ CFPI, pancreatic-insufficient CF patients; CFPS, pancreatic-sufficient CF patients; HC, healthy controls; Hz, heterozygotes. Login to comment

PMID: 19759008 [PubMed] Faa V et al: "Characterization of a disease-associated mutation affecting a putative splicing regulatory element in intron 6b of the cystic fibrosis transmembrane conductance regulator (CFTR) gene."

No. Sentence Comment

39 The CF genotype of the three patients was F508del/unknown, G542X/unknown, and exon 2 deletion (c.545811_164ϩ2186del8108ins182)/unknown (18). Login to comment

PMID: 19760540 [PubMed] Lommatzsch ST et al: "Genetics of cystic fibrosis."

No. Sentence Comment

63 The most common muta- Table 1 Most Common Genotype Based on Ethnicity Ethnicity Genotype Chromosome Frequency (%) Caucasian (N. European) ~F508 70-80 Caucasian (S. European) ~F508 50-55 African Americans ~F508 48 3120 þ 1 G-to-A 12 Ashkenazi Jews W1282X 48 ~F508 30 Hispanic (U.S.) ~F508 46 G542X 5.4 Adapted from Knowles et al.13 534 SEMINARS IN RESPIRATORY AND CRITICAL CARE MEDICINE/VOLUME 30, tion in this group is ~F508, which results in >99% of the protein being degraded as opposed to $75% in the normal individual.8 This mutation causes a three-base pair deletion in exon 10 specifically affecting the integral tertiary interaction between the N-terminus of NBD-1 and C-terminus of transmembrane segment-4 regulating CFTR channel gating.5,6,25 Interestingly, the ~F508 CFTR has been found to be a ''temperature sensitive`` mutant given that, in vitro, it can be delivered by gene therapy vectors to the apical membrane if cells are incubated at 23 to 308C.9,13 Class III and IV mutations typically confer more mild disease. Login to comment

PMID: 19774621 [PubMed] Penmatsa H et al: "Clinical and molecular characterization of S1118F-CFTR."

No. Sentence Comment

21 The Class I mutations constitute nonsense, splice and frame shift mutants that encode truncated forms of CFTR (e.g., G542X and W1242X). Login to comment

PMID: 19780730 [PubMed] Massie J et al: "Population-based carrier screening for cystic fibrosis in Victoria: the first three years experience."

No. Sentence Comment

103 Although we have promoted the uptake of CF carrier screening to both partners in the relationship it is evident Table 1 Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations identified in 2006-2008 CFTR gene mutation n p.508del 96 W1282X 5 c.3718-2477C > T 5 p.G551D 3 p.G542X 1 p.N1303K 1 p.507del 1 p.R560T 1 p.R553X 1 c.489+1G > T 1 p.V520F 0 c.1585-1G > A 0 Total 115 Carrierscreeningforcysticfibrosis (c)2009TheAuthors487 Journalcompilation(c)2009TheRoyalAustralianandNewZealandCollegeofObstetriciansandGynaecologists;49:484-489 Table 2 Carrier couples detected by cystic fibrosis population screening program, Victoria 2006-2008 Subjects Timing of CF carrier test (gestation) Conception Parents genotype Counselling Prenatal diagnosis Status of pregnancy Future plans 1 Pre-pregnancy Natural Both Genetic counsellor and CF physician CVS 12 weeks Termination of pregnancy 2008: Second pregnancy: CVS: carrier p508delp.508del Affected (p.508del/p.508del) 2 10 weeks Natural Both Genetic counsellor and CF physician CVS 12 weeks Continued p.508del Unaffected (no mutations) 3 11 weeks Natural Both Genetic counsellor CVS 13 weeks Continued p.508del Carrier (p.508del/-) 4 10 weeks Natural Both Genetic counsellor CVS 13 weeks Continued p.508del Carrier (p.508del/-) 5 11 weeks Natural Both Genetic counsellor CVS 13 weeks Continued p.508del Unaffected (no mutations) 6* 9 weeks IVF Both Genetic counsellor and CF physician CVS 12 weeks Termination of pregnancy Currently undergoing IVF conception with PGD.p.508del Affected (p.508del/p.508del) 7 Pre-pregnancy Not applicable Both Genetic counsellor and CF physician CVS 12 weeks Continued Did not attend PGD, established natural pregnancy 2 months after seen by genetic counsellor and respiratory physician p.508del Carrier p.508del 8** Pre-pregnancy Not applicable Both Genetic counsellor Not applicable Not applicable Likely to pursue PGD p.508del 9*** Pre-pregnancy Not applicable c.3718-2477C > T, Genetic counsellor and CF physician Not applicable Not applicable Likely to pursue PGD p.W1282X *This couple had an IVF pregnancy but were not offered carrier screening until nine weeks gestation. Login to comment
38 The following 12 mutations were screened using a polymerase chain reaction multiplex: p.508del, p.G551D, p.G542X, p.N1303K, c.1585-1G > A, p.I507del, p.R560T, p.W1282X, p.V520F, c.489+1G > T, p.R553X and c.3718-2477C > T. Login to comment

PMID: 19843100 [PubMed] Burgel PR et al: "Non-classic cystic fibrosis associated with D1152H CFTR mutation."

No. Sentence Comment

42 The CF genetic analysis panel used in France seeks for 32 mutations: G85E, 394delTT, 621+1G>T, 711+1G>T, R334W, R347P, R347H, 1078delT, 5T/7T/9T, A455E, F508del, I507del, V520F, 1717-1G>A, G542X, G551D, R553X, R560T, S549R (T>G), S549N, 1898+1G>A, 2183AA>G, 2184delA, 2789+5G>A, 3120+1G>A, R1162X, 3659delC, 3849+10kbC>T, W1282X, 3905insT, 3876delA, N1303K. Login to comment
98 Diagnostic features in 42 D1152H subjects according to the other CFTR mutation class Subject Sex (M/F) Other CFTR mutation Sweat Cl- mean (mmol/l) Age at diagnosis (years) Presentation at diagnosis Class I mutations 1 F W1282X 58 4 Pneumonia recurrent bronchitis 2 F W1282X 25 74 Bronchiectasis 3 M W1282X 43 33 CBAVD 4 M G542X 48 39 CBAVD 5 M G542X 72 27 CBAVD 6 F S1206X 18 13 Recurrent bronchitis+ diarrhea 7 F 394delTT 19 41 Bronchiectasis 8 F 394delTT 25 18 Bronchiectasis 9 F Q552X 56 43 Bronchiectasis Class II mutations 10 F F508del 13 42 Bronchiectasis 11 F F508del 40 32 Bronchiectasis 12 F F508del 52 23 Bronchiectasis 13 M F508del 51 15 Bronchiectasis 14 F F508del 100 24 Bronchiectasis 15 M F508del 79 26 Bronchiectasis 16 F F508del - 43 Bronchiectasis 17 M F508del - 23 Bronchiectasis 18 F F508del 19 55 Bronchiectasis 19 F F508del 25 33 Bronchiectasis 20 F F508del 78 15 Bronchiectasis 21 M F508del 90 40 Bronchiectasis 22 F F508del 44 42 Bronchiectasis 23 M F508del 88 11 Bronchiectasis 24 F F508del 63 47 Bronchiectasis 25 F F508del 43 33 Bronchiectasis 26 M F508 del 62 49 Bronchiectasis 27 M F508del 20 - CBAVD 28 M F508del - 27 CBAVD 29 M F508del 42 36 CBAVD 30 M F508del 36 34 CBAVD 31 M F508del 40 36 CBAVD 32 M F508del 41 30 CBAVD 33 M F508del 82 9 Asymptomatic genetic counseling 34 M F508del - 0 Neonatal screening 35 F F508del 53 0 Neonatal screening 36 F F508del 35 0 Neonatal screening 37 M F508del 35 0 Neonatal screening Class III mutation 38 F S549N 75 31 Bronchiectasis Class IV mutations 39 M E116K 80 41 ABPA+ diarrhea 40 M D1152H 34 34 CBAVD 41 M R1070Q 56 38 CBAVD Class V mutation 42 M 3849+10kbC>T 31 40 Asymptomatic genetic counseling ABPA, allergic bronchopulmonary aspergillosis; CBAVD, congenital bilateral absence of the vas deferens. Login to comment
120 Nasal epithelial physiologic properties in eight CF subjects carrying the D1152H mutation Nasal bioelectric properties Subject Other CFTR mutation Sweat Cl- mean (mmol/l) Maximal PD (mV) Amil (mV) Cl-/amil (mV) Iso/Cl- (mV) Wilchanski`s indexa Class I mutations 2 W1282X 25 -44 38 -2 -14 0.7 3 W1282X 43 -34 9 -1 1 1.0 4 G542X 48 -16 12 -3 -1 0.7 6 S1206X 18 -44 28 -11 0 0.7 7 394delTT 19 -25 25 -15 -15 0.3 8 394delTT 25 -42 23 -4 -4 0.7 Class II mutation 18 F508del 19 -19 9 0 0 1.0 Class V mutation 42 3849+10 kb C>T 31 -19 9 1 3 1.6 Cl- , chloride; PD, potential difference; Amil, amiloride; Iso, isoproterenol. Login to comment

PMID: 19845690 [PubMed] Moya-Quiles MR et al: "CFTR mutations in cystic fibrosis patients from Murcia region (southeastern Spain): implications for genetic testing."

No. Sentence Comment

19 By contrast, G542X showed a frequency higher than that for the entire Spanish population (7.7%) (4), although closer to that reported for the Andalucia Region (11.4%) (10). Login to comment

PMID: 19897426 [PubMed] Picci L et al: "A 10-year large-scale cystic fibrosis carrier screening in the Italian population."

No. Sentence Comment

48 Forty-seven different CFTR mutations/gene alterations were chosen and analysed: ΔF508, G85E, 541delC, D110H, R117H, 621+1G→T, 711+5G→A, R334W, R334Q, T338I, R347H, R347P, R352Q, S466X, ΔI507, E527G, 1717-1G→A, 1717-8G→A, G542X, S549N, S549R A→C, G551D, Q552X, R553X, D579G, 1874insT, E585X, 1898+3A→G, 2183AA→G, 2184delA, R709X, 2789+5G→A, 3132delTG, 3199del6, 3272-26A→G, L1077P, L1065P, R1066H, M1101K, D1152H, R1158X, R1162X, 3849+10KbC→T, G1244E, W1282X, N1303K and 4016insT. Login to comment
89 Mutations found in the homozygous (n=2) and heterozygous (n=20) diagnosed foetuses are the following: ΔF508/ΔF508 (n=1), 711+5G→A/711+5G→A (n=1), ΔF508/P5L (n=1), 2183AA→G/S42F (n=1), ΔF508/ D1445N (n=1), 711+5G→A/ΔF508 (n=1), G542X/E527G (n=1), N1303K/1717-1 G→A (n=1), R117H/E527G (n=1), ΔF508/2183AA→G (n=1), ΔF508/D1152H (n=1), R347H/ ΔF508 (n=1), ΔF508/G542X (n=2), ΔF508/N1303K (n=2), R1162X/ΔF508 (n=3), N1303K/D1152H (n=3). Login to comment
97 CF mutation General adult population MAR population n=1879 n=236 ΔF508 42.6 45.7 2183AA→G 5.9 5.9 R1162X 5.7 8.2 N1303K 5.4 5.9 G542X 4.2 3.7 D1152H 3.9 5.0 R553X 3.7 3.1 R117H 3.3 1.8 711+5G→A 2.8 4.1 Q552X 2.8 0.4 2789+5G→A 2.2 3.1 1717-1G→A 2.6 2.8 E527G 2.4 - G85E 2.4 0.9 R334Q 0.9 0.4 W1282X 0.7 0.9 R334W 0.6 - 1898+3A→G 0.5 0.4 R1158X 0.4 - R1066H 0.4 0.4 T338I 0.4 1.8 3849+10Kb C→T 0.4 1.3 3272-26 A→G - 0.9 3132delTG - 0.9 3659 del C - 0.4 4016 ins T - 0.4 1717-8G→A - 0.4 R347H - 0.4 ΔI507 - 0.4 R1070Q - 0.4 Other (16) 5.4 - Table 2a List of CFTR compound heterozygotes in the adult general population. Mutation Health status Disorder Gender Age (years) Notes and refs ΔF508/A238V Infertile CBAVD M 36 (A) ΔF508/R352W Infertile CBAVD M 45 (A) R553X/R334Q M 38 ΔF508/R347H M 53 [17] S42F/D372E (1251T→G) M 39 (A) (B) ΔF508/D110H Infertile M 38 ΔF508/L1414S (4373T→C) Infertile CBAVD M 44 (A) (B) ΔF508/V201M, D1270N & R74W Infertile CBAVD M 44 (A) [18,19] 2183AA→G/L206W Infertile CBAVD M 40 (A) 711+5G→A/ L206W Infertile CBAVD M 40 (A) Table 2b List of CFTR compound heterozygotes in the population enrolled for medically assisted reproduction. Login to comment
98 Mutation Disorder Gender Age (years) Notes and refs ΔF508/R117H M 47 (C) [20,21] ΔF508/R117H F 36 (C) [20,21] ΔF508/R117H M 43 (C) [20,21] G542X/D1152H M 40 (C) R1162X/2789+5G→A CBAVD M 44 (C) R117H/2789+5G→A CBAVD M 42 (C) N1303K/D110H CBAVD M 32 (C) N1303K/D1152H M 40 (C) 2789+5G→A/R1066H M 40 (C) Abbreviations: CBAVD: Congenital Bilateral Absence of the Vas Deference; M: Male; F: Female. Login to comment
105 Among the subjects tested, 9 resulted to be compound heterozygotes: ΔF508/R117H (n=3), G542X/D1152H (n=1), R1162X/2789+5G→A (n=1), R117H/2789 + 5G→A (n = 1), N1303K/D110H (n = 1), N1303K/D1152H (n = 1), 2789 + 5G→A/R1066H (n = 1) (Table 2b). Login to comment
139 In our study a rare mutation such as S1235R was found to be moderately frequent (1/77) and despite being normally classified as "mild", association with a second CFTR gene mutation (G542X) can lead to idiopathic chronic pancreatitis [23]. Login to comment

PMID: 19903491 [PubMed] Kreindler JL et al: "Cystic fibrosis: exploiting its genetic basis in the hunt for new therapies."

No. Sentence Comment

527 It restored translation of dystrophin with premature stop mutations in human muscle cells in vitro and mdx mice in vivo (Welch et al., 2007), and restored translation of human G542X CFTR in a transgenic CFTR -/- mouse (Du et al., 2008). Login to comment

PMID: 19917960 [PubMed] Berk DR et al: "Aquagenic wrinkling of the palms in cystic fibrosis: comparison with controls and genotype-phenotype correlations."

No. Sentence Comment

57 (%) 12 (46) 23 (52) Mean age, y 9.3 11.5 CFTR genotype NA ⌬F508/⌬F508 27 ⌬F508/unidentified 4 ⌬F508/R553X 2 ⌬F508/1898 ϩ 1G ~ A 2 ⌬F508/G542X 1 ⌬F508/G551D 1 ⌬F508/W1282X 1 ⌬F508/1717 ϩ 1G ~ A 1 ⌬F508/3120 ϩ 1G ~ A 1 ⌬F508/3849 ϩ 10KBC→T 1 ⌬F508/S1251N 1 R560T/unidentified 1 2184insA/4357 2A→G 1 Abbreviations: CF, cystic fibrosis; NA, not applicable. Login to comment
59 (%) 12 (46) 23 (52) Mean age, y 9.3 11.5 CFTR genotype NA ⌬F508/⌬F508 27 ⌬F508/unidentified 4 ⌬F508/R553X 2 ⌬F508/1898 ϩ 1G ~ A 2 ⌬F508/G542X 1 ⌬F508/G551D 1 ⌬F508/W1282X 1 ⌬F508/1717 ϩ 1G ~ A 1 ⌬F508/3120 ϩ 1G ~ A 1 ⌬F508/3849 ϩ 10KBC→T 1 ⌬F508/S1251N 1 R560T/unidentified 1 2184insA/4357 2A→G 1 Abbreviations: CF, cystic fibrosis; NA, not applicable. Login to comment

PMID: 19942933 [PubMed] Faucz FR et al: "CFTR allelic heterogeneity in Brazil: historical and geographical perspectives and implications for screening and counseling for cystic fibrosis in this country."

No. Sentence Comment

174 Prevalence of deltaF508, G551D, G542X, and R553X mutations among cystic fibrosis patients in the North of Brazil. Login to comment
11 We previously reported mutation heterogeneity in Brazilian CF patients by direct analysis of the p.F508del mutation and other common sequence alterations (p.G542X, p.N1303 K, p.G551D and p.R553X). Login to comment
20 We previously studied the p.F508del and other four mutations (p.G542X, p.N1303 K, p.G551D and p.R553X) that are common worldwide in the Brazilian population. Login to comment
42 Table 1 Frequencies of some mutations in different regions from Brazil South Southeast North Northeast Mutation PR and SC19 PR and SC11 RS35 SP34 RJ36 MG11 PA37 BA38 p.F508del 45.54% (51/112) 46.94% (92/196) 48.7% (75/154) 50.00% (96/192) 28.42% (54/190) 47.37% (54/114) 22.73% (15/66) 8.68% (25/288) p.G542X 6.25% (7/112) 7.65% (15/196) 3.25% (5/154) 4.17% (8/192) 2.10% (4/190) 7.02% (8/114) 0.00% (0/66) nt p.N1303K 4.46% (5/112) 5.10% (10/196) 0.00% (0/154) 2.08% (4/192) nt 0.00% (0/114) nt nt p.G85E 3.57% (4/112) 2.04% (4/196) nt nt 4.73% (9/190) 3.51% (4/114) nt nt p.R334W 3.57% (4/112) 3.06% (6/196) 1.30% (2/154) nt 2.63% (5/190) 3.51% (4/114) nt nt p.R1162X 3.57% (4/112) 5.61% (11/196) 0.00% (0/154) nt 0.53% (1/190) 3.51% (4/114) nt nt c.2183AA4G 2.68% (3/112) 1.53% (3/196) nt nt 0.00% (0/190) 0.00% (0/114) nt nt p.W1282X 2.68% (3/112) 2.55% (5/196) 0.65% (1/154) 0.52% (1/192) 0.00% (0/190) 0.88% (1/114) nt nt p.R553X 1.78% (2/112) 1.02% (2/196) 0.65% (1/154) 0.52% (1/192) 0.00% (0/190) 0.00% (0/114) 0.00% (0/66) nt p.G551D 0.00% (0/112) 0.00% (0/196) 0.00% (0/154) 1.04% (2/192) 0.53% (1/190) 0.00% (0/114) 4.55% (3/66) nt Othera 25.89% (29/112) 24.49% (48/196) 45.45% (70/154) 56.25% (108/192) 61.05% (116/190) 65.79% (54/114) 72.73% (48/66) 91.32% (263/288) P¼0.9226b P¼0.0007c Abbreviations: BA, Bahia state; MG, Minas Gerais state; nt, not tested; PA, Para´ state; PR, Parana´ state; RJ, Rio de Janeiro state; RS, Rio Grande do Sul state; SC, Santa Catarina state; SP, Sa˜o Paulo state. Login to comment
53 This can be showed when we compare the occurrence of the eight most frequent mutations in Italy (which consists of B70% of all mutations in this country) with those of other populations (Table 3).14,53,54 Faucz et al.19 found nine mutations with a frequency higher than 1% (p.F508del: 45.5%; p.G542X: 6.3%; p.N1303K: 4.5%; p.G85E, p.R334W and p.R1162X: total of 3.6%; c.2183AA4G and p.W1282X: 2.7%; and p.R553X: 1.8%) in CF patients from PR and SC (south of Brazil). Login to comment
58 Table 3 The eight more frequent cystic fibrosis mutations in Italy and the comparison between the frequency of these mutations in south of Brazil with the frequency in Italy, Portugal, Germany and Europe Mutation South of Brazil11,19 Italy53 Portugal14 Germany54 Europe14 p.F508del 46.43% (143/308) 48.92% (745/1 523) 44.49% (202/454) 68.39% (4 199/6 140) 66.78% (18 149/27 177) p.G542X 7.14% (22/308) 5.91% (90/1 523) 1.32% (6/454) 1.51% (93/6 140) 2.64% (717/27 177) p.N1303K 4.87% (15/308) 5.91% (90/1 523) 0.66% (3/454) 1.32% (81/6 140) 1.64% (446/27 177) p.R1162X 4.87% (15/308) 1.58% (24/1 523) 0.22% (1/454) 0.07% (4/6 140) 0.51% (139/27 177) p.W1282X 2.60% (8/308) 1.77% (27/1 523) 0.00% (0/454) 0.24% (15/6 140) 1.00% (272/27 177) c.2183AA4G 1.95% (6/308) 2.63% (40/1 523) 0.00% (0/454) 0.00% (0/6 140) 0.36% (99/27 177) p.R553X 1.30% (4/308) 1.38% (21/1 523) 0.00% (0/454) 1.61% (99/6 140) 0.75% (204/27 177) c.1717-1G4A 0.97% (3/308) 1.77% (27/1 523) 0.00% (0/454) 0.50% (31/6 140) 0.83% (226/27 177) Others 29.87% (92/308) 30.14% (459/1 523) 53.30% (242/454) 26.35% (1 618/6 140) 25.48% (6925/27 177) P¼0.6401a Po0.0001b Po0.0001b Po0.0001b Numbers of chromosomes with the mutation/number of analyzed chromosomes are given in parentheses. Login to comment
64 The p.G542X mutation is found more frequently in SP (19.6%) and MG (13.8%) than in other states, such as, RJ (2.1%), RS (4.9%), SC (6.2%) and PR (8.7%).18,36 Cabello et al.36 found the c.3120+1G4A mutation in 3.7% of the alleles in RJ; they explained that this higher frequency was most probably the result of the ethnic composition of the RJ population, which generally has a higher proportion of African Brazilians (see Table 1 to compare other mutations found in Brazil). Login to comment

PMID: 19951905 [PubMed] Grocock CJ et al: "The variable phenotype of the p.A16V mutation of cationic trypsinogen (PRSS1) in pancreatitis families."

No. Sentence Comment

47 Exon 3 of SPINK1 was sequenced to identify any possible p.N34S mutations and CFTR was tested in all cases for p.DF508, p.G542X, p.N1303K, p. R117H, 621+1 G-T, 1898+1GA, p.W1282X and p.G551D and in some cases with an additional 24 markers according to the recommendations of the American College of Medical Genetics (ACMG) and the American College of Obstetricians and Gynaecologists (ACOG).15 In this study affected p.A16V carriers were also tested for mutations in CTRC exons 2, 3 and 7. Login to comment

PMID: 19952026 [PubMed] Cleveland RH et al: "Cystic fibrosis genotype and assessing rates of decline in pulmonary status."

No. Sentence Comment

56 Measurement Tools All chest radiographic, FEV1, and FVC studies were performed at the study institution during the observed life spans Table 2 Patients according to CF Genotype Group Parameter Genotype Class Pancreatic Exocrine Status* No. of Patients Group S (severe pancreatic and pulmonary phenotypes) Subgroup A (class I and class I) 5 G542X/W1282X I/I PI 2 W1282X/W1282X I/I PI 1 621ϩ1G-T/Y1092X I/I PI 1 3120ϩ1G-A/3120ϩ1G-A I/I PI 1 Subgroup B (class I and class II or III) 16 G542X/⌬F508 I/II PI 6 W1282X/⌬F508 I/II PI 3 Q493X/⌬F508 I/II PI 2 R553X/⌬F508 I/II PI 2 1717-1G/⌬F508 I/II PI 1 621ϩ1G-T/⌬F508 I/II PI 1 2184delA/G551D I/III PI 1 Subgroup C (class II and class II or III) 68 D1507/⌬F508 II/II PI 3 N1303K/⌬F508 II/II PI 2 ⌬F508/⌬F508 II/II PI 57 G551D/⌬F508 II/III PI 6 Group M (mild pancreatic and pulmonary phenotypes) Miscellaneous severe and miscellaneous mild 4 ⌬F508/G85E II/IV PS 2 ⌬F508/R117H II/IV PS 1 D1507/R352Q II/IV PS 1 Miscellaneous mild and miscellaneous mild . Login to comment

PMID: 20100616 [PubMed] Havasi V et al: "Association of cystic fibrosis genetic modifiers with congenital bilateral absence of the vas deferens."

No. Sentence Comment

68 Portuguese CFTR alleles Spanish CFTR alleles Turkish CFTR alleles 5T 22 F508del 11 5T 20 F508del 14 5T 9 D1152H 14 R334W 5 D443Ya 3 D110H 3 R117H 3 G576Aa 3 F508del 2 S1235R 3 R668Ca 3 3041-11del7 2 N1303K 2 G542X 2 1767del6 2 P205S 2 R117H 2 2789þ5G>A 2 D614G 2 V232D 2 CFTRdele2(ins186) 2 G542X 1 L997F 1 3120þ1G>A 1 L206W 1 H609R 1 G1130A 1 V562I 1 N1303H 1 M952I 1 I507del 1 L206W 1 365insT 1 3272-26A>G 1 3272-26A/G 1 E585X 1 2789þ5G>A 1 L15P 1 2752-15C>G 1 G576Aa 1 R347H 1 R334Q 1 R668Ca 1 2689insG 1 R347H 1 CFTRdele2,3 1 R1070W 1 E831X 1 L1227S 1 I 1027T 1 R1070W 1 E831X 1 3272-26A>G 1 L997F 1 I853F 1 A349V 1 6T 1 Note: CFTR ¼ cystic fibrosis transmembrane conductance regulator. Login to comment

PMID: 20108119 [PubMed] Joergensen M et al: "Incidence, prevalence, etiology, and prognosis of first-time chronic pancreatitis in young patients: a nationwide cohort study."

No. Sentence Comment

48 1G [ T, R1162X, 1717-1G [ A, 3659delC, G542X, 2183A [ G, W1282X, 1078delT, 711 ? Login to comment

PMID: 20154695 [PubMed] Harmon GS et al: "Pharmacological correction of a defect in PPAR-gamma signaling ameliorates disease severity in Cftr-deficient mice."

No. Sentence Comment

204 Hamosh, A., Rosenstein, B.J. & Cutting, G.R. CFTR nonsense mutations G542X and W1282X associated with severe reduction of CFTR mRNA in nasal epithelial cells. Login to comment

PMID: 20167849 [PubMed] Bienvenu T et al: "Cystic fibrosis transmembrane conductance regulator channel dysfunction in non-cystic fibrosis bronchiectasis."

No. Sentence Comment

58 In DB-1, 12 patients carried a severe loss-of-function mutation: 3 patients carried a class 1 mutation (G542X, 2183AA.G, and W1282X), and 9 patients carried the F508del class 2 mutation; 10 patients carried a mild mutation predicted to retain some residual CFTR function: 7 patients carried the IVS8-5T class 5 mutation, and 3 patients carried a class 4 mutation (S1235R, R347P-I148T, and R117H-7T) (Table 1). Login to comment
79 GENOTYPE AND PHENOTYPE OF PATIENTS WITH DIFFUSE BRONCHIECTASIS BEARING ONE CYSTIC FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR MUTATION Patient No. Age (yr) Sex (M/F) CFTR Mutation Sweat Cl2 (mmol/L) Basal PD (mV) NPD Index Age at Onset (yr) FEV1 (% pred) Bacterial Colonization 1 46 F F508del/2 10 215 0.44 20 124 Pa 2 51 M S1235R/2 8 219 0.56 10 40 Sa/Pa 3 19 F R347P-I148T/2 13 219 0.48 10 91 None 4 31 F F508del/2 35 220 0.20 2 76 None 5 34 M IVS8-5T/2 10 221 0.51 2 27 None 6 49 F IVS8-5T/2 15 222 0.30 40 92 None 7 20 F IVS8-5T/2 13 223 0.42 16 90 None 8 38 M F508del/2 9 224 0.85 20 ND None 9 65 M F508del/2 21 224 0.88 60 99 None 10 52 F F508del/2 20 226 0.37 5 91 Pa 11 72 F G542X/2 15 226 0.37 40 68 None 12 67 F IVS8-5T/2 26 226 0.82 40 97 None 13 51 F W1282X/2 17 228 0.12 29 27 Pa 14 59 M R117H-7T/2 31 229 0.88 49 89 None 15 56 F F508del/2 17 230 0.41 40 75 None 16 49 F F508del/2 21 232 0.58 45 67 None 17 46 F 2183AA.G/2 23 233 0.26 45 132 None 18 19 F IVS8-5T/2 19 234 0.45 5 82 None 19 70 M IVS8-5T/2 20 238 0.34 50 64 None 20 22 F F508del/2 25 241 0.86 20 82 Sa 21 77 M IVS8-5T/2 26 242 1.00 65 86 None 22 73 M F508del/2 21 245 0.91 25 70 Pa Definition of abbreviations: Cl2 5 chloride; F 5 female; M 5 male; ND 5 not determined; NPD index 5 nasal potential difference index 5 e(response to øCl2 and iso/response to amil); a cut off . Login to comment
82 GENOTYPE AND PHENOTYPE OF PATIENTS WITH DIFFUSE BRONCHIECTASIS BEARING TWO CYSTIC FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR MUTATIONS Patient No. Age (yr) Sex (M/F) CFTR Mutations Sweat Cl2 (mmol/L) Basal PD (mV) NPD Index Age at Onset (yr) FEV1 (% pred) Bacteria Colonization 1 55 F F508del/D1152H 19 219 1.00 54 99 Sa 2 71 F F508del/G576A-R668C 29 223 0.44 70 114 None 3 24 M G542X/3849110kbCT 52 224 1.22 10 78 Pa 4 41 F 394delTT/D1152H 19 225 0.30 41 89 Sa 5 31 M 3849110kbC.T/3849110kbC.T 35 230 0.64 2 30 Sa/Pa 6 74 F G542X/S912L 40 233 0.19 60 106 None 7 50 M W1282X/D1152H 35 236 1.00 10 32 Pa 8 42 F F508del/D1152H 13 240 0.68 30 32 Pa 9 56 F F508del/IVS8-5T 30 242 0.70 10 70 None 10 45 F 394delTT/D1152H 25 242 0.71 18 62 Sa/Pa 11 74 F W1282X/D1152H 25 244 0.66 12 56 Pa 12 23 F S1206X/D1152H 19 244 0.68 13 107 None 13 41 F R553X/R851L-T351S 31 248 0.50 35 72 Pa 14 58 M F508del/R117H-7T 46 251 0.61 45 35 Sa/Pa 15 53 F F508del/R347H 49 258 0.63 40 77 Pa Definition of abbreviations: Cl2 5 chloride; F 5 female; M 5 male; NPD index 5 nasal potential difference index 5 e(response to øCl2 and iso/response to amil); a cut off . Login to comment

PMID: 20334484 [PubMed] Nikolic A et al: "Novel cftr gene sequence variation in Serbian patient with idiopathic disseminated bronchiectasis."

No. Sentence Comment

28 Detection of novel CFTR gene sequence variation 1811+1G→T: a) Analysis of CFTR exon 11 on DGGE gel: 1 - wt/wt, 2 - wt/wt, 3 - G542X/wt, 4 - 1811+1G→T/wt; b) Results of automated DNA sequencing of CFTR exon 11. Login to comment

PMID: 20381036 [PubMed] Mocanu E et al: "All azoospermic males should be screened for cystic fibrosis mutations before intracytoplasmic sperm injection."

No. Sentence Comment

50 Of these, 83% were F508del, 3.7% R117H, G551D, and 621þ1G>T, and 1.85% R560T, G542X, and I507del. Login to comment

PMID: 20386322 [PubMed] Gorter RR et al: "Clinical and genetic characteristics of meconium ileus in newborns with and without cystic fibrosis."

No. Sentence Comment

25 The mutations tested for include the most common mutations DF508, F508C, G542X, R553X, N1303K, R1162X, and E60X, which represent 94% to 98% of the known mutations in the CFTR gene and are found in more than 99% of the Dutch population with CF. Login to comment
65 One child was G542X homozygous. Login to comment
104 It has been reported that in newborns carrying DF508 or G542X, a higher incidence of MI is found, whereas G551D and R117H are associated with a decreased MI incidence (19,21,22). Login to comment

PMID: 20393308 [PubMed] Chandrasekharan S et al: "Impact of gene patents and licensing practices on access to genetic testing for cystic fibrosis."

No. Sentence Comment

182 The ACMG specifically indicated that "Asian-Americans and Native Americans without significant Caucasian admixture should be informed of Table 1 Recommended core mutation panel for cystic fibrosis carrier screening in the general population Standard mutation panel R560T, ⌬F508a , R553Xb , R1162X, ⌬I507, 2184delA, G542X, G551Db , W1282X, N1303K, 621ϩ1G⌬T, R117H, 1717-1G⌬A, A455E, G85E, R334W, R347P, 711ϩ1G⌬T, 1898ϩ1G⌬A, 3849ϩ10kbC⌬T, 2789ϩ5G⌬A, 3659delC, and 3120ϩ1G⌬A Additional testable mutations I506Vc , I507Vc , F508Cc , and 5T/ 7T/9Td a University of Michigan/HSC Patent No. US 5,776,677. b Johns Hopkins University, Patent No. US 5,407,796. c Benign variants. Login to comment

PMID: 20416310 [PubMed] Ooi CY et al: "Genetic testing in pancreatitis."

No. Sentence Comment

53 Interpretation of Mutations Requires an Understanding of Their Functional Consequences Mutation group Reported mutations Complex allele: These mutations are recognized to occur on a single allele R117H ϩ T G576A ϩ R668C F508del ϩ I1027T Benign sequence alterations: These mutations have no known clinical consequence R74Q R297Q R74W 621 * 25 AϾG 3500-19 CϾT T164S C855I I1139V CFTR-related disorder associated: These mutations have been described in individuals with CF-like single organ disease (such as pancreatitis, sinopulmonary disease, or obstructive azoospermia), but do not fulfill the diagnostic criteria for CF 5T R117H D1270N L320V Q1352H 1818-18 GϾA S1235R CF causing F508del Q1476X R553X K710X G542X G551D F311L 2789-5 GϾA 2183AAϾG 711ϩ3 AϾG 3849ϩ10kb CϾT 1341ϩ1GϾA D1152Ha F1074La R553X Unknown clinical consequence F575Y L1260P G194R G1069R L997F K598E F834L R785Q To illustrate this point, mutations identified by extensive mutation testing in a cohort of patients with recurrent acute or chronic pancre- atitis14 are listed according to their clinical consequences (based on current consensus guidelines13 and functional and/or clinical reports; available: http://www.genet.sickkids.on.ca). Login to comment

PMID: 20423679 [PubMed] Bodas M et al: "The NF-kappaB signaling in cystic fibrosis lung disease: pathophysiology and therapeutic potential."

No. Sentence Comment

102 Recent data suggest that the higher inflammation in ΔF508 CF could be a consequence of fewer CFTR molecules at the membrane, as would be predicted also with other rare CF stop mutations such as G542X (McCormick et al., 2002). Login to comment

PMID: 20494257 [PubMed] Dungan JS et al: "Carrier screening for cystic fibrosis."

No. Sentence Comment

102 However, in instances of a positive family history of affected individuals, but with no known mutation, further Table 2 Mutation panel recommended by ACOG and ACMG (listed in order of decreasing frequency in non-Hispanic Caucasian population) F508 del delI507 R347P R1162X G542X R553X 71111G>T 2184delA G551D R117H R560T 189811G>A 62111G>T 3849110kbC>T 3569delC R334W W1282X 1717À1G>T A455E 312011G>T N1303K 278915G>A G85E Data from Watson MS, Cutting GR, Desnick RJ, et al. Cystic fibrosis population carrier screening: 2004 revision of American College of Medical Genetics mutation panel. Login to comment

PMID: 20512161 [PubMed] de Becdelievre A et al: "Notable contribution of large CFTR gene rearrangements to the diagnosis of cystic fibrosis in fetuses with bowel anomalies."

No. Sentence Comment

48 Table 1 Reasons of screening for large rearrangements In group 1 (first-hand referrals): 17/450 First step of the study: one CF mutation identified (n¼8) F508del (n¼6), 394delTT (n¼1), Q1352H (n¼1) Abnormal AF-DE (n¼4) Consanguinity in the couple (n¼1) Very suggestive ultrasound signsa (n¼4) In group 2 (second-hand referrals): 53/219 First step of the study: one CF mutation identified in another laboratory (n¼45) F508del (n¼36), N1303K (n¼3), G542X (n¼2), G551D, R553X, W1282X, 3849+10kbC4T (n¼1 for each) Abnormal AF-DE (n¼1) Consanguinity in the couple and presence of the [R74W;V201M;D1270N] complex allele (n¼1) Very suggestive ultrasound signsa (n¼6) aVery suggestive ultrasound signs mean that several abnormal signs were associated and/or clinicians insisted on a comprehensive study of the CFTR gene. Login to comment

PMID: 20521170 [PubMed] Hale JE et al: "Cystic fibrosis newborn screening: using experience to optimize the screening algorithm."

No. Sentence Comment

47 Extensive follow-up Table 1 Children who are followed at a cystic fibrosis (CF) center who were not identified by CF newborn screening (NBS) Presentation Status at last update NBS IRT%, age at dx Genotype Sweat [Cl- ] (MEq/L)a Five CF infants with false-negative CF NBS results FTT, upper respiratory infections, chronic cough Pancreatic sufficient, sinus disease, positive cultures for Staph. aureus and H. flu 84.2%, 3 months DF508/R117H 67 Meconium ileus 93.9%, birth G542X / unknown 57.7, 67.4 FTT, recurrent pneumonia, asthma 62.3%, 4 years D828G / 3271+18 C or T 62 Asthma 78.6%, 3 years D1270N / R74W 86.5 Chronic cough and sinusitis 74.1%, 4 years R75Q / unknown (second mutation not identified by sequencing) 82, 68 Four additional infants followed at CF center who do not (yet) carry a CF diagnosis Chronic cough Pancreatic sufficient, asthma, moderate Staph. aureus and H. flu 39.7%, 5 years DF508 / unknown 39 Chronic cough; sweat-tested and genotyped after parents found to be carriers during pregnancy with younger sibling Does not carry CF diagnosis, pancreatic sufficient, exercise-induced asthma, normal PFTs, cultures Staph. aureus 94.6%, 3 years DF508/R117H 56 Two siblings who are well; genotyped for family history Positive cultures for Staph. aureus and H.flu 21.3%, 71.2% (sib) DF508 / R117H 20, not done IRT Immunoreactive trypsinogen, FTT failure to thrive, PFT pulmonary function test a Value(s) reported from independent visits of infants with positive CF NBS results has allowed the MA CF NBS program to incorporate communication of relative risk of CF following a positive NBS result that is based upon combined consideration (multi-analyte profiling) of both the IRT concentration and the screening-genotype results. Login to comment

PMID: 20532200 [PubMed] Kosova G et al: "The CFTR Met 470 allele is associated with lower birth rates in fertile men from a population isolate."

No. Sentence Comment

135 The most common CF causing mutations in Europeans (i.e. DF508, G542X, N1303K, W1282X) and the most common mutation in the Hutterites, M1101K [16], all reside on haplotypes carrying the ancestral, Met470 allele in exon 10 [29], the 9T allele at the polyT locus, and (by inference) the TG10 or TG11 alleles at the (TG)m locus in intron 8 [5]. Login to comment

PMID: 20538955 [PubMed] Sermet-Gaudelus I et al: "Clinical phenotype and genotype of children with borderline sweat test and abnormal nasal epithelial chloride transport."

No. Sentence Comment

162 CLINICAL CHARACTERISTICS OF CHILDREN WITH EQUIVOCAL DIAGNOSES AND NASAL POTENTIAL DIFFERENCE DIAGNOSTIC SCORE <0.27 Pt Mutation Age (yr) NPD Score Sweat Cl2 Chronic CF Pulmonary Disease CF Pathogens Airway Obstruction CF Lung Imaging FEV1 (%) BMI Others 1 F508del/S977F A-D 8 0.181 43 RLRTI, chronic productive cough S. aureus No Bronchiectasis 80 14.5 No Bronchial thickening Atelectasis 2 0/0 4 0.121 43 No S. aureus Yes Air trapping NA 13 Pancreatic extracts 0-0 Bronchial thickening 3 0/0 15 20.032 46 RLRTI S. aureus, P. aeruginosa Yes Air trapping 74 14 Polyposis 0-0 Bronchiectasis 4 F508del/0 2 20.249 57 RLRTI P. aeruginosa Yes Air trapping NA 16 No A-0 5 N1303K/(TG12)T5 11.8 20.263 47 RLRTI S. aureus, P. aeruginosa No Bronchial thickening ND 20 No A-B 6 F508del/L206W 5.9 20.278 40 RLRTI S. aureus No Bronchial thickening 115 22 Chronic pancreatitis A-AB 7 R668C/0 15 20.403 40 RLRTI None Yes Bronchiectasis 112 20 No B-0 Air trapping 8 F508del/L997F A-B 1 20.594 38 RLRTI, chronic productive cough P. aeruginosa No Bronchial thickening NA 16 CF hepatopathy 9 G576A;R668C/S1235R 8 20.659 31 0 None Wheezing Normal 100 20 No B-B 10 G542X/0 5 20.718 49 RLRTI, chronic productive cough S. aureus No Bronchial thickening NA 18 No A-0 11 0/0 7 20.742 37 RLRTI None No Normal 106 18 No 0-0 12 F508del/D110E 16 20.777 50 No S. aureus No No 100 21 No A-AB 13 F508del/R1070W 7 21.006 40 RLRTI S. aureus Wheezing Bronchial thickening 110 14 No A-AB 14 F508del-L467F/0 12 21.897 55 RLRTI, chronic productive cough S. aureus No Bronchiectasis 109 17 Pansinusitis A-0 15 F508del/H1054D 9 22.327 59 RLRTI, chronic productive cough S. aureus No Bronchial thickening 100 20 DIOS A-D Definition of abbreviations: A, B, AB, and D: A 5 CF-causing mutation; B 5 mutation that results in a CFTR-RD (clinical entities associated with CFTR mutations that do not meet the current diagnostic criteria for CF); AB 5 wide-spectrum mutation that may belong to either group A or group B; D 5 mutation of uncertain clinical relevance; BMI 5 body mass index; CF 5 cystic fibrosis; CFTR 5 gene encoding cystic fibrosis transmembrane conductance regulator; DIOS 5 distal intestinal obstructive syndrome; NA 5 not applicable; ND 5 not determined; NPD 5 nasal potential difference; P. aeruginosa 5 Pseudomonas aeruginosa; Pt 5 patient; RLRTI 5 recurrent lower respiratory tract infection; S. aureus 5 Staphylococcus aureus. Login to comment

PMID: 20622033 [PubMed] Sermet-Gaudelus I et al: "Ataluren (PTC124) induces cystic fibrosis transmembrane conductance regulator protein expression and activity in children with nonsense mutation cystic fibrosis."

No. Sentence Comment

136 Patients with end-of-treatment total chloride transport hyperpolarization in either cycle were more likely to show both intrinsic and stimulated chloride transport changes; such changes are demonstrated in an example of pretreatment and end-of-treatment nasal TEPD tracings from a 14-year-old female patient with a G542X/DF508 genotype and a UGA premature stop codon type who received the higher dose of ataluren in Cycle 1 (Figure 2). Login to comment
138 Of these genotypes, G542X was the most common; in the 14 patients with this genotype, 6 (43%) met the criterion for a total chloride transport response and 7 (50%) showed hyperpolarization of total chloride transport. Login to comment
139 An examination of the data in the two patients who were homozygous for stop mutations in both alleles (one with G542X/G542X and one with R1162X/ R1162X) did not suggest that these patients were more likely to have an improvement in total chloride transport than patients who were heterozygous for a nonsense mutation in only one allele. Login to comment
159 k Two patients were homozygous for nonsense mutations (G542X/G542X, n 5 1; R1162X/R1162X, n 5 1). Login to comment
189 TOTAL CHLORIDE TRANSPORT RESPONSE AND HYPERPOLARIZATION BY NONSENSE MUTATION TYPE Nonsense Mutation Type Responses* n/N† % Response Rate Hyperpolarizations‡ n/N† % Hyperpolarization Rate Q493X (UAG) 1/3 33 1/3 33 G542X (UGA) 8/14 57 7/14 50 R553X (UGA) 1/2 50 1/2 50 W846X (UGA) 0/1 0 0/1 0 W882X (UAG) 1/1 100 1/1 100 E1104X (UGA) 1/2 50 0/2 0 R1162X (UGA) 1/2 50 2/2 100 W1282X (UGA) 2/4 50 2/4 50 Q1313X (UAA) 0/1 0 0/1 0 * At least a 25 mV total chloride transport improvement in either cycle. Login to comment
190 † Patients with nonsense mutations in both cystic fibrosis transmembrane conductance regulator alleles are counted only once (G542X/G542X, n 5 1; R1162X/R1162X, n 5 1). Login to comment
234 However, our data do extend the range of nonsense mutations studied beyond the three responsive nonsense mutation genotypes (G542X, W1282X, and 3849110 kB C/T) evaluated in adults with CF (29). Login to comment
235 Our findings indicate that multiple genotypes (Q493X, G542X, R553X, W882X, E1104X, R1162X, and W1282X) can be responsive to ataluren therapy. Login to comment

PMID: 20638569 [PubMed] Goetzinger KR et al: "An update on cystic fibrosis screening."

No. Sentence Comment

12 The DF508 mutation causes a protein misfold that inhibits migration of the CFTR protein from the endoplasmic reticulum to the cell membrane.1,7 Other common mutations include G542X, R553X, W1282X, N1303K, 62111 G-to-T, 1717-1 G-to-A, and R117H.8 These result in a spectrum of protein dysfunction ranging from the production of unstable RNA to CFTR cell surface instability.7 PHENOTYPIC VARIATION IN CFTR MUTATIONS Although 70% of CF patients are either homozygotes or compound heterozygotes for these 8 common mutations, there is tremendous variation in their phenotype. Login to comment

PMID: 20644644 [PubMed] Hunter MJ et al: "Expression of wild-type CFTR suppresses NF-kappaB-driven inflammatory signalling."

No. Sentence Comment

138 Our data predict that the higher inflammation in CF cells could be a consequence of fewer wt-CFTR molecules at the membrane, as would be predicted to occur with stop mutants such as G542X that occur in a minority of CF patients and the clinical data supports the view that the presence of CFTR mutants such as G551D-CFTR that traffic normally but fail to transport chloride at all, nevertheless reduce lung damage to a degree [36]. Login to comment

PMID: 20657600 [PubMed] Giuliani R et al: "Identification of the second CFTR mutation in patients with congenital bilateral absence of vas deferens undergoing ART protocols."

No. Sentence Comment

58 INNO-LiPA CFTR19 INNO-LiPA CFTR17 INNO-LiPA CFTR Italian regional [delta]F508 621+1G>T 1259insA G542X 3849+10kbC>T 4016insT N1303K 2183AA>G 4382delA W1282X 394delTT 852del22 G551D 2789+5G> A R1162X D579G 1717-1G>A 3659delC G1244E R553X R117H G1349D CFTRdele2,3 (21 kb) R334W I502T [delta]I507 R347P L1065P 711+1G>T G85E R1158X 3272-26A>G 3905insT 1078delT T338I R560T A455E S549R(A>C) 1898+1G>A S1251N 2143delA 711+5G>A 991del5 I148T E60X D1152H 3199del6 3120+1G>A 2184delA 1898+3A>G, R1070Q Q552X Poli-T tract variations R1066H R347H 621+3A>G R334Q E217G Abbreviation: CFTR, cystic fibrosis transmembrane conductance regulator. Login to comment
64 The detected genotypes consisted of [delta] F508/5T in five cases (pats. 1-5), G542X/5T in two cases (pats. 6 and 7) and W1282X/5T in the last patient (pat. 8). Login to comment
81 Patient First-level CFTR screening CFTR Italian MLPA analysis DHPLC analysis Final genotype (36 mutations + 5T allele) regional kit 1 [delta]F508/5T - - - [delta]F508/5T 2 [delta]F508/5T - - - [delta]F508 /5T 3 [delta]F508/5T - - - [delta]F508/5T 4 [delta]F508/5T - - - [delta]F508/5T 5 [delta]F508 /5T - - - [delta]F508/5T 6 G542X/5T - - - [delta]F508/5T 7 G542X/5T - - - [delta]F508/5T 8 W1282X/5T - - - W1282X/5T 9 [delta]F508/wt [delta]F508/T338I - - [delta]F508/T338I 10 [delta]F508/wt [delta]F508/wt [delta]F508/wt [delta]F508/wt [delta]F508/wt 11 5T/wt 5T/T338I - - 5T/T338I 12 5T/wt 5T/wt 5T/del ex1 - 5T/del ex1 13 5T/wt 5T/wt 5T/del ex19 - 5T/del ex19 14 5T/wt 5T/wt 5T/wt 5T/2811G/T 5T/2811G/T 15 5T/wt 5T/wt 5T/wt 5T/I105N 5T/I105N 16 5T/wt 5T/wt 5T/wt 5T/wt 5T/wt 17 5T/wt 5T/wt 5T/wt 5T/wt 5T/wt 18 5T/wt 5T/wt 5T/wt 5T/wt 5T/wt 19 5T/wt 5T/wt 5T/wt 5T/wt 5T/wt 20 5T/wt 5T/wt 5T/wt 5T/wt 5T/wt 21 5T/wt 5T/wt 5T/wt 5T/wt 5T/wt 22 5T/wt 5T/wt 5T/wt 5T/wt 5T/wt 23 5T/wt 5T/wt 5T/wt 5T/wt 5T/wt Detection rate 8/23 (34.8%) 2/15 (13.3%) 2/13 (15.3%) 2/11 (18.1%) 14/23 (60.8%) Abbreviations: CFTR, cystic fibrosis transmembrane conductance regulator; DHPLC, denaturing high-performance liquid chromatography; MLPA, multiple ligation-dependent probe amplification; wt, wildtype. Login to comment
117 This mutation has also been detected in two CBAVD patients in compound heterozygosity with the G542X mutation [8]. Login to comment

PMID: 20711182 [PubMed] Luciani A et al: "Defective CFTR induces aggresome formation and lung inflammation in cystic fibrosis through ROS-mediated autophagy inhibition."

No. Sentence Comment

918 Patients # 1 2 3 4 5 6 7 8 9 10 Sex; Age* F 13, 2 M 14, 3 F 13,4 M 13, 1 F 13, 6 M 13,3 M 29 F 19 M 11 F 24 Age at diagnosis* 0, 6 0, 3 0, 8 2, 3 11, 0 1,5 7,2 2,0 0,4 7,0 Genotype F508del/ F508del F508del/ W1282X F508del/ N1303K F508del/ G542X F508del/ F508del F508del/ F508del F508del/ G542X F508del/ W1282X F508del/ F508del F508del/ W1282X Pancreatic insufficiency Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Chronic respiratory infection (PA) Yes No No No Yes Yes No Yes Yes No Mean FEV1, % predicted 69 78 73 80 69 81 72 64 72 75 # patient's number; *, (years,months) (c) 2010 Macmillan Publishers Limited. Login to comment

PMID: 20714932 [PubMed] Sommerburg O et al: "Initial evaluation of a biochemical cystic fibrosis newborn screening by sequential analysis of immunoreactive trypsinogen and pancreatitis-associated protein (IRT/PAP) as a strategy that does not involve DNA testing in a Northern European population."

No. Sentence Comment

2 Methods Prospective quantitation of PAP and genetic analysis for the presence of four mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene most prevalent in southwest Germany (F508del, R553X, G551D, G542X) were performed in all newborns with IRT> 99.0th percentile. Login to comment
58 DNA analysis was performed for the four most common CFTR mutations in southwest Germany (F508del, R553X, G551D, G542X) (Lindner et al. 1992; Tummler et al. 1996) in parallel with biochemical analysis from the same dried blood spot. Login to comment
65 IRT testing Mutation analysis F508del, R553X, G551D, G542X CF NBS positive, Recall for sweat testing NBS negative IRT > 99.0 P. no 1. Login to comment
77 These newborns were included in the study, and their samples were further analysed by measurements of PAP and CFTR mutation analysis. Out of these 632 IRT-positive newborns, 98 (0.13% of all newborns screened for CF) showed elevated PAP values, and 56 (0.08% of all newborns screened for CF) were positive in the genetic analysis. Out of these 56, homozygosity for F508del was detected in 6 cases, and 1 case was compound heterozygous for F508del /G542X and F508del /G551D. Login to comment
78 In the remaining 48 newborns, one mutation was found in 39 (36 F508del, 2 G551D, and 1 G542X) and 9 newborns had initial results which were inconclusive because PCR amplification of DNA from dried blood spots on Guthrie cards failed. Login to comment
110 In the second column, the results for both screening strategies are given CF patient True result for PAP/DNA Meconium ileus IRT (ng/ml) PAP (ng/ml) initial DNA result Age at referral (weeks) Mean of sweat Cl- measures (mmol/l) Age at diagnosis (weeks) Subsequent investigation Further DNA analysis 1 FN/FN No 36.0 n.d. n.d. 10 84 12 No special F508del/S1251N 2 TP/TP No 95.5 2.56 F508del/G542X 5 84 6 No special n.d. 3 TP/TP No 132.5 5.81 F508del/ - 4 95 5 No special n.d.a 4 TP/FN No 152.5 2.70 - / - 8b 44 10 ICMc CFTRdele2,3/ - c 5 TP/TP No 204.0 1.00 F508del/G551D 6 95 6 No special n.d. 6 TP/TP Yes 245.0 1.00 F508del/F508del - n.d.d 1 No special n.d. 7 TP/TP No 220.5 1.70 F508del/F508del 8b 82 10 No special n.d. 8 FN/FN No 139.0 0.95 - / - 15b 93 16 No special N1303K/R709X 9 TP/TP Yes 197.5 1.20 F508del/F508del - n.d.d 1 No special n.d. 10 TP/TP Yes 143.5 1.10 F508del/F508del - 92 1 No special n.d. 11 TP/TP No 114.0 1.45 F508del/ - 7b 116 7 No special F508del/p.Q552X 12 TP/TP No 174.5 2.60 F508del/F508del 4 88 5 No special n.d. 13 TP/TP Yes 81 1.30 F508del/F508del 1 n.d.d 1 No special n.d. 14 TP/FN No 198.5 9.45 - / - 8b 103 8 No special CFTRdele2,3/ E664X PAP IRT/PAP strategy, DNA IRT/DNA strategy, TP true positive, FN false negative a Further DNA analysis was not performed in the local CF centre after the health insurance of the patient refused to pay for further DNA analysis. Login to comment
117 Values for IRT/PAP are given for the cut-off value of ≥1.0 ng/mL used in this study and extrapolated for cut-off value of >0.9 ng/mL Patient group Number Newborns screened for CF (April 2008- November 2009) 73,759 CF patients detected (including failsafe protocol) 13 CF patients not detected (missed by all protocols) 1 Prevalence 1: 5268 (2,857-9,493) Screening strategy IRT/DNA (p.F508del, p.G551D, p.R553X, p.G542X) IRT/PAP (cut-off ≥1.0 ng/mL) IRT/PAP (suggested cut-off >0.9 ng/mL) Detected CF patients 10 12 13 False negative results 4 2 1 False positive results 46 86 99 Sensitivity 0.714 (0.478-0.951) 0.857 (0.674-0.999) 0.928 (0.794-0.999) Specificity 0.999 (0.999-0.999) 0.999 (0.998-0.999) 0.999 (0.998-0.999) Positive predictive value 0.179 (0.078-0.278) 0.122 (0.058-0.187) 0.116 (0.057-0.175) Negative predictive value 0.999 (0.999-0.999) 0.999 (0.999-0.999) 0.999 (0.999-0.999) 50 100 150 200 250 300 0 1 2 3 4 5 6 7 8 9 10 Non-CF CF Cut-off 1.0 ng/ml a IRT [ng/ml] PAP[ng/ml] Non-CF CF 0 1 2 3 b 9 10 11 p < 0.02 p < 0.0001 Non-CF carriers PAP[ng/ml] Fig. 3a, b Relationship between IRT and PAP concentrations and summary of PAP concentrations in non-CF and CF newborns. Login to comment

PMID: 20797923 [PubMed] Farra C et al: "Mutational spectrum of cystic fibrosis in the Lebanese population."

No. Sentence Comment

6 Five mutations - not previously reported in the Lebanese population - were identified; these are: S549N, G542X, 2043delG, 4016insG, and R117H-7T. Login to comment
27 Family Origin Community CM Sex CF mutations Age at diagnosis CP Sweat test 1 Bekaa Maronite No M W1282X Mount Lebanon Maronite F 4010del4 M W1282X/4010del4 1 year Pu Positive 2 North Sunnite Yes M N1303K North Sunnite F N1303K M N1303K/N1303K 7 months Pu, Gi, GR Positive 3 South Shiite Yes M F508del Shiite F F508del M F508del/F508del 2 years Pu, Gi, GR Positive 4 Mount Lebanon Greek-orthodox Yes M F508del Mount Lebanon Maronite F W1282X M F508del/W1282X 2 weeks Gi Positive 5 North Sunnite No M S549N North Sunnite F G542X M S549N/G542X 19 years Pu, Gi Positive 6 Bekaa Sunnite Yes M N1303K Bekaa Sunnite F N1303K M N1303K/N1303K 8 months Gi, GR Positive 7 Beirut Maronite No M 2789+5GNA Beirut Greek-Orthodox F F508del M F508del/2789+5GNA 6 months Pu, Gi, GR Positive 8 North Sunnite Yes M 2043delG North Sunnite F 2043delG M 2043delG/2043delG 6 weeks Gi No data 9 North Sunnite Yes M R117H-7T North Sunnite F R117H-7T M R117H-7T/R117H-7T 3 months Pu Positive 10 South Sunnite Yes M 4016insG South Sunnite F 4016insG M 4016insG/4016insG 3 months Pu Positive M 4016insG/4016insG 5 months Pu Positive 11 Mount Lebanon Maronite No M N1303K Mount Lebanon Greek-Catholic F N1303K M N1303K/N1303K 3 months Pu, Gi Positive 12 North Maronite No M S4X Mount Lebanon Maronite F N1303K M N1303K/S4X 1 month Pu, Gi, Gr Positive 13 Bekaa Greek-Catholic No M F508del No data Maronite F 4010del4 F F508del/4010del4 11 months Pu, Gi Positive 14 No data Greek-Catholic No M W1282X No data Maronite F F508del F W1282X/F508del 2 years No data Positive 15 Mount Lebanon Baptist No M F508del Mount Lebanon Maronite F N1303K F F508del/N1303K 3 years Pu, Gi, Gr Positive 16 North Sunnite Yes M F508del North Sunnite F F508del F F508del/F508del 9 months Pu, Gi, Gr Negative 17 North Sunnite Yes M N1303K Sunnite F N1303K F N1303K./N1303K 2 years Pu, Gr Positive 18 North Sunnite No M F508del North Sunnite F F508del F F508del/F508del 7 months Pu, Gi, Gr Positive 19 North Maronite No M F508del No data Maronite F F508del M F508del/F508del 7 years Pu, Gi, Gr Positive 20 Beirut Maronite No data M S4X No data Maronite F S4X M S4X/S4X 9 months Pu, Gi No data (continued on next page) diagnosis was based mainly on the clinical picture according to the consensus criteria [16] and was confirmed when possible by a positive sweat chloride test. Login to comment
39 These mutations were W1282X, 4010del4, N1303K, F508del, S549N, G542X, 2043delG, R117H-7T, 2789 + 5G NA, 4016insG, and S4X. Login to comment
42 Five mutations that were not previously reported in the Lebanese population were identified, these are: S549N, G542X, 2043delG, 4016insG and R117H-7T. Login to comment
51 Common CFTR mutations in the Lebanese population Frequency of CF alleles (%) Lebanona Palestine [17] Jordan [24] Syria [29] Saudi Arabia, United Arab Emirates, Oman, Qatar, Kuwait, and Jordan [1] Saudi Arabia [3,25] Bahrain [27] F508 del 36.3 23.5 7.4 1 patient 12 15 7.7 W1282X 13.8 10.6 N1303K 20 21 1.5 3-14 4010del4 7.5 2.3 S4X 6.3 2789+5GNA 2.5 2043delG 2.5 7 30.8 4016insG 2.5 R117H-7T 2.5 G542X 1.3 1.2 4096-28G→A 1.3 E672del 1.3 M952I 1.3 S549N 1.3 a Mutations in a total of 80 identified CF alleles in the Lebanese population from this study combined with Desgeorges et al. (1997) [2]. Login to comment

PMID: 20829696 [PubMed] Sloane PA et al: "Cystic fibrosis transmembrane conductance regulator protein repair as a therapeutic strategy in cystic fibrosis."

No. Sentence Comment

100 Surface localized full-length CFTR was substantially improved in cross-sections of intestinal tissues following administration to CF mice carrying the G542X mutation and restored CFTR function by Ussing chamber analysis in intestinal samples of mice after 2 weeks of treatment with ataluren. Login to comment

PMID: 20847077 [PubMed] Simmonds NJ et al: "Cystic fibrosis and survival to 40 years: a study of cystic fibrosis transmembrane conductance regulator function."

No. Sentence Comment

57 76 (80.9%) patients were homozygous DF508 and the remainder were DF508 compound heterozygotes (with genotype G551D (n55), G542X (n53), N1303K (n53), 1717-1GRA (n52), 621-1GRT (n51), R1162X (n51), 2789+3delG (n51), 3659delC (n51) and D1507 (n51)); no significant difference between the groups for any genotype was present. Login to comment

PMID: 20923678 [PubMed] Ooi CY et al: "Type of CFTR mutation determines risk of pancreatitis in patients with cystic fibrosis."

No. Sentence Comment

55 PIP Scores for Common, Well-Defined CFTR Mutations Mutation Canadian Consortium for CF Genetic Studies Verona CF Centre Mutation classTotal PI Total PIϩPS PIP score Total PI Total PIϩPS PIP score 621ϩ1GϾT 96 96 1.00 4 4 1.00 I-III 711ϩ1GϾT 36 36 1.00 1 1 1.00 I-III R553X 24 24 1.00 9 9 1.00 I-III I507del 11 11 1.00 12 12 1.00 I-III G542X 74 75 0.99 22 22 1.00 I-III F508del 1276 1324 0.96 181 188 0.96 I-III 1717-1GϾA 20 21 0.95 23 24 0.96 I-III W1282X 19 20 0.95 2 2 1.00 I-III N1303K 45 48 0.94 30 31 0.97 I-III R1162X 12 13 0.92 21 22 0.95 I-III G551D 59 67 0.88 0 0 - I-III G85E 16 22 0.73 4 5 0.80 I-III A455E 18 37 0.49 0 0 - IV-V 2789ϩ5GϾA 6 16 0.38 3 11 0.27 IV-V R334W 1 10 0.10 0 0 - IV-V 3849ϩ10kbCϾT 2 22 0.09 0 1 0.00 IV-V R117H 1 25 0.04 0 0 - IV-V NOTE. Login to comment

PMID: 20932301 [PubMed] Green DM et al: "Mutations that permit residual CFTR function delay acquisition of multiple respiratory pathogens in CF patients."

No. Sentence Comment

74 For Pa, the hazard ratio Table 1 Classification of CFTR alleles Category Mutation Specific mutations Class I Defective Protein Synthesis (nonsense, frameshift, aberrant splicing) 1078delT, 1154 insTC, 1525-2A > G, 1717-1G > A, 1898+1G > A, 2184delA, 2184 insA, 3007delG, 3120+1G > A, 3659delC, 3876delA, 3905insT, 394delTT, 4010del4, 4016insT, 4326delTC, 4374+1G > T, 441delA, 556delA, 621+1G > T, 621-1G > T, 711+1G > T, 875+1G > C, E1104X, E585X, E60X, E822X, G542X, G551D/R553X, Q493X, Q552X, Q814X, R1066C, R1162X, R553X, V520F, W1282X, Y1092X Class II Abnormal Processing and Trafficking A559T, D979A, ΔF508, ΔI507, G480C, G85E, N1303K, S549I, S549N, S549R Class III Defective Channel Regulation/Gating G1244E, G1349D, G551D, G551S, G85E, H199R, I1072T, I48T, L1077P, R560T, S1255P, S549 (R75Q) Class IV Decreased Channel Conductance A800G, D1152H, D1154G, D614G, delM1140, E822K, G314E, G576A, G622D, G85E, H620Q, I1139V, I1234V, L1335P, M1137V, P67L, R117C, R117P, R117H, R334W, R347H, R347P, R347P/ R347H, R792G, S1251N, V232D Class V Reduced Synthesis and/or Trafficking 2789+5G > A, 3120G > A, 3272-26A > G, 3849+10kbC > T, 5T variant, 621+3A > G, 711+3A > G, A445E, A455E, IVS8 poly T, P574H was increased 3 fold for those with 'Minimal` function when compared to those with 'Residual` function. Login to comment

PMID: 21083385 [PubMed] Accurso FJ et al: "Effect of VX-770 in persons with cystic fibrosis and the G551D-CFTR mutation."

No. Sentence Comment

70 (%)‡4(100)4(100)4(100)4(100)4(100)20(100)4(100)8(100)7(100)19(100) Age-yr Median36314126213024232121 Range19to4822to5122to5019to3419to3319to5118to4218to4020to3818to42 Body-massindex Median23232420212322222322 Range22to2920to2419to2719to2417to2617to2921to2320to2320to2520to25 CFTRgenotype G551D/F508del3(75)4(100)4(100)2(50)3(75)16(80)4(100)7(88)5(71)16(84) G551D/1078delT1(25)----1(5)---- G551D/G551D----1(25)1(5)---- G551D/N1303K---1(25)-1(5)---- G551D/R553X---1(25)-1(5)---- G551D/3849+10kbC→T--------1(14)1(5) G551D/621+1G→T-------1(12)-1(5) G551D/G542X--------1(14)1(5) FEV1 Median%ofpredictedvalue57665663495677657669 Range%ofpredictedvalue48to9744to10942to6546to10242to5842to10953to11242to12240to10640to122 40to<70%ofpredictedvalue -no. Login to comment
65 (%)‡4(100)4(100)4(100)4(100)4(100)20(100)4(100)8(100)7(100)19(100) Age-yr Median36314126213024232121 Range19to4822to5122to5019to3419to3319to5118to4218to4020to3818to42 Body-massindex Median23232420212322222322 Range22to2920to2419to2719to2417to2617to2921to2320to2320to2520to25 CFTRgenotype G551D/F508del3(75)4(100)4(100)2(50)3(75)16(80)4(100)7(88)5(71)16(84) G551D/1078delT1(25)----1(5)---- G551D/G551D----1(25)1(5)---- G551D/N1303K---1(25)-1(5)---- G551D/R553X---1(25)-1(5)---- G551D/3849+10kbC→T--------1(14)1(5) G551D/621+1G→T-------1(12)-1(5) G551D/G542X--------1(14)1(5) FEV1 Median%ofpredictedvalue57665663495677657669 Range%ofpredictedvalue48to9744to10942to6546to10242to5842to10953to11242to12240to10640to122 40to<70%ofpredictedvalue -no. Login to comment

PMID: 21184098 [PubMed] de Becdelievre A et al: "Comprehensive description of CFTR genotypes and ultrasound patterns in 694 cases of fetal bowel anomalies: a revised strategy."

No. Sentence Comment

138 [2125C[T] 28 - - MP Born, CF, MI [G542X]? Login to comment

PMID: 21228336 [PubMed] Brown MB et al: "Low abundance of sweat duct Cl- channel CFTR in both healthy and cystic fibrosis athletes with exceptionally salty sweat during exercise."

No. Sentence Comment

114 Mutations tested in this panel were ⌬F508, R334W, S549N, 3659delC, ⌬I507, I347P, A559T, S1255X, 1898ϩ1GϾA, R347H, N1303K, 1898ϩ5GϾT, 3876delA, A455E, 394delTT, 2183GGϾA, 3905insT, 3120ϩ1GϾA, V520F, 2184delA, G85E, Y1092X, 711ϩ1GϾT, 2307insA, Y122X, S549R, M1101K, 1078delT, 2789ϩ5GϾA, G551D, G542X, 621ϩ1GϾT, R560T, W1282X, 1717-1 GϾA, 3849 ϩ 10KbCϾT, R553X, R117H, and R1162X. Login to comment
119 Mutations tested in this panel were ⌬F508, R334W, S549N, 3659delC, ⌬I507, I347P, A559T, S1255X, 1898ϩ1GϾA, R347H, N1303K, 1898ϩ5GϾT, 3876delA, A455E, 394delTT, 2183GGϾA, 3905insT, 3120ϩ1GϾA, V520F, 2184delA, G85E, Y1092X, 711ϩ1GϾT, 2307insA, Y122X, S549R, M1101K, 1078delT, 2789ϩ5GϾA, G551D, G542X, 621ϩ1GϾT, R560T, W1282X, 1717-1 GϾA, 3849 ϩ 10KbCϾT, R553X, R117H, and R1162X. Login to comment

PMID: 21233271 [PubMed] Wilschanski M et al: "Chronic ataluren (PTC124) treatment of nonsense mutation cystic fibrosis."

No. Sentence Comment

104 Ataluren treatment was associated with an on-treatment total chloride response in both patients with the G542X and W1282X mutations. Login to comment
110 Changes in total chloride transport were TABLE 1 Baseline patient characteristics Ataluren dose level Low# High" Combined Age yrs 21 (19-57) 27 (19-45) 26 (19-57) Sex Male 8 2 10 Female 4 5 9 BMI 22.3 (15.4-27.8) 21.8 (19.0-26.6) 21.8 (15.4-27.8) Sweat chloride+ mEq?L-1 88 (47-109) 89 (49-106) 88 (47-109) Nasal total chloride transport1 mV 1.6 (-1.6-9.3) -0.3 (-2.3-1.9) 0.7 (-2.3-9.3) Pulmonary function % prede FEV1 64 (44-106) 65 (46-92) 65 (44-106) FVC 82 (63-109) 77 (57-101) 78 (57-109) Pathological lung infection 12 6 18 Pseudomonas aeruginosa 11 6 17 Mycobacterium abscessus 2 0 2 Methicillin-resistant Staphylococcus aureus 1 0 1 None 0 1 1 Pancreatic insufficiency Exocrine 11 6 17 Endocrine 2 5 7 Abnormalities of liver-related serum parameters 3 2 5 ALT 0 2 2 AST 1 0 1 Alkaline phosphatase 2 1 3 GGT 0 0 0 Bilirubin 1 0 1 LDH 1 0 1 Genotype allele 1/allele 2 G542X (UGA)/DF508 2 0 2 G542X (UGA)/W1282X (UGA) 0 1 1 G542X (UGA)/N1303K 0 1 1 W1282X (UGA)/DF508 8 2 10 W1282X (UGA)/W1282X (UGA) 1 2 3 W1282X (UGA)/3849+10kB CRT## (UAA) 0 1 1 3849+10kB CRT## (UAA)/DF508 1 0 1 Time from last ataluren dose in prior study months 10.5 (9.3-12.2) 10.5 (8.5-11.5) 10.5 (8.5-12.2) Data are presented as n or median (range). Login to comment
121 Rather than using the mean NPD values obtained from both nostrils (as in the primary analyses), we also analysed outcome 5 0 Response -5 -15 -10 Changefrombaseline totalchloridetransportmV CFTR mutation type G542X/ΔF508 W1282X/ΔF508 W1282X/ΔF508 W1282X/ΔF508 W1282X/ΔF508 W1282X/ΔF508 W1282X/ΔF508 W1282X/ΔF508 W1282X/ΔF508 W1282X/ΔF508 W1282X/G542X W1282X/W1282X W1282X/W1282X W1282X/W1282X G542X/N1303K G542X/ΔF508 W1282X/ΔF508 W1282X/3849+10KBC→T 4, 4 and 8 mg·kg-1 (n=11) 10, 10 and 20 mg·kg-1 (n=7) FIGURE 1. Login to comment
191 Total chloride transport improvements were noted in patients with both G542X and W1282X premature stop codon mutations, confirming data from our prior study [20] and from other ataluren trials [42], indicating that multiple nonsense mutation genotypes can be responsive to ataluren therapy. Login to comment

PMID: 21240931 [PubMed] Noy E et al: "Combating Cystic Fibrosis: In Search for CF Transmembrane Conductance Regulator (CFTR) Modulators."

No. Sentence Comment

19 Class I mutations are found in ~10% of CF patients, and the most common ones are G542X and W1282X, the latter being particularly common in Ashkenazi Jews. Login to comment

PMID: 21257352 [PubMed] Salvatore D et al: "An overview of international literature from cystic fibrosis registries. Part 3. Disease incidence, genotype/phenotype correlation, microbiology, pregnancy, clinical complications, lung transplantation, and miscellanea."

No. Sentence Comment

1264 The 3 most common mutations associated with MI were F508del, G542X, and W1282X. Login to comment

PMID: 21275046 [PubMed] Noy E et al: "Combating cystic fibrosis: in search for CF transmembrane conductance regulator (CFTR) modulators."

No. Sentence Comment

19 Class I mutations are found in ~10% of CF patients, and the most common ones are G542X and W1282X, the latter being particularly common in Ashkenazi Jews. Login to comment

PMID: 21296036 [PubMed] Ivady G et al: "Distribution of CFTR mutations in Eastern Hungarians: relevance to genetic testing and to the introduction of newborn screening for cystic fibrosis."

No. Sentence Comment

77 CFTR mutation Germany 1994 Romania 2008 Austria 1997 Slovakia 2008 Hungary 1992 This study deltaF508 (c.1521_1523 delCTT) 72.0% 56.3% 74.6% 38.2% 64.3% 70.0% G551D (c.1652 GNA) 1.0% N/F 1.6% N/F N/F N/F R553X (c.1657 CNT) 2.3% N/F N/F 1.2% 2.4% N/F G542X (c.1624 GNT) 1.4% 3.9% 2.4% 2.4% 1.2% 3.75% 621+1 GNT (c.489+1 GNT) 0.1% 0.8% N/F N/F N/F N/F 1717-1 GNA (c.1585-1 GNA) 0.9% N/F 0.8% 0.6% 1.2% 1.25% W1282X (c.3846 GNA) 0.7% 2.3% N/F N/F 1.2% N/F N1303K (c.3909 CNG) 2.3% 0.8% N/F 1.2% 1.2% 5.0% R347P (c.1040 GNC) 1.6% N/F 1.6% 1.2% N/A 1.25% CFTRdele2,3(21 kb) 1.5%a 1.6% 2.6%a 1.1%a N/A 5.0% 2184insA (c.2052_2053 insA) 0.6% N/F N/F 2.4% N/A 5.0% L101X (c.302 TNG) N/F N/F N/F N/F N/A 2.5% Q220X (c.658 CNT) N/F N/F N/F N/F N/A 1.25% S466X (c.1397 CNG) N/F N/F N/F N/F N/A 1.25% E831X (c.2491 GNT) N/F N/F N/F 0.6% N/A 1.25% Y1092X (c.3276 CNA) 0.3% N/F N/F N/F N/A 1.25% Legend: data for Germany [8], Romania [9], Austria [10], Slovakia [11] and Hungary [3]; N/A: not analyzed; N/F: not found, a frequencies reported by Dork et al. in 2000 [6], mutations included in the Elucigene CF29 v2 assay are formatted in italics; the original "legacy name" is followed by the recommended mutation nomenclature [17]. Login to comment

PMID: 21354377 [PubMed] Geborek A et al: "Association between genotype and pulmonary phenotype in cystic fibrosis patients with severe mutations."

No. Sentence Comment

95 Class I/class I Class I/class II Class II/class II 1717-1 G-NA/1717-1 G-NA n=1 3659delC/S945L n=1 F508del/F508del n=165 3659delC/3659delC n=5 3659delC/F508del n=23 F508del/S945L n=5 3659delC/394delTT n=7 394delTT/F508del n=38 394delTT/394delTT n=4 621+1 G-NT/F508del n=6 R553X/E60X n=1 E60X/F508del n=4 G542X/F508del n=1 R553X/F508del n=2 W79R/F508del n=1 W1282X/F508del n=1 1717-1 G-NA/F508del n=1 Total 18 78 170 The other class combinations are not shown. Login to comment
98 Class I Class II Class III Class IV Class V 1717-1 G-NA F508del G551D 297 C-NA 2789+5 G-NA 3659delC S945L R560T R117C 3849+10 kb CNT 394delTT R347P A455E R553X T 3381 3849+10 kb C-T 621+1 G-NT E60X G542X W79R W1282X decline of pulmonary function was more rapid in patients with pancreatic insufficiency, mainly class II mutations, compared to CF patients with normal pancreatic function [4]. Login to comment

PMID: 21388895 [PubMed] Baker MW et al: "Optimal DNA tier for the IRT/DNA algorithm determined by CFTR mutation results over 14 years of newborn screening."

No. Sentence Comment

36 In 6 non-Caucasian cases (three African American, two Native American and one Hispanic), five had at least one F508del allele, and one was compound heterozygote of G542X/1812-1 GNA. There were 8 screening false negative cases, including 5 in period 1, and 3 in period 2. Login to comment
75 CFTR mutationa Proportion of allele Frequency of allele (%) Cumulative detection (%)b F508del 137/214 64.02 92.52 3849+10KbCNT 6/214 2.80 92.52c G542X 5/214 2.34 94.39 N1303K 4/214 1.87 98.13 R117H 4/214 1.87 99.07 R553X 3/214 1.40 99.07 1717-1GNA 2/214 0.93 99.07 G551D 1/214 0.47 100 R347P 1/214 0.47 100 A455E 1/214 0.47 100 W1282X 1/214 0.47 100 621+1GNT 1/214 0.47 100 a The other 11 mutations in ACMG 23 mutation panel are G85E, 711+1GNT, R334W, I507del, R560T, 1898+1GNA, 2184delA, 2789+5GNA, 3120+1GNA, R1162X and 3659delC. Login to comment

PMID: 21429822 [PubMed] Coiana A et al: "Preconceptional identification of cystic fibrosis carriers in the Sardinian population: A pilot screening program."

No. Sentence Comment

88 Mutation nomenclaturea Alleles (%) T338I (p.Thr338Ile) 26 (65.0) F508del (p.Phe508del) 9 (22.5) N1303K (p.Asn1303Lys) 1 (2.5) 2183AANG (c.2051_2052delAAinsG) 1 (2.5) 621+1GNT (c.489+1GNT) 1 (2.5) exon 2 del (c.54-5811_164+2187del8108ins182) 1 (2.5) R347P (p.Arg347Pro) 1 (2.5) The 3849+10kbCNT (c.3717+12191CNT), G85E (p.Gly85Glu), 2789+5GNA (c.2657+5GNA), W1282X (p.Trp1282X), G1244E (p.Gly1244Glu), 711+5GNA (c.579+5GNA), 711+1GNT (c.579+1GNA), 4016insT (p.Ser1297PhefsX5), G542X (p.Gly542X), 1717-1GNA (c.1585-1GNA), R553X (p.Arg553X), Q552X (p.Gln552X), G551D (p.Gly551Asp), S549R (ANC) (p.Ser549Arg), I507del (p.Ile507del), F508C (p.Phe508Cys), I502T (p.Ile502Thr), 1706del17 (p.Gln525LeufsX37), 1677delTA (p.Tyr515X), R117H (p.Arg117His), D1152H (p.Asp1152His), L1065P (p.Leu1065Pro), R1066H (p.Arg1066His), L1077P (p.Leu1077Pro), 4382delA (p.Glu1418ArgfsX14), R1162X (p.Arg1162X), R1158X (p.Arg1158X), 1259 insA (p.Gln378AlafsX4), 852del22 (p.Gly241GlufsX13), S912X (p.Ser912X), and 991del5bp (p.Asn287LysfsX19) mutations included in the CF panel were not detected in the population tested. Login to comment

PMID: 21474639 [PubMed] Rohlfs EM et al: "Cystic fibrosis carrier testing in an ethnically diverse US population."

No. Sentence Comment

65 The median fluorescent intensity was determined, and the presence or absence of mutant and wild-type alleles was evaluated from the ratio of the mutant signal to the wild-type signal for the following mutations: c.1155_1156dupTA, c.2657ϩ5GϾA, c.3717ϩ12191CϾT, p.A455E, p.D1152H, p.F508del, p.G542X, p.G551D, p.I507del, p.L206W, p.N1303K, p.R117H, p.W1282X, and c.54-5940_ 273ϩ10250del21kb. Login to comment
123 CFTR mutationsa Individuals, n p.F508del/p.R117H 16 5T/9T 1 7T/9T 15 p.F508del/p.D1152H 3 p.R117H/p.R117H, 7T/7T 2 p.D1152H/p.D1152H 2 p.W1282X/p.D1152H 2 p.D1152H/p.G551D 1 c.3717ϩ12191CϾT/p.R352Q 1 c.3717ϩ12191CϾT/c.3717ϩ12191CϾT 1 p.F508del/c.3717ϩ12191CϾT 1 p.F508del/p.L206W 1 p.F508del/p.R117C 1 p.F508del/p.R347H 1 p.F508del/p.R347P 1 p.R117H/p.W1282X, 7T/7T 1 p.R117H/p.G551D, 7T/7T 1 p.R117H/p.G542X, 7T/9T 1 a Human Genome Variation Society nomenclature [Ogino et al. (23)]. Login to comment

PMID: 21514289 [PubMed] Earley MC et al: "Implementation of the first worldwide quality assurance program for cystic fibrosis multiple mutation detection in population-based screening."

No. Sentence Comment

129 Allele Allele Allele Allele p.Gly85Glu G85E (0.26) p.Arg117His R117H (0.54) c.489+1 GNT 621+1 GNT (1.3) p.Phe508del F508del (66.31) p.Arg347Pro R347P (0.36) p.lle507del I507del (0.90) p.Gly551Asp G551D (1.93) c.2052delA 2184delA (0.15) c.1585-1 GNA 1717-1 GNA (0.44) p.Gly542X G542X (2.64) c.3528delC 3659delC (0.28) p.Asn1303Lys N1303K (1.27) p.Arg553X R553X (1.21) p.Arg560Thr R560T (0.30) p.Arg1162X R1162X (0.30) c.2657+5 GNA 2789+5 GNA (0.38) c.3717+12191 CNT 3849+10kbCNT (0.85) c.2988+1 GNA 3120+1 GNA (0.86) p.Trp1282X W1282X (2.20) p.Ala455Glu A455E (0.26) c.1766+1 GNA 1898+1 GNA (0.13) c.579+1 GNT 711+1 GNT (0.35) p.Arg334Trp R334W (0.37) c.54-5940 _273+10250del21kb CFTR dele2,3 p.Ser549Asn S549N (0.14) c.1584 GNA 1716 G→A c.2051_2052delAAinsG 2183AANG (0.1) c.3140-26ANG 3272-26ANG c.262_263delTT 394delTT p.Arg1066Cys R1066C (0.03) p.Arg1066His R1066H c.1022_1023insTC 1154insTC c.2989-1 GNA 3121-1 GNA c.(?_2989)_(3139_? Login to comment

PMID: 21538969 [PubMed] Ren CL et al: "Clinical outcomes in infants with cystic fibrosis transmembrane conductance regulator (CFTR) related metabolic syndrome."

No. Sentence Comment

60 Infants in both groups received treatment with inhaled tobramycin if they had a positive Pa OP culture, and treatment in both groups was associated with eradication of TABLE 1-CFTR Gene Mutation Panel Used by New York CF NBS Program F508del I50e7del G542X G551D W1282X N1303K R553X 621þ1G>T R117H 1717-1G>A A455E R560T R1162X G85E R334W R347P 711þ1G>T 1898þ1G>A 2184delA 1078delT 3849þ10kbC>T 2789þ5G>A 3659delC I148T 3120þ1G>A 3876delA V520F S549R S549N 3849þ4 A-G 3905insT R347H Reflex testing for 5T polymorphism is performed if R117H is detected. Login to comment
78 TABLE 3- Clinical Features and Outcomes of the CRMS Infants Patient number Gender Race/ ethnicity Mean age at 1st sweat (weeks) Mean sweat chloride (range) CFTR gene mutations identified Follow up time (months) Fecal elastase (mcg/gm stool) History of Pa infection History of hospitalization 1 Male Caucasian 4 46 (38-54) F508del/R117H/7T 36 303 Yes No 2 Male Caucasian 5 40 (40-43) F508del/R117H/7T 60 500 Yes No 3 Female Caucasian 3 29 (27-31) F508del/R117H/7T 60 488 No No 4 Male Caucasian 3 34 (33-38) F508del/none 26 383 No No 5 Male Caucasian 3 45 (40-50) F508del/none 72 424 No No 6 Female Caucasian 3 35 (32-38) F508del/none 9 454 No No 7 Male Caucasian 3 41 (36-46) F508del/none 39 462 No No 8 Female Caucasian 5 50 (46-52) F508del/none 72 440 No Yes 9 Male Caucasian 4 43 (41-45) F508del/Y1032C 14 401 No No 10 Male Caucasian 3 52 (50-54) G542X/none 21 500 No No 11 Female Caucasian 8 34 (30-38) R560T/none 9 433 No No 12 Female Hispanic 6 36 (32-40) R334W/R117H/7T 24 500 Yes No Mean sweat chloride levels represent the mean of all tests performed in the neonatal period. Login to comment
61 Infants in both groups received treatment with inhaled tobramycin if they had a positive Pa OP culture, and treatment in both groups was associated with eradication of TABLE 1- CFTR Gene Mutation Panel Used by New York CF NBS Program F508del I50e7del G542X G551D W1282X N1303K R553X 621þ1G>T R117H 1717-1G>A A455E R560T R1162X G85E R334W R347P 711þ1G>T 1898þ1G>A 2184delA 1078delT 3849þ10kbC>T 2789þ5G>A 3659delC I148T 3120þ1G>A 3876delA V520F S549R S549N 3849þ4 A-G 3905insT R347H Reflex testing for 5T polymorphism is performed if R117H is detected. Login to comment
79 TABLE 3- Clinical Features and Outcomes of the CRMS Infants Patient number Gender Race/ ethnicity Mean age at 1st sweat (weeks) Mean sweat chloride (range) CFTR gene mutations identified Follow up time (months) Fecal elastase (mcg/gm stool) History of Pa infection History of hospitalization 1 Male Caucasian 4 46 (38-54) F508del/R117H/7T 36 303 Yes No 2 Male Caucasian 5 40 (40-43) F508del/R117H/7T 60 500 Yes No 3 Female Caucasian 3 29 (27-31) F508del/R117H/7T 60 488 No No 4 Male Caucasian 3 34 (33-38) F508del/none 26 383 No No 5 Male Caucasian 3 45 (40-50) F508del/none 72 424 No No 6 Female Caucasian 3 35 (32-38) F508del/none 9 454 No No 7 Male Caucasian 3 41 (36-46) F508del/none 39 462 No No 8 Female Caucasian 5 50 (46-52) F508del/none 72 440 No Yes 9 Male Caucasian 4 43 (41-45) F508del/Y1032C 14 401 No No 10 Male Caucasian 3 52 (50-54) G542X/none 21 500 No No 11 Female Caucasian 8 34 (30-38) R560T/none 9 433 No No 12 Female Hispanic 6 36 (32-40) R334W/R117H/7T 24 500 Yes No Mean sweat chloride levels represent the mean of all tests performed in the neonatal period. Login to comment

PMID: 21594783 [PubMed] Linde L et al: "Nonsense-mediated mRNA decay and cystic fibrosis."

No. Sentence Comment

234 2. For quantification of CFTR W1282X transcript levels in HeLa and MCF7 cells, transfected with the CFTR constructs RNA is extracted according to the manufacturer`s protocol and RT reactions are performed to obtain cDNA. Real-time PCR is performed using the LightCycler with the Patients RelativeRNAlevel 0 0.1 0.2 0.3 0.4 0.5 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 W /3849 W /G542X W /W W /ΔF508 W /ΔF508 W /W W /ΔF508W /ΔF508W /ΔF508W /ΔF508W /ΔF508W /ΔF508 W /ΔF508W /ΔF508W /ΔF508 Response to readthrough treatment No response Fig. 10.1. Login to comment

PMID: 21607646 [PubMed] Venerando A et al: "Understanding protein kinase CK2 mis-regulation upon F508del CFTR expression."

No. Sentence Comment

79 This drug is claimed to restore full-length CFTR bearing stop mutations that normally induce nonsense-mediated CFTR decay (for example, the G542X stop mutation in CFTR and others like it that together account for about 10% of CFTR mutants). Login to comment
80 At the very least, this drug, which was developed to create read-through at single stop codons such as G542X, should reverse the above 'gold standard` sweat test, but it absolutely fails to do so, thus adding further doubt to our ability to fully understand the path from CFTR defect to disease. Login to comment

PMID: 21652558 [PubMed] Rogan MP et al: "Cystic fibrosis transmembrane conductance regulator intracellular processing, trafficking, and opportunities for mutation-specific treatment."

No. Sentence Comment

65 Five Classes of Defective CFTR Protein Processing Based on Gene Mutation Although .1,500 mutations of CFTR have been identified, only four specific mutations besides F508del reach a frequency of 1% to 3%: G551D, W1282X, G542X, and N1303K. Login to comment
61 Five Classes of Defective CFTR Protein Processing Based on Gene Mutation Although .1,500 mutations of CFTR have been identified, only four specific mutations besides F508del reach a frequency of 1% to 3%: G551D, W1282X, G542X, and N1303K. Login to comment

PMID: 21658649 [PubMed] Bombieri C et al: "Recommendations for the classification of diseases as CFTR-related disorders."

No. Sentence Comment

217 In one study [123], three CFTR mutations (p.F508del, p.G542X and c.579+1G>T (previously named 711+1G>T)) were detected in 8.9% of 449 ACP patients, although the mutation detection rate was not significantly different from that observed in patients with alcoholic liver disease (3.0%) nor that expected in the geographical area under investigation (3.2%). Login to comment

PMID: 21762191 [PubMed] Ghorbel M et al: "Screening of DeltaF508 mutation and IVS8-poly T polymorphism in CFTR gene in Tunisian infertile men without CBAVD."

No. Sentence Comment

91 Table 2 Genotype frequencies of IVS8-polyT tract variants in infertile men and controls IVS8-polyT genotype frequencies (%) 5T/5T 7T/7T 9T/9T All infertile patients (n = 129) 1.55 69.76 4.65 Azoospermia (n = 57) 3.50 73.68 5.26 Oligospermia (n = 39) 0 71.79 5.12 Normospermia (n = 33) 0 60.60 3.03 Controls (n = 54) 0 59.25 3.70 Table 3 Microdeleted STSs and IVS8-polyT genotype in patients with Y chromosome microdeletions (n = 7) Number of microdeleted patients Y chromosome microdeleted AZF loci and STSs IVS8-polyT genotype in CFTR gene Azoospermia (n = 57) 1 AZFa (SY86) 9T/9T 1 AZFa (SY84) 7T/7T Oligospermia (n = 48) 1 AZFa (SY86) 9T/9T 1 AZFa (SY86) 7T/7T 1 AZFa (SY84) 7T/7T 1 AZFa + b (SY86 + SY134) 7T/7T Normospermia (n = 43) 1 AZFc (SY254) 7T/7T patients (Boucher et al., 1999); it also agrees with data reported by Tuerlings et al. (1998) showing no increase in 5T allele and in three frequent CFTR mutations (deltaF508, A455E and G542X) among patients with oligozoospermia. Login to comment

PMID: 21779978 [PubMed] Rowe SM et al: "Suppression of CFTR premature termination codons and rescue of CFTR protein and function by the synthetic aminoglycoside NB54."

No. Sentence Comment

5 In polarized airway epithelial cells expressing either a CFTR-W1282X or - G542X cDNA, treatment with NB54 increased stimulated short-circuit current (ISC) with greater efficiency than gentamicin. Login to comment
6 NB54 and gentamicin induced comparable increases in forskolin-stimulated ISC in primary airway epithelial cells derived from a G542X/F508del CF donor. Login to comment
7 Systemic administration of NB54 to Cftr-/- mice expressing a human CFTR-G542X transgene restored 15-17% of the average stimulated transepithelial chloride currents Electronic supplementary material The online version of this article (doi:10.1007/s00109-011-0787-6) contains supplementary material, which is available to authorized users. Login to comment
32 We also show that NB54 restores a comparable level of CFTR expression and function as gentamicin in transgenic mice expressing a human CFTR-G542X cDNA. Login to comment
43 Primary human airway epithelial cells were derived from lung explants of CF subjects who provided written informed consent and were confirmed to harbor two severe CFTR mutations (including the G542X premature termination codon) by methods described previously [24, 25]. Login to comment
65 Mouse lines and treatment protocols The CFTR-G542X mice used in this study contained the Cftrtm1Cam knockout [30] and expressed a human CFTR transgene with the G542X premature stop mutation [17, 31, 32] (referred to as Cftr-/- hCFTR-G542X mice). Login to comment
107 To test the more common CFTR-G542X allele and examine dose dependence, CFBE41o- human airway cells transduced with an adenovirus vector expressing a CFTR-G542X cDNA were tested following treatment with gentamicin or NB54. Login to comment
116 We obtained primary HBE cells from a compound heterozygote subject (G542X/F508del) following a lung Fig. 3 Increased W1282X-CFTR dependent short-circuit current following incubation of synthetic aminoglycosides. Login to comment
122 *P<0.05; **P<0.005; ±SEM, n=16 Fig. 4 Short-circuit current assay of CFBE41o-cells transduced with an adenovirus expressing CFTR-G542X following treatment with gentamicin, NB30, or NB54. Login to comment
123 a Representative short-circuit current tracings of CFBE41o-cells were grown on air-liquid interface, transduced with adenovirus encoding CFTR-G542X, allowed to recover 48 h, and exposed to aminoglycosides (500 μg/ml) for 24 h. Login to comment
127 b Mean stimulated short-circuit currents measured in CFBE41o-cells transduced with adenovirus CFTR-G542X following treatment with the indicated doses of gentamicin or NB54. Login to comment
142 Readthrough of CFTR-G542X in vivo induced by the synthetic aminoglycoside NB54 To examine whether NB54 could suppress a CFTR PTC in vivo, we next utilized a transgenic human CFTR-G542X (hCFTR-G542X) mouse line [17, 31-33]. Login to comment
143 In this mouse model, the hCFTR-G542X transgene is expressed from the rat intestinal FABP promoter in a mouse Cftr-/- background. Login to comment
144 Samples from the ileum of untreated Cftr+/+ littermates carrying the transgene were used as positive controls (Fig. 6a), while corresponding samples from untreated Cftr-/- mice carrying the hCFTR-G542X transgene were used as negative controls (Fig. 6b). Login to comment
146 Fully differentiated primary airway cells derived from a CF (G542X/ F508Del) donor were grown at air-liquid interface until terminally differentiated (e.g., 90% ciliated), and then treated with NB54, gentamicin, or vehicle (500 μg/ml) for the times indicated, then mounted in modified Ussing chambers under voltage clamp conditions. Login to comment
150 Representative short-circuit current tracings are shown from a untreated Cftr+/+ hCFTR-G542X mice (WT control), b untreated Cftr-/- hCFTR-G542X (negative control), c gentamicin-treated Cftr-/- hCFTR-G542X (60 mg/kg), and d NB54-treated Cftr-/- hCFTR-G542X (120 mg/kg). Login to comment
151 e Scatter plot of the total ISC data from Cftr-/- hCFTR-G542X mice (untreated, gentamicin treated, and NB54 treated) that combines the forskolin/IBMX and carbachol responses. Login to comment
156 A scatter plot of the total ISC (ΔISC following forskolin/ IBMX + carbachol) from all Cftr-/- hCFTR-G542X mice (untreated, gentamicin treated, and NB54 treated) is presented in Fig. 6e, while an analysis of that data is represented in Fig. 6f. In Cftr+/+ hCFTR-G542X mice, ileal tissues yielded a mean cAMP-stimulated ISC of 161 μA/cm2 10 min after forskolin/IBMX addition, and a further increase in ISC of 209 μA/cm2 following the addition of carbachol (a muscarinic agonist that transiently enhances the cAMP-dependent chloride secretory response in intestinal tissues by activating Ca2+ -dependent potassium channels in the basolateral plasma membrane [37]). Login to comment
158 In contrast, stimulated responses were effectively absent in untreated Cftr-/- hCFTR-G542X control mice. Login to comment
161 We initially compared the relative efficacy of gentamicin and NB54 to restore activated ISC, a measure of full-length CFTR protein function resulting from suppression of the hCFTR-G542X mutation. Login to comment
169 Next, we examined the ability of NB54 to induce readthrough and restore CFTR activity in the Cftr-/- hCFTR-G542X transgenic mouse model. Login to comment
176 Only background staining was observed in untreated Cftr-/- hCFTR-G542X mice (Fig. 7a). Login to comment
193 We tested the ability of these compounds to suppress two CFTR PTCs (G542X and W1282X) in a variety of CF cellular models, including heterologous CFTR expression systems, immortalized CF cell lines, and primary HBE cells isolated from a CF lung. Login to comment
194 In addition, we examined the ability of these compounds to suppress the human CFTR-G542X mutation in a transgenic mouse model. Login to comment
199 The maximal ISC measured in CFBE41o-airway epithelial monolayers stably transduced with a lentivirus vector expressing CFTR-W1282X or an adenovirus vector expressing CFTR-G542X was consistently higher with NB54 than gentamicin, and NB54 was also nontoxic at these doses (Figs. Login to comment
201 NB54 also induced a cAMP-stimulated ISC that was comparable to gentamicin in primary HBE cells carrying the CFTR-G542X mutation, and the induction of that response occurred sooner than we observed with gentamicin treatment (Fig. 5). Login to comment
208 a Samples from untreated Cftr-/- hCFTR-G542X, b samples from Cftr-/- hCFTR-G542X mice treated with 60 mg/kg gentamicin, and c samples from Cftr-/- hCFTR-G542X mice treated with 120 mg/kg NB54. Login to comment
213 As a further test of the ability of NB54 to suppress CF-related PTCs, we examined the propensity of NB54 to restore human CFTR expression in Cftr-/- hCFTR-G542X transgenic mice (Fig. 6). Login to comment
214 We found that NB54 induced significant and dose-dependent increases in stimulated ISC in Cftr-/- hCFTR-G542X transgenic mice, resulting in 15.8% of the current measured in WT mice at a dose of 120 mg/kg. Login to comment
218 Since it was demonstrated in a previous study that gentamicin and PTC124 (ataluren) restored a comparable level of CFTR activity in the same hCFTR-G542X Cftr-/- mouse model [17], the level of CFTR function restored by NB54 should be similar to PTC124 as well. Login to comment
261 Am J Respir Cell Mol Biol 37:57-66 17. Du M, Liu X, Welch EM, Hirawat S, Peltz SW, Bedwell DM (2008) PTC124 is an orally bioavailable compound that promotes suppression of the human CFTR-G542X nonsense allele in a CF mouse model. Login to comment
285 Nat Genet 4:35-41 31. Du M, Jones JR, Lanier J, Keeling KM, Lindsey RJ, Tousson A, Bebok Z, Whitsett JA, Dey CR, Colledge WH et al (2002) Aminoglycoside suppression of a premature stop mutation in a Cftr-/- mouse carrying a human CFTR-G542X transgene. Login to comment
286 J Mol Med 80:595-604 32. Du M, Keeling KM, Fan L, Liu X, Kovacs T, Sorscher E, Bedwell DM (2006) Clinical doses of amikacin provide more effective suppression of the human CFTR-G542X stop mutation than gentamicin in a transgenic CF mouse model. J Mol Med 84:573-582 33. Du M, Keeling KM, Fan L, Liu X, Bedwell DM (2009) Poly-L-aspartic acid enhances and prolongs gentamicin-mediated suppression of the CFTR-G542X mutation in a cystic fibrosis mouse model. J Biol Chem 284:6885-6892 34. Login to comment

PMID: 21783433 [PubMed] Costa C et al: "A recurrent deep-intronic splicing CF mutation emphasizes the importance of mRNA studies in clinical practice."

No. Sentence Comment

51 The mutations in trans of c.870-1113_1110delGAAT were mostly frequent severe mutations: p.Phe508del (n=5 families); c.1624GNT, p.Gly542X (G542X) (n = 3 families); and c.1657CNT, p.Arg553X (R553X) (n=1 family). Login to comment

PMID: 21811577 [PubMed] Sorio C et al: "Defective CFTR expression and function are detectable in blood monocytes: development of a new blood test for cystic fibrosis."

No. Sentence Comment

202 Case Gender Age at diagnosis (years) CFTR genotype* Age (years) Sweat Cl- mEq/L** FEV1 % mean values 2009 Pa PI NPD results*** CF-index 1 F 0 3132delTG 1497delGG 34 129 75 yes yes nd 222,10 2 F 0 R1162X R1162X 43 144 52 yes yes nd 229,65 3 M 0 R1162X R1162X 10 102 59 no yes 1,02 210,18 4 M 0 R1162X R1162X 25 115 81 no yes 1,07 267,11 5 M 7 G542X 711+5 G.A 24 105 59 yes yes nd 25,84 6 M 1 CFTRdele1 G542X 36 107 22 yes yes nd 2113,92 7 M 0 G542X G542X 16 110 71 yes yes 0,97 280,20 8 F 1 Q552X CFTRdele17a-18 35 99 72 yes yes 2,08 2219,81 9 M 16 R1162X 3849+10 Kb C.T 42 74 43 yes no 1,02 271,47 10 M 0 R1162X R1162X 32 105 45 yes yes 1,43 2114,67 11 M 1 F508del F508del 16 86 71 no yes nd 260,04 12 F 0 F508del F508del 16 88 118 no yes nd 248,20 13 M 0 F508del F508del 33 118 51 yes yes nd 265,49 14 M 7 F508del F508del 37 89 37 yes yes nd 2359,82 15 F 0 F508del F508del 27 118 71 yes yes nd 267,26 16 F 8 1717-1 G.A F508del 38 140 74 yes yes nd 2136,80 17 F 0 R1158X F508del 32 95 60 yes yes 1,77 228,31 18 M 7 G542X F508del 39 110 46 yes yes nd 247,52 19 M 0 Q39X F508del 17 101 79 no yes 1,11 264,20 20 F 1 R1162X F508del 41 188 60 no yes 0,94 296,73 21 M 13 3849+10 Kb C.T F508del 24 76 78 yes no 4,67 26,33 22 M 0 W1282X 621+1G.T 33 119 77 yes yes 1,27 242,74 23 F 4 R553X 2789+5 G.A 31 92 44 yes no 7,4 260,94 24 F 11 F508del R553X 39 116 55 yes yes nd 2113,67 25 M 12 F508del 3849+10 Kb C.T 27 51 71 yes no 1,12 298,84 26 F 0 F508del G542X 19 109 109 yes yes nd 2173,24 27 F 0 F508del R1162X 32 94 86 yes yes 1,34 270,16 28 F 0 F508del W57X (TAG) 27 99 78 yes yes 1,21 269,33 29 M 0 F508del Q552X 24 94 41 yes yes 1,50 272,75 30 M 20 F508del 3849+10 Kb C.T 43 58 60 no no 1,13 2112,56 31 M 0 F508del R1162X 12 99 65 no yes 2,14 280,92 32 M 4 F508del 3849+10 Kb C.T 17 60 100 no no nd 2121,31 33 F 1 F508del 1717-1 G.A 26 105 73 yes yes 2,05 255,66 34 F 11 F508del 3849+10 Kb C.T 40 85 59 yes no nd 2152,23 35 F 4 F508del 1717-1 G.A 44 130 97 yes yes nd 2116,56 36 M 13 F508del 3849+10 Kb C.T 43 70 65 yes no CF 265,10 37 F 19 F508del unknown 29 95 100 no no nd 240,53 38 M 6 F508del unknown 15 92 87 yes no nd 270,17 39 F 0 G542X N1303K 34 108 97 yes yes nd 296,14 40 M 50 G1249R IVS8 T5TG12 50 61 74 no no nd 2199,15 41 F 10 2183 AA.G IVS8 T5TG15/T7TG10 45 79 29 yes no 1,9 286,27 42 F 1 G85E unknown 43 120 107 yes no nd 249,21 43 F 0 3272-26 A.G I507del 21 113 88 no no nd 236,79 44 M 8 F508del D1152H 10 77 107 no no nd 210,85 *Cystic Fibrosis mutation database reference: http://www3.genet.sickkids.on.ca/cftr/app. Login to comment

PMID: 9565413 [PubMed] Parad RB et al: "Buccal cell DNA mutation analysis for diagnosis of cystic fibrosis in newborns and infants inaccessible to sweat chloride measurement."

No. Sentence Comment

58 The brushes were then discarded and 60 ␮L 1 M Tris, pH 8.0, was added to the tubes.7 CFTR mutation analysis was performed for 12 mutations (⌬F508, G551D, G542X, 621ϩ1G3T, ⌬I507, 1717-1G3A, R117H, N1303K, W1282X, R560T, R553X, and 3849ϩ10kb C3T). Login to comment
107 Genotypes and Sweat Chloride Confirmation by Diagnostic Category Diagnostic Category Number of Patients (%) Primary SC Before Genotype Genotype Confirmatory SC After Genotyping (mEq/L) Affected 6 (21) 1 inadequate volume 2 ⌬F508/⌬F508 2 ND* 2 G542X/W1282X 2 ND* 1 ⌬F508/N Ն60 1 W1282X/W1282X Ն60 Unaffected 19 (68) Confirmed (SC Ͻ40) 1 inadequate volume 9 N/N 9 Ͻ40 Presumed (no SC*) 10 N/N 10 ND* Unknown (indeterminate) 3 (11) 3 Ն 40, Ͻ60 mEq/L 3 N/N 3 ND* Total 28 (100) * ND, not done. Login to comment
110 Genotype GI* 25 (89) Newborn bowel obstruction Meconium plug 10 N/N Meconium ileus 1 ⌬F508/⌬F508 1 W1282X/W1282X 3 N/N Atresia or other obstruction 4 N/N In utero dilated bowel 2 ⌬F508/G542X In utero abdominal calcification 1 N/N Neonatal idiopathic cholestasis 1 N/N Failure to thrive 1 N/N Respiratory 3 (11) CLD ϩ P aeruginosa in trachea 1 N/N Chronic cough 1 N/N Bronchiolitis 1 ⌬F508/⌬F508 Total 28 (100) * Secondary reasons: 4/25 positive family history, 3/25 CLD, 3/22 in utero abdominal abnormality. Login to comment
142 Genotype Ͻ2 kg Premature or intrauterine growth restriction 14 (50) 2 Transient in utero dilated bowel (twins), affected sibling 2 G542X/W1282X* 1 In utero abdominal calcifications 1 N/N 10 Meconium plug (3 with CLD, 1 in utero dilated bowel) 10 N/N 1 CLD/P aeruginosa in tracheal aspirate 1 N/N Ͼ2 kg Inadequate sweat amount or inconclusive SC 5 (18) 1 Meconium ileus, affected sibling 1 ⌬F508/⌬F508* 1 Scrotal swelling, in utero abdominal calcifications 1 N/N 1 Chronic cough 1 N/N 1 Affected relative 1 N/N 1 Failure to thrive, affected uncle 1 N/N Sweat lab inaccessible: 9 (32) 1 Bronchiolitis 1 ⌬F508/⌬F508* Patient intensive care unit- bound or no laboratory in hospital 8 Bowel obstruction 5 Meconium ileus 1 ⌬F508/N* 1 W1282X/W1282X* 3 N/N 3 Small bowel atresia 3 N/N Total 28 (100) * Affectd. Login to comment

PMID: 9623690 [PubMed] Mahadeva R et al: "Alpha1-antitrypsin deficiency alleles and the Taq-I G-->A allele in cystic fibrosis lung disease."

No. Sentence Comment

51 The 39 "other" CF mutations in the normal α1-AT phenotype 508/other group were: six patients G551D, three R117H, three 621+1G→T, two R1162X, two G542X and one each had P67L, 1078delT, 2711delT, 1717-1G→A, V520F, 1898+1G→T, W1310X and N1303K in addition to the ∆F508 mutation. Login to comment

PMID: 9662393 [PubMed] Lizardi PM et al: "Mutation detection and single-molecule counting using isothermal rolling-circle amplification."

No. Sentence Comment

23 We designed an allele-discriminating probe for a 46-nt target sequence in the CFTR G542X gene locus (Fig. 2a). Login to comment
35 Allele discrimination using HRCA and genomic DNA An alternative probe design for a 46-nt target sequence in the CFTR G542X gene locus (Fig. 2c) was used in this experiment. Login to comment
51 a, Sequence of the hybridizing arms of a circularizable probe, and two alternative 8-base gap probes designed for the CFTR G542X locus. Login to comment
64 c, Sequence of the hybridizing arms of a circularizable gap-fill probe designed for the CFTR G542X mutation locus. Login to comment
80 Human lymphocytes that were either wild-type, homozygous or heterozygous for the G542X locus were used as a DNA source. Login to comment
81 An assay was performed where G542X probes of the gap-fill design (Fig. 2c) were extended and ligated using genomic DNA targets, and amplified using HRCA. Login to comment
91 We prepared slides containing an oligonucleotide probe (P1) specific for a 39-base sequence adjacent to the G542X locus of the CFTR gene. Login to comment
118 We performed an assay to measure the ratio of mutant to wild type strands at the G542X locus in genomic DNA samples that had been constructed to simulate the presence of rare somatic mutations. Login to comment
122 a, Design of primers used to amplify an 89-base probe that had been extended by DNA polymerase copying of 7 nt (shown in small type) from the G542X target region, and circularized by DNA ligase. Login to comment
126 Lanes 1-7 were seeded, respectively, with 2×105, 2×104, 2×103, 2×102, 2×101, 2×101 (repeat), or zero molecules of G542X circularized mutant probe. Login to comment
128 c, Detection of the G542X point mutation. Login to comment
129 DNA samples from homozygous wild type, heterozygous or homozygous mutant cultured lymphocytes were denatured by heating for 4 min at 96 °C, and mixed with the gap-fill open circle probe for the G542X locus shown in 6A. Login to comment
142 P1 is designed to form 39 bp with the G542X target, and the 5´ terminus of P1 contains a 5´-phosphate to permit ligation. Login to comment
163 To test the feasibility of padlock probe detection on deproteinized DNA, we ligated the G542X padlock probe (Fig. 2a) on a sample of wild-type human genomic DNA which had been immobilized and denatured on a polylysine coated glass slide, at a density of approximately 480 haploid genomes per square mm. Login to comment
167 The same padlock probe, with a gap oligonucleotide specific for the wild-type G542X locus, was ligated on salt-extracted nuclei prepared by the 'halo` method11,12. Login to comment
179 a, Observation of non-condensed rolling circle DNA product from a padlock probe specific for the CFTR G542X wt locus, labelled with BUDR as a hapten, lying on the surface of a polylysine-coated slide. Login to comment
180 b,c, Observation of partly condensed (b) and fully condensed (c) rolling-circle amplification signals generated by CFTR G542X wt padlock probes that had been hybridized to nuclear 'halo` cytological preparations (see text for details). Login to comment
182 The frequency of nuclei displaying one or two RCA signals in halo preparations of wild-type cells was 197/2182 for the G542X locus wt probes, 1936/2573 for deltaF508 locus wt probes. Login to comment
236 The sequences are: CFTR G542X phosphorylated open circle probe (85 bases) for the gap oligo method, 5´-AAGAACTATATTGTCTTTCATTCTTGCATG- GTCACACGTCGTTCTAGTACGCTTCTAGTACGCTTTTCCACTCAGTG- TGATTCCA-3´; G542X wild type phosphorylated gap probe, 5´- CCTTCTCC-3´; G542X mutant phosphorylated gap probe, 5´- CCTTCTCA-3´; primer for rolling circle reaction, 542X.P1.18, 5´- ACGACGTGTGACCATGCA-3´. Login to comment
238 Primers for the HRCA reactions performed with gap-fill probe were: first primer, 542X.P1-23, 5´- CTAAAGCTGAGACATGACGAGTC-3´; alternative second primers for allele discrimination, 542X.P2-23-C, 5´-CTCAGTGTGATTCCACCTTC-3´ or 542X.P2-23-A, 5´-CTCAGTGTGATTCCACCTTCACA-3´; G542X artificial wild type target, 5´-TTGCAGAGAAAGACAATATAGTTCTTGGAGAAG- GTGGAATCACACTGAGTGGA-3´; G542X artificial mutant target, 5´- TTGCAGAGAAAGACAATATAGTTCTTTGAGAAGGTGGAATCACACTG- AGTGGA-3´. Login to comment
242 Oligonucleotides for the RCA-CACHET method, carbon spacers in parenthesis: phosphorylated P1-G542X, 5´-GAGAAGGTGGAATCACACTGAGTG- GAGGTCAACGAGCAATTTTTTTTTTT-(C7-NH2)-3´; P2wt, 3´-GTT- CTTGATATAACAGAAAGTTTT-(C18)-TTTTTATGATCACAGCTGAGGA- TAGGACATGCGA-3´; P2mu, 3´-TTTCTTGATATAACAGAAAGTTTT- (C18)-TTTTTACGTCGTCCGTGCTAGAAGGAAACACGCA-3´; pre-made amplification circles with cognate detector tags, Cwt, 5´-CGCATGTCCTAT- CCTCAGCTGTGATCATCAGAACTCACCTGTTAGACGCCACCAGCTCC- AACTGTGAAGATCGCTTAT-3´; detector tag Fl-det1c-dinitrophenol (DNP), FITC-TCAGAACTCACCTGTTAG-3´-DNP; detector tag Fl-det1d- DNP, FITC-ACTGTGAAGATCGCTTAT-3´-DNP; Cmu, 5´-GCGTGTTTC- CTTCTAGCACGGACGACGTATATGATGGTACCGCAGCCAGCATCACC- AGACTGAGTATCTCCTATCACT-3´; detector tag Cy3-det2b-DNP, Cy3- TATATGATGGTACCGCAG-3´-DNP; detector tag Cy3-det2c-DNP, Cy3- TGAGTATCTCCTATCACT-3´-DNP. Login to comment
249 Cell lines of known genotypes for the G542X locus (GM07828[+/+], GM11497B[+/-], GM11496[-/-]) were purchased from Corriell Cell Repositories. Login to comment
255 The circularizable G542X probe and an equimolar mixture of the two allele-specific gap oligonucleotides were ligated in the presence of the mutant sequence artificial DNA target. Login to comment
256 Circular DNA resulting from the ligation of G542X gapped probes were amplified with ø29 DNA polymerase, and the amplified ssDNA was cloned and sequenced. Login to comment
257 The resulting sequence contained only T at the position of the G542X mutation in 20 independent clones, indicating that only the mutant gap oligonucleotide had been ligated and amplified. Login to comment
258 With the wild-type template, the RCA product contained only G at the G542X site in 20 clones (data not shown). Login to comment
272 The oligonucleotide P1-G542X was immobilized over an area of 1 mm in diameter on the surface of a glass slide activated with reactive groups. Login to comment
274 Covalent coupling was obtained by reaction of a primary amine attached to the 3´ end of the P1-G542X oligonucleotide. Login to comment
275 Genomic DNA preparations obtained from human cell lines that were either wild type or homozygous mutant at the CFTR-G542X locus were mixed in different pre-determined ratios (mutant/wild type equal to 1:0, 1:1, 1:25 and 1:100) and then amplified by PCR as described17. Login to comment
305 Padlock probe ligationin situ was performed for 2 h at 52 °C by incubating 18 µl of reaction mixture under a cover slip sealed with rubber cement as follows: 150 nM phosphorylated G542X 89-mer probe, 1200 nM wild type G542X gap probe, in 20 mM Tris•HCl (pH 8.3), 50 mM KCl, 0.5 mM NAD, 10 mM MgCl2, 150 µg/ml acetylated BSA, 0.01% Triton X-100 and 0.7 U/µl Ampligase DNA ligase. Login to comment

PMID: 9688848 [PubMed] Jiang C et al: "Partial restoration of cAMP-stimulated CFTR chloride channel activity in DeltaF508 cells by deoxyspergualin."

No. Sentence Comment

139 The ability of DSG to influence the presence of endogenous mutant ⌬F508-CFTR at the plasma membrane was also assessed in IBE-1 cells, an immortalized human CF intrahepatic biliary epithelial cell line that harbors the ⌬F508 and G542X (premature stop mutation at residue 542) mutations (8). Login to comment

PMID: 9709387 [PubMed] Wilschanski M et al: "Pathology of pancreatic and intestinal disorders in cystic fibrosis."

No. Sentence Comment

84 The next most common mutations are G542X, G551D, N1303K and W1282X, each of which account for 1% to 2.5% of CF chromosomes throughout the world. Login to comment
85 Two are missense mutations (G55 ID, N1303K) resulting in an amino acid substitution of the protein product, while G542X and W1 282X are nonsense mutations which give rise to a premature stop codon, leading to the expression of no CFTR or a non-functional truncated protein. Login to comment
97 Molecular consequences of cftr gene mutations Several classification systems have been developed in an attempt to define the large number of cftr gene mutations on 43 I =ON 4o0 o 00 4O0 40 40 I II 111 IV V Normal NOmAfl Missnso G542X Missmnse Missense Missense A455E Fremeshift AA dIeIIOn 05510 R117H Allerndve 39soTT AF508 spiRlng Spl$oeJunculon 3849t10kbC4T1717-1G-4A Figure 4 Molecular consequences of cystic fibrosis transmembrane conductance regulator mutations. Login to comment
152 A small number of more Table 1 Classification of cystic fibrosis gene mutation as severe, mild or indeterminate with respect to pancreatic function Severe Mild Variable (classes 1, I/ or 111) (classes IV or V) (classes IV or V) AF508 R117H G85E 1148T R334W 2789+5G-*A G480C R347P G551D A455E R560T P574H N1303K 3849+1 Okb C-+T G542X G551S W1282X P5748 621 +1 G-T R352Q 1717-1G-T T3381 556delA Adapted from Ref 20 with permission recently described mutations [G85E and 278+5G-÷AI are less clearly determinant with respect to the pancreatic sufficient and pancreatic insufficient phenotypes. Login to comment
168 An early study suggested that the nonsense mutation G542X is associated with an increased risk of meconium ileus, but this association has not been confirmed in a study of larger patient cohort. Login to comment

PMID: 9719372 [PubMed] Muller F et al: "Cystic fibrosis screening: a fetus with hyperechogenic bowel may be the index case."

No. Sentence Comment

28 In all cases screening covered at least the eight mutations most frequently observed in France and North America, that is, AF508, AI507, 1717-1G--*A, G542X, G551D, R553X, W1282X, and N1303K. Login to comment
31 Other mutations were shown by ASO (allele Table 1 Fetal andparental mutations ofcysticfibrosis and pregnancy outcome in 209 cases ofhyperechogenicfetal bowel Prenatal genetic screening No CFTR mutation detected (n= 188) * Heterozygous CFTR mutation detected (n= 15) Fetus AF508/x (n=13) Fetus G55 1 D/x, father x/x, mother G55 1D/x (n= 1) Fetus G542X/x, father G542X/x, mother x/x (n=1) Homozygous CFTR mutation detected (n=6) Fetus AF508/AF508, father AF508/x, mother AF508/x (n=5) Fetus AF508/G542X, father G542X/x, mother AF508/x (n=1) Outcome Normal infant (n= 148) IUD or miscarriage (n= 14) Trisomy 21, TOP (n=3) Tetrasomy 12p, TOP (n=1) CMV/toxoplasmosis infection, TOP (n=7) Multiple malformations, TOP (n=2) Neonatal death unrelated to CF (n=3) Bowel atresia (n=8) Neonatal gastric haemorrhage (n= 1) Sudden infant death syndrome (n= 1) Normal infant (n=5) IUD (n=3) Digestive atresia, surgical treatment (n=3) TOP, fetal ascites (n= 1) Cystic fibrosis with meconium ileus at birth (n= 1) Normal infant (n= 1) Normal infant (n= 1) CF affected: TOP (n=2) CF affected: IUD (n= 1) CF affected: one neonatal death, one survivor (n=2) CF affected: TOP (n=1) CF=cystic fibrosis; x/x=no CFTR mutation detected; CFTR=CF transmembrane regulator; TOP=termination of pregnancy; IUD=intrauterine death; CMV=cytomegalovirus infection. Login to comment
49 Six fetuses were homozygous for CFTR mutations (five AF508/AF508, one compound heterozygous AF508/G542X). Login to comment
51 Fifteen fetuses were found to be heterozygous for one of the CFTR mutations tested: 13 AF508, one G542X, and one G551D. Login to comment

PMID: 9725921 [PubMed] Sharer N et al: "Mutations of the cystic fibrosis gene in patients with chronic pancreatitis."

No. Sentence Comment

32 DNA Studies We extracted DNA from buccal cells obtained by having the patients rinse their mouths with 10 ml of 4 percent sucrose.19 The CFTR locus was examined for the 22 mutations that together account for 95 percent of all such mutations in patients with cystic fibrosis in the northwest of England.20 The amplification- refractory mutation system Elucigene CF(4)m kit (Zeneca Diagnostics, Macclesfield, United Kingdom) was used to detect the four most common mutations: ∆F508, G551D, G542X, and 621+1(G→T)21; the polymerase chain reaction, restriction-enzyme analysis, and allele-specific oligonucleotide hybridization facilitated the detection of R560T, R117H, 1898+1(G→A), R553X, S549N, 1717¡1(G→A), N1303K, W1282X, E60X, 1154insTC, R347P, 3659delC, Q493X, V520F, R334W, ∆I507, 3849+10Kb(C→T), and 1078delT. Login to comment

PMID: 9725922 [PubMed] Cohn JA et al: "Relation between mutations of the cystic fibrosis gene and idiopathic pancreatitis."

No. Sentence Comment

34 Pancreatograms were assessed for the severity of chronic pancreatitis according to published criteria by a reviewer who was unaware of the patients` histories (Table 1).19 DNA Studies We extracted DNA from blood samples20 and tested for 16 CFTR mutations - ∆F508, W1282X, R117H, 621+1(G→T), R334W, R347P, A455E, ∆I507, 1717¡1(G→A), G542X, S549N, G551D, R553X, R560T, N1303K, and 3849+10Kb(C→T) - using reverse dot blot strips (Roche Molecular Systems, Alameda, Calif.). Login to comment

PMID: 9725928 [PubMed] Durie PR et al: "Pancreatitis and mutations of the cystic fibrosis gene."

No. Sentence Comment

12 The next most common mutations, G542X, G551D, N1303K, and W128X, each account for only 1 to 2.5 percent of known cystic fibrosis chromosomes. Login to comment

PMID: 9727805 [PubMed] Robertson NH et al: "Development and validation of a screening test for 12 common mutations of the cystic fibrosis CFTR gene."

No. Sentence Comment

12 The CFTR gene mutations that are detected by the test are 1717-1G>A, G542X, W1282X, N1303K, ∆F508, 3849+ 10kbC>T, 621+1G>T, R553X, G551D, R117H, R1162X and R334W, which are described by KAZAZIAN [10] and papers cited therein. Login to comment
48 The A-tube contains ARMS primers specific for the 1717-1G>A, G542X, W1282X, N1303K, ∆F508 and 3849+10kb C>T mutations. Login to comment
73 - Analysis of the 754 chromosomes tested Mutation Independent typing method* Totals 1717-1G>A G542X W1282X N1303K ∆F508 3849+10kbC>T 621+1G>T R553X G551D R117H R1162X R334W Other/none Number of samples Total number of chromosomes ASO ASO ASO ASO Electrophoresis Digest (HphI) Digest (MseI) Digest (HincII) Digest (NdeI) ASO Digest (DdeI) Digest (MspI) 16 10 16 12 89 11 7 15 16 13 11 6 532 377 754 *: Confirmatory typing as detailed in references cited within [10]. Login to comment
75 (97) (130) (160) (212) (240) (279) (329) (487) (487) (383) (325) (285) (243) (200) (160) (140) (97) (100) (150) (200) (250) (300) (350) (400) (450) (500) (550) apoB apoB ∆F508(N) ODCODC 3849+10kbC>T 1717-1G>A G542X W1282X N1303K ∆F508(M) R334W R1162X R117H G551D R553X 621+1G>T A-tube B-tube Marker Fig. 1. Login to comment
84 Where rare non-∆F508 compound heterozygotes have been obtained (3849+10kbC>T/W1282X; 3849+10kb C>T/G542X; G542X/N1303K; G542X/W1282X; G551D/ R553X; N1303K/1717-1G>A; G542X/17171G>A; N1303K/ W1282X; R553X/R334W) and analysed, both mutations were correctly identified. Login to comment
99 1: 1717-1G>A/+; 2: G542X/+; 3: W1282X/+; 4: N1303K/+; 5: ∆F508/+; 6: 3849+10kbC>T/+; 7: +/+; 8: +/+; 9: ∆F508/∆F508; 10: 621+1G>T/+; 11: R553X/+; 12: G551D/+; 13: R117H/+; 14: R1162X/ +; 15: R334W/+; 16: +/+; 17: +/+; 18: ∆F508/∆F508; 19: ∆F508/+. Login to comment
102 1: +/+; 2: 1717-1G>A/+; 3: G542X/+; 4: W1282X/+; 5: N1303K/+; 6: ∆F508/+; 7: 3849+10kbC>T/+; 8: 621+1G>T/+; 9: R553X/+; 10: G551D/+; 11: R117H/+; 12: R1162X/+; 13: ∆F508/∆F508; 14: R334W/+. Login to comment
104 15: +/+; 16: +/+; 17: R553X/+; 18: +/+; 19: ∆F508/+; 20: +/+; 21: +/+; 22: R117H/∆F508; 23: ∆F508/∆F508; 24: +/+: 25: G542X/N1303K; 26: no deoxyribonucleic acid (DNA) control. Login to comment
107 The CF(12)m test screens for the CF mutations 1717-1G>A, G542X, W1282X, N1303K, ∆F508, 3849+10kbC>T, 621+ 1G>T, R553X, G551D, R117H, R1162X and R334W, the most common CF mutations in Caucasians and Ashkenazi Jews. Login to comment
119 Furthermore, the finding from another study [15], which compared multiplex ARMS screening for the ∆F508, G551D, G542X and 621+1G>T alleles [8] with alternative routine procedures for the same alleles, was that multiplex ARMS was the preferred method. Login to comment

PMID: 9731023 [PubMed] Pradal U et al: "Nasal potential difference in congenital bilateral absence of the vas deferens."

No. Sentence Comment

39 ⌬F508, R117H, R1162X, 2183AA→G, N1303K, 3849 ϩ 10KbC→T, G542X, 1717-1G→A, R553X, Q552X, G85E, 711 ϩ 5G→A, 3132delTG and 2789 ϩ 5G→A were tested using for R117H two specifically designed primers which create a CFoI restriction site when the mutation is absent, and for all the other mutations a reverse dot blot assay (19). Login to comment
64 Age (yr) Sweat Cl- (mmol/L) Sweat Naϩ (mmol/L) CFTR Mutation PolyT Variant NPD* (mV) Main Anamnestical and Clinical Data 1 37 35 51 G542X/- 7/9 -16.2 SA† and HI‡ in sputum culture 2 24 62 72 ⌬F508/- 7/9 -12.3 Sinusitis 3 32 88 86 ⌬F508/- 9/9 -16.5 Relation of a CF patient, sinusitis, previous tuberculous lymphadenitis, 4 39 16 39 -/- 7/7 -10.3 chronic cough, diabetes 5 40 8 22 -/- 7/9 -12.8 - 6 37 6 12 -/- 5/7 -14.7 Asthma 7 29 34 37 ⌬F508/- 7/9 -10.1 Primary tuberculosis infection 8 32 44 55 ⌬F508/- 9/9 -13.7 HI in sputum culture 9 44 40 43 ⌬F508/- 5/9 -16.9 Nasal polyposis, biliary stones, chronic sinusitis 10 40 39 52 -ր- 7/7 -11.7 SA sputum culture, bilateral inguinal hernia 11 36 32 50 ⌬F508/R117H 7/9 -29.1 Funnel chest, pulmonary hyperinflation 12 32 65 70 ⌬F508/- 7/9 -46.7 SA sputum culture * Basal nasal potential difference. Login to comment
69 CFTR gene mutations were found in eight patients (seven ⌬F508 and one G542X), the 5T variant in two. Login to comment

PMID: 9736775 [PubMed] Larriba S et al: "Testicular CFTR splice variants in patients with congenital absence of the vas deferens."

No. Sentence Comment

18 RESULTS CFTR analysis Eight different mutations (R117H, L206W, V232D, ∆F508, G542X, 711+1G→T, D1270N and 2789+5G→A) were found in nine of the 12 CBAVD patients, yielding a CFTR mutation frequencyof75%.ThreepatientspresentedtwoCFTRmutations, with one of them homozygous for the V232D mutation. Login to comment
26 CFTR genotype, IVS8-6 poly(T) allele and proportion of exon 9+ (E9+) and exon 9- (E9-) CFTR transcripts in testicular and epididymal biopsies Sample Phenotype CF mutation IVS8-6(T) Testis Epididymis n E9+ (%) E9- (%) n E9+ (%) E9- (%) 1 Non-CBAVD N/N 9T/9T 5 99 ± 0 1 ± 0 2 Non-CBAVD N/N 7T/7T 2 96 ± 2 4 ± 2 3 Non-CBAVD N/N 7T/7T 3 98 ± 0 2 ± 0 4 Non-CBAVD N/N 7T/7T 3 97 ± 1.5 3 ± 1.5 5 Non-CBAVD R334W/N 7T/7T 3 94 ± 1 6 ± 1 6 Non-CBAVD N/N 7T/7T 2 95 ± 1 5 ± 1 7 CBAVD V232D/V232D 9T/9T 4 96 ± 1.5 4 ± 1.5 8 CBAVD ∆F508/N 9T/9T 2 99 ± 0 1 ± 0 9 CBAVD ∆F508/D1270N 7T/9T 2 98 ± 1 2 ± 1 10 CBAVD G542X/2789+5G→A 7T/9T 2 96 ± 1 4 ± 1 11 CBAVD N/N 7T/7T 3 96 ± 2 4 ± 2 2 90 ± 3 10 ± 3 12 CBAVD N/N 7T/7T 2 94 ± 2 6 ± 2 5 78 ± 5 22 ± 5 13 CBAVD R117H/N 7T/7T 2 99 ± 0 1 ± 0 4 95 ± 2 5 ± 2 14 CBAVD G542X/5T 5T/9T 3 30 ± 2 70 ± 2 15 CBAVD ∆F508/5T 5T/9T 2 80 ± 5 20 ± 5 16 CBAVD L206W/5T 5T/9T 2 58 ± 2 42 ± 2 17 CBAVD 711+1G→T/5T 5T/7T 3 77 ± 4 23 ± 4 18 CBAVD 5T/N 5T/7T 5 71 ± 2 29 ± 2 The mean proportion of E9+ and E9- CFTR transcripts is calculated as the mean of the proportions found for each sample. Login to comment
112 Each sample of genomic DNA was first studied for the most common CF mutations in the Spanish population, ∆F508 and G542X. Login to comment

PMID: 9736778 [PubMed] Vankeerberghen A et al: "Characterization of 19 disease-associated missense mutations in the regulatory domain of the cystic fibrosis transmembrane conductance regulator."

No. Sentence Comment

87 Maturation pattern of RD mutations and their associated phenotype found in patients with the indicated genotype (when the mutation is associated with CF, only the pancreas status is given) Mutation A-form B-form C-form Clinical data Genotype Phenotype Reference I601F + + - I601F/G542X PS M. Schwarz, personal communication L610S + + - Unknown Unknown A613T + + - Unknown Unknown D614G + + - D614G/unknown PI 14 I618T + + - I618T/dF508 PS G.R. Cutting, personal communication L619S + + - L619S/unknown PI B. Tümmler, personal communication H620P + + - H620P/R1158X PS M. Schwarz, personal communication H620Q + + + H620Q/dF508 PI T. Dörk, personal communication G622D + + + G622D/unknown Oligospermia J. Zielenski, personal communication G628R + + - Unknown Unknown L633P + + - L633P/3659delC M. Schwarz, personal communication D648V + + + D648V/3849+10kb C/T PI C. Ferec, personal communication T665S + + + Unknown Unknown F693L + + + F693L/W1282X Healthy C. Ferec; CF Genetic Analysis Consortium R766M + + + R766M/R792G CBAVD D. Glavac, personal communication R792G + + + R766M/R792G CBAVD D. Glavac, personal communication A800G + + + A800G/unknown CBAVD 34 I807M + + + I807M/unknown CBAVD Our observation E822K + + + E822K/unknown PI 35 E826K + + + E826K/unknown Thoracic sarcoidosis C. Bombieri, personal communication +, the protein matures up to that form; -, the protein does not reach the respective maturation step. Login to comment

PMID: 9788722 [PubMed] Petreska L et al: "Molecular basis of cystic fibrosis in the Republic of Macedonia."

No. Sentence Comment

40 The screening procedures of 17 other known CF mutations included detection of mutations in the PCR products of positive controls and samples by: a) direct analysis on PAGE for A1507 and 1677delTA, simultaneously to AF508; b) hybridization with ASOs for mutation R117H (21), 1717-1GdA (22), G542X (22), N1303K (23), and W1316X (24), and c) restriction digestion `followed by agarose or polyacrylamide gel electrophoresis (exon 3 PCR product digested with HinfI for CUE, exon 4 with HinfI for 444delA, exon 5 with RsaI for 711 + 5G --*A,exon 7 with HhaI for R347H or with RsaI for Q359K/T360, exon 11 with HincII for both G551D and R553X, exon 19 with DdeI for R1162X or with HphI for 3849G+A, a 175 bp PCR fragment of exon 13 with HaeIII for 2556insAT) (4). Login to comment
65 Only G542X and N1303K were found among the 17 more common mutations that, besides AF508, were screened by direct detection. Login to comment
70 Frequency of mutations identified in CF chromosomesfrom the Republic of Macedonia Mutation (location) Number of chromosomeswith mutation Ethnic group (fraction%) Method of detection XV-2clKM19 haplo- References (96) type AF508 (exon 10) 79 (47.6) All groups 12% PAGE BD (3) G542X (exon 11) 6 (3.6) All groups Dot blot B (22) N1303K (exon 21) 3 (1.8) MKa(2.8%) Dot blot B (23) 621t l G + T 2 (1.2) MK (1.9%) SSCP B (30) fintron 4) (intron 5) (exon 19) (exon 4) (intron 11) 711t3A-rG 2 (1.2) ALb (3.8%) SSCP A (31)c 384% +A 2 (1.2) MK (1.9%) SSCP C (32) 457TAT+G 1 (0.6) MK (0.9%) SSCP B (33) 1811+1G-.C l(0.6) MK (0.9%) DGGE 8 Hphl dig. Login to comment
72 Clinical feaiures of the CF patients from Macedonia Genotype Number of CF patients (%) PI PS Shwachman scorea Age of onset GI- (mmljl) NDb AF508/AF508 AF508/G542X AF508/N1303K AF508/711+3A-.G AF508/711+W+G AF508/621+lG+T AF508/621+1G+T AF508/1811+1G-*C AF508/457TAT-*G AF508/3849G+A G542X/3849G+A N1303K/ND V1397E/ND AF508/ND NDiND Total 26 (31.3) 5 (6.0) 2 (2.4) 2 (2.4) 2 (2.4) 1 (1.2) 1 (1.2) 1 (1.2) 1 (1.2) 1 (1.2) 1 (1.2) 13 (15.7) 27 (32.5) 83 (100.0) 26 5 2 1 1 1 1 1 1 1 1 1 7 4 1 15 7 63 13 25-85 30-60 38 84 82 35 78 80 83 50 82 83 I 30-60 20-90 ~~~~~ 1-6 months 1 month 3 months 1 month 1 month 2 months 2.5 years 2 months 2 months 2 months 1 month 6 years 3 weeks Variable Vanable ~ ~ ~~~ 80-210 116-166 180-200 80 120 170 156 240 150 98 190 65 65 65-2300 2 65-130 (ps) 58-230 (PO 5 65-130 (PS) 7 a Shown is the most recent Shwachman score. Login to comment
79 Genotype-phenotype data Nine different genotypes were observed in 41/83 (49.4%) unrelated families: AF508/AF508 (n =26), AF508/457TAT-,G (n = l), AF508/621+1G+T (n = 2), AF508/G542X (n = 5), AF508/N1303K (n =2), AF508/38496-,A (n= I), G542X/ 384963 A (n = l), AF508/711 +3A G (n = 2), AF508/1811+1G-C (n = 1). Login to comment
98 They include the 'oldest` G542X (found in different ethnic groups) and N1303K mutations (found only among Macedonians), and one additional mutation, 621 +lG+T, that is among the world`s most common CF alleles. Login to comment

PMID: 9790686 [PubMed] Clancy JP et al: "Cystic fibrosis transmembrane conductance regulator (CFTR) nucleotide-binding domain 1 (NBD-1) and CFTR truncated within NBD-1 target to the epithelial plasma membrane and increase anion permeability."

No. Sentence Comment

4 Furthermore, when clinically relevant CFTR proteins truncated within NBD-1 (R553X or G542X) are expressed, surface localization and enhanced halide permeability are again established. Login to comment
32 Expression of CFTR containing the clinically relevant mutations R553X or G542X, which each contain >70% of the NBD-1 motif, produce polypeptides that also target the cell membrane and enhance halide permeability in a manner similar to isolated NBD-1. Login to comment
45 Recombinant vaccinia viruses containing wtCFTR and CFTR containing a premature stop codon at position 542 (G542X) or 553 (R553X) under the regulatory control of the T7 promoter was generated from constructs in the pTM1 vector (15) using standard techniques (16). Login to comment
75 Immunoprecipitation of NBD-1, G542X, R553X, and wtCFTR. Login to comment
87 Digital Confocal Immunofluorescent Microscopy of COS-7 Cells Expressing wt or ∆F508 CFTR, G542X, or R553X. Login to comment
157 Expression of R553X and G542X CFTR in Mammalian Epithelial Cell Lines. Login to comment
160 We chose to study two clinically relevant mutant CFTR molecules possessing premature stop codons, G542X and R553X. Login to comment
161 These mutations are found in approximately 5% of the CF population (34) and include 72% (G542X) to 79% (R553X) of the NBD-1 (aa 432-586). Login to comment
162 Figure 6 shows detection of 35 S-labeled truncated proteins [~53 kDa (G542X); ~55 kDa (R553X)] from COS-7 cell lysates following vaccinia-based expression. Login to comment
176 This antibody recognizes an epitope in the first predicted extracellular loop of CFTR TM-1, which is shared by wtCFTR, R553X, and G542X. Login to comment
179 Figure 7 indicates a plasma membrane staining pattern in cells without detergent permeabilization following wtCFTR, R553X, and G542X expression, but not ∆F508 CFTR. Login to comment
181 These studies provide evidence of plasma membrane targeting by CFTR possessing either the G542X or R553X mutations. Login to comment
182 To determine whether either R553X or G542X CFTR had positive effects on basal cellular halide permeability, we performed SPQ analysis in COS-7 cells expressing these mutant cDNAs (Figure 8). Login to comment
185 The effects of R553X, G542X, and NBD-1 on COS-7 cell basal halide permeability were qualitatively and quantitatively similar (compare with Figure 5B). Login to comment
199 FIGURE 6: Immunoblot of wt, R553X, and G542X CFTR in COS-7 cells. Cells were labeled with translabel for 20 min at 12 h after infection and immunoprecipitated with anti-NBD-1 antibody as described in the Experimental Procedures. Lane A ) wtCFTR, lane B ) G542X, lane C ) R553X. Login to comment
202 Expression of truncated CFTR (R553X CFTR and G542X CFTR, Figures 6, 7, and 8) produces a protein which also targets the eukaryotic plasma membrane, enhancing cellular basal halide permeability. Login to comment
203 Neither R553X nor G542X produces cAMP-regulated halide permeability, and no full-length CFTR could be detected by immunoprecipitation, indicating that suppression of the premature termination codons is not responsible for the ion transport results shown here (39, 40). Login to comment
204 The enhanced basal halide permeability conferred by R553X and G542X is qualitatively and quantitatively similar to that produced by NBD-1 (Figure 5). Login to comment
205 We suggest that the truncated CFTR proteins G542X and R553X contain adequate domains and the appropriate cellular signals to fold into functional peptides and localize to the cell membrane. Login to comment
206 The common halide permeability enhancing effects produced by G542X, R553X, and isolated NBD-1 suggest that these three polypeptides share common amino acids (422-542 of the complete CFTR molecule) which may be able to activate halide permeability in several epithelial cell types. Login to comment
207 On the basis of the findings that R553X and G542X retain surface localizing and residual halide transport function, we recently studied five patients possessing at least one of these alleles, but found no evidence of residual Cl-secretion during a nasal potential difference protocol (25). Login to comment
211 In either case, our results clearly establish that, unlike class II CFTR mutations (34), R553X and G542X CFTR are capable of escaping intracellular degradation, targetting the plasma membrane, and forming functional proteins that maintain some residual halide transport function. Login to comment
213 FIGURE 7: Localization of wtCFTR, R553X, and G542X to the cell surface in COS-7 cells by confocal immunocytochemistry. Login to comment
217 Lower panels from left to right are (D) G542X without permeabilization, (E) R553X without permeabilization, and (F) vT7 controls with permeabilization. Login to comment
218 FIGURE 8: R553X or G542X expression increases halide permeability in COS-7 cells. Cells grown on glass coverslips were studied by SPQ as in Figure 5. Login to comment
221 (A) Dequench of the G542X expressing cells was significantly elevated above control cells (P < 0.0001 compared with vT7 or LacZ conditions). Login to comment

PMID: 9842999 [PubMed] Cartault F et al: "Detection of more than 91% cystic fibrosis mutations in a sample of the population from Reunion Island and identification of two novel mutations (A309G, S1255L) and one novel polymorphism (L49L)"

No. Sentence Comment

30 Ten CFTR mutations identified in 69 CF families from Reunion Island Mutationa Exonlintron CF alleles Percentage Ama E.10 72 52 Y122X E.4 33 24 A455E E.9 3 2.2 G551D E.11 2 1.4 1717-1G-+A i.10 1 0.7 G542X E.ll 1 0.7 116ldelC E.7 1 0.7 A3G9G E.7 1 0.7 zag+ 5~-+A i.14b 1 0.7 3120tlG-A i.16 11 a Unknown mutations 12 8.7 aCystic Fibrosis Genetic Analysis Consortium: Web site: http // w.genet.sickkids.on.ca/cftr/ CFTR represents the missense mutation A309G (Fig. 1A). Login to comment

PMID: 9862818 [PubMed] Taylor CJ et al: "Chronic pancreatitis and mutations of the cystic fibrosis gene."

No. Sentence Comment

29 To date, more than 700 mutations have been identified in the CF gene; most, with the exception of G551D, G542X and 621+1 (G-A) are rare, aVecting <1% of CF chromosomes. Login to comment
61 Reproduced with permission from Wilschanski et al.2 V Missense A455E Alternative splicing 3849+10kbC (f) IV Missense R117H (e) III Missense G551D (d) II Missense AA deletion ∆F508 (c) I Nonsense G542X Frameshift 394delTT Splice junction 1717-1G (b) Normal (a) T A Chronic pancreatitis and mutations of the cyctic fibrosis gene group.bmj.comon August 8, 2011 - Published bygut.bmj.comDownloaded from doi: 10.1136/gut.44.1.8 1999 44: 8-9Gut C J TAYLOR cystic fibrosis gene Chronic pancreatitis and mutations of the http://gut.bmj.com/content/44/1/8.full.html Updated information and services can be found at: These include: References http://gut.bmj.com/content/44/1/8.full.html#related-urls Article cited in: http://gut.bmj.com/content/44/1/8.full.html#ref-list-1 This article cites 4 articles, 2 of which can be accessed free at: service Email alerting box at the top right corner of the online article. Login to comment

PMID: 9877480 [PubMed] Fajac I et al: "Relationships between nasal potential difference and respiratory function in adults with cystic fibrosis."

No. Sentence Comment

34 Only three patients had a normal sweat test: one was homozygotic for the ∆F508 mutation and two patients were compound heterozygotic for the G542X and 3849+10 kb cytosine (C) → thymine (T) mutations and for the R1070Q and D1152H mutations, respectively. Login to comment

PMID: 9895335 [PubMed] Cremonesi L et al: "Validation of double gradient denaturing gradient gel electrophoresis through multigenic retrospective analysis."

No. Sentence Comment

31 Mutations and polymorphisms analyzed in the CFTR gene. Position Denaturant gradient Mutation Exon 1 40-90% 125G/Ca,b M1V (A3G at 133) 175insT 182delT Exon 3 10-60% W57G (T3G at 301) 356G/Aa G85E (G3A at 386) Exon 4 20-70% R117H (G3A at 482) 541delC 621ϩ1G3T I148T (T3C at 575) Exon 5 20-70% E193K (G3A at 709) Intron 5 20-70% 711ϩ3A3G Exon 7 20-70% 1078delT R334W (C3T at 1132) T338I (C3T at 1145) R347P (G3C at 1172)b R347H (G3A at 1172) R352Q (G3A at 1187) Exon 10 20-70% M470V (1540A/G)a ⌬F508 (del 3 bp at 1652) Intron 10 10-60% 1717-1G3A Exon 11 10-60% G542X (G3T at 1756) 1784delG R553X (C3T at 1789) Exon 12 10-60% D579G (A3G at 1868) E585X (G3T at 1885) Intron 12 10-60% 1898ϩ3A3G Exon 13 30-80% 2183AA3G E730X (G3T at 2320) L732X (T3G at 2327) 2347delG Exon 14a 10-60% T854T (2694T/G)a V868V (2736G/A)a Intron 14b 30-80% 2789ϩ5G3A Exon 15 20-70% M952I (G3C at 2988)b Exon 17a 20-70% L997F (G3C at 3123)b Exon 17b 20-70% F1052V (T3G at 3286) R1066C (C3T at 3328) R1066H (G3A at 3329) A1067T (G3A at 3331) Exon 18 20-70% D1152H (G3C at 3586)b Exon 19 30-80% R1158X (C3T at 3604) Exon 20 20-70% S1251N (G3A at 3384) W1282X (G3A at 3978) Exon 21 20-70% N1303K (C3G at 4041)b Exon 22 30-80% G1349D (G3A at 4178) 4382delA Exon 24 30-80% Y1424Y (4404C/T)a a Polymorphism. Login to comment

PMID: 9917439 [PubMed] Wilschanski M et al: "Clinical and genetic risk factors for cystic fibrosis-related liver disease."

No. Sentence Comment

32 The correlation between liver disease and CF genotype was studied in seven mutations associated with the severe phenotype: ⌬F508, R553X, 1717-1G-ϾA, G542X, W1282X, N1303K, and G551D.2,14 No significant cor- From the *Department of Pediatrics, Cystic Fibrosis Center, Shaare Zedek Medical Center, Hebrew University, Jerusalem; ‡Cystic Fibrosis Center, Carmel Medical Center, Haifa; §Cystic Fibrosis Center, Sheba Medical Center, Tel Hashomer; ࿣Cystic Fibrosis Center, Schneider Children`s Medical Center, Petah Tikva; ¶Cystic Fibrosis Center, Soroka Medical Center, Ben Gurion University, Beer Sheba; #Cystic Fibrosis Center, Rambam Medical Center, Haifa; **Cystic Fibrosis Center, Hadassah University Hospital, Jerusalem; ‡‡Department of Medical Statistics, Ichilov Medical Center, Tel Aviv; and §§Department of Genetics, Life Sciences Institute, Hebrew University, Jerusalem, Israel. Login to comment
50 Forced expiratory volume in 1 second, and forced vital capacity, were measured and expressed as a percentage of predicted values for height and sex, using previously described standardized pulmonary equations.17 Current height and weight percentiles were computed using the tables of Tanner.18 Mutation Analysis All the patients were screened for all of the CFTR mutations previously identified in the Israeli CF population.15,16 Patients were classified according to severity of genotype: patients with severe genotype were homozygous or compound heterozygous to ⌬F508, W1282X, G542X, N1303K, 405ϩ1G3A, delTATT 4010, 1717-1G-ϾA. Login to comment
117 Classification of Identified Genotype According to Severity of Disease Severe n Milder n Variable n Unclassified n ⌬F508/⌬F508 52 3849 ϩ 10kbC 3 T/⌬F508 7 ⌬F508/G85E 1 S549R/S549R 1 W1282X/W1282X 30 3849 ϩ 10kbC 3 T/405 ϩ 1G3A 3 G85E/G85E 5 S549R/G542X 2 ⌬F508/W1282X 39 3849 ϩ 10 kbC 3 T/W1282X 7 G85E/5T 1 S549R/W1282X 1 ⌬F508/G542X 10 3849 ϩ 10kbC 3 T/G85E 1 ⌬F508/5T 1 ⌬F508/W1089X 1 W1282X/G542X 12 W1282X/5T 2 Y1092X/Y1092X 1 W1282X/N1303K 7 W1282X/5T 1 Q359K-T360K/? Login to comment
121 12 N1303K/T4010 2 G542X/? Login to comment
122 3 N1303K/G542X 3 405 ϩ 1G3A/? Login to comment
123 1 N1303K/N1303K 6 Q359K-T360K/ 4 Q359K-T360K ⌬F508/405 ϩ 1G3A 5 W1282X/1717-1G 3 A 1 G542X/G542X 1 N1303K/1717-1G 3 A 1 Total 173 18 16 36 ARTICLES high prevalence of liver disease. Login to comment

PMID: 12938099 [PubMed] Keyeux G et al: "CFTR mutations in patients from Colombia: implications for local and regional molecular diagnosis programs."

No. Sentence Comment

8 The results of this pilot study in Colombian patients from various ethnic admixture show six main mutations: p.F508del (41.8%), c.1811+1.6kbA>G (6.5%), p.G542X (3.8%), p.S549R (2.2%), p.W1282X (1.1%) and p.R1162X (1.1%). Login to comment
38 The second and third mutations in frequency in Colombian patients are c.1811+1.6kbA>G (6.5%) and p.G542X (3.8%), respectively. The distribution of these mutations over the country is heterogeneous, since, for instance, most c.1811+1.6kbA>G chromosomes are found in Bogotá (10.5%), whereas some Departments do not exhibit this mutation. Login to comment
50 CFTR Mutation Frequencies in Colombian Cystic Fibrosis Patients MUTATION ANTIOQUIA BOGOTA BOLIVAR CALDAS VALLE OTHER COLOMBIA n=34 n=76 n=20 n=10 n=24 n=20 n=184 N (%) N (%) N (%) N (%) N (%) N (%) N (%) p.F508del 16 (47.1) 31 (40.8) 5 (25) 6 (60.0) 10 (41.7) 9 (45.0) 77 (41.8) c.1811+1.6KbA>G 0 8 (10.5) 2 (10.0) 0 1 (4.2) 1 (5.0) 12 (6.5) p.G542X 0 4 (5.3) 0 0 2 (8.3) 1 (5.0) 7 (3.8) p.S549R 1 (2.9) 3 (3.9) 0 0 0 0 4 (2.2) p.W1282X 0 1 (1.3) 0 0 1 (4.2) 0 2 (1.1) p.R1162X 0 0 2 (10.0) 0 0 0 2 (1.1) p.A559T 1 (2.9) 0 0 0 0 0 1 (0.5) p.Y1092X 0 0 1 (5.0) 0 0 0 1 (0.5) p.R334W 0 0 0 0 1 (4.2) 0 1 (0.5) c.1215delG 0 1 (1.3) 0 0 0 0 1 (0.5) c.2185_2186insC 0 0 0 0 0 1 (5.0) 1 (0.5) c.2789+5G>A 0 0 0 0 1 (4.2) 0 1 (0.5) c.3120+1G>A 0 0 1 (5.0) 0 0 0 1 (0.5) c.3849+1G>A 0 1 (1.3) 0 0 0 0 1 (0.5) p.R1066C 0 1 (1.3) 0 0 0 0 1 (0.5) p.N1303K 1 (2.9) 0 0 0 0 0 1 (0.5) c.3500-2A>G* 1 (2.9) 0 0 0 0 0 1 (0.5) c.1323_1324insA* 0 0 1 (5.0) 0 0 0 1 (0.5) p.H609R* 0 0 0 0 0 1 (5.0) 1 (0.5) Unidentified 14 (41.2) 26 (34.2) 8 (40.0) 4 (40.0) 8 (33.3) 7 (35) 67 (36.4) The regions of the country where few patients were studied are grouped as other. Login to comment
66 As shown in Table 2, the five worldwide main mutations (p.F508del, p.G542X, p.R1162X, p.W1282X and p.N1303K) account for 48% to 66% of the mutations in IberoAmerican countries: Colombia (48.3%) (present study) and Mexico (49%) (Orozco et al. 2000) are very similar and have the lowest frequencies, whereas Brazil (61.7%) (CFGAC, 1999) and Argentina (66.2%) (Chertkoff et al., 1997) have the highest frequencies and are much closer to the values observed in Spanish CF patients (66.4%) (Estivill et al., 1997). Login to comment
69 Comparison of the Spectrum of CFTR Mutations in Colombia and Other Ibero-American Countries COLOMBIA1 SPAIN2 MEXICO3 ARGENTINA4 BRAZIL5 MUTATION n=92 n=1356 n=194 n=228 n=272 % % % % % p.F508del 41.8 54.42 40.72 57 45.6 p.G542X 3.8 7.7 6.18 3.94 6.6 p.W1282X 1.1 0.5 0 3.07 2.2 p.R1162X 1.1 1.3 0 0.43 4.4 p.N1303K 0.5 2.5 2.06 1.75 2.9 c.1811+1.6KbA>G 6.5 1.5 0 0.43 0 p.S549R 2.2 0.07 0 0 0 p.A559T 0.5 0 0 0 0 p.Y1092X 0.5 0.01 0.51 0 0 p.R334W 0.5 0.9 0 0 2.9 c.1215delG 0.5 0 0 0 0 c.2185_2186insC 0.5 0 0 0 0 c.2789+5G>A 0.5 0.7 0 0.43 0 c.3120+1G>A 0.5 0 0 0 0 c.3849+1G>A 0.5 0 0 0 0 p.R1066C 0.5 0.7 0 0.43 0 c.3500-2A>G (novel) 0.5 0 0 0 0 c.1323_1324insA (novel) 0.5 0 0 0 0 p.H609R (novel) 0.5 0 0 0 0 Other a (# mutations) - (32) 1.8 (30) 5.28 (9) 4.89 (8) 6.98 Unknown 36.4 17.9 25.25 27.63 28.3 a The frequencies of the other rare mutations found in Spain, Mexico, Argentina and Brazil are pooled together, and the number of different mutations is given in parenthesis. Login to comment

PMID: 15300780 [PubMed] Wong LJ et al: "Detection of CFTR mutations using temporal temperature gradient gel electrophoresis."

No. Sentence Comment

89 For example, the p.Q98X and p.Q98R mutations in exon 4; and p.S466X and p.S492F mutations in exon 10, were detected in the temperature range of 52-607C and 51- 577C, respectively. The p.G542X, p.R553X, p.S549N, and p.A559T in exon 11; p.A561E, c.189811G.A, and c.189813A.G in exon 12; and p.W1204X in exon 19; were detected in the temperature range of 51 to 567C. Login to comment
96 Detection of known mutations and polymorphisms by TTGE Base substitution Mutation Exon or intron Homozygote or heterozygote Polymorphism or mutation # Alleles detected 1 c.386G.A p.G85E 3 Heterozygote Mutation 2 2 c.575T.C p.I148T 4 Heterozygote Mutation 2 3 c.406-1G.A Splice Int 4 Heterozygote Mutation 9 4 c.71111G.T Splice Int 5 Heterozygote Mutation 1 5 c.1059_1069del 3bp p.F311del 7 Heterozygote Mutation 2 6 c.1132C.T p.R334W 7 Heterozygote Mutation 2 7 c.1652_1655del 3bp p.F508del 10 Heterozygote Mutation 94 8 Homozygote Mutation 12 c.1540A/G p.M470V 10 Heterozygote Polymorphism 15 9 Homozygote Polymorphism 4 c.1756G.T p.G542X 11 Heterozygote Mutation 13 10 c.1784G.A p.G551D 11 Heterozygote Mutation 1 11 c.1778G.A p.S549N 11 Heterozygote Mutation 4 12 c.1789C.T p.R553X 11 Homozygote Mutation 2 13 c.1807G.A p.A559T 11 Heterozygote Mutation 2 14 c.189811G.A Splice Int 12 Heterozygote Mutation 1 15 c.1949del84bp Frameshift 13 Heterozygote Mutation 3 16 c.278915G.A Splice Int 14b Heterozygote Mutation 2 17 c.312011G.A Splice Int 16 Heterozygote Mutation 9 18 c.3171delC Frameshift 17a Heterozygote Mutation 1 19 c.3398G.A p.W1089X 17b Heterozygote Mutation 1 20 c.3425G.A p.W1098X 17b Heterozygote Mutation 1 21 c.3616C.T p.R1162X 19 Heterozygote Mutation 2 22 c.3791delC Frameshift 19 Heterozygote Mutation 1 23 c.3821delT Frameshift 19 Heterozygote Mutation 1 24 c.3876delA Frameshift 20 Heterozygote Mutation 4 25 c.3905insT Frameshift 20 Heterozygote Mutation 1 26 c.4041C.G p.N1303K 21 Heterozygote Mutation 2 Total 194 The translation starts at c.133 of CFTR CDNA sequence in GenBank Acc. Login to comment

PMID: 16134171 [PubMed] Cohn JA et al: "Increased risk of idiopathic chronic pancreatitis in cystic fibrosis carriers."

No. Sentence Comment

93 Abnormal CFTR Genotypes Detected in 52 Patients with ICPa Genotype categorya ] Patients Genotypes detectedb Compound heterozygotes and homozygotes 3 p.F508del / p.L967S p.D1152H / p.D1152H p.V920M / p.L967S Heterozygotes, common mutation causing classic CFa 7 p.F508del /^ ('ve subjects)c p.R560T/^ p.G542X /^ Heterozygotes, uncommon mutation causing variable phenotype 3 p.S1235R /^ p.A209S /^ p.L997F/^ Heterozygotes, common CBAVD-associated mutation 2 IVS8(5T) /^ (two subjects) a Common CF-mutations consistently cause classic CF in compound heterozygotes and homozygotes [Rosenstein and Cutting, 1998]. Login to comment

PMID: 17020473 [PubMed] Nectoux J et al: "A frequent large rearrangement in the CFTR gene in cystic fibrosis patients from Reunion Island."

No. Sentence Comment

41 p.F508del and p.G542X were previously associated with the haplotype B (rarely A, D) (Sereth et al. 1993; Cuppens et al. 1994). Login to comment
52 GENOTYPE OF CF PATIENTS FROM REUNION ISLAND WHO WERE FOUND TO CARRY AT LEAST ONE CFTR MUTATION-NEGATIVE ALLELE Present Patient Sex age (years) Cl-test Genotype Phenotype MUC971 F 6 87-91 p.V520I : unidentified PS-CF (bronchitis, mild disease) MUC696 M 10 37-70 c.3849 ϩ 45G l A : unidentified PS-CF (bronchitis) R105C F 82 56-106 p.A309G : unidentified PS-CF (H. influenzae colonization, bronchitis) MUC900 M 7 71-147 p.F508del : unidentified PI-CF R131C F 16 39-70 p.F508del : unidentified PS-CF (B. cepacia colonization, bronchitis) R89C F 20 23-107 p.F508del : unidentified PS-CF R71C F 17 58-90 p.G542X : unidentified PI-CF (S. aureus and P. aeruginosa colonization) R48C F 19 81 Unidentified : unidentified PI-CF (meconium ileus) R44C F 11 70 Unidentified : unidentified PI-CF (died at the age of 11 years) MUC74 M 6 125 Unidentified : unidentified PI-CF (bronchitis, mild disease) PS, pancreatic sufficiency; PI, pancreatic insufficiency; H, Haemophilus; B, Burkholderia; P, Pseudomonas; S, Staphylococcus. Login to comment

PMID: 17331079 [PubMed] Alonso MJ et al: "Spectrum of mutations in the CFTR gene in cystic fibrosis patients of Spanish ancestry."

No. Sentence Comment

8 Specific geographic distributions for the most common mutations, p.F508del, p.G542X, c.1811 + 1.6kbA > G and c.1609delCA, were confirmed. Login to comment
45 (%) p.F508del # E.10 1009 (51.74) p.G542X # E.11 150 (7.69) p.N1303K # E.21 57 (2.92) c.1811 + 1.6kbA > G I.11 36 (1.84) p.R334W # E.7 35 (1.79) p.L206W E.6a 32 (1.64) c.711 + 1G > T # I.5 31 (1.58) p.Q890X E.15 28 (1.43) p.R1162X # E.19 25 (1.28) c.2789 + 5G > A # I.14b 24 (1.23) p.R1066C E.17b 23 (1.18) p.I507del # E.10 21 (1.07) c.1609delCA E.10 18 (0.92) c.712-1G > T I.5 18 (0.92) c.3272-26A > G I.17a 18 (0.92) c.2183AA > G # E.13 16 (0.82) p.G85E # E.3 15 (0.77) c.2869insG E.15 15 (0.77) p.W1282X # E.20 15 (0.77) p.V232D E.6a 14 (0.71) p.A1006E * E.17a 12 (0.61) c.2184insA E.13 11 (0.56) p.K710X E.13 11 (0.56) TOTAL (n = 23) 1,634 (83.72) * , the complex allele [p.A1006E; p.V562I; IVS8-6(5T)] #, CF mutations identified with the Celera Diagnosis Cystic Fibrosis v2 genotyping assay and the Inno-Lipa CFTR12, CFTR17 + Tn Samples with microsatellite haplotypes 16/45-46-47 (IVS8CA/IVS17bTA) were submitted to direct analysis of the c.1811 + 1.6kbA > G mutation, which was found mainly associated with the 16-46 haplotype. Login to comment
61 The evaluation data from the specific regions contributing to this study showed that the c.2789 + 5G > A mutation was, along with p.G542X, the second most common mutation (9/86, 10.5%) among the Balearic Islands` alleles, whereas mutation c.1609delCA had its highest prevalence in Aragon (10/109, 9%). Login to comment
90 The p.F508del mutation showed frequencies ranging from 86% (North) to 46% (South) in the Iberian Peninsula (Casals et al. 1992; Coto et al. 1994; Borrego et al. 1994; Telleria et al. 1999) as well as a 14% prevalence of the p.G542X mutation in the Mediterranean Coastal area (Casals et al. 1993). Login to comment
94 In fact, this splicing mutation has also been reported with frequencies ≥ 1% in France (Claustres et al. 2000), Italy (Bonizzato et al. 1995), Greece (Kanavakis et al. 2003) and Turkey (Kilinc et al. 2002), suggesting that, like p.G542X, c.2789 + 5G > A was spread across the Mediterranean Sea. Login to comment
99 Some high frequencies such as those found for the p.G542X mutation have been attributed to the Spanish ancestry of the Mexican (Orozco et al. 2000) and Brazilian (Bernardino et al. 2000) populations. Login to comment
105 Our impression is that Table 3 Common CF mutations identified in this study and in several Latin American populations Mutation This study Hispanic1 Mexico2 Colombia3 Brazil4 Argentina5 Chile6 p.F508del 51.7 51.6 40.7 41.8 48.4 58.6 45.0 p.G542X 7.7 4.0 6.2 3.8 8.8 4.1 7.0 p.N1303K 2.9 0.8 2.0 0.5 2.5 2.7 - c.1811 + 1,6kbA > G 1.8 - - 6.5 - 0.9 - p.R334W 1.8 1.6 - 0.5 2.5 1.1 2.0 p.L206W 1.6 - - - 0.6 - - c.711 + 1G > T 1.6 - - - - - - p.Q890X 1.4 - - - - - - p.R1162X 1.3 0.8 - 1.1 2.5 0.4 2.0 c.2789 + 5G > A 1.2 - - 0.5 0.3 0.7 - p.R1066C 1.2 1.6 - 0.5 - 0.2 - p.I507del 1.0 - 2.6 - - 0.7 - c.2183AA > G 0.8 - 1.0 - 0.2 - p.G85E 0.7 0.8 0.5 - 1.3 0.7 - p.W1282X 0.7 0.8 - 1.1 1.3 2.7 5.0 c.3849 + 10kbC > T 0.4 4.0 0.5 - - 0.9 3.0 p.S549N - 2.4 2.6 - - - - c.3120 + 1G > A - 1.6 - 0.5 - - - c.3876delA - 5.6 - - - - - c.406-1G > A - 1.6 1.5 - - - - c.935delA - 1.6 1.0 - - - - p.R75X - 0.8 1.5 - - - - c.2055del9 - - 1.0 - - - - p.I506T - - 1.0 - - - - c.3199del6 - - 1.0 - - - - p.S549R 0.4 - - 2.2 - 0.2 - c.1717-1G > A 0.2 - - - 0.3 1.1 - p.G551D 0.2 0.8 0.5 - - - 1.0 p.R553X 0.4 - 0.5 - 0.6 0.2 1.0 No. Login to comment

PMID: 17440499 [PubMed] Keymolen K et al: "Clinical outcome of preimplantation genetic diagnosis for cystic fibrosis: the Brussels' experience."

No. Sentence Comment

66 Table 1 Assessment of CF risk Couples with PGD (n ¼ 47) Couples without PGD (n ¼ 22) All couples (n ¼ 69)(%) CF risk assessment Affected child or foetus 23 14 37 (53.6) CBAVD (without other CF complaints) 7 3 10 (14.5) During fertility work-up (not CBAVD) 10 10 (14.5) Positive family history 3 2 5 (7.2) CF patient (with CBAVD in males) 4 4 (5.8) Unknown 2 2 (2.9) Preconceptual screening 1 1 (1.4) Table 2 Reasons for choosing PGD Couples with PGD (n ¼ 47) Couples without PGD (n ¼ 22) All couples (n ¼ 69) Reason for choosing/informing about PGD Fertility problems 24 7 31 (44.9%) Objection to abortion 15 2 17 (24.6%) History of termination of pregnancy 8 1 9 (13%) Unknown 11 11 (15.9%) Other 1 1 (1.4%) Table 3 Genotypes of the couples with PGD cycles Female partner Male partner Number of couples with this genotype p.F508del/- p.F508del/- 17 p.F508del/- p.R117H/- (7T/9T) 1 p.2789+5G4A/- p.D110H/p.D110H 1 p.G542X/- p.F508del/- 1 p.R334Q/- p.F508del/- 1 p.R553X/- p.F508del/- 2 p.1717-1G4A p.2183AA4G/5T 1 p.F508del/- p.F508del/? Login to comment
67 2 p.1303K/- p.G542X/p.R117H 1 p.F508del/- 5T/? Login to comment
69 2 p.F508del/- p.N1303K/- 1 p.Q493X/- p.F508del/- 1 p.F508del/- p.R1162X/- 1 p.4218insT/- p.N1303K/- 1 p.G673X/- p.F508del/- 1 p.W1282X/- p.G542X/- 1 p.F508del/- p.W1282X/- 1 p.W1282X/- p.F508del/- 2 p.F508del/- p.G551D/- 1 p.D1168G/- p.L206W/- 1 If we express these results per cycle with oocyte retrieval, this means that in each cycle there was an average of 12.5 COCs, giving 5.1 embryos to be biopsied with an 80% chance of having an embryo transfer and a 22.2% chance of having an ongoing pregnancy with the delivery of a child. Login to comment

PMID: 19462466 [PubMed] Azad AK et al: "Mutations in the amiloride-sensitive epithelial sodium channel in patients with cystic fibrosis-like disease."

No. Sentence Comment

238 The NPD was measured between a Ringer`s solution-filled exploring bridge on the nasal mucosa of the floor of the nasal cavity, and a reference bridge on the abraded skin of the forearm in a CF patient compound heterozygous for p.F508del and p.G542X in CFTR, a patient heterozygous for p.W493R-SCNN1A and p.F508del-CFTR, and a normal subject. Login to comment

PMID: 19883345 [PubMed] Christie LM et al: "Outcomes of a cystic fibrosis carrier testing clinic for couples."

No. Sentence Comment

72 This provides each individual with information on their carrier status, and accurate residual risks of 1 CFTR mutations tested for in individuals whose partner was a carrier of p.F508del* p.F508del p.F316leufsX p.I507del p.R347P p.G542X p.S1251N p.G551D p.E60X p.N1303K p.W1282X c.1585-1G>A p.D1152H p.R553X c.2988+1G>A c.489+G>T c.2657+5G>A p.R117H c.1766+1G>A p.R1162X c.579+1G>A c.3717+10kbC>T p.G85E p.R334W p.K684fs p.A455E p.I148T p.K684fs p.R560T p.T1176fs CFTR = gene encoding cystic fibrosis transmembrane conductance regulator. Login to comment

PMID: 20502448 [PubMed] Joergensen MT et al: "Genetic, epidemiological, and clinical aspects of hereditary pancreatitis: a population-based cohort study in Denmark."

No. Sentence Comment

57 The samples were also tested for 33 CFTR mutations, and all 6 classeswererepresented:394delTT,p.R553X,621+1G>T,p.R1162X, 1717-1G>A,3659delC,p.G542X,2183AA>G,p.W1282X,1078delT, 711+1G>T, F508del, p.S549N, I507del, p.S549R, 2184delA, p.G551D, p.G85E, p.N1303K, p.R560T, p.R117H, p.R347H, p.R347P, p.R334W, 2789+5G>A, 3849+10kbC>T, p.A445E, 3120+1G>A, p.V520F,1898+1G>A,3876delA,3905insT,andIVS8-5T.DNAwas amplified by multiplex PCR (Hybaid 4 A62, Middlesex, UK). Login to comment

PMID: 21036675 [PubMed] Lay-Son G et al: "Cystic fibrosis in Chilean patients: Analysis of 36 common CFTR gene mutations."

No. Sentence Comment

5 Mutations with frequencies greater than 1% were p.F508del (30.3% of alleles), p.R334W (3.3%), p.G542X (2.4%), c.3849+10Kb CNT (1.7%), and p.R553X (1.2%). Login to comment
52 In addition, another 4 mutations had a frequency greater than 1% (p.R334W, p.G542X, c.3849+10Kb CNT, and p.R553X), encompassing 8.5% of the total alleles or 20.2% of detected alleles, while 6 mutations were found in only one family. Login to comment
70 Several other prevalent mutations in our Chilean cohort are common in Southern European countries (i.e: p.R334W, p.G542X, and p.R1162X), and even more prevalent in the Canary Islands (4%; 14.3%-25% and 6.1%, respectively) [14,15], a point of halting for the Spanish expeditions to America, including Columbus' first journey [16]. Login to comment
81 Mutation This study Rios et al. [4] Molina et al. [5] Repetto et al. [6] Perez et al. [13] CFGAC [2] (n=578) (%) (n=72) (%) (n=36) (%) (n=100) (%) (n=4102) (%) (n=43,849) (%) Chile Chile Chile Chile Latin-Americaa Worldwide Unknown 58.0 66.6 61.1 34.0 36.7 22.7 p.F508del 30.6 29.2 30.6 45.0 47.1 66.0 p.R334W 3.1 - - 2.0 0.8 0.1 p.G542X 2.4 0 8.3 7.0 5.0 2.4 c.3849+10Kb CNT 1.7 - - 3.0 0.3 0.2 p.R553X 1.2 4.2 0 1.0 0.4 0.7 p.R1162X 0.9 - - 2.0 1.0 0.3 p.1078delT 0.5 - - 0 b0.1 0.1 p.G85E 0.5 - - - 0.8 0.2 p.W1282X 0.2 - - 5.0 1.0 1.2 c.3120+1 GNA 0.2 - - - 0.3 - c.711+1 GNT 0.2 - - - 0.1 0.1 p.R117H 0.2 - - 0 b0.1 0.3 p.A455E 0.2 - - 0 0 0.1 p.I148T 0.2 - - - - - p.G551D 0 0 0 1.0 0.1 1.6 p.N1303K 0 0 0 0 1.8 1.3 c.621+1 GNT 0 - - 0 0.2 0.7 c.1717-1 GNA 0 - - 0 0.3 0.6 p.I507del 0 - - 0 0.2 0.2 p.R347P 0 - - 0 0 0.2 c.2789+5 GNA 0 - - - 0.2 0.1 c.1898+1 GNA 0 - - - 0.1 0.1 c.2184delA 0 - - - b0.1 0.1 p.S549N 0 - 0 - 0.1 0.1 c.3659delC 0 - - 0 0.1 0.1 p.R560T 0 - - - 0 0.1 c.1811+1.6Kb ANG 0 - - - 0.4 - c.2183AANG 0 - - 0 0.1 - p.S549R 0 - - - 0.1 - c.3272-26 ANG 0 - - - 0.1 - c.3199del6 0 - - - b0.1 - p.E60X 0 - - 0 0 - c.3905insT 0 - - - 0 - p.S1251N 0 - - 0 - - CFTRdele2,3 0 - - - - - p.R347H 0 - - - - - p.V520F 0 - - - - - p.Q552X 0 - - - - - c.394delTT 0 - - - - - c.711+1 GNA 0 - - - - - c.2143delT 0 - - - - - c.3876delA 0 - - - - - a Data from Chilean patients published in Rios et al., Molina et al., and Repetto et al. [4-6] included in this publication were excluded in this table to avoid repetition. Login to comment

PMID: 19467940 [PubMed] Tomaiuolo R et al: "An MBL2 haplotype and ABCB4 variants modulate the risk of liver disease in cystic fibrosis patients: a multicentre study."

No. Sentence Comment

30 Later, a CF patient homozygous for the G542X mutation was described, who had a severe liver phenotype, unlike the six previously reported cases bearing the same CFTR genotype, who were free of any liver involvement [9]. Login to comment
41 To reduce the possible influence of the CFTR genotype on the liver, we selected only patients who were homozygotes for the F508del mutation (about 80%) or compound heterozygotes for the F508del and another severe (class 1, 2 or 3) CFTR mutation (i.e., c.1717-1G>A; p.G542X; p.NI303K; c.1782delT; c.182delT; c.3659delC; c.4016insT; dele17a-18; p.E585X; p.R553X). Login to comment

PMID: 12121192 [PubMed] Skov M et al: "Itraconazole treatment of allergic bronchopulmonary aspergillosis in patients with cystic fibrosis."

No. Sentence Comment

62 Af.+others Others Negative Not done 1 M 30 F508/W1282X x x x 2 M 21 x x x x 3 F 27 F508/unknown x x x 4 M 21 F508/3659delC x x x 5 F 15 F508/394delTT x x x 6 M 13 x F508/G542X x x x 7 F 14 x x x x 8 M 13 F508/1571delG x x x 9 M 13 x x x x 10 F 15 x x x x 11 M 13 x x x x 12 F 13 x x x x 13 F 13 x x x x 14 F 12 x x x x 15 M 17 F508/3905insT x x x 16 M 11 x x x x 17 M 9 x x x x 18 F 7 x x x x 19 M 8 x x x x 20 F 16 x x x x 21 F 8 x x x x Totals 11M/10F median 13 n=14 n=7 n=9 n=12 n=14 n=7 n=3 n=6 n=1 n=2 n=9 * Age at end of the study. Login to comment

PMID: 1381146 [PubMed] Fuller CM et al: "CFTR!"

No. Sentence Comment

366 AF508/AF508 G551D/G551D G542X/G458V G542X/G542X R553X/W1316X N369X/unknown R553X/R553X G551S/G551S G368Xlunknown AF508/R117H PI PI PI PI PI PI PI PS PS PS Severe 116 Severe 181 Severe 49 Mild 49 Mild 50 Mild 102 Moderate-Severe 13 Mild 181 Mild 102 Mild 55 Comparison of genotype with phenotype for some CF-associated mutations. Login to comment
416 Cutting et al. (50) have investigated two individuals heterozygous for two different nonsense mutations (S 1255X, G542X and Wl316X, R553X). Login to comment
418 Interestingly, an individual homozygous for the G542X mutation had milder clinical symptoms than a relative with severe CF who was heterozygous [G542X, G458V (49)]. Login to comment
419 The G542X mutation falls near the end of the first NBF region; presumably the protein would be truncated after this point. Login to comment

PMID: 1375156 [PubMed] Bremer S et al: "Quantitative expression patterns of multidrug-resistance P-glycoprotein (MDR1) and differentially spliced cystic-fibrosis transmembrane-conductance regulator mRNA transcripts in human epithelia."

No. Sentence Comment

139 A few other mutations were analyzed either by allele-specific oligonucleotide hybridization (R117H, 1717-1G --f A) (Dean et al., 1990; Kerem et al., 1990) or by allele-specific PCR (G542X, N1303K) (Kerem et al., 1990; Osborne et al., 1991). Login to comment

PMID: 22709980 [PubMed] Chen H et al: "Regulation of male fertility by CFTR and implications in male infertility."

No. Sentence Comment

73 Mutations/ variants Phenotypes Reference F508del Non-obstructive azoospermia, oligozoospermia, oligoasthenozoospermia, oligoasthenoteratozoospermia Stuppia et al. (2005), Schulz et al. (2006) R117H Non-obstructive azoospermia, oligozoospermia, oligoasthenozoospermia, oligoasthenoteratozoospermia Schulz et al. (2006) W1282X Non-obstructive azoospermia, Stuppia et al. (2005) G542X Non-obstructive azoospermia, Stuppia et al. (2005) 5T/7T/9T Non-obstructive azoospermia, oligozoospermia Kanavakis et al. (1998), Stuppia et al. (2005), Schulz et al. (2006), Tamburino et al. (2008), Tomaiuolo et al. (2011) Conti, 2003; Wu et al., 2006; Geng et al., 2009; Schmid et al., 2010; Tresguerres et al., 2011). Login to comment
72 Mutations/ variants Phenotypes Reference F508del Non-obstructive azoospermia, oligozoospermia, oligoasthenozoospermia, oligoasthenoteratozoospermia Stuppia et al. (2005), Schulz et al. (2006) R117H Non-obstructive azoospermia, oligozoospermia, oligoasthenozoospermia, oligoasthenoteratozoospermia Schulz et al. (2006) W1282X Non-obstructive azoospermia, Stuppia et al. (2005) G542X Non-obstructive azoospermia, Stuppia et al. (2005) 5T/7T/9T Non-obstructive azoospermia, oligozoospermia Kanavakis et al. (1998), Stuppia et al. (2005), Schulz et al. (2006), Tamburino et al. (2008), Tomaiuolo et al. (2011) Conti, 2003; Wu et al., 2006; Geng et al., 2009; Schmid et al., 2010; Tresguerres et al., 2011). Login to comment

PMID: 23071149 [PubMed] Okiyoneda T et al: "Fixing cystic fibrosis by correcting CFTR domain assembly."

No. Sentence Comment

14 Class I mutations include nonsense mutations (G542X and R553X), generating premature termination codons and frame-shift mutations that lead to truncated and/or and nonfunctional protein (Fig. 1). Login to comment
45 (A) Class I mutations (e.g., G542X) impair production of CFTR full-length protein by induction of premature termination codons (PTC). Login to comment

PMID: 22698459 [PubMed] Lubamba B et al: "Cystic fibrosis: insight into CFTR pathophysiology and pharmacotherapy."

No. Sentence Comment

982 Class Mutation prototypes Consequences Severe CF phenotype I G542X, W1282X, R553X, 3950delT CFTR is not synthesized because of stop codons or splicing defects II F508del, N1303K CFTR is synthesized but in an immature form (only partly glycosylated, misfolded, not released from the endoplasmic reticulum) and is mostly degraded by the ubiquitin-proteasomal pathway III G551D CFTR is synthesized and transported to the plasma membrane, but its activation and regulation by ATP or cAMP are disrupted Milder CF phenotype IV R334W, G314E, R347P, D1152H CFTR is synthesized and expressed at the plasma membrane, but chloride conductance is reduced V 3849+10 kb C>T, 3272-26 A>G CFTR synthesis or processing is partly defective Severe CF phenotype VI 1811+1.6 kb A>G CFTR is synthesized, but membrane stability or conductance of ions other than chloride is reduced Fig. 2. Login to comment

PMID: 22311127 [PubMed] Watts KD et al: "Hispanic Infants with cystic fibrosis show low CFTR mutation detection rates in the Illinois newborn screening program."

No. Sentence Comment

39 Mutation Frequency Table 1 shows the mutations found in Illinois patients diagnosed with CF after a positive NBS and compares these to mutations documented in Hispanic Caucasian Table 1 CFTR mutation frequency detected by Illinois newborn screen Mutation IL Newborn Screen CFF Patient Registry Total alleles Non-Hispanic Caucasian Hispanic Caucasian African American Ethnicity/Race Missing Hispanic Caucasian ΔF508 63.9% 71.6% 36.7% 33.3% 58.3% 44.7% R117H 7.7% 10.1% 3.3% - - 0.3% G542X 1.9% 2.0% - - 4.2% 4.1% 3120+1G>A 1.9% 0.7% 3.3% 33.3% - 0.7% ΔI507 1.4% 0.7% - - 8.3% 1.3% G551D 1.4% 2.0% - - - 0.5% 3659delC 1.4% 1.3% 3.3% - - 0.1% 3849+10 kbC>T 1.4% - 6.7% 16.7% - 1.0% ΔF311 1.4% - 6.7% - 4.2% 0.03% 1288insT 0.5% - 3.3% - - 0% 621+1G>T 0.5% - 3.3% - - 0.4% G85E 1.0% - 3.3% - 4.2% 0.3% 2184delA 0.5% - 3.3% - - 0.2% S549N 0.5% - 3.3% - - 0.7% R334W 1.0% 0.7% - 16.7% - 1.0% N1303K 1.0% - - - 8.3% 1.6% Other 4.4% 6.2%a 0% 0% 0% 12.8%b Unknown 8.2% 4.7% 23.5% 0% 12.5% 15.7% a R347P, 1898+1G>A, 2789+5G>A, 3272-26A>G, 3876delA, CFTRdel2,3, W1282X occurred in non-Hispanic Caucasian patients only with an allele frequency of 0.5% of the entire IL NBS population b In the 2004 CFF Patient Registry 12.8% of alleles are not included in the above table because they occur in less than 1% of the population. Login to comment
42 The most common were ΔF508, R117H, G542X, G551D, 3120 +1G>A, ΔI507, 3659delC, 3849 +10kb C>T, and ΔF311, showing overlap but not concordance with the most common mutations reported by the CF Foundation (CFF) Annual Data Report 2009 (ΔF508, G542X, G551D, R117H, W1282X, N1303K and R553X). Login to comment

PMID: 22950544 [PubMed] Marson FA et al: "Polymorphisms in ADRB2 gene can modulate the response to bronchodilators and the severity of cystic fibrosis."

No. Sentence Comment

47 The patients underwent two perspiration tests of chlorine and sodium with chlorine levels equal to or greater than 60 mEq/L, and/or identification of two mutations in CFTR gene [F508del, G542X, G551D, R553X, R1162X, I618T and N1303K]. Login to comment
73 Table 1 Characteristics of patients included in the study (N = 122)1 Male 48.8 % Age 246.68 ± 168,73 months (87 - 932 months) Caucasoid 93.4% BMI - Thinness and Thinness accentuated 22.3% SaO2 94.87 ± 4.53 (66 - 99) Bhalla 9.41 ± 5.57 (0 - 25) Kanga 19.37 ± 5.01 (11 - 40) Shwachman-Kulczycki 65.41 ± 16.02 (20 - 95) FVC (%) 78.27 ± 22.86 (19 - 135) FEV1 (%) 70.28 ± 26.17 (17 - 125) FEV1/FVC (%) 83.83 ± 15.79 (37 - 137) FEF25-75% 58.50 ± 34.83 (7 - 150) FVC (%) reversibility 0.92 ± 10.48 (-27 - 32) FEV1 (%) reversibility 2.15 ± 9.45 (-12 - 31) FEV1/FVC (%) reversibility 2.84 ± 9.69 (-19 - 47) FEF25-75% reversibility 7.24 ± 9.43(-12 - 30) Nasal Polyps 21.7% Diabetes mellitus 20.8% Osteoporosis 20.8% Pancreatic insufficiency 76% Meconium ileus 9.1% P. aeruginosa status 2 53.7% P. aeruginosa mucoid status 2 45.5% B. cepacia status 2 9.1% A. xylosoxidans status 2 9.9% S. aureus status 2 78.5% CFTR mutation F508del/F508del 29 (24%) F508del/G542X 10 (8.3%) F508del/N1303K 3 (2.5%) F508del/R1162X 3 (2.5%) F508del/R553X 1 (0.8%) G542X/I618T 1 (0.8%) G542X/R1162X 1 (0.8%) F508del/No identified mutation 26 (21.5%) G542X/No identified mutation 4 (3.3%) No identified mutation 43 (35.3%) N - Sample size; BMI - body mass index; % - percentage; FVC - forced vital capacity; FEV1 - forced expiratory volume in the first second; FEF25-75% - forced expiratory flow between 25 and 75% of CVF. 1. Continuous variables expressed as mean ± SD (range). Login to comment
42 The patients underwent two perspiration tests of chlorine and sodium with chlorine levels equal to or greater than 60 mEq/L, and/or identification of two mutations in CFTR gene [F508del, G542X, G551D, R553X, R1162X, I618T and N1303K]. Login to comment
93 Buscher et al. (2002) [17] used the following markers: Table 1 Characteristics of patients included in the study (N = 122)1 Male 48.8 % Age 246.68 &#b1; 168,73 months (87 - 932 months) Caucasoid 93.4% BMI - Thinness and Thinness accentuated 22.3% SaO2 94.87 &#b1; 4.53 (66 - 99) Bhalla 9.41 &#b1; 5.57 (0 - 25) Kanga 19.37 &#b1; 5.01 (11 - 40) Shwachman-Kulczycki 65.41 &#b1; 16.02 (20 - 95) FVC (%) 78.27 &#b1; 22.86 (19 - 135) FEV1 (%) 70.28 &#b1; 26.17 (17 - 125) FEV1/FVC (%) 83.83 &#b1; 15.79 (37 - 137) FEF25-75% 58.50 &#b1; 34.83 (7 - 150) FVC (%) reversibility 0.92 &#b1; 10.48 (-27 - 32) FEV1 (%) reversibility 2.15 &#b1; 9.45 (-12 - 31) FEV1/FVC (%) reversibility 2.84 &#b1; 9.69 (-19 - 47) FEF25-75% reversibility 7.24 &#b1; 9.43(-12 - 30) Nasal Polyps 21.7% Diabetes mellitus 20.8% Osteoporosis 20.8% Pancreatic insufficiency 76% Meconium ileus 9.1% P. aeruginosa status 2 53.7% P. aeruginosa mucoid status 2 45.5% B. cepacia status 2 9.1% A. xylosoxidans status 2 9.9% S. aureus status 2 78.5% CFTR mutation F508del/F508del 29 (24%) F508del/G542X 10 (8.3%) F508del/N1303K 3 (2.5%) F508del/R1162X 3 (2.5%) F508del/R553X 1 (0.8%) G542X/I618T 1 (0.8%) G542X/R1162X 1 (0.8%) F508del/No identified mutation 26 (21.5%) G542X/No identified mutation 4 (3.3%) No identified mutation 43 (35.3%) N - Sample size; BMI - body mass index; % - percentage; FVC - forced vital capacity; FEV1 - forced expiratory volume in the first second; FEF25-75% - forced expiratory flow between 25 and 75% of CVF. 1. Continuous variables expressed as mean &#b1; SD (range). Login to comment

PMID: 22658665 [PubMed] Ooi CY et al: "Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations in pancreatitis."

No. Sentence Comment

847 Total PI Total PI+PS PIP score 621+1G>T 96 96 1.00 Classes I - III 711+1G>T 36 36 1.00 Classes I - III R553X 24 24 1.00 Classes I - III I507del 34 34 1.00 Classes I - III G542X 74 75 0.99 Classes I - III F508del 1276 1324 0.96 Classes I - III 1717-1G>A 20 21 0.95 Classes I - III W1282X 19 20 0.95 Classes I - III N1303K 45 48 0.94 Classes I - III R1162X 12 13 0.92 Classes I - III G551D 59 67 0.88 Classes I - III G85E 16 22 0.73 Classes I - III A455E 18 37 0.49 Classes IV - V 2789+5G>A 6 16 0.38 Classes IV - V R334W 1 10 0.10 Classes IV - V 3849+10kbC>T 2 22 0.09 Classes IV - V R117H 1 25 0.04 Classes IV - V Mutation Canadian Consortium for CF Genetic Studies Mutation class The PIP score for a specific mutation is the ratio between the pancreatic insufficient patients carrying the mutation (Total PI) and all pancreatic insufficient and sufficient patients (Total PI+PS) carrying the same mutation in a homozygous state or heterozygous in a combination with a severe mutation such as F508del, G551D or a Class I mutation. Login to comment
855 CFTR mutation Total PI Total PI + PS PIP score CFTR mutation Total PI Total PI + PS PIP score 621+1G>T 96 96 1.00 G542X 74 75 0.99 711+1G>T 36 36 1.00 F508del 1276 1324 0.96 I507del 34 34 1.00 1717-1G>A 20 21 0.95 R553X 24 24 1.00 W1282X 19 20 0.95 Q493X 11 11 1.00 N1303K 45 48 0.94 S489X 11 11 1.00 R1162X 12 13 0.92 1154insTC 10 10 1.00 Y1092X 12 13 0.92 3659delC 9 9 1.00 I148T 10 11 0.91 CFTRdele2 7 7 1.00 V520F 9 10 0.90 4016insT 7 7 1.00 G551D 59 67 0.88 E60X 7 7 1.00 L1077P 5 6 0.83 R560T 7 7 1.00 R1066C 5 6 0.83 R1158X 7 7 1.00 2184insA 9 12 0.75 3905insT 6 6 1.00 2143delT 3 4 0.75 I148T;3199del6 5 5 1.00 1161delC 3 4 0.75 2183AA>G 5 5 1.00 3120+1G>A 3 4 0.75 1898+1G>A 5 5 1.00 S549N 3 4 0.75 2347delG 4 4 1.00 G85E 16 22 0.73 Q1313X 3 3 1.00 R117C 2 3 0.67 Q220X 3 3 1.00 M1101K 19 30 0.63 2184delA 3 3 1.00 P574H 3 5 0.60 1078delT 3 3 1.00 474del13BP 1 2 0.50 L1254X 3 3 1.00 R352Q 1 2 0.50 E585X 3 3 1.00 Q1291H 1 2 0.50 3876delA 2 2 1.00 A455E 18 37 0.49 S4X 2 2 1.00 R347P 6 15 0.40 R1070Q 2 2 1.00 2789+5G>A 6 16 0.38 F508C 2 2 1.00 L206W 6 18 0.33 DELI507 2 2 1.00 IVS8-5T 4 16 0.25 Q1411X 2 2 1.00 3272-26A>G 1 4 0.25 365-366insT 2 2 1.00 R334W 1 10 0.10 R709X 2 2 1.00 3849+10kbC>T 2 22 0.09 1138insG 2 2 1.00 P67L 1 14 0.07 CFTRdele2-4 2 2 1.00 R117H 1 25 0.04 3007delG 2 2 1.00 R347H 0 5 0.00 Q814X 2 2 1.00 G178R 0 3 0.00 394delTT 2 2 1.00 E116K 0 2 0.00 406-1G>A 2 2 1.00 875+1G>C 0 2 0.00 R75X 2 2 1.00 V232D 0 2 0.00 CFTRdel2-3 2 2 1.00 D579G 0 2 0.00 E193X 2 2 1.00 L1335P 0 2 0.00 185+1G>T 2 2 1.00 Mild mutations (based on PIP scores) are shaded in gray. Login to comment

PMID: 22892530 [PubMed] Sobczynska-Tomaszewska A et al: "Newborn screening for cystic fibrosis: Polish 4 years' experience with CFTR sequencing strategy."

No. Sentence Comment

57 Mutations D537N and P731L have not been Period of NBS CF Method The most frequent mutations in Polish population under analysis September 2006 - December 2007 Estonia Asper Biotech assay E60X, G85E, 394delTT, R117H, R117P, R117L, I148T, 621G>A, 711+1G>T, 711+5G>A, 1078delT, R334W, R347H, R347P, R347L, IVS8-T, A455E, I507del, F508del, 1717-1G>A, G542X, p.G551D, Q552X, R553X, R553G, R560T, R560K, 1898+1G>A, 1898+1G>T, 1898+1G>C, 2143delT, 2184delA, 2183AA>G, 2789+5G>A, 3120+1G>A, 3199del6, 3272-26A>G, R1162X, 3659delC, 3849+10kbC>T, 3905insT, S1235R, S1251N, W1282X, W1282C, N1303K, CFTRdele2,3 January 2007 - June 2009 Sanger sequencing of exons: 4, 7, 10, 11, 13, 21, fragment of intron 19 F508del, CFTRdele2,3, 3849+10kbC>T, R117H+IVS8-T*, R334W, R347P, 1717-1G>A, G542X, R553X, K710X, 2184insA, 2143delT, 2183AA>G, N1303K July 2009 - currently Sanger sequencing of exons: 7, 10, 11, 13, 17b, 20, 21, fragment of intron 19 F508del, CFTRdele2,3, 3849+10kbC>T, R334W, R347P, 1717-1G>A, G542X, R553X, K710X, 2184insA, 2143delT, 2183AA>G, N1303K, 3272-26A>G**, W1282X** * removed from DNA analysis since July 2009 , **added into DNA analysis since July 2009 Figure 1 NBS CF in Poland. Login to comment
72 Table 2 Genotypes of CF newborns with mutations not included into common commercial kits applied in Poland and European countries* Genotype Number of cases [F508del]; [1767-8T4A*] 1 [F508del];[2184insA*] 6 [F508del];[E33X*] 1 [F508del];[F1286C*] 1 [F508del];[G314R*] 1 [F508del];[K710X*] 1 [F508del];[W1282R*] 1 [F508del];[1898 þ 1G4C*] 1 [F508del];[3600 þ 2insT*] 1 [F508del];[F1052V*] 1 [F508del];[V1240G*] 1 [F508del];[T582I*] 1 [2143delT];[R1102X*] 1 [2143delT];[2721del11*] 1 [3272-26A4G];[K967S*] 1 [CFTRdele2,3];[Y1092X*] 1 [K710X*];[K710X*] 1 [L732X*];[3600 þ 2insT*] 1 [N1303K];[2184insA*] 1 [N1303L];[T1036I*] 1 [R553X];[3182ins8*] 1 [2143delT];[V1240G*] 1 [R553X];[Trp356X*] 1 [L997F*];[1210-12T[5];1210-13G4T] 1 Total 29 Table 3 Frequency of CFTR mutations in Polish CF patients from newborns screening programme CFTR mutations Frequency according to Bobadilla et al15 Frequency according to NBS CF results (all ¼ 442 CF alleles) Name Position % % F508del Exon11 57.1 62.4 3849 þ 10kbC4T Intron 22 2.7 3.0 G542X Exon 12 2.6 1.6 1717-1G4A Intron 11 2.4 1.4 R553X Exon 12 1.9 2.5 CFTRdele2,3 Exons 2 and 3 1.8 6.2 N1303K Exon 24 1.8 2.1 2143delT Exon 14 No data 2.8 2184insA Exon 14 No data 1.8 2183AA4G Exon 14 No data 1.6 W1282X Exon 23 0.7 1.5 R334W Exon 8 No data 0.7 R347P Exon 8 No data 0.5 G551D Exon 12 0.5 0.0 K710X Exon 14 No data 0.7 3272-26A4G Intron 19 No data 0.7 3600 þ 2insT Intron 21 No data 0.5 1898 þ 1G4C Intron 13 No data 0.5 V1240G Exon 23 No data 0.5 Othersa - No data 10.0 Abbreviations: CF, cystic fibrosis; NBS CF, newborn screening for CF. Login to comment

PMID: 22874010 [PubMed] Marson FA et al: "The ACE gene D/I polymorphism as a modulator of severity of cystic fibrosis."

No. Sentence Comment

28 Determination of mutations in the CFTR gene Determination of mutations in the CFTR gene was performed in the Laboratory of Molecular Genetics for mutations by polymerase chain reaction (F508del) and restriction fragment length polymorphism method (G542X, R1162X, R553X, G551D and N1303K). Login to comment
70 The patients` CFTR genotypes were: 44 patients (24.44%) without identified mutation, 51 (28.33%) with one identified mutation (25% F508del/-, 2.78% G542X/-, 0.56% R1162X/-) and 85 (47.22%) patients with two identified mutations (31.67% F508del/F508del, 6.67% F508del/G542X, 2.78% F508del/R1162X, 2.22% F508del/N1303K, 0.56% F508del/ R553X, 0.56% F508del/S4X, 0.56% F508del/1717-1 G > A, 0.56% G542X/R1162X, 0.56% G542X/I618T, 0.56% G542X/2183A > G and 0.56% R1162X/R1162X). Login to comment
27 Determination of mutations in the CFTR gene Determination of mutations in the CFTR gene was performed in the Laboratory of Molecular Genetics for mutations by polymerase chain reaction (F508del) and restriction fragment length polymorphism method (G542X, R1162X, R553X, G551D and N1303K). Login to comment
69 The patients` CFTR genotypes were: 44 patients (24.44%) without identified mutation, 51 (28.33%) with one identified mutation (25% F508del/-, 2.78% G542X/-, 0.56% R1162X/-) and 85 (47.22%) patients with two identified mutations (31.67% F508del/F508del, 6.67% F508del/G542X, 2.78% F508del/R1162X, 2.22% F508del/N1303K, 0.56% F508del/ R553X, 0.56% F508del/S4X, 0.56% F508del/1717-1 G > A, 0.56% G542X/R1162X, 0.56% G542X/I618T, 0.56% G542X/2183A > G and 0.56% R1162X/R1162X). Login to comment

PMID: 22581207 [PubMed] Krulisova V et al: "Prospective and parallel assessments of cystic fibrosis newborn screening protocols in the Czech Republic: IRT/DNA/IRT versus IRT/PAP and IRT/PAP/DNA."

No. Sentence Comment

81 According to the protocol, this result indicated the sequencing of the Table 1 Parallel comparison of CF NBS protocols IRT/DNAa /IRT IRT/PAP IRT/PAP/DNAa Newborns screened (N) 106,522 106,522 106,522 IRT positives (N; %) 1,158 (1.09) 3,155 (2.96) 3,155 (2.96) PAP positives (N; %) - 260 (0.24) 260 (0.24) Median age (range) at the availability of DNA-testinga results (days) 36 (9-222b ) - 36 (9-222b ) 1 and/or 2 CF mutations detected (N; %) 76 (0.07) - 27 (0.03) Recalled newborns for repeated IRT examination (N; %) 47 (0.04) - - Positive CF NBS (N; %) 123 (0.12) 260 (0.24) 27 (0.03) Positive IRT in newborns recalled for repeated examination (N) 1 - - ST indicated (N; %) 77 (0.07) 260 (0.24) 27 (0.03) ST carried out (N; % of indicated ST) 72c (93.51) 204c (78.46) 24c (88.89) CF carriers (N) 55 - 12 Prevalence of CF carriers 1 in 21 - 1 in 22 Diagnosed CF patients (N) 19 16 15 False positives based on performed ST (N; % of all cases screened) 99d (0.09) 188 (0.18) 9 (0.01) Newborns with equivocal diagnosis [F508del/R117H-IVS-8 T(7) and ST<30 mmol/L; N] 2 - 0 False negatives (N) 2 5 6 Total of CF patients detected (N) 21e Median age (range) at diagnosis (days) 36 (9-57)e CF prevalence 1 in 5,072e Sensitivity (TP/TP+FN) 0.9048 0.7619 0.7142 Specificity (TN/TN+FP) 0.9991 0.9982 0.9999 PPV (TP/TP+FP) 0.1610 0.0784 0.625 N number, % of all cases screened, TP true positives, FN false negatives, TN true negatives, FP false positives, PPV positive predictive value, ST sweat test a CF-causing mutations covered by Elucigene assays ("legacy" nomenclature) with the CF-EU1Tm accounting for: p.Arg347Pro (R347P), c.2657+ 5G>A (2789+5G>A), c.2988+1G>A (3120+1G>A), c.579+1G>T (711+1G>T), p.Arg334Trp (R334W), p.Ile507del (I507del), p.Phe508del (F508del), c.3718-2477C>T (3849+10kbC>T), p.Phe316LeufsX12 (1078delT), p.Trp1282X (W1282X), p.Arg560Thr (R560T), p.Arg553X (R553X), p.Gly551Asp (G551D), p.Met1101Lys (M1101K), p.Gly542X (G542X), p.Leu1258PhefsX7 (3905insT), p.Ser1251Asn (S1251N), c.1585-1G>A (1717-1G>A), p.Arg117His (R117H), p.Asn1303Lys (N1303K), p.Gly85Glu (G85E), c.1766+1G>A (1898+1G>A), p.Lys684AsnfsX38 (2184delA), p.Asp1152His (D1152H), c.54-5940_273+10250del (CFTRdele2,3), p.Pro67Leu (P67L), p.Glu60X (E60X), p.Lys1177SerfsX15 (3659delC), c.489+1G>T (621+1G>T), p.Ala455Glu (A455E), p.Arg1162X (R1162X), p.Leu671X (2143delT), c.1210-12T[n] (IVS8-T(n) variant), including additional mutations in the CF-EU2Tm : p.Gln890X (Q890X), p.Tyr515X (1677delTA), p.Val520Phe (V520F), c.3140-26A>G (3272-26A>G), p.Leu88IlefsX22 (394delTT), p.Arg1066Cys (R1066C), p.Ile105SerfsX2 (444delA), p.Tyr1092X (C>A) (Y1092X(C>A)), p.Arg117Cys (R117C), p.Ser549Asn (S549N), p.Ser549ArgT>G (S549R T>G), p.Tyr122X (Y122X), p.Arg1158X (R1158X), p.Leu206Trp (L206W), c.1680-886A>G (1811+1.6kbA>G), p.Arg347His (R347H), p.Val739TyrfsX16 (2347delG) and p.Trp846X (W846X) b failed DNA isolation from DBS, including repetition of DNA-testing c deceased patient or non-compliance with referrals (five CF carriers in IRT/DNA/IRT, 56 newborns in IRT/PAP, three CF carriers in IRT/PAP/DNA) d comprising newborns with repeated IRT (47 newborns) e aggregate data from all protocols entire CFTR coding region in both newborns, and led to the identification of p.Ile336Lys (I336K) and p.Glu1104Lys (E1104K) mutations. Login to comment
109 Table 2 False negatives due to mean PAP concentrations below the cut-off IRT (ng/mL) PAP (ng/mL) CFTR Genotypea Sweat chloride concentration (mmol/L) Patient 1 174 0.93 F508del/ F508del 109.6 Patient 2 337 0.49 F508del/ F508del 98.7 Patient 3 203 0.42 F508del/ F508del 103.7 Patient 4 115 0.67 F508del/ I507del 93.2 Patient 5b 87.8 1.43 G542X/ E1104K 74.5 a legacy nomenclature b pancreatic sufficient patient (fecal Elastase-1 level was 507 μg/g) IRT/PAP and IRT/PAP/DNA protocols Five CF patients were false negative within the IRT/PAP protocol due to low PAP concentrations (Table 2). Login to comment

PMID: 22739718 [PubMed] Pettit RS et al: "Cystic fibrosis transmembrane conductance regulator-modifying medications: the future of cystic fibrosis treatment."

No. Sentence Comment

140 Ataluren not only has therapeutic applicability in patients with CF and class I CFTR mutations, but may be effective in other diseases, such as Duchenne muscular dystrophy.27 Ataluren was originally studied in a mouse model, where it restored chloride to 24-29% of normal levels in mice with CF and a G542X mutation.28 Following positive animal studies, ataluren was administered to 62 healthy adults in increasing doses, from 3 mg/kg to 200 mg/kg per dose.29 The doses were well tolerated until more than 150 mg/kg was administered; these doses caused headache, dizziness, and gastrointestinal adverse effects. Login to comment
246 Du M, Liu X, Welch EM, et al. PTC124 is an orally bioavailable compound that promotes suppression of the human CFTR-G542X nonsense allele in a CF mouse model. Login to comment

PMID: 22300503 [PubMed] Barben J et al: "Retrospective analysis of stored dried blood spots from children with cystic fibrosis and matched controls to assess the performance of a proposed newborn screening protocol in Switzerland."

No. Sentence Comment

28 If IRT is elevated (N99th percentile) a screening test with the seven most common CFTR mutations in Switzerland (F508del, 3905insT, G542X, R553X, W1282X, 1717-1 GNA, N1303K) [12] will be used to confirm the suspicion. Login to comment
46 In brief, this assay is based on DNA amplification of four fragments containing the mutations (F508del, 3905insT, G542X, R553X, W1282X, 1717-1 GNA, and N1303K) by PCR, followed by hybridization with short, allele-specific oligonucleotide probes labeled with europium, terbium, or samarium chelates. Login to comment
80 CFTR mutations Alleles found Percentage of total Homozygous (n) F508del a 86 68.2 30 3905insT a 4 3.2 1 G542X a 3 2.4 - R553X a 3 2.4 1 W1282X a 2 1.6 - 1717-1 GNA a 2 1.6 - N1303K a 0 0.0 - S549R 3 2.4 1 Q525X 3 2.4 - Y1092X 2 1.6 - 3120+1 GNA b 2 1.6 1 2347delG 2 1.6 - 2176insC 1 0.8 - 3659delC 1 0.8 - 3359delCTCTG 1 0.8 - W1089X 1 0.8 - 711+1 GNT 1 0.8 - D1152H 1 0.8 - G1244E 1 0.8 - R1066C 1 0.8 - R31C 1 0.8 - R347P 1 0.8 - R74W 1 0.8 - S945L 1 0.8 - T501I 1 0.8 - K68X 1 0.8 - Total 126 100.0% 34 a Seven most common CF-gene mutations in Switzerland ("Swiss panel")=79.4% (100/126) of alleles. Login to comment

PMID: 22302635 [PubMed] Cornel MC et al: "Improving test properties for neonatal cystic fibrosis screening in the Netherlands before the nationwide start by May 1st 2011."

No. Sentence Comment

69 This protocol was expected to identify 25 CF patients on an annual basis, additional to four infants already diagnosed because of meconium ileus (Health Council of 1 Using the LiPA test (INNO-LiPA CFTR 19 en INNO-LiPA CFTR 17+Tn; Innogenetics, Gent, Belgium) the following CFTR mutations can be detected: exon 2-3del (21 kb), 394delTT, E60X, G85E, R117H, 621+1G>T, 711+1G>T, 711+5G>A, 1078delT, R334W, R347P, A455E, I507del, F508del, 1717-1G>A, G542X, G551D, Q552X, R553X, R560T, 1898+1G>A, 2143delT, 2183AA>G, 2184delA, 2789+5G>A, 3120+1G>A, 3199del6, 3272-26A>G, 3659delC, R1162X, 3849+10kbC>T, 3905insT, S1251N, W1282X en N1303K. Login to comment
70 This test also identifies the CFTR polymorphism Tn in intron 8 which is important in cases where the mutation R117H is detected. Login to comment

PMID: 21999194 [PubMed] Agarwal R et al: "Link between CFTR mutations and ABPA: a systematic review and meta-analysis."

No. Sentence Comment

56 (1996)[30] 11ABPA53chronic bronchitis Asthma,pulmonaryinfiltrates,CB, immediateAfskintestpositivity,totalIgE >1000ngml)1 ,positiveAfprecipitins, elevatedAfIgG/IgE,bloodeosinophilia, sweatchloride<40mmoll)1 /(United States) BothgroupssixmutationsF508del, G542X,GS51D,R553X,W1282X andN1303K;ninemoremutations inABPA:R117H,R347P,R347H, R334W,A455E,G551S, 2789+5G>A,D1152H,and 3849+10kbC>T ReverseASOanalysis andDGGEwithDNA sequencing 1patientcarried2CF (F508del;R347H)and5 carried1CF(4F508del; 1R117H).Mutationsseenin 6/11ABPAvs.1/53 controls Aronetal. Login to comment
58 (2001)[32] 21ABPA43allergic asthma; 142healthy controls Asthma,pulmonaryinfiltrates,CB, immediateAfskintestpositivity,totalIgE >450IUml)1 ,positiveAfprecipitins, elevatedAfIgG/IgE,bloodeosinophilia >500ll)1 .Sweatchloride <60mmoll)1 /(Belgium) R117H,621-1G>T,R334W, F508del,I507del10,1717-1G>A, G542X,R553X,G551D,R1162X, 3849+10kbC>T,W1282X, N1303K Heteroduplexand acrylamidegel electrophoresis, ARMS,nestedPCR followedby electrophoresisand DNAsequencing OneCFTRmutationin6/21 patients(F508del[n=2], G542X[n=1],R1162X [n=1],1717-1G>A [n=1],andR117H[n=1]) vs.2/43asthmatics(1CFTR mutation;(F508del, 1717-1G>Aand6/142 controls Eatonetal. Login to comment
59 (2002)[33] 31ABPAHealthycontrols (n=34) Asthma(n=51) Asthma,positiveSPTtoAf,totalIgE >1000ngml)1 ,elevatedAf-IgE,positive precipitinstoAf,bloodeosinophilia >350ll)1 ,pulmonaryinfiltratesonCXR orCBonCT/(NewZealand) 16CFmutations-F508del,I507del, R117H,W1282X,621+1G>T, R334W,R347P,A455E, 1717-1G>A,G542X,5549N, G551D,R553X,R560T,N1303Kand 3849+10kbC>T ASOhybridisationand DGGEwithDNA sequencing 4/31(F508del[n=3], R117H[n=1])vs.2/51 asthma(F508del[n=1], R117H[n=1])vs.1/34 healthycontrols ABPA,allergicbronchopulmonaryaspergillosis;ARMS,amplificationrefractorymutationsystem;ASO,allele-specificoligonucleotide;CB,centralbronchiectasis;CFTR,cysticfibrosis transmembraneconductanceregulator;DGGE,denaturinggradientgelelectrophoresis;OR,oddsratio CFTRmutationclass(classI--1717-1G>A,R1162X,G542X;classII--F508del,N1303K;classIV--R347H,R117H). Login to comment

PMID: 22449949 [PubMed] Le Henaff C et al: "The F508del mutation in cystic fibrosis transmembrane conductance regulator gene impacts bone formation."

No. Sentence Comment

20 The expression of CFTR protein has been identified by immunohistochemistry in human bone cells.19 We previously reported the expression of CFTR mRNA and protein in primary human osteoblasts (cells that form bone) and showed that inhibition of CFTR-mediated Cl- channel activity affects the release of osteoprotegerin and prostaglandin E2, two key regulators of bone formation.20 We recently discovered a defective CFTR Cl- channel activity and a deficit of osteoprotegerin production by primary osteoblasts from a 25-year-old CF patient with the F508del/G542X mutation in CFTR.21 One study in patients with CF with at least one F508del allele showed a direct association between the F508del mutation and low BMD in both sexes.22 However, the impact of the F508del allele mutation in CFTR on bone formation and bone mass remains unknown. Login to comment
19 The expression of CFTR protein has been identified by immunohistochemistry in human bone cells.19 We previously reported the expression of CFTR mRNA and protein in primary human osteoblasts (cells that form bone) and showed that inhibition of CFTR-mediated Clafa; channel activity affects the release of osteoprotegerin and prostaglandin E2, two key regulators of bone formation.20 We recently discovered a defective CFTR Clafa; channel activity and a deficit of osteoprotegerin production by primary osteoblasts from a 25-year-old CF patient with the F508del/G542X mutation in CFTR.21 One study in patients with CF with at least one F508del allele showed a direct association between the F508del mutation and low BMD in both sexes.22 However, the impact of the F508del allele mutation in CFTR on bone formation and bone mass remains unknown. Login to comment

PMID: 22310382 [PubMed] Diana A et al: "A large deletion causes apparent homozygosity for the D1152H mutation in the cystic fibrosis transmembrane regulator (CFTR) gene."

No. Sentence Comment

63 We speculate that the D1152H, acting as a mild mutation, has a dominant effect on the severe dele17a-18. Login to comment
64 Orgad et al. (2002) reported a case of hyperechogenic bowel loops and MI in a fetus carrying the combination of D1152H and G542X mutations, but they did not describe the clinical follow-up of the newborn. Login to comment

PMID: 22468138 [PubMed] Elliott AM et al: "Rapid detection of the ACMG/ACOG-recommended 23 CFTR disease-causing mutations using ion torrent semiconductor sequencing."

No. Sentence Comment

26 Amplicons were then pooled together in equimolar concentrations and purified using the T A B L E 1 Data Generation from Three PGM Runs Run Total number of reads Total bases (Mbp) AQ17 total bases (Mbp) AQ17 avg. read length CF WT 101,211 8.5 6.5 68 CF 23 pooled mutants 222,247 18.6 12.52 64 CF mutant 135,000 11.7 8.8 72 T A B L E 2 CFTR Variant Coverage, Mutant Read Percentage, and Base-Call Accuracy from a WT Library Using PGM Sequencing Variant cDNA position Coverage Mutant read % Accuracy/base G85E c.254G Ͼ A 408 0 99.5 R117H c.350G Ͼ A 3627 0 99.9 621 ϩ 1G Ͼ T c.489 ϩ 1G Ͼ T 245 0 99.6 711 ϩ 1G Ͼ T c.579 ϩ 1G Ͼ T 2660 0 99.9 R334W c.1000C Ͼ T 5419 0 99.7 R347P c.1040G Ͼ C 3562 0 99.4 A455E c.1364C Ͼ A 10,340 0 99.9 ⌬I507 c.1519_1521delATC 6507 0 98.6 ⌬F508 c.1521_1523delCTT 6507 0 99.4 1717-1G Ͼ A c.1585-1G Ͼ A 2086 0 99.2 G542X c.1624G Ͼ T 854 0 97.8 G551D c.1652G Ͼ A 3901 0 99 R553X c.1657C Ͼ T 3915 0 99.9 R560T c.1679G Ͼ C 3924 0 99.6 1898 ϩ 1G Ͼ A c.1766 ϩ 1G Ͼ A 1793 0 97.6 2184delAa c.2052delA 2001 35% 63.6 2789 ϩ 5G Ͼ A c.2657 ϩ 5G Ͼ A 293 0 100 3120 ϩ 1G Ͼ A c.2988 ϩ 1G Ͼ A 2408 0 100 R1162X c.3484C Ͼ T 9610 0 98.1 3659delC c.3528delC 9271 0 100 3849 ϩ 10kbC Ͼ T c.3717 ϩ 12191C Ͼ T 10,157 0 99.9 W1282X c.3846G Ͼ A 4789 0 95.6 N1303K c.3909C Ͼ G 3236 0 99.5 a The 2184delA variant lies in a homopolymer stretch of seven adenines and is not detected accurately as a result of homopolymer-length sequencing errors. Login to comment
67 For this data set, the PGM 314 chip output was 18.6 Mbp, with ϳ67% aligning to the CFTR T A B L E 3 PGM CFTR Variant Coverage and Mutant Read Percentage from a Pooled Mutant Library Representing All 23 ACMG/ACOG Mutations Variant cDNA position Coverage Mutant read % Predicted read % Genotype G85E c.254G Ͼ A 93 33 50 Het R117H c.350G Ͼ A 6228 39 50 Het 621 ϩ 1G Ͼ T c.489 ϩ 1G Ͼ T 1243 46 50 Het 711 ϩ 1G Ͼ T c.579 ϩ 1G Ͼ T 1352 29 50 Het R334W c.1000C Ͼ T 13,284 8 25 Het R347P c.1040G Ͼ C 9454 27 25 Het A455E c.1364C Ͼ A 19,527 43 50 Het ⌬I507 c.1519_1521delATC 15,587 14 25 Het ⌬F508 c.1521_1523delCTT 15,587 68 50 Homo 1717-1G Ͼ A c.1585-1G Ͼ A 3584 36 50 Het G542X c.1624G Ͼ T 610 41 50 Het G551D c.1652G Ͼ A 6714 16 17 Het R553X c.1657C Ͼ T 6670 15 17 Het R560T c.1679G Ͼ C 6395 22 17 Het 1898 ϩ 1G Ͼ A c.1766 ϩ 1G Ͼ A 3293 49 50 Het 2184delAa c.2052delA 2256 63 50 Het 2789 ϩ 5G Ͼ A c.2657 ϩ 5G Ͼ A 1765 54 50 Het 3120 ϩ 1G Ͼ A c.2988 ϩ 1G Ͼ A 7447 40 50 Het R1162X c.3484C Ͼ T 19,060 54 50 Het 3659delC c.3528delC 28,321 30 50 Het 3849 ϩ 10kbC Ͼ T c.3717 ϩ 12191C Ͼ T 27,102 46 50 Het W1282X c.3846G Ͼ A 9219 48 50 Het N1303K c.3909C Ͼ G 4842 49 50 Het a The 2184delA variant lies in a homopolymer stretch of seven adenines and is not accurately detected as a result of homopolymer-length sequencing errors. Login to comment
83 Analysis of the data correctly identified the two heterozygous mutations ⌬F508 and G542X, with mutant read distributions of 47% and 41%, respectively (Table 4 and Fig. 2). Login to comment
86 Using samples characterized previously, we analyzed the PGM`s data out- T A B L E 4 PGM CFTR Variant Coverage and Mutant Read Percentage from an Individual Harboring Two Disease-Causing CFTR Mutations Variant cDNA position Coverage Mutant read % G85E c.254G Ͼ A 237 0 R117H c.350G Ͼ A 3774 0 621 ϩ 1G Ͼ T c.489 ϩ 1G Ͼ T 936 0 711 ϩ 1G Ͼ T c.579 ϩ 1G Ͼ T 2018 0 R334W c.1000C Ͼ T 10,899 0 R347P c.1040G Ͼ C 7720 0 A455E c.1364C Ͼ A 14,525 0 ⌬I507 c.1519_1521delATC 8855 0 ⌬F508 c.1521_1523delCTT 8855 47 1717-1G Ͼ A c.1585-1G Ͼ A 2216 0 G542X c.1624G Ͼ T 2035 41 G551D c.1652G Ͼ A 4581 0 R553X c.1657C Ͼ T 4545 0 R560T c.1679G Ͼ C 4774 0 1898 ϩ 1G Ͼ A c.1766 ϩ 1G Ͼ A 2702 0 2184delAa c.2052delA 2837 18.5 2789 ϩ 5G Ͼ A c.2657 ϩ 5G Ͼ A 860 0 3120 ϩ 1G Ͼ A c.2988 ϩ 1G Ͼ A 4347 0 R1162X c.3484C Ͼ T 12,039 0 3659delC c.3528delC 7169 0 3849 ϩ 10kbC Ͼ T c.3717 ϩ 12191C Ͼ T 11,588 0 W1282X c.3846G Ͼ A 6187 0 N1303K c.3909C Ͼ G 4479 0 a The 2184delA variant lies in a homopolymer stretch of seven adenines and is not accurately detected as a result of homopolymer-length sequencing errors. Login to comment
96 In agreement, using the GAIIx, we were FIGURE 2 SoftGenetics PGM sequence analysis illustrating the CFTR mutations ⌬F508 (A) and G542X (B) in a single CF sample. Login to comment
66 For this data set, the PGM 314 chip output was 18.6 Mbp, with b03;67% aligning to the CFTR T A B L E 3 PGM CFTR Variant Coverage and Mutant Read Percentage from a Pooled Mutant Library Representing All 23 ACMG/ACOG Mutations Variant cDNA position Coverage Mutant read % Predicted read % Genotype G85E c.254G b0e; A 93 33 50 Het R117H c.350G b0e; A 6228 39 50 Het 621 af9; 1G b0e; T c.489 af9; 1G b0e; T 1243 46 50 Het 711 af9; 1G b0e; T c.579 af9; 1G b0e; T 1352 29 50 Het R334W c.1000C b0e; T 13,284 8 25 Het R347P c.1040G b0e; C 9454 27 25 Het A455E c.1364C b0e; A 19,527 43 50 Het èc;I507 c.1519_1521delATC 15,587 14 25 Het èc;F508 c.1521_1523delCTT 15,587 68 50 Homo 1717-1G b0e; A c.1585-1G b0e; A 3584 36 50 Het G542X c.1624G b0e; T 610 41 50 Het G551D c.1652G b0e; A 6714 16 17 Het R553X c.1657C b0e; T 6670 15 17 Het R560T c.1679G b0e; C 6395 22 17 Het 1898 af9; 1G b0e; A c.1766 af9; 1G b0e; A 3293 49 50 Het 2184delAa c.2052delA 2256 63 50 Het 2789 af9; 5G b0e; A c.2657 af9; 5G b0e; A 1765 54 50 Het 3120 af9; 1G b0e; A c.2988 af9; 1G b0e; A 7447 40 50 Het R1162X c.3484C b0e; T 19,060 54 50 Het 3659delC c.3528delC 28,321 30 50 Het 3849 af9; 10kbC b0e; T c.3717 af9; 12191C b0e; T 27,102 46 50 Het W1282X c.3846G b0e; A 9219 48 50 Het N1303K c.3909C b0e; G 4842 49 50 Het a The 2184delA variant lies in a homopolymer stretch of seven adenines and is not accurately detected as a result of homopolymer-length sequencing errors. Login to comment
82 Analysis of the data correctly identified the two heterozygous mutations èc;F508 and G542X, with mutant read distributions of 47% and 41%, respectively (Table 4 and Fig. 2). Login to comment
85 Using samples characterized previously, we analyzed the PGM`s data out- T A B L E 4 PGM CFTR Variant Coverage and Mutant Read Percentage from an Individual Harboring Two Disease-Causing CFTR Mutations Variant cDNA position Coverage Mutant read % G85E c.254G b0e; A 237 0 R117H c.350G b0e; A 3774 0 621 af9; 1G b0e; T c.489 af9; 1G b0e; T 936 0 711 af9; 1G b0e; T c.579 af9; 1G b0e; T 2018 0 R334W c.1000C b0e; T 10,899 0 R347P c.1040G b0e; C 7720 0 A455E c.1364C b0e; A 14,525 0 èc;I507 c.1519_1521delATC 8855 0 èc;F508 c.1521_1523delCTT 8855 47 1717-1G b0e; A c.1585-1G b0e; A 2216 0 G542X c.1624G b0e; T 2035 41 G551D c.1652G b0e; A 4581 0 R553X c.1657C b0e; T 4545 0 R560T c.1679G b0e; C 4774 0 1898 af9; 1G b0e; A c.1766 af9; 1G b0e; A 2702 0 2184delAa c.2052delA 2837 18.5 2789 af9; 5G b0e; A c.2657 af9; 5G b0e; A 860 0 3120 af9; 1G b0e; A c.2988 af9; 1G b0e; A 4347 0 R1162X c.3484C b0e; T 12,039 0 3659delC c.3528delC 7169 0 3849 af9; 10kbC b0e; T c.3717 af9; 12191C b0e; T 11,588 0 W1282X c.3846G b0e; A 6187 0 N1303K c.3909C b0e; G 4479 0 a The 2184delA variant lies in a homopolymer stretch of seven adenines and is not accurately detected as a result of homopolymer-length sequencing errors. Login to comment
95 In agreement, using the GAIIx, we were FIGURE 2 SoftGenetics PGM sequence analysis illustrating the CFTR mutations èc;F508 (A) and G542X (B) in a single CF sample. Login to comment

PMID: 22271776 [PubMed] Vernooij-van Langen AM et al: "Novel strategies in newborn screening for cystic fibrosis: a prospective controlled study."

No. Sentence Comment

110 Table 2 Immunoreactive trypsinogen and pancreatitis-associated protein concentrations, CFTR gene mutation analysis and sweat tests in infants with cystic fibrosis detected by newborn screening IRT (mg/litre) PAP (mg/litre) Mutation 1 Mutation 2 Sweat test chloride (mmol/litre) 1 438 5.3 F508del F508del 74 2 284 1.8 F508del F508del 88 3 266 9.8 F508del F508del 97 4 237 1.8 F508del F508del 11 and 74 5 197 4.3 F508del F508del 69 6* 191 12.6 F508del C.3889dupT 94 7 164 14.4 F508del G542X 102 8 129 4.3 F508del F508del Failed 9 110 2.2 F508del F508del 94 10 109 2.0 F508del F508del 51 11 105 4.4 F508del F508del 149 12 155 2.6 F508del F508del 111 13 191 12.6 F508del F508del 4 14 116 15.8 F508del F508del Failed 3 times 15 293 5.7 F508del 2184A 120 16* 228 15.8 F508del 1294_1300del 99 17 218 4.5 F508del G85E 99 18 153 4.0 F508del S1251N 77 19* 141 15.8 F508del E730X 82 20z 78 0.8 F508del A455E 65 21y 114 11.2 F508del F508del Failed 22y 109 0.8 F508del F508del 78 23y 93 1.3 F508del F508del e 24y 75 6.7 F508del F508del 78 *Second mutation detected by sequencing. Login to comment
109 Table 2 Immunoreactive trypsinogen and pancreatitis-associated protein concentrations, CFTR gene mutation analysis and sweat tests in infants with cystic fibrosis detected by newborn screening IRT (mg/litre) PAP (mg/litre) Mutation 1 Mutation 2 Sweat test chloride (mmol/litre) 1 438 5.3 F508del F508del 74 2 284 1.8 F508del F508del 88 3 266 9.8 F508del F508del 97 4 237 1.8 F508del F508del 11 and 74 5 197 4.3 F508del F508del 69 6* 191 12.6 F508del C.3889dupT 94 7 164 14.4 F508del G542X 102 8 129 4.3 F508del F508del Failed 9 110 2.2 F508del F508del 94 10 109 2.0 F508del F508del 51 11 105 4.4 F508del F508del 149 12 155 2.6 F508del F508del 111 13 191 12.6 F508del F508del 4 14 116 15.8 F508del F508del Failed 3 times 15 293 5.7 F508del 2184A 120 16* 228 15.8 F508del 1294_1300del 99 17 218 4.5 F508del G85E 99 18 153 4.0 F508del S1251N 77 19* 141 15.8 F508del E730X 82 20z 78 0.8 F508del A455E 65 21y 114 11.2 F508del F508del Failed 22y 109 0.8 F508del F508del 78 23y 93 1.3 F508del F508del e 24y 75 6.7 F508del F508del 78 *Second mutation detected by sequencing. Login to comment

PMID: 22427236 [PubMed] Rosendahl J et al: "CFTR, SPINK1, CTRC and PRSS1 variants in chronic pancreatitis: is the role of mutated CFTR overestimated?"

No. Sentence Comment

72 The following CFTR variants were analysed with specific FRET probes: p.E60X, p.R75Q, p.G85E, p.R117H, p.I148T, c.621 +1G>T (IVS4+1G>T), c.711+1G>T (IVS5+1G>T), c.1078delT, p.R334W, p.R347P, 9-13TG, 5-9T, p.A455E, p.M470V, p.F508del, c.1716G>A (p.E528E), c.1717-1G>A (IVS10-1G>A), p.G542X, p.S549N, p.R553X, p.R560T, c.1898+1G>A (IVS12 +1G>A), c.2143delT, c.2183AA>G, c.2562T>G, c.2657+5G>A (IVS14B+5G>A), p.L997F, p.I1005R, p.Y1092X, p.D1152H, p.R1162X, c.3659delC, p.S1235R, p.S1251N, p.W1282X, p.N1303K, and c.4389G>A. Login to comment
140 Variant distribution in patients aged >20 and <20 years In younger patients, overall PRSS1 variants were 2.9-fold more common (>20 years: 9/239, 3.8%; <20 years: 46/421, 10.9%; p¼0.001, OR 3.1, 95% CI 1.5 to 6.5), whereas overall SPINK1 variants were similarly distributed (56/239, 23.4%; 73/421, Table 2 CFTR variants detected by melting curve analysis Gene Variant Patients Controls p Value OR (95% CI) CFTR (CF-causing, severe) p.F508del 44/660 (6.7%) 48/1758 (2.7%) <0.0001 2.5 (1.7 to 3.9) p.R117H (5T/7T) 2/660 (0.3%) 1/1758 (0.06%) NS e p.G542X 1/660 (0.2%) 1/1758 (0.06%) NS e c.1717-1G>A 3/660 (0.5%) 1/1758 (0.06%) NS e p.E585X 0/660 1/1758 (0.06%) NS e c.2183AA>G 0/660 1/1758 (0.06%) NS e p.R1158X 1/660 (0.2%) 0/1758 NS e p.R1162X 1/660 (0.3%) 0/1758 NS e p.N1303K 3/660 (0.5%) 0/1758 NS e Total 55/660 (8.3%) 53/1758 (3%) <0.0001 2.9 (2 to 4.3) CFTR (CF-causing mild) p.R117H (7T/7T) 13/660 (2%) 8/1758 (0.5%) 0.0009 4.4 (1.8 to 10.7) p.R117H (7T/9T) 3/660 (0.5%) 1/1758 (0.06%) NS e p.R347H 1/660 (0.2%) 0/1758 NS e p.R347P 1/660 (0.2%) 0/1758 NS e p.A455E 1/660 (0.2%) 0/1758 NS e c.2657+5G>A 1/660 (0.2%) 0/1758 NS e p.D1152H 3/660 (0.5%) 5/1758 (0.3%) NS e Total 23/660 (3.5%) 14/1758 (0.8%) <0.0001 4.5 (2.3 to 8.8) CFTR (non CF-causing) p.R74Q 2/660 (0.3%) 0/1758 NS e p.R75Q (het)* 29/660 (4.4%) 59/1758 (3.4%) NS e p.R75Q (hom)* 2/660 (0.3%) 1/1758 (0.06%) NS e p.Y84H 0/660 1/1758 (0.06%) NS e p.A120T 0/660 1/1758 (0.06%) NS e p.I148T* 4/660 (0.6%) 11/1758 (0.6%) NS e p.I507V 1/660 (0.2%) 2/1758 (0.1%) NS e p.F508C 1/660 (0.2%) 0/1758 NS e c.1716+12T>C 0/660 1/1758 (0.06%) NS e p.E528E (het)* 36/660 (5.5%) 82/1758 (4.7%) NS e p.E528E (hom)* 0/660 2/1758 (0.1%) NS e c.1898+8C>G 0/660 1/1758 (0.06%) NS e p.H667Y 1/660 (0.2%) 0/1758 NS e p.R668C 5/660 (0.8%) 3/1758 (0.2%) NS e p.G691R 0/660 1/1758 (0.06%) NS e p.L997F 5/660 (0.8%) 6/1758 (0.3%) NS e p.S1235R 10/660 (1.5%) 18/1758 (1.0%) NS e Total (excluded)* 25/660 (3.8%) 45/1758 (2.6%) NS e CFTR (CF-causing) Total (all) 78/660 (11.8%) 67/1758 (3.8%) <0.0001 3.4 (2.4 to 4.8) CFTR (all) Total (excluded)* 103/660 (15.6%) 112/1758 (6.4%) <0.0001 2.7 (2 to 3.6) The table is divided into three parts. Login to comment
69 The following CFTR variants were analysed with specific FRET probes: p.E60X, p.R75Q, p.G85E, p.R117H, p.I148T, c.621 +1G>T (IVS4+1G>T), c.711+1G>T (IVS5+1G>T), c.1078delT, p.R334W, p.R347P, 9-13TG, 5-9T, p.A455E, p.M470V, p.F508del, c.1716G>A (p.E528E), c.1717-1G>A (IVS10-1G>A), p.G542X, p.S549N, p.R553X, p.R560T, c.1898+1G>A (IVS12 +1G>A), c.2143delT, c.2183AA>G, c.2562T>G, c.2657+5G>A (IVS14B+5G>A), p.L997F, p.I1005R, p.Y1092X, p.D1152H, p.R1162X, c.3659delC, p.S1235R, p.S1251N, p.W1282X, p.N1303K, and c.4389G>A. Login to comment
135 Variant distribution in patients aged >20 and <20 years In younger patients, overall PRSS1 variants were 2.9-fold more common (>20 years: 9/239, 3.8%; <20 years: 46/421, 10.9%; p&#bc;0.001, OR 3.1, 95% CI 1.5 to 6.5), whereas overall SPINK1 variants were similarly distributed (56/239, 23.4%; 73/421, Table 2 CFTR variants detected by melting curve analysis Gene Variant Patients Controls p Value OR (95% CI) CFTR (CF-causing, severe) p.F508del 44/660 (6.7%) 48/1758 (2.7%) <0.0001 2.5 (1.7 to 3.9) p.R117H (5T/7T) 2/660 (0.3%) 1/1758 (0.06%) NS e p.G542X 1/660 (0.2%) 1/1758 (0.06%) NS e c.1717-1G>A 3/660 (0.5%) 1/1758 (0.06%) NS e p.E585X 0/660 1/1758 (0.06%) NS e c.2183AA>G 0/660 1/1758 (0.06%) NS e p.R1158X 1/660 (0.2%) 0/1758 NS e p.R1162X 1/660 (0.3%) 0/1758 NS e p.N1303K 3/660 (0.5%) 0/1758 NS e Total 55/660 (8.3%) 53/1758 (3%) <0.0001 2.9 (2 to 4.3) CFTR (CF-causing mild) p.R117H (7T/7T) 13/660 (2%) 8/1758 (0.5%) 0.0009 4.4 (1.8 to 10.7) p.R117H (7T/9T) 3/660 (0.5%) 1/1758 (0.06%) NS e p.R347H 1/660 (0.2%) 0/1758 NS e p.R347P 1/660 (0.2%) 0/1758 NS e p.A455E 1/660 (0.2%) 0/1758 NS e c.2657+5G>A 1/660 (0.2%) 0/1758 NS e p.D1152H 3/660 (0.5%) 5/1758 (0.3%) NS e Total 23/660 (3.5%) 14/1758 (0.8%) <0.0001 4.5 (2.3 to 8.8) CFTR (non CF-causing) p.R74Q 2/660 (0.3%) 0/1758 NS e p.R75Q (het)* 29/660 (4.4%) 59/1758 (3.4%) NS e p.R75Q (hom)* 2/660 (0.3%) 1/1758 (0.06%) NS e p.Y84H 0/660 1/1758 (0.06%) NS e p.A120T 0/660 1/1758 (0.06%) NS e p.I148T* 4/660 (0.6%) 11/1758 (0.6%) NS e p.I507V 1/660 (0.2%) 2/1758 (0.1%) NS e p.F508C 1/660 (0.2%) 0/1758 NS e c.1716+12T>C 0/660 1/1758 (0.06%) NS e p.E528E (het)* 36/660 (5.5%) 82/1758 (4.7%) NS e p.E528E (hom)* 0/660 2/1758 (0.1%) NS e c.1898+8C>G 0/660 1/1758 (0.06%) NS e p.H667Y 1/660 (0.2%) 0/1758 NS e p.R668C 5/660 (0.8%) 3/1758 (0.2%) NS e p.G691R 0/660 1/1758 (0.06%) NS e p.L997F 5/660 (0.8%) 6/1758 (0.3%) NS e p.S1235R 10/660 (1.5%) 18/1758 (1.0%) NS e Total (excluded)* 25/660 (3.8%) 45/1758 (2.6%) NS e CFTR (CF-causing) Total (all) 78/660 (11.8%) 67/1758 (3.8%) <0.0001 3.4 (2.4 to 4.8) CFTR (all) Total (excluded)* 103/660 (15.6%) 112/1758 (6.4%) <0.0001 2.7 (2 to 3.6) The table is divided into three parts. Login to comment

PMID: 22423042 [PubMed] Gonska T et al: "Role of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) in patients with chronic sinopulmonary disease."

No. Sentence Comment

66 All P values are two-sided with a Table 2-CFTR Genotypes Identified in Subjects With Idiopathic Sinopulmonary Disease CF Causing/CF Causing CF Causing/CFTR Mutation CFTR Mutation/CFTR Mutation CF Causing/Unknown CFTR Mutation/Unknown F508del/A455E 3x F508del /D1152H 2x D579G/D579G 2x F508del /26x R764X/2 F508del/S1251N R75X/V456A 758delC/2 F508del/L967S 1716G.A/5T 1716G.A/2 F508del/5T R75Q/5T R117H (7T)/23x F508del/3212T.C 5T/23x G542X/D1152H 1717-1G.A/Q1291H Patients are grouped according to the identified CFTR alterations on allele 1/allele 2. Login to comment

PMID: 22137130 [PubMed] Cordovado SK et al: "CFTR mutation analysis and haplotype associations in CF patients."

No. Sentence Comment

7 Chromosomes containing the F508del (p.Phe508del), G542X (p.Gly542X) and N1303K (p.Asn1303Lys) mutations shared a common haplotype subgroup, consistent with a common ancient European founder. Login to comment
101 CFTR mutation 1 Gene location CFTR mutation 2 Gene location CFTR mutation 3 Gene location S549N Ex12 3120+1G→A Intron 18 -102T→A Promoter F508del Ex11 G542X Ex12 185+4A→T Intron1 F508del Ex11 F508del Ex11 I1027T Ex19 F508del Ex11 W1282X Ex23 I1027T Ex19 only by the number of repeats of the IVS8CA microsatellite; 32 chromosomes contained 17 repeats and 29 chromosomes contained 23 repeats. Login to comment
102 The F508del haplotype that contained 23 repeats of the IVS8CA microsatellite was identical to the predicted haplotypes associated with G542X (N=6 of 6), N1303K (N=6 of 6), del Ex17a, b and 18 (N=1 of 1), and 3849+10 kb C→T (N=1 of 2). Login to comment
104 Mutation N alleles c.966T>G(5'flanking) c.234T>A(5'flanking)a c.-8G>C(5'UTR) c.-4G>C(Exon1) c.274-179G>A(Intron3) c.743+40A>G(Intron6) c.744-31TTGA(5_7)(Intron6) c.869+11C>T(Intron7) c.869+88T>A(Intron7) c.1209+43T>G(Intron9) IVS8CA(15-23)(Intron9) TG(10-13)_T(5-9)(Intron9) c.1393-61A>G(Intron10) M470V(Exon11) F508del(Exon11) c.1766+152T>A(Intron13) c.1767-231T>C(Intron13) c.1767-136T>C(Intron13) c.1767-132A>G(Intron13) c.2562T>G(Exon15) c.2604A>G(Exon15) c.2619+86_2619+87del(Intron15) c.2619+106T>A(Intron15) c.2909-92G>A(Intron17) IVS17bCA(11-17)(Intron20) c.3368-140A>C(Intron20) c.3469-65C>A(Intron21) F508del 32 TT- TT- TT- TT- TT- TT- TT- TT- TT- TT- TT- TT- TT- TT- TT- TT- TT- TT- TT- TT- TT- TT- TT- TT- TT- TT- TT- TT- TT- TT- TT- TT- GA- AA- AA- AA- AA- AA- AA- AA- AA- AA- AA- AA- AA- AA- AA- AA- AA- AA- AA- AA- AA- AA- AA- AA- AA- AA- AA- AA- AA- AA- A5- 55- 55- 55- 66- 66- 66- 66- 66- 66- 66- 66- 66- 66- 55- 55- TT- TT- TT- TT- TT- TT- TT- TT- TT- TT- TT- TT- TT- TT- TT- TT- TT- TT- TT- TT- TT- TT- TC- TT- TT- TT- TC- TT- TT- TT- TT- TT- TT- TT- TT- TT- TT- TT- TT- TT- TT- TG- TT- TT- TT- TT- TT- TT- TT- TT- TT- TT- TT- T17- 10_9- G- F508del- TA- 13C F508del 29 G23- 10_9- G- F508del- TA- 13C F508del 1 G21- 10_9- G- GG- G-F508del- TA- 13C F508del 1 G17- 10_9- G- F508del- A- G- delTA- 17- C- A N1303K 6 G542X 6 3849+10kbC→T 1 del Ex17a, b, Ex18 1 GG- GG- GG- 23- 10_9- GG-F508- T- TA- 13- C A455E 1 G22- 10_9- G- F508- T- TA- 13- C 621+1G→T 5 G21- 10_9- G- GG- GG- F508C- TA- 13- C 711+1G→T 3 3272-26A→G 2 3659delC 2 R347P 2 G16- 11_7- A- A-F508- TA- 13C del Ex 2, 3 2 del Ex 17a,17b 2 Normal 1 R334W 2 G17- 11_7- A- AA- AA- AA- AA- AA- AA- AA- AA- AA- AA- AA- AA- AA- AA- AA- AA- AA- AA- AA- AA- AA- AA- AA- AA- AA- AA-AA- AA- AA- AA- AA- AA- AA- AA- AA- AA- AA- AA- AA- AA- AA- AA- AA- AA- A-AA- AA- AA- AA- AA- AA- AA- AA- AA- AA- AA- AA- AA- AA- F508- TA- 13C 2183AA→G 2 G16- 10_7- F508- TATA- TATA- TATA- TATA- TATA- TATA- 13C del Ex 2 1 G16- 11_7- F508- 14C 1288insTA 1 G16- 12_7- F508- 13C Normal 1 G16- 12_7- F508- 13C R1162X 1 G17- 10_7- F508- 13C del Ex 2,3 1 G16- 11_7- F508- A17- C del Ex 17a,17b 1 GA- TT- TT- TT- TT- TT- TT- TT- TT- TT- TT- TT- TT- TT- TT- TT- TT- TT- TT- TT- TT- TT- TT- TT- TT- TT- TT- TT- TT- TT- TT- TT- TT- TT- TT- TT- TT-16- 11_7- F508- 14- C G85E 1 G16- 11_7- F508- 15C 1898+1G→A 1 G16- 11_7- F508- G13- C no mut detected 1 GT- TT- T16- 10_7- F508- 13C no mut detected 1 G16- 10_7- F508- 17A W1282X 2 G17- 10_7- F508- 17A W1282X 4 GC- CC- C17- 10_7- F508- delTA- 17- A Q39X 1 I507del 1 3849+10kbC→T 1 R560T 2 1717-1G→A 2 G551D 3 G16- 10_7- F508- delTA- 17- A G551D 2 1154insTC 1 G16- 10_7- F508- delTA- 17- 1717- 17A 1717-1G→A 1 2789+5G→A 1 GG- GG- GG- GG- GG- GG- GG- GG- GG- GG- GG- GG- GG- GG- GG- GG- GG- GG- GG- GG- GG- GG- GG- GG- GG- GG- GG- GG- GG- GG- GG- G17- 10_7- F508- AdelTA- A R1066C 1 GG- 17- 10_7- F508- delTA- A R1066H 1 GG- GG- GG- GG- GG- GG- GG- GG- GG- GG- GG- GG- GG- GG- GG- GG- G17- 9_7- F508- delTAC R553X 3 GG- GG- CA- AA- AA- AA- A17- 12_7- F508- delTA- 11- C 3121-1G→A 1 C17- 12_7- F508- delTA- 11- C R334W 1 G17- 12_7- F508- TA- 13- C (TG)13T5b 1 G17- 13_5- F508- delTA- 13- C CC- CC- CC- CC- CC- CC- CC- CC- CC- CC- CC- CC- CC- CC- CC- CC- CC- R117H 1 CA- 6C- TT- 15- 12_5- AG- F508- T- TT- AT- ATA- TG- 13A- C R117H1 1 CA- 6C- TT- 16- 12_5- AG- F508- T- TT- AT- ATA- TG- 13A- C 1717-1G→A 1 R117Hb 1 GA- 6C- TT- 16- 10_7- AA- F508- A- TC- AG- AdelTA- TG- 13A- C 144c a Variation found in a sample where the haplotype could not be predicted. Login to comment
118 Half (N=77) of the 152 chromosomes examined shared a common haplotype subgroup which was associated with three of the most prevalent CF-causing mutations, F508del, G542X, and N1303K. Login to comment
119 To understand CFTR mutations, a previous study assessing the origin of 27,177 CF chromosomes from 29 European countries and three North African countries described the five most common CF-causing mutations: F508del (66.8%), G542X (2.6%), N1303K (1.6%), G551D (1.5%) and W1282X (1.0%) [22]. Login to comment
120 Similarly, Bobadilla et al. described the five most common CF-causing mutations in the U.S., which included F508del (68.6%), G542X (2.4%), G551D (2.1%), W1282X (1.4%) and N1303K (1.3%) [23]. Login to comment
121 Hence, F508del, G542X, and N1303K are the more common mutations in Caucasians from Europe and the United States. Login to comment
123 The haplotypes identified in the present study were consistent with the Spanish patient findings, showing that F508del, G542X, and N1303K again share a common haplotype subgroup [24]. Login to comment
124 Of our 62 F508del containing chromosomes (excluding the one probable recombinant), 29 predicted haplotypes are identical across 27 polymorphisms from the promoter to intron 21 to the G542X containing haplotypes (N=6) and the N1303K containing haplotypes (N=6). Login to comment
140 For example, when a newborn specimen is positive for R117H and either F508del, G542X or N1303K, and also carries both an 5T and a 9T variant, a clinician could use haplotype information to proceed with a strong probability that the 9T variant is in cis with F508del, G542X or N1310K and not R117H (Table 3). Login to comment

PMID: 22277159 [PubMed] Guha S et al: "Implications for health and disease in the genetic signature of the Ashkenazi Jewish population."

No. Sentence Comment

344 Lerer I, Sagi M, Cutting GR, Abeliovich D: Cystic fibrosis mutations delta F508 and G542X in Jewish patients. Login to comment
343 Lerer I, Sagi M, Cutting GR, Abeliovich D: Cystic fibrosis mutations delta F508 and G542X in Jewish patients. Login to comment

PMID: 22256939 [PubMed] Massie RJ et al: "Lessons learned from 20 years of newborn screening for cystic fibrosis."

No. Sentence Comment

14 From 1991 to 2006, babies with an IRT level > 99th percentile had CFTR gene mutation analysis for p.F508del and, from 2007, for 12 CFTR mutations (p.F508del, p.G551D, p.G542X, p.N1303K, c.1585- 1G>A, p.I507del, p.R560T, p.W1282X, p.V520F, c.489+1G>T, p.R553X, c.3718-2477C>T). Login to comment

PMID: 22020151 [PubMed] Amato F et al: "Extensive molecular analysis of patients bearing CFTR-related disorders."

No. Sentence Comment

69 Allele Frequency and CFTR Mutations in Patients Bearing CFTR-RDs Mutation (traditional name) HGVS nomenclature15 CBAVD (118 alleles)* RP (42 alleles)* DB (38 alleles)* Total (198 alleles)* TG12-T5-470V 34 (28.8) 2 (4.8) 10 (26.3) 46 (23.2) F508del c.1521_1523del 19 (16.1) 7 (16.7) 4 (10.5) 30 (15.2) 3195del6 c.3063_3069del 9 (7.6) 0 0 9 (4.5) N1303K c.3909CϾG 3 (2.5) 1 (2.4) 4 (10.5) 8 (4.0) G542X c.1624GϾT 4 (3.4) 1 (2.4) 1 (2.6) 6 (3.0) D1152H c.3454GϾC 1 (0.8) 2 (4.8) 2 (5.3) 5 (2.5) G85E c.254GϾA 2 (1.7) 3 (7.1) 0 5 (2.5) 1525-1delG c.1394de 3 (2.5) 1 (2.4) 0 4 (3.0) 4016insT c.3885insT 2 (1.7) 1 (2.4) 0 3 (1.5) 2789ϩ5GϾA c.2657ϩ5GϾA 0 3 (7.1) 0 3 (1.5) Q1476X c.4426CϾT 3 (2.5) 0 0 3 (1.5) 2183AAϾG c.2051_2052delinsG 1 (0.8) 1 (2.4) 0 2 (1.0) R553X c.1657CϾT 1 (0.8) 1 (2.4) 0 2 (1.0) L568F c.1704GϾT 2 (1.7) 0 0 2 (1.0) R1158X c.3472CϾT 2 (1.7) 0 0 2 (1.0) V920M c.2758GϾA 1 (0.8) 0 1 (2.6) 2 (1.0) 711ϩ1GϾT c.579ϩ1GϾT 0 1 (2.4) 0 1 (0.5) D614G c.1841AϾG 1 (0.8) 0 0 1 (0.5) 2184insA c.2052del 0 1 (2.4) 0 1 (0.5) 621ϩ1GϾT c.489ϩ1GϾT 1 (0.8) 0 0 1 (0.5) R1438W c.4312CϾT 0 1 (2.4) 0 1 (0.5) E193X c.577GϾT 0 1 (2.4) 0 1 (0.5) G1244E c.3731GϾA 1 (0.8) 0 0 1 (0.5) K68E c.202AϾG 1 (0.8) 0 0 1 (0.5) R347P c.1040GϾC 1 (0.8) 0 0 1 (0.5) 621ϩ3AϾG c.489ϩ3AϾG 1 (0.8) 0 0 1 (0.5) L997F c.2991GϾC 0 1 (2.4) 0 1 (0.5) F508C c.1523TϾG 1 (0.8) 0 0 1 (0.5) Total 94 (79.7) 28 (66.7) 22 (57.9) 144 (72.7) Undetected 24 (20.3) 14 (33.3) 16 (42.1) 54 (27.3) *Data are given as number (percentage). Login to comment
86 Six mutations were present in Ͼ2.0% of chromosomes (namely, 3195del6, N1303K, G542X, D1152H, 1525-1delG, and G85E). Login to comment

PMID: 23082198 [PubMed] Sousa M et al: "Measurements of CFTR-Mediated Cl(-) Secretion in Human Rectal Biopsies Constitute a Robust Biomarker for Cystic Fibrosis Diagnosis and Prognosis."

No. Sentence Comment

64 CFTR Genotyping Following screening of the 6 most common CFTR-disease causing mutations in the region of Campinas (Brazil) [27-29]: F508del, G551D, G542X, R1162X, N1303K, R553X, an extended CFTR mutation search (see Methods S1) was performed when only one/none mutation was found (Table S2, with both traditional and standard nomenclatures [30]). Login to comment
103 As to the 5 individuals showing inconclusive Ussing chamber measurements, one individual had one CF-disease causing mutation (G542X) and two individuals had RD- related mutations (V562I and G576A). Login to comment
105 Functional classification of rarer mutations also results from these analyses, namely (Table S1): 3120+1G.A as class I (2 siblings with 3120+1G.A/R1066C, absence of CFTR-function and severe phenotypes); 1716+18672A.G as class V (2 other siblings with F508del/1716+18672A.G, residual CFTR function 228-34%- and mild CF); I618T as class IV (in a patient with G542X/I618T, 37% CFTR function and mild disease); and L206W as class IV or CFTR-RD mutation (in a patient with F508del/L206W and the highest CFTR function 257%- and very mild disease). Login to comment

PMID: 22052729 [PubMed] Dugueperoux I et al: "Nonvisualization of fetal gallbladder increases the risk of cystic fibrosis."

No. Sentence Comment

107 The gene analysis indicated that the couple carried the F508del (c.1521_1523delCTT) and the G542X (c.1624 G > T) mutations and that the fetus was CF-affected. Login to comment

PMID: 21875427 [PubMed] Field PD et al: "CFTR mutation screening in an assisted reproductive clinic."

No. Sentence Comment

36 In total, 17 different mutations were identified in this cohort of patients presenting for infertility care, with G551D/c.1652G>A, G542X/c.1624G>T, N1303K/c.3909C>G and 621+ 1G>T/c.489+1G>T being identified at a higher rate (but not significant) than the antenatal population.4 Conversely, F508delCTT/c.1521_1523delCTT, 3849+10kbC>T/c. Login to comment
37 Table 1 A breakdown of the CFTR mutations identified in the infertile patient population, the percentage of those mutations identified, the percentage of the infertile population screened, the percentage of the same mutations identified in the antenatal population by Massie et al. and figures published by Bobadilla et al. for the corresponding CFTR mutations in a global population study 'Legacy Mutation Name` and HGVS convention nomenclature* Number of mutations identified in infertile population Percentage of mutations identified in infertile population (%) Percentage of mutations identified in antenatal population4 (%) Percentage of mutations identified in a global population5 (%) F508delCTT / c.1521_1523delCTT 185 70.9 88.89 75.48 R117H / c.350G>A 36 13.8 0.63 G551D / c.1652G>A 12 4.6 2.78 3.82 G542X / c.1624G>T 6 2.3 0.93 1.83 N1303K / c.3909C>G 4 1.5 0.93 0.95 621+1G>T / c.489+1G>T 5 1.9 0.93 0.96 I507del / c.1519-1521delATC 2 0.8 0.53 3659delC / c.3528delC 2 0.8 R1162X / c.3484C>T 1 0.4 0.20 3120+1G>A / c.2988+1G>A 1 0.4 2184-delA / c.2052delA 1 0.4 3849+10kbC>T / c.3717-2477C>T 1 0.4 4.63 2789+5G>A / c.2657+5G>A 1 0.4 0.93 R347P / c.1040G>A 1 0.4 0.16 1717-1G>A / c.1585-1G>A 1 0.4 0.81 R553X / c.1657C>T 1 0.4 S549R / c.1647T>G 1 0.4 Total CFTR mutations identified 261 Total patients screened 5600 Incidence of CF carriers at QFG 1 in 21.5 (4.66%) CF, cystic fibrosis; CFTR, CF transmembrane receptor. Login to comment

PMID: 22035343 [PubMed] Sebro R et al: "Cystic fibrosis mutations for p.F508del compound heterozygotes predict sweat chloride levels and pancreatic sufficiency."

No. Sentence Comment

64 CFTR mutation classification for compound heterozygotesa Mutations n (%) Biological classification Grantham score SIFT Q493X 3 (3) Ib - - G542X 21 (20) Ib,c,e - - R553X 4 (4) Ib,e - - Y1092X 2 (2) Ib - - R1158X 1 (1) NA - - W1282X 9 (9) Ib,e - - G85E 4 (4) IIIb 98 0.01 R117H 4 (4) IVb,c 29 0.60 R334W 1 (1) IVb 101 0.02 R347P 1 (1) IVb 103 0.05 R352Q 1 (1) NA 43 0.35 G551D 20 (19) IIIb,c 94 0.00 R560T 3 (3) IIIb 71 0.00 D1270N 1 (1) NA 23 0.01 N1303K 6 (6) IIg 94 0.00 I507del 3 (3) IId - - 394delTT 1 (1) NAc - - 621+1G>T 7 (7) Ib,f - - 711+1G>T 2 (2) Ib - - 1717-1G>A 5 (5) Ib,c,e,f - - 1898+1G>A 2 (2) NA - - 2789+5G>A 3 (3) Vb - - 3659delC 1 (1) Ib - - 3849+10kbC>T 2 (2) Vb,c,f - - 3905insT 1 (1) Ib - - NA, not applicable; SIFT, Sorting Intolerant from Tolerant. a The following mutations biological classification scores could not be verified: 1898+G-A, 394delTT, D1270N, R352Q, and R1158X. Login to comment

PMID: 21976147 [PubMed] Safinejad K et al: "The prevalence of common CFTR mutations in Iranian infertile men with non-CAVD obstructive azoospermia by using ARMS PCR techniques."

No. Sentence Comment

0 GENETICS The prevalence of common CFTR mutations in Iranian infertile men with non-CAVD obstructive azoospermia by using ARMS PCR techniques Kyumars Safinejad & Mojtaba Darbouy & Sayed Mahdi Kalantar & Sirus Zeinali & Reza Mirfakhraie & Leila Yadegar & Masoud Houshmand Received: 9 May 2011 /Accepted: 24 August 2011 /Published online: 6 October 2011 # Springer Science+Business Media, LLC 2011 Abstract Purpose To evaluate five common cystic fibrosis transmembrane conductance regulator (CFTR) mutations (ΔF508, G542X, R117H, W1282X and N1303K) in the Iranian infertile men with noncongenital absence of vas deferens (CAVD) obstructive azoospermia. Login to comment
3 Results The common CFTR mutations were found positive in 5/53)9.43%(for ΔF508 and 4/53)7.55%(for G542X mutation of all patients tested. Login to comment
34 The aim of this study was to evaluate five common CF mutations (ΔF508, G542X, R117H,W1282X, N1303K)by use of the multiplex and single ARMS system among Iranian men with non-CAVD obstructive azoospermia (including those with idiopathic epididymal or ejaculatory duct obstruction) as the first descriptive study. Login to comment
38 The diagnosis of non-CAVD obstructive azoospermia is based on the following examinations: normal semen volume; normal testicular size; presence of the vas deferens by clinical examination; normal levels of serum follicle-stimulating hormone (FSH);azoospermia; absence or low levels of fructose and presence of spermatozoa in sample extracted by percutaneous sperm aspiration(PESA).No other symptoms of CF such as chronic lung inflammation/infection, pancreatic Table 1 Allelic and Genotypic Frequencies in Iranian infertile men with non-CAVD obstructive azoospermia Mutation No. of chromosomes carry CF allele %(Allelic frequencies) Genotype No. of patients %(Genotypic frequencies) ΔF508 5/106 4.7 ΔF508/+ 5 9.43 G542X 4/106 3.77 G542X/+ 4 7.55 R117H 0/106 0 R117H/+ 0 0 W1282X 0/106 0 W1282X/+ 0 0 N1303K 0/106 0 N1303K/+ 0 0 Normal 97/106 91.5 +/+ 44 83 Total 106/106 100.00 Total 53 100.00 insufficiency and intestinal obstruction have been reported in clinical file of our patients. Login to comment
40 All DNA samples were analyzed, using the primer sequence and single and multiplex ARMS-PCR technique as described by Ferrie et al. [21], for the following mutations: ΔF508, N1303K, G542X,W1282X,R117H mutations.W1282X and R117H mutations were analyzed by single ARMS-PCR technique and ΔF508, N1303K and G542X mutations were analyzed simultaneously by multiplex ARMS-PCR technique. Login to comment
41 ARMS PCR program for ΔF508, N1303K, G542X,R117H began with a 5 min incubation at 94°C,andProceeded with 28 cycles, each containing 15 s of denaturation at 94°C,30 s of annealing at appropriate temperature and 30 s of extension at 72°C;with a 10 min incubation at 72°C completing the amplification. Login to comment
43 Results Heterozygote frequency for ΔF508 mutation has been 5/53 (%9.43) and for G542X mutation, it has been 4/53(%7.55) in all patients tested where as other common mutations (R117H, W1282X, N1303K) were not detected in our samples. Login to comment
45 In other words, frequency for ΔF508 mutation was 5/106 (%4.7) and for G542X mutation it proved 4/106(3.77) in all chromosomes tested. Login to comment
52 Among 53 patients with non-CAVD obstructive azoospermia, five were heterozygotes for ΔF508 mutation (9.43%), and four patients carried G542X mutation (7.55%) whereas other mutations (N1303K, W1282X andR117H) were not detected in our samples. Login to comment

PMID: 21843195 [PubMed] Nathan AM et al: "First study of the F508del mutation in Malaysian children diagnosed with cystic fibrosis."

No. Sentence Comment

48 Letters to the Editor Journal of Paediatrics and Child Health 47 (2011) 572-575 (c) 2011 The Authors Journal of Paediatrics and Child Health (c) 2011 Paediatrics and Child Health Division (Royal Australasian College of Physicians) Table1Summaryoftheclinicalcharacteristics,sweattestresultsandcysticfibrosistransmembraneconductanceregulatormutationstudiesofthepatientsdiagnosedwithcysticfibrosisinUniversity MalayaMedicalCenterfrom2000to2009 PatientAgeat presentation PresentingsymptomsOtherfindingsConsanguinityRaceSweatconductivity (mmol/l) KS score Mutations Rin3monthsRecurrentpneumoniaandFTTPseudo-Bartter`ssyndromeYesIndian13440†Nonedetected Nes8yearsSeverepersistentasthmaFTTNoIndian12450F508del/unknown Abd4monthsSeverepneumoniaandventilator dependent FTTYesYemeni11730F508del/F508del Ben7yearsCirrhosisoftheliverwithportal hypertension FTTUnknown(adopted)Unknown14080†Nonedetected(7T polymorphism) Sak3monthsRecurrentpneumoniaandFTTNDYesIndian11350F508del/F508del Ngan3yearsPseudo-Bartter`ssyndromeNDNoChinese13790Notdone(parentsrefused) LJH5monthsPseudo-Bartter`ssyndromeRecurrentpneumoniaNoChinese/Indonesian9465F508delnegative Josh5monthsPseudo-Bartter`ssyndromeandFTTNDNoIndian8585†Nonedetected Nur3monthsChronicdiarrhoeaandFTTPseudo-Bartter`ssyndromeNoMalay/Chinese13085‡†R553X/nonedetected Vin4monthsRecurrentpneumoniaandFTTNDNoChinese12260F508delnegative Muh5yearsPoorlycontrolledasthmaNDNoMalay10765F508delnegative Naz3monthsFTTandsteatorrhoeaRecurrentlunginfectionsand pseudo-Bartter`s NoMalay14675F508delnegative Additionalmutationsscreenedinthefourpatients:†F508del,I506/7del,G551D,G542X,R553X,R117C,R117H,621+1G>T,V520F,A455E,N1303K,3849+10kbC>T.‡R334W,R347P,A455E,S549N,R560T, 3659delC,W1282X.FTT,failuretothrive;KS,Schwachman-Kulczycki(KS)score;ND,nodata. Login to comment

PMID: 21931512 [PubMed] Polizzi A et al: "Genotype-phenotype correlation in cystic fibrosis patients bearing [H939R;H949L] allele."

No. Sentence Comment

60 The other four patients were compound heterozygotes respectively for G542X, 1259insA, G1349D, F508del and the two associated mutation in exon 15 [H939R;H949L]. Login to comment
61 The mutations G542X, 1259insA, G1349D, F508del have already been described as severe CF-asssociated mutation (Casals et al., 1993; Morral et al., 1993; Morral et al., 1994; Kerem et al., 1995; Estivill et al., 1997; Shrimpton et al., 1997; Rowntree and Harris 2003; Bompadre et al., 2007; Castellani et al., 2008). Login to comment
64 Also the G542X prevents the synthesis of full-length, normal CFTR protein due to the creation of a premature termination codon (Rich et al., 1993; Rowntree and Harris, 2003). Login to comment
66 Patients characteris* Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Mutation in trans with [H939R;H949L] R248T G542X 1259insA G1349D F508del Sex male male male male male Present age (years) 15 15 17 20 25 Age at diagnosis (years) 14 3 0 10 10 Airways colonization No SA SA SA PA, BC Age of first colonization (years) / 9 6 12 14 BMI (kg/m2 ) 21.9 17.0 15.1 17.6 17.5 FEV1 as % predicted 84.4 114.8 80.9 93.2 53.7 Sweat chloride concentration (mEq/L) 78 100 108 92 95 S-K score 100 70 60 75 40 Brasfield scorez N/A 5 11 7 21 Pancreas status PS PI PI PI PI Diagnosis CFTR-RD CF CF CF CF SA = Staphilococcus aureus, PA = Pseudomonas aeruginosa, BC = Burkholderia cepacia; N/A = not applicable; S-K = Shwachman-Kulczycki: the system is based on four parameters (general activity, physical examination, growth and nutrition and chest radiograph x-ray), and is rated as a) excellent: 86-100 b) good: 71-85, c) mild: 56-70, d) moderate: 41-55, and e) severe: < 40 (Shwachman and Kulczyzki, 1958); z scoring system from 3 "mild" to 25 "most severe" (Brett et al., 1992) after x-ray; PS/PI = Pancreatic sufficiency/insufficiency. Login to comment
71 In our study, the four patients carrying the complex allele [H939R;H949L] associated in trans with the severe mutations G542X, 1259insA, G1349D and F508del presented the classic CF phenotype. Login to comment

PMID: 19896304 [PubMed] Edelman A et al: "Twenty years after cystic fibrosis gene identification: Where are we and what are we up to?"

No. Sentence Comment

97 Our initial pilot study showed that systemic administration of gentamycin, an antibiotic known to suppress two PTCs found in CFTR (G542X and R553X) when expressed in HeLa cells, improves the clinical status of patients bearing the Y122X mutation. Login to comment

PMID: 22291775 [PubMed] Barboza MA et al: "Hypertonic saline solutions do not influence the solubility of sputum from secretor and non-secretor cystic fibrosis patients."

No. Sentence Comment

27 Seven patients had the ΔF508 mutation and one had the G542X mutation in the CFTR gene. Login to comment

PMID: 23056764 [PubMed] Dooki MR et al: "Detecting Common CFTR Mutations by Reverse Dot Blot Hybridization Method in Cystic Fibrosis First Report from Northern Iran."

No. Sentence Comment

8 deltaF508, N1303K, G542X, R347H and W1282X using Reverse Dot Blot method. Login to comment
22 Only four (p.G542X, p.N1303K, p.G551D and p.W1282X) have overall frequencies higher than 1%[5]. Login to comment
23 Intriguingly, p.G542X and p.N1303K are found on the same haplotype background as ∆F508, suggesting that they arose in the same population[6]. Login to comment
27 We selected five mutations, deltaF508, N1303K, G542X, R347H and W1282X based on previous reports in Iran and neighboring countries. Login to comment
67 Table 1: Human cystic fibrosis transconductance regulator probes CFTR probe sequenceLocation in the CFTR geneProbe name 5'-NH2-GAAACACCAAAGATGATA-3'Exon10∆F508-N 5'-NH2-GGAAACACCAATGATATT-3'Exon10∆F508-MUT 5'-NH2-TATAGTTCTTGGAGAAGGTG3'Exon11G542X-N 5'-NH2-TATAGTTCTTTGAGAAGGTG-3'Exon11G542X-MUT 5'-NH2-GCTTTCCTCCACTGTTG-3'Exon20W1282X-N 5'-NH2-CAACAGTGAAGGAAAGC-3'Exon20W1282X-MUT 5'-NH2-AGAAAAAACTTGGATCC-3'Exon21N1303K-N 5'-NH2-GGGATCCAACTTTTTTCT-3'Exon21N1303K-MUT 5'-NH2-AATTGTTCTGCGCATGG-3'Exon7R347H-N 5'-NH2-CATTGTTCTGCCCATGGC-3'Exon7R347H-MUT Table 2: Human cystic fibrosis transmembrane conductance regulator primers Cystic fibrosis primer sequence Exon amplified Cystic fibrosis primer name Cystic fibrosis mutation tested 5'-Biotin-AGACCATGCTCAGATCTTCCAT-3' 5'-Biotin-GCAAAGTTCATTAGAACTGATC-3' 7 CF7-F CF7-R R347P 5'-Biotin-GCAGAGTACCTGAAACAGGA-3' 5'-Biotin-CATTCACAGTAGCTTACCCA-3' 10 CF10-F CF10-R ∆F508 5'-Biotin-CAACTGTGGTTAAAGCAATAGTGT-3' 5'-Biotin-GCACAGATTCTGAGTAACCATAAT-3' 11 CF11-F CF11-R G542X 5'-Biotin-TGGGCCTCTTGGGAAGAACT-3' 5'-Biotin-CTCACCTGTGGTATCACTCC-3' 20 CF20-F CF20-R W1282X 5'-Biotin-GGTAAGTACATGGGTGTTTC-3' 5'-Biotin-CAAAAGTACCCTGTTGCTCCA-3' 21 CF21-F CF21-R N1303K Genotype Analysis: Mutation screening of the CFTR gene in 60 alleles by reverse dot blot hybridization for five common mutations showed that 13 (21.6%) alleles were ∆F508. Login to comment
69 The other four mutations tested (N1303K, G542X, R 347H and W1282X) were not encountered in these patients. Login to comment
80 The other four mutations tested: N1303K, G542X, R347H and W1282X, were not found in these patients. Login to comment
88 Specifically, the four most common Turkish mutations were found in Iran, including ∆F508, c.1677delTA, p.G542X, and c.2183AA>G. Login to comment
89 The "Mediterranean mutation", p.G542X, is reported to be of Phoenician origin[7-9,29,31]. Login to comment
98 Consequently, it is believed that the incidence of cystic fibrosis is also similarly high, and that the low incidence commonly believed to be associated cystic fibrosis is also similarly high, and that the Table 5: Comparison of the frequency of common CFTR mutations ∆F508, N1303K, G542X, R347H , W1282X in Europe and North Africa with Iran and some neighboring countries Region or Country Mutation Type Reference ∆F508 W1282X N1303K G542X R347H Europe and N Africa 66.8 1 1.6 2.6 0.8-3.6 6 Turkey 24.5-27 ND 2.9-3.7 2.6-4.9 3-3.6 6, 23, 25 Saudi Arabia 13 ND 2 ND ND 27, 28 India 19-27 ND ND ND ND 24, 26 Iran 16-17.8 0-4 4.3-5.5 1.6-3.6 1.6-3.6 7, 8, 9 Mazandaran 21.6 0 0 0 0 Present study ND: Not detected low incidence commonly believed to be associated with this non-European population is likely to be due to under-diagnosis. Login to comment
139 Jalalirad M, Houshmand M, Mirfakhraie R, et al. First study of CF mutations in the CFTR gene of Iranian patients: detection of DeltaF508, G542X, W1282X, A120T, R117H, and R347H mutations. Login to comment
219 Loirat F, Hazout S, Lucotte G. G542X as a probable Phoenician cystic fibrosis mutation. Login to comment
140 Jalalirad M, Houshmand M, Mirfakhraie R, et al. First study of CF mutations in the CFTR gene of Iranian patients: detection of DeltaF508, G542X, W1282X, A120T, R117H, and R347H mutations. Login to comment
222 Loirat F, Hazout S, Lucotte G. G542X as a probable Phoenician cystic fibrosis mutation. Login to comment

PMID: 22156145 [PubMed] Peleg L et al: "The D1152H cystic fibrosis mutation in prenatal carrier screening, patients and prenatal diagnosis."

No. Sentence Comment

180 of mutations Group of mutations 2001 Ashkenazi Jews 7 Group A Non-Ashkenazi Jews 11 Group A þ B Georgian Jews 12 Group A þ B þ T360K/Q359K 9.2004-7.2005 Yemenite Jews 12 Groups A þ B þ I1234V Iraqi Jews 12 Groups A þ B þY1092X 8.2005-12.2007 Iraqi Jews 14 Groups A þ B þY1092X þ 3121-1G-A 1.2008-2010 14 mutations for all 14 Groups A þ B þ C Georgian Jews 15 Groups A þ B þ C þ T360K/Q359K Arabic population 19 Groups A þ B þ C þ D Group A: G542X, W1282X, N1303K, F508del, 3849 þ 10KbC-T, 1717-1G-A, D1152H Group B: W1089X, G85E, 405 þ 1G-A, S549R(T-G) Group C: Y1092X, 3121-1G-A, I1234V Group D: 4010delTATT, S549I, 3120 þ 1Kbdel18.6Kb, 2183AA-G, R75X Between 2005-2008 the Iraqi population was screened for an additional mutation 2751 þ 1insT. Login to comment

PMID: 21909392 [PubMed] Roth EK et al: "The K+ channel opener 1-EBIO potentiates residual function of mutant CFTR in rectal biopsies from cystic fibrosis patients."

No. Sentence Comment

46 CFabsent CFresidual CFTR genotype Number of individuals CFTR genotype Number of individuals F508del/F508del 10 F508del/Y161C 1 F508del/W57X 1 F508del/V232D 1 F508del/G85E 3 F508del/R334W 2 F508del/120del23 1 F508del/T338I 1 F508del/182delT 1 F508del/I1234V 1 F508del/G542X 1 F508del/3272-26 A.G 1 F508del/A561E 1 F508del/3849+10 kb C.T 1 F508del/Y1092X 1 F508del/4005 +5727 A.G 1 F508del/N1303K 1 F508del/G576A 1 F508del/1525-1 G.A 2 N1303K/R334W 1 F508del/Q39X 1 F1052V/M1137R 1 F508del/Q552X 1 1898+3 A.G/ 1898+3 A.G 1 G85E/G85E 1 R334W/3199del6 1 Q552X/R1162X 1 R334W/X 1 A561E/A561E 2 dele2,3/X 1 R764X/1717-1 G.A 1 R1158X/2183AA.G 1 R1158X/R560T 1 doi:10.1371/journal.pone.0024445.t001 luminal and basolateral surfaces of the epithelium were perfused continuously with a solution of the following composition (mmol/ L): NaCl 145, KH2PO4 0.4, K2HPO4 1.6, D-glucose 5, MgCl2 1, Ca-gluconate 1.3, pH 7.4, at 37uC. Login to comment
203 Du M, Liu X, Welch EM, Hirawat S, Peltz SW, et al. (2008) PTC124 is an orally bioavailable compound that promotes suppression of the human CFTR- G542X nonsense allele in a CF mouse model. Login to comment

PMID: 21966101 [PubMed] Prasad R et al: "Molecular basis of cystic fibrosis disease: an Indian perspective."

No. Sentence Comment

106 G542X, second most common mutation (5%) in Hispanic Caucasians [42], was not found in our population. Login to comment

PMID: 22439061 [PubMed] Mesoraca A et al: "The use of DHPLC (Denaturing High Performance Liquid Chromatography) in II level screening of the CFTR gene in Prenatal Diagnosis."

No. Sentence Comment

100 48 Journal of Prenatal Medicine 2010; 4 (3): 45-50 Table III Mutations found with II level screening through DHPLC Mutations of mutated alleles DF508 29 W1282X 3 N1303K 8 1717-1G®A 2 3659delC 1 G85E 1 2789 +5G®A 2 R553X 2 R1162X 1 R117H 1 G542X 3 Total 53Table I Mutations found through I level screeningMutations analysed with I level screening through OLA CFTR Mutations Position on the CFTR gene DF508 Exon 10 3849+10KbC®T Intron 19 R334W Exon 7 W1282X Exon 10 V520F Exon 10 3905insT Exon 20 N1303K Exon 21 3876delA Exon 20 1717-1G®A Exon 11 3659delC Exon 19 DI507 Exon 10 A455E Exon 9 G85E Exon 3 2789 +5G®A Exon 14 / Intron 14 2183AA®G Exon 13 1898+1G®A Exon 12 / Intron 12 R347P Exon 7 R347H Exon 7 R560T Exon 11 1078delT Exon 7 R553X Exon 11 711+1G®T Exon 5 / Intron 5 G551D Exon 11 R1162X Exon 19 S549R Exon 11 R117H Exon 4 S549N Exon 11 621+1G®T Exon 4 G542X Exon 11 394delTT Exon 3 3120+1G®ðA Exon 16/ Intron 16 2184delA Exon 13 Table II Mutations found through I level screening Mutations Positions on CFTR gene R1066C Exon 17 b L1065P Exon 17 b A1006E Exon 19 R75Q Exon 3 D537E Exon 11 W1134X Exon 18 W1145X Exon 18 L1077P Exon 17b C524X Exon 11 Total 9 The use of DHPLC (Denaturing High Performance Liquid Chromatography) in II level screening of the CFTR gene in Prenatal Diagnosis Journal of Prenatal Medicine 2010; 4 (3): 45-50 49 tion was to provide the couple with adequate counselling in order to better understand the genotype-phenotype correlation in the various associations of mutations. Login to comment

PMID: 19615439 [PubMed] Davidson H et al: "An immunocytochemical assay to detect human CFTR expression following gene transfer."

No. Sentence Comment

162 TwotransfectedCF samples (1DF508/G542X,11585-1G>A/P67L) and three transfected non-CF samples were negative for plasmid-expressed CFTR. Login to comment
165 TwotransfectedCF samples (1DF508/G542X,11585-1G>A/P67L) and three transfected non-CF samples were negative for plasmid-expressed CFTR. Login to comment

PMID: 19909502 [PubMed] Kraemer R et al: "Long-term gas exchange characteristics as markers of deterioration in patients with cystic fibrosis."

No. Sentence Comment

84 According to the frequencies in our Table 1: Patient cohort (A), data base characteristics (B), and distribution of CFTR mutations (C) taken from the Bernese CF Registry (n = 178, 87.3% of a total number of 204 CF patients) A Patient cohort follow-up statistics Gender distribution of patients Blood gas tests within age periods n % - males 88 49.4 5 to 8 y 427/1457 29,3% - females 90 50.6 9 to 14 y 527/1457 36.2% 178 100 15 to 18 y 503/1457 34.5% From entire database, 26 patients (12.7%) excluded because of insufficient number of tests, (6) or age < 6 years (20) B Blood gas test and lung function measurement follow-up statistics Number of blood gas tests median (range) Blood gas tests per year of observation Total of tests 1457 1987 to 1993 326/1457 22.4% per child 8.1 (3-15) 1994 to 2000 539/1457 37.0% per year of observation 68.2 (37-90) 2001 to 2008 592/1457 40.6% C Distribution of CFTR mutations n % Inframe/inframe (F508del[2]) a 103 57.9 Inframe/nonsense b 22 12.4 Frameshift/F508del c 19 10.7 Frameshift/non-F508del d 12 6.7 Inframe/splicesite e 7 3.9 Miscellaneous f 15 8.4 Total 178 100.0 Equal distribution of CFTR genotypes over age range and over years of observation CFTR: cystic fibrosis transmembrane regulator population-specific CFTR genotype distribution, the patients were stratified into 6 groups consisting of (a) F508del homozygotes F508del[2| (inframe/inframe): n = 103 (57.9%), (b) R553X, G542X, Q525X and E585X compound heterozygotes with F508del (inframe/nonsense mutations): n = 22, (12.4%), (c) 3905insT compound heterozygotes 3905insT/F508del (frameshift/F508del): n = 19, (10.7%), (d) 3905insT compound heterozygotes with other than F508del (frameshift/non-F508del): n = 12, (6.7%), (e) 1717-1G>A, 621+1G<T and 4005+1G>A compound heterozygotes with F508del (inframe/splicesite): n = 7 (3.9%), and (f) miscellaneous genotypes n = 15, (8.4%). Login to comment
103 frequent CFTR genotypes inframe/inframe (F508del[2]), inframe/nonsense mutations (F508del/R553X, F508del/ G542X, F508del/Q524, F508del/E553), inframe/ frameshift (mainly F508del/3905insT), non-F508del/ frameshift, (mainly non-F508del/3905insT) and inframe/ splicesite genotypes were incorporated as fixed effects with "age at time of annual test" as covariate, and the patient-specific intercept as a random effect. Login to comment

PMID: 19457724 [PubMed] Moya-Quiles MR et al: "CFTR H609R mutation in Ecuadorian patients with cystic fibrosis."

No. Sentence Comment

14 There are two other reports of mutations on the CFTR gene in CF patients from Ecuador; in the first, the estimated Ecuadorian CF incidence was 1:11,252 and mutations were, in order of frequency, F508del (37.1%), G85E (8.9%), G542X (2.4%), N1303K (2.4%), G551D (1.6%) and R334W (0.8%), with a detection rate of 53.22% of the total CF chromosomes studied [7]. Login to comment
15 In the second report, a compilation of data from CFTR gene analysis in Latin American CF patients, four mutations were found: F508del (31.37%), G542X (1.96%), G85E (1.96%) and N1303K (1.96%), with 63.7% of Ecuadorian CF mutations remaining unidentified [6]. Login to comment
13 There are two other reports of mutations on the CFTR gene in CF patients from Ecuador; in the first, the estimated Ecuadorian CF incidence was 1:11,252 and mutations were, in order of frequency, F508del (37.1%), G85E (8.9%), G542X (2.4%), N1303K (2.4%), G551D (1.6%) and R334W (0.8%), with a detection rate of 53.22% of the total CF chromosomes studied [7]. Login to comment

PMID: 19318035 [PubMed] Seia M et al: "Borderline sweat test: Utility and limits of genetic analysis for the diagnosis of cystic fibrosis."

No. Sentence Comment

59 In order to evaluate the relationship between the presence of CFTR mutation and sweat chloride concentration, we focused our attention on the 91 individuals (11.8%) in whom borderline sweat chloride values (31-59 mEq/l) were recorded (mean sweat electrolyte value was 40.0 mEq/l): 25 refused to be referred to the local Table 2 Demographic and clinical features of subjects with positive DNA analysis Patient Initials Gender Age at test years/ months Sweat chloride mEq/l Clinical indication DNA results IRT Right arm Left arm 1 CA M 49y5m 34 34 CBAVD G542X/5T-TG12 ND 2 SA M 45y2m 45 43 Pancreatitis F508del/R117H-7T ND 3 PD F 43y7m 33 38 Recurrent bronchitis F508del/5T-TG12 ND 4 CA M 36y1m 31 29 CBAVD R117H-7T/R117C-7T ND 5 SC M 36y1m 33 40 Pneumonia F508del/D1152H ND 6 MG M 25Y5m 41 45 CBAVD Q552X/D1152H NEG 7 SG M 18y5m 49 54 Pancreatitis 4016insT/dupl.prom.-3 ND 8 LS F 10y4m 41 38 Pancreatitis D1152H/L997F NEG 9 CM M 8y3m 30 31 Pneumonia F1052V/A120T NEG 10 PT M 7y3m 41 39 Positive screening F508del/Y1032C POS 11 ME F 7y1m 44 44 Positive screening 2789+5GNA/5T-TG12 POS 12 PM F 6y4m 35 36 Positive screening 2183AANG/5T-TG12 POS 13 BM F 6y3m 36 39 Positive screening F508del/5T-TG12 POS 14 CD M 5y8m 40 41 Chronic bronchitis 5T-TG12/5T-TG12 NEG 15 CG F 4y5m 33 37 Recurrent bronchitis R553X/L997F POS 16 CS F 3y8m 53 58 Family history G542X/D614G POS 17 VA M 4y2m 49 43 Pneumonia E831X/5T-TG12 ND 18 SC M 3y4m 39 39 Positive screening R352Q/G213E POS 19 CC F 2y3m 31 31 Positive screening F508del/5T-TG12 POS 20 CA F 2y5m 51 52 Recurrent bronchitis E831X/5T-TG12 ND 21 MR F 3y+7m 29 31 Family history G542X/5T-TG12 POS 22 CM F 2y3m 60 58 Pneumonia T338I/L997F POS 23 LM F 2y1m 50 52 Positive screening F508del/E1473X POS 24 CGE F 0y8m 46 47 Positive screening E92K/5T-TG13 POS 25 NF M 0y7m 32 30 Positive screening F508del/P5L POS 26 RG M 0y7m 45 40 Positive screening N1303K/P5L POS 27 PE M 47y4m 60 58 Nasal polyposis R1066H/UN ND 28 LS M 39y9m 39 38 Azoospermy N1303K/UN ND 29 TM M 38y4m 40 45 Azoospermy N1303K/UN ND 30 DF M 34y2m 52 58 Bronchiectasis 3849+10 kbCNT/UN ND 31 TV F 30y5m 35 34 Recurrent bronchitis L997F/UN ND 32 FA F 18y7m 53 49 Family history Del es.2/UN NEG 33 DG M 17y8m 43 47 Recurrent bronchitis 5T-TG12/UN NEG 34 LN F 13y7m 54 53 Nasal poliposis, malnutrition R74W-V855I/UN NEG 35 FKT M 15y4m 54 53 Chronic bronchitis R352Q/UN NEG 36 BM M 10y9m 48 51 Chronic bronchitis T1263I/UN NEG 37 SV F 11y1m 60 58 Chronic bronchitis R347H/UN NEG 38 CV F 10y10m 38 39 Recurrent bronchitis 5T-TG12/UN NEG 39 BF F 9y10m 37 38 Chronic bronchitis L997F/UN NEG 40 CA M 8y2m 33 32 Pneumonia F508del/UN NEG 41 RX F 8y7m 29 31 Chronic bronchitis V920L/UN NEG 42 MG F 4y3m 51 51 Positive screening F508del/UN POS Sweat chloride concentration and mutations/variants detected are also reported. Login to comment
98 This represents the most frequent variant in borderline subjects according to literature [4], followed by F508del (7.69%), G542X (2.31%) and N1303K (2.31%) that are the most common mutations in Caucasian population. Login to comment
57 In order to evaluate the relationship between the presence of CFTR mutation and sweat chloride concentration, we focused our attention on the 91 individuals (11.8%) in whom borderline sweat chloride values (31-59 mEq/l) were recorded (mean sweat electrolyte value was 40.0 mEq/l): 25 refused to be referred to the local Table 2 Demographic and clinical features of subjects with positive DNA analysis Patient Initials Gender Age at test years/ months Sweat chloride mEq/l Clinical indication DNA results IRT Right arm Left arm 1 CA M 49y5m 34 34 CBAVD G542X/5T-TG12 ND 2 SA M 45y2m 45 43 Pancreatitis F508del/R117H-7T ND 3 PD F 43y7m 33 38 Recurrent bronchitis F508del/5T-TG12 ND 4 CA M 36y1m 31 29 CBAVD R117H-7T/R117C-7T ND 5 SC M 36y1m 33 40 Pneumonia F508del/D1152H ND 6 MG M 25Y5m 41 45 CBAVD Q552X/D1152H NEG 7 SG M 18y5m 49 54 Pancreatitis 4016insT/dupl.prom.-3 ND 8 LS F 10y4m 41 38 Pancreatitis D1152H/L997F NEG 9 CM M 8y3m 30 31 Pneumonia F1052V/A120T NEG 10 PT M 7y3m 41 39 Positive screening F508del/Y1032C POS 11 ME F 7y1m 44 44 Positive screening 2789+5GNA/5T-TG12 POS 12 PM F 6y4m 35 36 Positive screening 2183AANG/5T-TG12 POS 13 BM F 6y3m 36 39 Positive screening F508del/5T-TG12 POS 14 CD M 5y8m 40 41 Chronic bronchitis 5T-TG12/5T-TG12 NEG 15 CG F 4y5m 33 37 Recurrent bronchitis R553X/L997F POS 16 CS F 3y8m 53 58 Family history G542X/D614G POS 17 VA M 4y2m 49 43 Pneumonia E831X/5T-TG12 ND 18 SC M 3y4m 39 39 Positive screening R352Q/G213E POS 19 CC F 2y3m 31 31 Positive screening F508del/5T-TG12 POS 20 CA F 2y5m 51 52 Recurrent bronchitis E831X/5T-TG12 ND 21 MR F 3y+7m 29 31 Family history G542X/5T-TG12 POS 22 CM F 2y3m 60 58 Pneumonia T338I/L997F POS 23 LM F 2y1m 50 52 Positive screening F508del/E1473X POS 24 CGE F 0y8m 46 47 Positive screening E92K/5T-TG13 POS 25 NF M 0y7m 32 30 Positive screening F508del/P5L POS 26 RG M 0y7m 45 40 Positive screening N1303K/P5L POS 27 PE M 47y4m 60 58 Nasal polyposis R1066H/UN ND 28 LS M 39y9m 39 38 Azoospermy N1303K/UN ND 29 TM M 38y4m 40 45 Azoospermy N1303K/UN ND 30 DF M 34y2m 52 58 Bronchiectasis 3849+10 kbCNT/UN ND 31 TV F 30y5m 35 34 Recurrent bronchitis L997F/UN ND 32 FA F 18y7m 53 49 Family history Del es.2/UN NEG 33 DG M 17y8m 43 47 Recurrent bronchitis 5T-TG12/UN NEG 34 LN F 13y7m 54 53 Nasal poliposis, malnutrition R74W-V855I/UN NEG 35 FKT M 15y4m 54 53 Chronic bronchitis R352Q/UN NEG 36 BM M 10y9m 48 51 Chronic bronchitis T1263I/UN NEG 37 SV F 11y1m 60 58 Chronic bronchitis R347H/UN NEG 38 CV F 10y10m 38 39 Recurrent bronchitis 5T-TG12/UN NEG 39 BF F 9y10m 37 38 Chronic bronchitis L997F/UN NEG 40 CA M 8y2m 33 32 Pneumonia F508del/UN NEG 41 RX F 8y7m 29 31 Chronic bronchitis V920L/UN NEG 42 MG F 4y3m 51 51 Positive screening F508del/UN POS Sweat chloride concentration and mutations/variants detected are also reported. Login to comment
96 This represents the most frequent variant in borderline subjects according to literature [4], followed by F508del (7.69%), G542X (2.31%) and N1303K (2.31%) that are the most common mutations in Caucasian population. Login to comment

PMID: 18938114 [PubMed] Collazo T et al: "Common mutations in Cuban cystic fibrosis patients."

No. Sentence Comment

2 In this study, we have analyzed seven common CF mutations (p.F508del, p.G542X, p.R1162X, p.N1303K, p.R334W, p.R553X and c.3120+1G>A) taking into account the ethnic origin of the Cuban population which is mainly influenced by Spanish and sub-Sahara African contribution. Login to comment
25 Seven CF mutations were analyzed: p.F508del, p.G542X, p.R1162X, p.N1303K, p.R334W, p.R553X, c.3120+ 1G>A in all patients. Login to comment
26 Amplification Refractory of Mutations Specific (ARMS) [6] was carried out to detect four mutations: p.F508del, p.G542X, p.R1162X, p.N1303K. Login to comment
36 Concerning the frequency of p.G542X mutation (6.8%), a high prevalence of this mutation has also been reported in Mexico (6.2%) [14] and Costa Rica (25%) [18], strongly suggesting the Spanish influence in all cases. Login to comment

PMID: 18992954 [PubMed] Henckaerts L et al: "Cystic fibrosis transmembrane conductance regulator gene polymorphisms in patients with primary sclerosing cholangitis."

No. Sentence Comment

91 There was Table 4 Summary of the 37 CFTR variants studied in the exploratory phase INNO-LiPA CFTR 19 INNO-LiPA CFTR17+Tn Update F508del 621+1GfiT G542X 3849+10kbCfiT N1303K 2183AAfiG W1282X 394delTT G551D 2789+5GfiA 1717-1GfiA R1162X R553X 3659delC CFTRdele2,3(21kb) R117H I507del R334W 711+1GfiT R347P 3272-26AfiG G85E 3905insT 1078delT R560T A455E 1898+1GfiA 2143delT S1251N E60X I148T 2184delA 3199del6 711+5GfiA 3120+1GfiA Tn Q552X Fig. 1. Login to comment

PMID: 18831980 [PubMed] Li L et al: "Increased SULT1E1 activity in HepG2 hepatocytes decreases growth hormone stimulation of STAT5b phosphorylation."

No. Sentence Comment

349 [24] Du M, Jones JR, Lanier J, Keeling KM, Lindsey JR, Tousson A, et al. Aminoglycoside suppression of a premature stop mutation in a Cftr-/- mouse carrying a human CFTR-G542X transgene. Login to comment
354 Aminoglycoside suppression of a premature stop mutation in a Cftr-/- mouse carrying a human CFTR-G542X transgene. Login to comment

PMID: 18499536 [PubMed] Visca A et al: "Improvement in clinical markers in CF patients using a reduced glutathione regimen: an uncontrolled, observational study."

No. Sentence Comment

43 65 64 71 28.5 28 30 9 5 6 PA PA none 3, F, 19 DF508/G1244E 47 48 55 43 43 48 3 3 9 PA b PAb PA 4, M, 5 DF508/R347P NA NA NA 17 17.5 19 33 33 40 SA SA none 5, M, 24 W1282G/G542X 60 58 70 51 51.5 57 3 3 7 BC BC BC 6, F, 14 3659delC/? Login to comment
64 15.1 15.3 1 0 36 30 3, F, 19 DF508/G1244E 16.3 18.3 0 0 9 18 4, M, 5 DF508/R347P 14.7 15.4 0 1 11 11 5, M, 24 W1282G/G542X 17.8 19.7 1 0 16 20 6, F, 14 3659delC/? Login to comment

PMID: 18467194 [PubMed] Frentescu L et al: "The study of cystic fibrosis transmembrane conductance regulator gene mutations in a group of patients from Romania."

No. Sentence Comment

5 Other frequent mutations noted are: G542X (3.9%), W1282X (2.3%), and CFTRdele2,3(21 kb)(1.6%); the remaining mutations have frequencies below 1%. Login to comment
35 Nine patients were tested for 13 mutations [F508del, 1677delTA, I507del, R117H, R553X, 621+ 1GNT, R334W, R347P, G55D, G542X, W1282X, N1303K, CFTR dele2,3(21 kb)] in the Department of Human Genomics, Institute for Molecular Biology and Genetics, National Academy of Science, Kiev, Ukraine (Table 1). Login to comment
39 The following 117 samples were analyzed in DCMB, for a variable number of common mutations between 3 and 26, starting with F508del, I507del and 1677delTA, and continuing with the commercial kits CF-3 (G542X, W1282X and N1303K), CF-8 [F508del, I507del, 1677delTA, CFTRdele2,3 (21 kb), 2143delT, 2184insA, 394delTT, 3821delT], both produced by the Research Center for Medical Genetics, Moscow, Russia, and Elucigene CF20. Login to comment
47 For other Table 1 PCR primers and references for the analysis of 13 common mutations in the CFTR gene Mutation Name of primers Restriction enzyme Reference R334W 7F MspI [10] R347P 7R Hin6I R117H 4A Hin6I [11] 621+1GNT 4B HincII N1303K N1303F DdeI [12] N1303R W1282X W1182F MnlI [13] W1282R [14] G551D 11i5 HincII [15] R553X 11i3 Sau3A G542X 11ex3` MvaI [11] G542X F508del CF2 [3] I507del CF3 [16] 1677delTA C16B [17] C16D [18] [19] CFTRdele2,3(21 kb) CFTRdel2,3F [20] CFTRdel2,3R [13] Control primers for exon 3: 3i-5 3i-3 common mutations, the CF-3 kit was used, and/or restriction enzyme digestions of PCR products were performed, followed by the analysis of restriction products by agarose gel electrophoresis (Table 1); alternatively, the kits from Belgium and UK mentioned above, were used for selected samples, especially for heterozygous patients with F508del and an unknown mutation. Login to comment
60 From the total number of 128 patients with CF we detected both mutations in the majority of them (77), one mutation in 30 Table 2 Distribution of CFTR gene mutations in the group of 128 patients with CF Mutation Number of chromosomes Percent of chromosomes (128 patients, 256 chromosomes) Cumulative frequency F508del 144 56.3% 56.3% G542X 10 3.9% 60.2% W1282X 6 2.3% 62.5% CFTRdele2,3(21 kb) 4 1.6% 64.1% 621+1GNT 2 0.8% 64.8% N1303K 2 0.8% 65.6% 2183AANG 2 0.8% 66.4% R1070Q 2 0.8% 67.2% 457TATNG 1 0.4% 67.6% R117H 1 0.4% 68.0% R334W 1 0.4% 68.4% R735K 1 0.4% 68.8% R785X 1 0.4% 69.1% E831X 1 0.4% 69.5% 3849+10 kb(CNT) 1 0.4% 69.9% R1162X 1 0.4% 70.3% 3272-26ANG 1 0.4% 70.7% 1677delTA 1 0.4% 71.1% 1717-2ANG 1 0.4% 71.5% E585X 1 0.4% 71.9% 2789+5GNA 1 0.4% 72.3% Unknown 71 27.7% 100.0% Total 256 100.0% Fig. 1. Login to comment
66 In the cohort of 142 relatives tested, we found 61 chromosomes with F508del, 6 with W1282X, 4 with G542X, and one of each with N1303K, CFTRdele2,3(21 kb), and 1717-2ANG. Login to comment
77 The most frequent five mutations in Europe are: F508del 66.8%; G542X 2.6%; N1303K 1.6%; G551D 1.5% and W1282X 1% [5]. Login to comment
92 Regarding the mutations detected, we noted a moderate heterogeneity with 21 mutations detected, the Table 3 Distribution of genotypes in CF patients from Romania (n=128; 256 chromosomes) Genotype Number Ethnicity F508del/F508del 46 Romanian 42 Hungarian 3 Gypsy 1 F508del/x 25 Romanian 23 Hungarian 1 Turkish-Romanian 1 F508del/G542X 8 Romanian F508del/CFTRdele2,3(21 kb) 4 Romanian 3 Hungarian 1 F508del/W1282X 3 Romanian F508del/F508del/R117H 1 Romanian F508del/R334W 1 Romanian F508del/621+1GNT 1 Romanian F508del/N1303K 1 Romanian F508del/2183AANG 1 Romanian F508del/3849+10 kb(CNT) 1 Romanian F508del/3272-26ANG 1 Romanian F508del/R1162X 1 Romanian F508del/R785X 1 Romanian F508del/1717-2ANG 1 Romanian F508del/2789+5GNA 1 Romanian G542X/G542X 1 Romanian W1282X/W1282X 1 Romanian N1303K/457TATNG 1 Romanian 621+1GNT/2183AANG 1 Romanian W1282X/x 1 Romanian R1070Q/E585X 1 Romanian R1070Q/x 1 Romanian E831X/x 1 Gypsy R735K/x 1 Romanian 1677delTA/x 1 Romanian x/x 21 Romanian 18 Hungarian 2 Gypsy 1 presence of common mutations (excepting the Celtic mutation G551D), and a similarity with the mutations detected in Italy, France and Spain [5]. Login to comment

PMID: 18243066 [PubMed] Ratbi I et al: "Cystic fibrosis carrier frequency and estimated prevalence of the disease in Morocco."

No. Sentence Comment

27 We screened for 32 CFTR gene mutations (G85E, 394delTT, R117H, 621+1GNT, 711+1GNT, R334W, R347P, R347H, 1078delT, A455E, I507del, F508del, V520F, 1717-1GNA, G542X, G551D, R553X, R560T, S549R(TNG), S549N, 1898+1GNA, 2183AANG, 2184delA, 2789+5GNA, 3120 + 1G NA, R1162X, 3659delC, 3849 + 10kbC NT, W1282X, 3905insT, 3876delA, N1303K) and the (T)5 splicing variant of intron 8, using a commercial kit (CF v3 Genotyping Assay, Abbott, Rungis, France). Login to comment
64 Beside F508del, other frequent mutations were found among North African populations, in particular 711+1GNT, W1282X, N1303K, G542X and R1162X [1,4,6]. Login to comment

PMID: 18687795 [PubMed] Audrezet MP et al: "Validation of high-resolution DNA melting analysis for mutation scanning of the cystic fibrosis transmembrane conductance regulator (CFTR) gene."

No. Sentence Comment

51 Sequences of the Primers Used for CFTR Analysis by HRM, GC Size, Amplicon Length, Number of Positive Controls Validated for Each Exon, and Positive Controls for Routine Analysis Exon Primer Sequences GC length Amplicon length (bp) Introns Number of heterozygous- positive controls Number of homozygous- positive controls Recommended control 1 LSCFE1Fmod 5Ј-CCGCCGCCGTTGAGCGGCAGGCACC-3Ј 8 200 bp 74 4 125GϾC LSCFE1Rmod 5Ј-CCGCCGCCGGCACGTGTCTTT CCGAAGCT-3Ј 8 19 M1I 2 2i5b 5Ј-CAAATCTGTATGGAGACC-3Ј 0 194 bp 39 5 R31C 2i3Љ 5Ј-CAACTAAACAATGTACATGAAC-3Ј 0 4 296ϩ1GϾT 3 LSCFe3Fmod LSCFe3Rmod 5Ј-CGCCGTTAAGGGAAATAGGACAA CTAAAATA-3Ј 5 276 bp 44 10 2 R75Q 5Ј-CCGCCGATTCACCAGATTTCGTAGTC-3Ј 6 66 G85V 4 LSCFe4FmodC 5Ј-CCGCCGCCGCCCGTGTTGAAATT CTCAGGGT-3Ј 12 361 bp 52 14 1 R117H LSCFe4RmodC 5Ј-CCGCCGCCCACATGTACGATAC AGAATATATGTGCC-3Ј 9 26 574delA 5 LSCFE5Fmod 5Ј-CCGCCGGTTGAAATTATCTAACTTTCC-3Ј 6 201 bp 13 8 624delT LSCFE5Rmod 5Ј-CCGAACTCCGCCTTTCCAGTTGT-3Ј 3 48 711ϩ1GϾT 6a LSCF6aFmod2 5Ј-CCGCCGGGGTGGAAGAT ACAATGACACCTG-3Ј 5 317 bp 25 8 C225X LSCF6aRmod2 5Ј-CCGCCGCCGCGATGCATAGAG CAGTCCTGGTT-3Ј 11 66 L206W 6b LSCFE6bFmod 5Ј-CGCGCCGCCGGATTTAC AGAGATCAGAGAG-3Ј 10 239 bp 0 2 1 R258G LSCFE6Brmod 5Ј-CCGCCGCCGAGGTGGA GTCTACCATGA-3Ј 8 66 1001ϩ11CϾT 7 LSCFE7Fmod2 5Ј-CCGCCGCCCTCTCCCTGAATTT TATTGTTATTGTTT-3Ј 13 326 bp 7 11 1078delT LSCFE7Rmod2 5Ј-CCCGCCGCCCTATAATGCAG CATTATGGT-3Ј 10 7 1248ϩ1GϾT 8 LSCFE8Fmod 5Ј-CCGGAATGCATTAATGCTAT TCTGATTC-3Ј 4 199 bp 32 7 W401X LSCFE8Rmod 5Ј-CCCGCAGTTAGGTGTTTAG AGCAAACAA-3Ј 4 18 1249-5AϾG 9 LSCFe9Fmod2 5Ј-CCGCCGCCGGGAATTATTTGAGAA AGCAAAACA-3Ј 8 279 bp 0 3 D443Y LSCFe9Rmod2 5Ј-CCGCCGCGAAAATACCTTCCAG CACTACAAACTAGAAA-3Ј 8 57 A455E 10 LSCF10FmodD 5Ј-CGCCGTTATGGGAGAACTGG AGCCTTCAGAG-3Ј 5 275 bp 0 15 1 F508del LSCF10RmodD 5Ј-CCGCAGACTAACCGATTGAAT ATGGAGCC-3Ј 4 68 E528E 11 h11i5 5Ј-TGCCTTTCAAATTCAGATTGAGC-3Ј 0 197 bp 42 13 2 G542X 11i3ter 5Ј-ACAGCAAATGCTTGCTAGACC-3Ј 0 17 G551D 12 LSCFE12Fmod 5Ј-CGCGTCATCTACACTAGATGACCAG-3Ј 4 244 bp 43 15 G576A 1898 ϩ 1GϾALSCFE12Rmod 5Ј-CCGGAGGTAAAATGCAATCTATGATG-3Ј 3 63 13 LSCF13AFmod 5Ј-CCGCCGCCGGAGACATATTG CAATAAAGTAT-3Ј 9 38 20 I601F LSCF13ARmod 5Ј-GCCTGTCCAGGAGACAGGA GCATCTC-3Ј 2 R668C LSCF13BFmod 5Ј-CCGCCGCAATCCTAACTGAG ACCTTACACCG-3Ј 2 R668C LSCF13BRmod 5Ј-CCGCCGATCAGGTTCAGGA CAGACTGC-3Ј 3 346 bp 2184insA LSCF13CFmod 5Ј-CCGCGGTGATCAGCACTGGCCC-3Ј 6 301 bp 77 L749L LSCF13CRmod 5Ј-CCGCGCGCGCGGCCAGTTTCTTG AGATAACCTTCT-3Ј 13 259 bp V754M LSCF13DFmod 5Ј-CGTGTCACTGGCCCCTCAGGC-3Ј 1 221 bp I807M LSCF13DRmof 5Ј-CCGCCGCCGCTAATCCTATGA TTTTAGTAAAT-3Ј 9 220 bp 2622ϩ1GϾA LSCf13FFmod 5Ј-CGCGGTGCAGAAAGAAGAAAT TCAATCCTAACTG-3Ј 4 R668C LSCF13FRmod 5Ј-CCGCCGTGCCATTCATTTGT AAGGGAGTCT-3Ј 6 2184insA 14a LSCF14aFmodB 5Ј-CCGACCACAATGGTGGCAT GAAACTG-3Ј 3 239 bp 35 7 1 T854T LSCF14aRmodB 5Ј-CCGCCGACTTTAAATCCAGTAAT ACTTTACAATAGAACA-3Ј 6 7 W846X 14b LSCF14bFmod 5Ј-CCGGAGGAATAGGTGAAGAT-3Ј 2 179 bp 38 4 2752-5GϾT LSCF14bRmodb 5Ј-CCGTACATACAAACATAGTGGATT-3Ј 3 59 2789ϩ5GϾT 15 LSCFE15Fmod 5Ј-CGCGCCGTGTATTGGAAA TTCAGTAAGTAACTTTGG-3Ј 7 412 bp 33 16 T908S LSCFE15Rmod 5Ј-CCGCAGCCAGCACTGCCAT TAGAAA-3Ј 4 68 S945L (table continues) phisms that we have chosen to exclude. Login to comment
75 In addition to heterozygous variants, 10 homozygote samples carrying F508del, 394delT, R117H, G542X, S549R, 4016inT homozygous mutations, and R75Q, T854T, 1001ϩ11 CϾT, and Q1463Q homozygous variants, were also tested. Login to comment
76 Only mutations 394delT, R117H, G542X, 4016insT, and variants R75Q and 1001ϩ11 CϾ T provided positive results (Figure 5). Login to comment
115 Some homozygous variants detected: 394delT in exon 3, 1001ϩ11CϾT in exon 6b, G542X in exon 11, and 4016insT in exon 21. already been successfully applied to the analysis of TP53,22 phenylalanine hydroxylase gene,23 factor VIII,24 factor II, factor V, HFE,11,25,26 C-kit,27 EGFR HER2,28 RET,29 and CFTR.30 In this last study, the authors report the CFTR scanning by HRM after PCR amplification of 37 exon/intron fragments in 2 panels of 96 random white UK blood donors and 30 blinded DNA samples enriched for CF-causing variants. Login to comment
171 Results of CFTR Analysis by HRM on 136 Samples of Patients with Idiopathic Chronic Pancreatitis (ICP) Exon Number of positive samples Mutations identified Variants identified New positive controls 1 14 14 125GϾC 2 1 1 R31C 3 9 1 G85E 7 R75Q 1 R74W 4 4 1 R117G 1 I148T R117G 1 R117H 1 A120T 5 1 1 L188P L188P 6a 5 1 V201M 1 A221A A221A 3 875ϩ40 AϾG 6b 27 1 M284T 26 1001ϩ11CϾT M284T 7 1 1 L320V L320V 8 0 0 9 1 1 D443Y 10 16 8 F508del 8 E528E 11 1 1 G542X 12 6 4 G576A 1 Y577Y L568F 1 L568F 13 7 1 S737F 4 R668C S737F 1 V754M L644L 1 L644L 14a 53 52 T854T T854TϩI853I 1 T854TϩI853I 14b 0 0 15 3 1 L967S T908S 1 T908S 1 S945L 16 0 0 17a 10 7 L997F 1 3271ϩ18CϾT 3271 ϩ 3AϾG 1 3271 ϩ 3 AϾG 1 Y1014C 17b 3 1 L1096L L1096L 1 H1054DϩG1069R 1 3272-33AϾG H1054DϩG1069R 3272-33AϾG 18 2 1 D1152H E1124del 1 E1124del 19 5 5 S1235R poly 20 7 1 W1282X 5 P1290P 1 D1270N 21 2 1 N1303K 1 T1299T 22 0 0 23 1 0 4374ϩ13 AϾG 24 43 40 Q1463Q 2 Y1424Y 1 Q1463QϩY1024Y ing domain of a gene brings an excellent sensitivity for heterozygote detection that is very close to 100%. Login to comment

PMID: 18722008 [PubMed] Kerem E et al: "Effectiveness of PTC124 treatment of cystic fibrosis caused by nonsense mutations: a prospective phase II trial."

No. Sentence Comment

38 §Based on normative data for age, sex, and height.15 Table 1: Baseline characteristics Allele 1 Allele 2 Stop codon Total Treatment response* Change to normal range†; G542X ΔF508 UGA 3 3 (100%) 3 (100%) G542X W1282X UGA/UGA 1 0 1 (100%) G542X N1303K UGA 1 1 (100%) 1 (100%) W1282X ΔF508 UGA 13 10 (77%) 9 (69%) W1282X W1282X UGA/UGA 3 1 (33%) 1 (33%) W1282X 3849+10kB C→T‡ UGA/UAA 1 1 (100%) 1 (100%) 3849+10kB C→T‡ ΔF508 UAA 1 1 (100%) 1 (100%) Data are n or n (%). Login to comment
86 The predominant premature stop mutations in these 23 patients were W1282X and G542X (table 2). Login to comment
94 Table 3 also shows that the proportion of patients who had normal chloride transport (predefined as nasal PD at least as electrically negative as -5 mV) increased during PTC124 treatment (first cycle p=0·0003, second cycle p=0·020).14 Results showed that participants who had all three genotypes for premature stop mutations (G542X, W1282X, and 3849+10 kB C→T), including patients who had a nonsense mutation in a single CFTR allele or in both CFTR alleles, had a total chloride transport response or normalisation during at least one cycle of PTC124 treatment (table 2). Login to comment
104 In the two patients whose only nonsense mutation was G542X, total chloride transport became more electrically negative than -5 mV (ie, within the normal range) although in both patients the proportion of CFTR mRNA that contained a nonsense mutation was less than 10% of wild-type CFTR mRNA. Login to comment
141 We did not include cystic fibrosis patients who did not have a CFTR nonsense mutation (eg, ΔF508 homozygous) on the basis that safety data for PTC124 in these patients were not sufficient at the beginning of the G542X only W1282X only 3849+10KB 3849+10KB+W1282X G542x+W1282X r=0·57 R2 =0·32 p=0·046 0 -20·0 -17·5 -15·0 -12·5 -10·0 -7·5 -5·0 -2·5 0·0 10 20 30 40 50 Proportion of CFTR mRNA with a nonsense mutation relative to wild-type mRNA (%) Typical range for patients with cystic fibrosis* Normal range* Nonsense mutation NasalPD(mV) Figure 4: Correlation of most normal nasal potential difference (PD) during treatment in either cycle with proportion of CFTR mRNA that contained a nonsense mutation relative to wild-type MRNA CFTR=cystic fibrosis transmembrane conductance regulator. mRNA=messenger RNA. Login to comment
156 In two patients who had only the G542X mutation, total chloride transport changed to within the normal range although the proportion of their CFTR mRNA that contained a nonsense mutation was less than 10% of 65 60 55 50 45 40 35 30 25 20 15 10 5 0 60 50 55 45 40 35 30 25 20 15 10 5 0 80 85 90 95 100 75 70 65 80 85 90 95 100 75 70 65 60 50 55 45 p=0·037 p=0·350 p=0·027 p=0·212 p=0·448 p=0·015p<0·0001 p=0·625 40 35 30 25 20 15 10 5 0 0 1000 Bodyweight Time (days) Treatment phase 1* Treatment phase 2* Treatment phase 1* Treatment phase 2* Weight(kg) AbsoluteneutrophilcountpermLProportionofpredictednormalvalue(%) Proportionofpredictednormalvalue(%) 0 14 28 42 Time (days) 0 14 28 42 FEV1 FVC Absolute neutrophil count 2000 3000 4000 5000 6000 7000 Figure 5: Mean clinical measurements at baseline and end of each treatment phase FEV1=forced expiratory volume in 1 second. FVC=forced vital capacity. Login to comment
163 In this regard, preclinical work with PTC124 shows that ribosomal read-through of UGA-G (the sequence of G542X) is more efficient than that for UGA-A (the sequence of W1282X).8 Treatment with PTC124 was associated with small increases in FEV₁, FVC, and bodyweight in most patients, and with a reduction in neutrophil counts. Login to comment

PMID: 18456578 [PubMed] Castellani C et al: "Consensus on the use and interpretation of cystic fibrosis mutation analysis in clinical practice."

No. Sentence Comment

1236 Table 1 Geographical distribution of the most common mutations E60X Southern European S549N Indian CFTR Slavic - Eastern European G551D United Kingdom, Central Europe R75X Southern European, US-Hispanic Q552X Southern European, Italian 394delTT Nordic - Baltic sea region R553X Central European G85E Southern Europe A559T African-American 406-1GNA US-Hispanic R560T Northern Irish R117H European-derived populations 1811+1.6kbANG Spanish, US-Hispanic R117C Northern European 1898+1GNA United Kingdom, Central Europe 621+1GNT Southern European 1898+5GNT East Asian populations 711+1GNT French, French Canadian 2143delT Slavic - Eastern European 711+5GNA US-Hispanic 2183delAANG Southern Europe, Middle Eastern, Iranian, Latin American L206W Spanish and US-Hispanic 2184delA European-derived populations V232D Spanish and US-Hispanic 2789+5GNA European-derived populations 1078delT French Brittany Q890X Southern European R334W Southern European, Latin American 3120+1GNA African, Arabian, African-American, Southern Europe 1161delC Indian 3272-26ANG European-derived populations R347P European-derived, Latin America 3659delC Scandinavian R347H Turkish 3849+10kbCNT Ashkenazi-Jewish, Southern European, Middle Eastern, Iranian, Indian A455E Dutch R1066C Southern European 1609delCA Spanish, US-Hispanic Y1092X (CNA) Southern European I506T Southern European, Spanish M1101K US-Hutterite I507del European-derived populations 3905insT Swiss F508del European-derived populations D1152H European-derived populations 1677delTA Southern European, Middle Eastern R1158X Southern European 1717-GNA European-derived populations R1162X Italian, Amerindian, Latin America V520F Irish S1251N European-derived populations G542X Southern European, Mediterranean W1282X Ashkenazi-Jewish, Middle Eastern S549R(TNG) Middle Eastern N1303K Southern European, Middle Eastern Legend: these alleles occur with a frequency superior to 0.1% in selected populations. Login to comment
1239 Table 1 Geographical distribution of the most common mutations E60X Southern European S549N Indian CFTR Slavic - Eastern European G551D United Kingdom, Central Europe R75X Southern European, US-Hispanic Q552X Southern European, Italian 394delTT Nordic - Baltic sea region R553X Central European G85E Southern Europe A559T African-American 406-1GNA US-Hispanic R560T Northern Irish R117H European-derived populations 1811+1.6kbANG Spanish, US-Hispanic R117C Northern European 1898+1GNA United Kingdom, Central Europe 621+1GNT Southern European 1898+5GNT East Asian populations 711+1GNT French, French Canadian 2143delT Slavic - Eastern European 711+5GNA US-Hispanic 2183delAANG Southern Europe, Middle Eastern, Iranian, Latin American L206W Spanish and US-Hispanic 2184delA European-derived populations V232D Spanish and US-Hispanic 2789+5GNA European-derived populations 1078delT French Brittany Q890X Southern European R334W Southern European, Latin American 3120+1GNA African, Arabian, African-American, Southern Europe 1161delC Indian 3272-26ANG European-derived populations R347P European-derived, Latin America 3659delC Scandinavian R347H Turkish 3849+10kbCNT Ashkenazi-Jewish, Southern European, Middle Eastern, Iranian, Indian A455E Dutch R1066C Southern European 1609delCA Spanish, US-Hispanic Y1092X (CNA) Southern European I506T Southern European, Spanish M1101K US-Hutterite I507del European-derived populations 3905insT Swiss F508del European-derived populations D1152H European-derived populations 1677delTA Southern European, Middle Eastern R1158X Southern European 1717-GNA European-derived populations R1162X Italian, Amerindian, Latin America V520F Irish S1251N European-derived populations G542X Southern European, Mediterranean W1282X Ashkenazi-Jewish, Middle Eastern S549R(TNG) Middle Eastern N1303K Southern European, Middle Eastern Legend: these alleles occur with a frequency superior to 0.1% in selected populations. Login to comment

PMID: 18249184 [PubMed] Socher E et al: "FIT probes: peptide nucleic acid probes with a fluorescent base surrogate enable real-time DNA quantification and single nucleotide polymorphism discovery."

No. Sentence Comment

51 Human genomic DNA samples containing the G542X and the G551D mutations were obtained from the Coriell Institute for Medical Research and stored in H2O at a concentration of 100 ng/ll at À80 °C. Login to comment
177 In a paradigm study, we explored the usefulness of FIT probes by addressing the two most common cystic fibrosis single base mutations: G542X and G551D. Login to comment
192 For reasons of comparison, we chose to analyze the G542X mutation site by applying the well-established dual-labeled probe technology [20]. Login to comment
291 The analysis of two important single nucleotide polymorphisms in the CFTR gene, the G542X and G551D mutations, confirmed the ability of Orn(TO) FIT probes to make unambiguous SNP calls for genomic DNA by qPCR. Login to comment
52 Human genomic DNA samples containing the G542X and the G551D mutations were obtained from the Coriell Institute for Medical Research and stored in H2O at a concentration of 100 ng/ll at 80 &#b0;C. Login to comment
178 In a paradigm study, we explored the usefulness of FIT probes by addressing the two most common cystic fibrosis single base mutations: G542X and G551D. Login to comment
193 For reasons of comparison, we chose to analyze the G542X mutation site by applying the well-established dual-labeled probe technology [20]. Login to comment
292 The analysis of two important single nucleotide polymorphisms in the CFTR gene, the G542X and G551D mutations, confirmed the ability of Orn(TO) FIT probes to make unambiguous SNP calls for genomic DNA by qPCR. Login to comment

PMID: 17825628 [PubMed] Fichou Y et al: "Estimating the age of CFTR mutations predominantly found in Brittany (Western France)."

No. Sentence Comment

16 Only four additional mutations (i.e., G542X, G551D, Journal of Cystic Fibrosis 7 (2008) 168-173 www.elsevier.com/locate/jcf ☆ Data were presented at The American Society of Human Genetics 56th Annual Meeting, New Orleans, Louisiana, USA, October 9-13, 2006. Login to comment
30 Likewise, the G542X and N1303K mutations were estimated to be N34000 years old [14]. Login to comment
51 Primers amplifying the regions of interest were designed with PrimerQuestSM from Table 1 Genotypes of CF patients W846X2 1078delT G551D Mutation in trans Number Mutation in trans Number Mutation in trans Number ΔF508 6 ΔF508 21 ΔF508 18 R117C 1 1078delTa 2 E60K 1 ΔI507 1 4005+1GNA 2 W79X 1 Y563N 1 L610S 1 C225X 1 1078delTb 1 W846X2 b 1 F311L 1 621+1GNT 1 R1066H 1 R347H 1 2789+5GNA 1 1221delCT 1 G542X 1 3849+4ANG 1 1717-1GNA 1 G551D 1 3659delC 1 R553G 1 S942F 1 Y1092X 1 621+1GNT 1 2789+5GNA 1 4006-1GNA 1 Unidentified 1 Total 13 Total 31 Total 32 a One particular case: in this individual, the two chromosomes 7 are identical by descent. Login to comment

PMID: 17662673 [PubMed] Alibakhshi R et al: "Analysis of the CFTR gene in Iranian cystic fibrosis patients: identification of eight novel mutations."

No. Sentence Comment

8 The most common mutations were p.F508del (ΔF508) (18.1%), c.2183_2184delAAinsG (2183AANG) (6.5%), p.S466X (5.8%), p.N1303K (4.3%), c.2789+5GNA (4.3%), p.G542X (3.6%), c.3120+1GNA (3.6%), p.R334W (2.9%) and c.3130delA (2.9%). Login to comment
27 A few mutations, such as p.F508del, p.N1303K and p.G542X, are frequent worldwide. Login to comment
37 1 c.406-3TNC I3 T to C at 406-3 mRNA splicing defect 1 p.R170H E5 G to A at 641 Arg to His at 170 1 p.D192G E5 A to G at 707 Asp to Gly at 192 2 p.R334W E7 C to T at 1132 Arg to Trp at 334 4 c.1525-1GNA I9 G to A at 1525-1 mRNA splicing defect 2 p.F508del E10 Deletion of CTT from 1653 Deletion of Phe at 508 25 p.S466X E10 C to G at 1529 Ser to stop at 466 8 c.1677delTA E10 Deletion of TA from 1677 Frame shift 2 p.G542X E11 G to T at 1756 Gly to stop at 542 5 p.S549R E11 T to G at 1779 Ser to Arg at 549 2 p.A566D E12 C to A at 1829 Ala to Asp at 566 2 c.1898+1GNT I12 G→T at 1898+1 mRNA splicing defect 2 c.2183_2184delAAinsG E13 A to G at 2183 and deletion of A at 2184 Frame shift 9 c.2576delA E13 Deletion of A at 2576 Frame shift 1 c.2043delG E13 Deletion of A at 2043 Frame shift 1 c.2184insA E13 Insertion of A after 2184 Frame shift 1 p.R785X E13 C to T at 2485 Arg to stop at 785 2 c.2752-1_2756delGGTGGCinsTTG I14a/ Deletion of GGTGGC mRNA splicing defect 2 E14b From 2752-1 to 2756 and insertion TTG c.2789+5GNA I14b G to A at 2789+5 mRNA splicing defect 6 p.S945L E15 C to Tat 2966 Ser to Leu at 945 2 c.3120+1GNA I16 G to A at 3120+1 mRNA splicing defect 5 c.3121-1GNA I16 G to A at 3121-1 mRNA splicing defect 2 c.3130delA E17a Deletion of A at 3130 Frame shift 4 p.T1036I E17a C to T at 3239 Thr to Ile at 1036 1 p.R1066C E17b C to T at 3328 Arg to Cys at 1066 1 p.L1077P E17b T to C at 3362 Leu to Pro at 1077 1 p.T1086I E17b C to T at 3389 Thr to Ile at 1086 1 p.R1162X E19 C to T at 3616 Arg to stop at 1162 2 p.K1177X E19 A to T at 3361 Lys to stop at 1177 2 c.3850-24GNA I19 G to A at 3850-24 mRNA splicing defect? Login to comment
50 Mutations were detected as follows: In a first phase, all subjects were analyzed with an amplification refractory mutation system assay (ARMS-PCR), as described by Ferrie et al. [20], detecting the following mutations: p.F508del, p.N1303K, p.G542X, c.1717-1GNA, p.R553X, p.W1282X, p.G551D, c.621+1GNT, c.I507del and p.R560T. Login to comment
66 Results A total of 69 unrelated CF patients (38 male and 31 female; aged between 2 months and 15 years) of Iranian Table 2 Genotype of CFTR genes in 53 Iranian patients Genotype Exon/intron Number of patients p.F508del/p.F508del E10/E10 10 p.F508del/p.R1162X E10/E19 2 p.F508del/p.T1036I E10/E17a 1 p.F508del/p.R1066C E10/E17b 1 p.F508del/c.1342-?_1524+?del E10/E9 1 p.S466X/p.S466X E10/E10 4 c.2183_2184delAAinsG/ c.2183_2184delAAinsG E13/E13 4 c.2183_2184delAAinsG/c.186- ?_296+?del E13/E2 1 p.N1303K/p.N1303K E21/E21 2 p.N1303K/p.S945L E21/E15 1 p.N1303K/c.1677delTA E21/E10 1 p.G542X/p.G542X E11/E11 2 p.G542X/c.2789+5GNA E11/I14b 1 c.3120+1GNA/c.3120+1GNA I16/I16 2 c.3120+1GNA/c.3121-1GNA I16 1 c.3121-1GNA/p.T1086I I16/E17b 1 c.3130delA/c.3130delA E17a/E17a 2 p.D192G/p.D192G E5/E5 1 p.R334W/p.R334W E7/E7 1 p.R334W/p.S945L E7/E15 1 p.R334W/p.L1077P E7/E17b 1 c.1525-1GNA/c.1525-1GNA I9/I9 1 p.S549R/p.S549R E11/E11 1 p.A566D/p.A566D E12/E12 1 c.1898+1GNT/c.1898+1GNT I12/I12 1 c.2576delA/p.S1455X/ E13/E24 1 c.2184insA/c.1677delTA E10/E13 1 p.R785X/p.R785X E13/E13 1 c.2752-1_2756delGGTGGCinsTTG/ c.2752-1_2756delGGTGGCinsTTG I14a/E14b 1 c.2789+5GNA/c.2789+5GNA I14b/I14b 1 p.K1177X/p.K1177X E19/E19 1 c.406-?_1716+?del/c.406-?_1716+?del E4-E10/E4-E10 1 Total 53 origin were extensively studied for the presence of mutations in the CFTR gene, for the presence of the deep intronic 3849+10 kbC→T mutation, and large deletions/ duplications. Login to comment
67 Screening of the samples for ten mutations with an ARMS-PCR assay only revealed the identification of three mutations: p.F508del was found in 25 (18.1%) alleles, p.N1303K in six (4.3%) alleles, and p.G542X in five (3.6%) alleles (Table 1), the remainder mutations in the CFTR coding region, and its exon/intron junctions, were found by sequencing and the MLPA assay, which are given in Table 1. Login to comment
90 Eight other mutations were found with a frequency greater than 2%: c.2183_2184delAAinsG (6.5%), p.S466X (5.8%), p.N1303K (4.3%), c.2789+5GNA (4.3%), p.G542X (3.6%), c.3120+ 1GNA (3.6%), p.R334W (2.9%), and c.3130delA (2.9%). Login to comment
142 The p.G542X mutation accounts for 2.4% of the CFTR mutations worldwide [13,21]. Login to comment
144 Two patients carried p.G542X in homozygous state, of which one was consanguineous, and one was compound heterozygous with c.2789+5GNA. Login to comment
155 Possible explanations for failure to detect all mutations are: the mutations that are in intron sequences far from coding Table 3 CFTR mutation panel recommended for screening in Iranian CF patients Mutation Number of chromosomes Frequency p.F508del 25 18.1% c.2183_2184delAAinsG 9 6.5% p.S466X 8 5.8% p.N1303K 6 4.3% c.2789+5GNA 6 4.3% p.G542X 5 3.6% c.3120+1GNA 5 3.6% p.R334W 4 2.9% c.3130delA 4 2.9% Total 72 52.0% Table 4 Clinical features and some polymorphisms in 7 Iranian patients; in these patients a mutation could only be found on one CFTR gene Genotype PI/PS Sweat (Cl- ) TGm Tn (In8) GATT (In6a) 1001+11 (In6b) M470V p.K68E/U⁎ PI 80 TG10-T7_TG10-T7 GATT 7/7 C A c.406-8TNC/U PI 50 TG12-T7_TG11-T7 GATT 6/7 C A/G c.406-3TNC/U PI 90 TG11-T7_TG11-T7 GATT 7/7 C G p.R170H/U PS 80 TG11-T7_TG10-T7 GATT 7/7 C A/G c.3850-24GNA/U PI 55 TG11-T7_TG11-T7 GATT 7/7 C G c.2789+5GNA/U PI 50 TG11-T7_TG10-T7 GATT 7/7 C A/G c.2043delG/U PS 70 TG12-T7_TG10-T7 GATT 6/7 C A ⁎Unknown mutations; PS, indicates pancreatic sufficient; PI, pancreatic sufficient. Login to comment
65 Results A total of 69 unrelated CF patients (38 male and 31 female; aged between 2 months and 15 years) of Iranian Table 2 Genotype of CFTR genes in 53 Iranian patients Genotype Exon/intron Number of patients p.F508del/p.F508del E10/E10 10 p.F508del/p.R1162X E10/E19 2 p.F508del/p.T1036I E10/E17a 1 p.F508del/p.R1066C E10/E17b 1 p.F508del/c.1342-?_1524+?del E10/E9 1 p.S466X/p.S466X E10/E10 4 c.2183_2184delAAinsG/ c.2183_2184delAAinsG E13/E13 4 c.2183_2184delAAinsG/c.186- ?_296+?del E13/E2 1 p.N1303K/p.N1303K E21/E21 2 p.N1303K/p.S945L E21/E15 1 p.N1303K/c.1677delTA E21/E10 1 p.G542X/p.G542X E11/E11 2 p.G542X/c.2789+5GNA E11/I14b 1 c.3120+1GNA/c.3120+1GNA I16/I16 2 c.3120+1GNA/c.3121-1GNA I16 1 c.3121-1GNA/p.T1086I I16/E17b 1 c.3130delA/c.3130delA E17a/E17a 2 p.D192G/p.D192G E5/E5 1 p.R334W/p.R334W E7/E7 1 p.R334W/p.S945L E7/E15 1 p.R334W/p.L1077P E7/E17b 1 c.1525-1GNA/c.1525-1GNA I9/I9 1 p.S549R/p.S549R E11/E11 1 p.A566D/p.A566D E12/E12 1 c.1898+1GNT/c.1898+1GNT I12/I12 1 c.2576delA/p.S1455X/ E13/E24 1 c.2184insA/c.1677delTA E10/E13 1 p.R785X/p.R785X E13/E13 1 c.2752-1_2756delGGTGGCinsTTG/ c.2752-1_2756delGGTGGCinsTTG I14a/E14b 1 c.2789+5GNA/c.2789+5GNA I14b/I14b 1 p.K1177X/p.K1177X E19/E19 1 c.406-?_1716+?del/c.406-?_1716+?del E4-E10/E4-E10 1 Total 53 origin were extensively studied for the presence of mutations in the CFTR gene, for the presence of the deep intronic 3849+10 kbC࢐T mutation, and large deletions/ duplications. Login to comment
89 Eight other mutations were found with a frequency greater than 2%: c.2183_2184delAAinsG (6.5%), p.S466X (5.8%), p.N1303K (4.3%), c.2789+5GNA (4.3%), p.G542X (3.6%), c.3120+ 1GNA (3.6%), p.R334W (2.9%), and c.3130delA (2.9%). Login to comment
141 The p.G542X mutation accounts for 2.4% of the CFTR mutations worldwide [13,21]. Login to comment
143 Two patients carried p.G542X in homozygous state, of which one was consanguineous, and one was compound heterozygous with c.2789+5GNA. Login to comment
154 Possible explanations for failure to detect all mutations are: the mutations that are in intron sequences far from coding Table 3 CFTR mutation panel recommended for screening in Iranian CF patients Mutation Number of chromosomes Frequency p.F508del 25 18.1% c.2183_2184delAAinsG 9 6.5% p.S466X 8 5.8% p.N1303K 6 4.3% c.2789+5GNA 6 4.3% p.G542X 5 3.6% c.3120+1GNA 5 3.6% p.R334W 4 2.9% c.3130delA 4 2.9% Total 72 52.0% Table 4 Clinical features and some polymorphisms in 7 Iranian patients; in these patients a mutation could only be found on one CFTR gene Genotype PI/PS Sweat (Cl- ) TGm Tn (In8) GATT (In6a) 1001+11 (In6b) M470V p.K68E/UÌe; PI 80 TG10-T7_TG10-T7 GATT 7/7 C A c.406-8TNC/U PI 50 TG12-T7_TG11-T7 GATT 6/7 C A/G c.406-3TNC/U PI 90 TG11-T7_TG11-T7 GATT 7/7 C G p.R170H/U PS 80 TG11-T7_TG10-T7 GATT 7/7 C A/G c.3850-24GNA/U PI 55 TG11-T7_TG11-T7 GATT 7/7 C G c.2789+5GNA/U PI 50 TG11-T7_TG10-T7 GATT 7/7 C A/G c.2043delG/U PS 70 TG12-T7_TG10-T7 GATT 6/7 C A Ìe;Unknown mutations; PS, indicates pancreatic sufficient; PI, pancreatic sufficient. Login to comment

PMID: 17572159 [PubMed] Loumi O et al: "CFTR mutations in the Algerian population."

No. Sentence Comment

0 CFTR mutations in the Algerian population O. Loumia,⁎, C. Ferecb,⁎, B. Mercier b , J. Creff b , B. Fercot b , R. Denine c , J.P. Grangaudd a Faculté des Sciences Biologiques, Université des Sciences et de la Technologie Houari Boumediene, Bab-Ezzouar Alger, Algérie b INSERM U613, Laboratoire de Génétique Moléculaire, 46 rue Félix Le Dantec - 29200 Brest, France c Hôpital ISSAD HASANI Beni-messous, Laboratoire de Biochimie, Algérie d Faculté de Médecine, Université d`Alger, Algérie Received 22 March 2006; received in revised form 19 April 2007; accepted 24 April 2007 Available online 14 June 2007 Abstract The nature and frequency of the major CFTR mutations in the North African population remain unclear, although a small number of CFTR mutation detection studies have been done in Algeria and Tunisia, showing largely European mutations such as F508del, G542X and N1303K, albeit at different frequencies, which presumably emerged via population admixture with Caucasians. Login to comment
58 The V754M (G to A at position 2392) mutation has previously been reported to the Cystic Fibrosis Genetic Analysis Consortium by Roger Mountford and seems to confer moderate disease when it is associated either with 1812-1G→A or G542X. Login to comment
90 Table 1 CFTR mutations detected in 36 Algerian patients (N=72 CF chromosomes) Mutations Substitution nucleotide Substitution amino acid Localisation N % Cum. fr. hF508del del CTT Del phe 507/508 Exon 10 12 16.7 16.7 N1303K C→G 4041 Asn→Lys 1303 Exon 21 6 8.3 25.0 711+1G→T G→T711+1 MRNA splicing defect Intron 5 6 8.3 33.3 2183AA/G del A2184 Frameshift Exon 13 3 4.2 37.5 A→G 2183 1609delCA delCA Frameshift Exon 10 2 2.8 40.3 1812-1G→A G→A 1812-1 mRNA splicing defect Intron 11 2 2.8 43.1 V562I G→A 1816 Val→Ile 562 Exon 12 2 2.8 45.9 V754M G→A 2392 Val→Met 754 Exon 13 1 1.4 47.3 W1282X G→A 3978 Trp→Stop 1282 Exon 20 3 4.2 51.5 621+3A/Ga A→G 621+3 mRNA splicing defect Intron 4 1 1.4 52.9 4332delTGa delTG4332 Frameshift Exon 23 G542X G→T 1756 Gly→Stop 542 Exon 11 1 1.4 54.3 4271delC del A 4271 Frameshift Exon 23 1 1.4 55.7 S977F C→T 3062 Ser→Phe 97 Exon 16 1 1.4 57.1 21Kb del 21-kb del Del AA E2-E3 1 1.4 58.5 R74W C→T 352 Arg→Trp 74 Exon 3 0 0 D1270N G→A 3940 Asp→Asn 1270 Exon 20 0 0 Total 43 58.5 N=number of chromosomes; Cum. fr.=cumulative frequency. Login to comment
135 Surprisingly, none of the defined mutations (R553X, G551D, 1717-1G→A, G542X), which occur relatively frequently in exon 11 in Caucasian populations, was identified in our Algerian population except the G542X that has been identified once. Login to comment
140 The 21-kb deletion seems to confer severe disease when it is associated with the G542X mutation. Login to comment

PMID: 17560176 [PubMed] Viel M et al: "ENaCbeta and gamma genes as modifier genes in cystic fibrosis."

No. Sentence Comment

72 Twenty-one were homozygous for the Phe508del mutation and 17 were compound heterozygous or homozygous for two severe mutations (R553X:1717-1GNA, Phe508del:W1282X, Phe508del:1717-1GNA, 2 Phe508del:3659delC, Phe508del:N1303K, Phe508del:W57X, Phe508del:Q1411X, G542X:1380insT, Phe508del:R553X, Table 1 Parameters for amplification of the ENaCβ and ENaCγ gene fragments (GenBank accession number NM_000336 and NM_001039, respectively) Fragment Sequence of primers Annealing temperature (°C) ENaCβ Exon 2 2F 5' gtgtcccagctgatgtgcgt 3' 55 2R 5' tgaggccagctgtgcactcc 3' Exon 3 3F 5' acagactactatggagtggg 3' 55 3R 5' aagaaacacccatcagcctc 3' Exon 4 4F 5' gtcctgctagcagctcccac 3' 59 4R 5' caaccgtaacatgccactgt 3' Exon 5 5F 5' ctgccctgcagctgatgctg 3' 55 5R 5' ccctgcaacagctgatggtc 3' Exon 6 6F gtctcctttctgcctcagga 3' 59 6R 5' tcagaccctctaggactgcc 3' Exon 7 7F 5' aggtgcagaaagggcttcct 3' 63 7R 5' catgaggcgtgcaccaccttcccac 3' Exon 8 8F 5' ctgaccatgcctgtgttctc 3' 59 8R 5' ctctatggtcagagcctctg 3' Exon 9-10 9F 5' cagaggctcagcagggaaca 3' 63 10R 5' catcttatgcccagacttgt 3' Exon 11 11F 5' gatgctgcagatggcaactt 3' 55 11R 5' gagctgtcctgtgtccaaac 3' Exon 12 12F 5' acattagtcccggcccttct 3' 55 12R 5' ggtattgggagactcctaaa 3' Exon 13 13F 5' fgaggcaagaatgtgtggcct 3' 59 13R 5' tcttggctgctcagtgagtt 3' ENaCγ Exon 2 2F 5' agcacgcccgtcctcagagt 3' 57 2R 5' ccagtgtgtcactttcggga 3' Exon 3 3F 5' tgaggctgacacgtgttgat 3' 55 3R 5' tgcccctaagcagtgaaaga 3' Exon 4 4F 5' agtagcgataggaccgatgg 3' 55 4R 5' tcagagctgccagtccttag 3' Exon 5 5F 5' cccaacttcagctaagatgc 3' 55 5R 5' agatctccttggcacaggtt 3' Exon 6 6F 5' ttggatcacagcaggttgtc 3' 55 6R 5' gatctgttctctccaagcct 3' Exon 7 7F 5' ctgtctggtgctccttgcaa 3' 55 7R 5' ccagcttagatataactttg 3' Exon 8 8F 5' tgagcaaagacatgaatggc 3' 57 8R 5' agtgcctattgccaggacta 3' Exon 9-10-11 9F 5' tccaaagctcatgctgccct 3' 57 11R 5' acagaggaacagggtagagg 3' Exon 12 12F 5' ggatgccaaggctcttgatt 3' 52 12R 5' gccaggaagatgctcacatt 3' Exon 13 13F 5' aggttcctcttgatggtgt 3' 55 13R 5' ggtcctgactagatctgtct 3' Table 2 Parameters for dHPLC conditions Fragment Temperature (°C) ENaCβ Exon 2 62.3/63.3 Exon 3 59.5/60.7 Exon 4 62.2/63.4 Exon 5 59.5/61 Exon 6 63 Exon 7 61.6/62.6/63.6 Exon 8 62.8/64.8 Exon 9-10 61.5/62.5/65 Exon 11 61/62/63.5 Exon 12 69 Exon 13 61/63.3/64.8 ENaCγ Exon 2 60.8/63.2/66 Exon 3 61/61.4 Exon 4 60.6 Exon 5 59.5/60.5 Exon 6 56.5/59/60.5 Exon 7 63/63.6 Exon 8 59.5/63 Exon 9-10-11 60.7/61.5/62.7/64.7 Exon 12 59.5/61.7 Exon 13 61/62.2 Phe508del:I507del, Phe508del:4382delA, S549R:3120+ 1GNA, Phe508del:3120+1GNA, Y122X:Y122X; Phe508del:W846X; Phe508del:E60X). Login to comment
74 Their genotypes were: 2 G542X:3849+10kbCNT, Phe508del:3276-26ANG, Phe508del:A455E, 297-3CNT:W361R, S1251N:3849+10kbCNT, Phe508del:G178R, Phe508del:3849+10kbCNT, Phe508del:A561E, Phe508del: G1061R, 1717-1GNA:3272-26ANG, 2 Phe508del:R347P, Phe508del:G85E, L227R:L227R, R300G:3007delG, Phe508del:R347H, Phe508del:G1244E. Login to comment

PMID: 17481968 [PubMed] Storm K et al: "High incidence of the CFTR mutations 3272-26A-->G and L927P in Belgian cystic fibrosis patients, and identification of three new CFTR mutations (186-2A-->G, E588V, and 1671insTATCA)."

No. Sentence Comment

31 The Inno Lipa™ CFTR12 assay contains normal and mutant probes for 12 different CFTR mutations (ΔF508, G542X, N1303K, 1717-1G→A, W1282X, G551D, R553X, S1251N, R560T, 3905insT, Q552X, ΔI507). Login to comment
60 L927P (together with G542X and S1251N) is the fourth most common CFTR mutation, with a frequency of 2.4%. Login to comment

PMID: 16784904 [PubMed] Ciminelli BM et al: "Highly preferential association of NonF508del CF mutations with the M470 allele."

No. Sentence Comment

62 In particular, 12 Italian and the 3 Czech CF patients carried the F508del (that has been unambiguously assigned to the M allele 118/118 and 57/57 times in the present two samples, respectively, in agreement with previous reports); 1 carried the 2183AAYG (21/21); 1 carried the I507del (7/7), 1 carried the 1717- 1GYA (20/20) and 1 carried the G542X (19/19). Login to comment
121 Table 5 shows the estimated residual Table 4 CF mutations found in the 53 CF patients of the Bolzano province CF mutation Absolute and relative (%) frequencies Associated with(1) F508del 56 (52.8) M 711+5 G>A 10 (9.4) M R347P 3 (2.8) V S466X 1 (0.9) M 1717-1 G>A 1 (0.9) M G542X 1 (0.9) M G551D 2 (1.9) V 1874insT 1 (0.9) V 2183AA>G 3 (2.8) M 2789+5G>A 1 (0.9) M R1162X 24 (22.6) M N1303K 2 (1.8) M (1) Based on data of Table 1. Login to comment

PMID: 16423550 [PubMed] Ramirez AM et al: "Mutational spectrum of cystic fibrosis patients from Cordoba province and its zone of influence: implications of molecular diagnosis in Argentina."

No. Sentence Comment

16 The most frequent mutations worldwide (p.F508del, p.G542X, p.G551D, p.N1303K, and p.W1282X) have shown considerable diVerences in their frequencies depending on ethnic origin and geographic areas. Login to comment
44 Mutations (p.F508del, p.N1303K, p.G542X, p.R334W, c.2789 + 5G > A, c.3659delC, p.R553X, c.3849 + 10kbC > T, p.R1162X, c.621 + 1G > T, p.W1282X, p.R117H, c.1078delT, p.E60X, p.R347P, p.A455E, p.I507del, c.1717-1G > A, p.G551D, [c.2183A > G; c.2184delA] and p.S1251N) were analyzed by heteroduplex analysis on polyacrylamide gel electrophoresis [11,12] and by ampliWcation refractory mutation system [13] in all 78 patients. Login to comment
85 Haplotype (n D 20) No. of chromosomes (n D 64)a Mutations associated (No. of chromosomes) 23-31 14 p.F508del 17-31 7 p.F508del 17-7 7 p.R1066C (3), p.W277R, c.2789 + 5G > A, c.3120 + 1G > A, c.3849 + 10KbC > T 16-7 6 c.3272-26A > G (2), p.G27R, c.622-2A > G, unknown (2) 16-32 5 p.S589I (2), unknown (3) 16-30 3 IVS8-5T (2), unknown 23-33 2 p.G542X, p.R1283M 23-32 2 p.G542X 23-30 2 p.F508del, p.N1303K 24-31 2 p.N1303K 16-24 2 p.G85E 16-31 3 c.1898 + 1G > A, p.W1089X, unknown 16-46 2 c.1811 + 1.6KbA > G 16-25 1 c.711 + 1G > T 16-33 1 Unknown 16-44 1 c.1898 + 1G > A 16-45 1 p.Y913C 16-47 1 c.4005 + 1G > A 17-30 1 Unknown 23-7 1 [c.3199_3204delATAGTG; p.I148T] Table 2 Frequency of the mutations in the 78 CF Argentinean patients of Córdoba region a IdentiWed novel mutations. Login to comment
86 Mutation Exon/Intron CF alleles % p.F508del Exon 10 94 60.26 p.N1303K Exon 21 8 5.13 p.G542X Exon 11 7 4.49 p.R334W Exon 7 3 1.93 p.R1066C Exon 17b 3 1.93 c.2789 + 5G > A Intron 14b 3 1.93 p.G85E Exon 3 2 1.28 c.3659del C Exon 19 2 1.28 c.1811 + 1.6kbA > G Intron 11 2 1.28 c.1898 + 1G > A Intron 12 2 1.28 c.3272-26A > G Intron 17a 2 1.28 p.S589I Exon 12 2 1.28 p.R553X Exon 11 2 1.28 IVS8-5T Intron 8 2 1.28 c.3849 + 10kb C > T Intron 19 1 0.64 c.621 + 1G > T Intron 4 1 0.64 p.R1162X Exon 19 1 0.64 c.711 + 1G > T Intron 5 1 0.64 c.3120 + 1G > A Intron 16 1 0.64 p.Y913C Exon 15 1 0.64 c.4005 + 1G > A Intron 20 1 0.64 p.W1089X Exon 17b 1 0.64 p.R1283M Exon 20 1 0.64 [p.I148T;c.3199_3204del ATAGTG] Exon 4, Exon 17a 1 0.64 p.G27Ra Exon 2 1 0.64 p.W277Ra Exon 6b 1 0.64 c.622-2A > Ga Intron4 1 0.64 Unknown allele - 9 5.77 Wrst year of life he required several internments, for hydroelectric desequilibrium and persistent pulmonary infections causing failure to thrive. Login to comment
89 Fourteen mutations have a frequency higher than 1%, p.F508del (60.26%), p.N1303K (5.13%), p.G542X (4.49%), and three mutations, p.R334W, p.R1066C, c.2789 + 5G> A (1.93%), and another eight, p.G85E, c.3659delC, c.1811 + 1.6kbA > G, c.1898 + 1G > A, c.3272-26A > G, p.S589I, p.R553X, and 5T (1.28%). Login to comment
119 Other most signiWcant diVerences were that in Buenos Aires, besides the p.F508del, only Wve mutations showed frequencies higher than 1%, being their percentages the following ones: p.F508del 58.64%, p.G542X 4.1%, p.W1282X 2.73%, p.N1303K 2.73%, and the last two ones p.R334W and c.1717-1G > A with 1.14%. Login to comment
123 In addition, it is important to denote that in our series the most frequent mutations found were p.F508del, p.N1303K, p.G542X, p.R334W, p.R1066C, and c.2789+5G>A, however, the last two ones were rare in Buenos Aires series (p.R1066C, 0.23%) and others were not found (p.S589I, c.3272-26A>G, c.1898+1G>A, c.711+1G>T, c.3199_ 3204delATAGTG, p.W1089X, p.R1283M, p.Y913C, c.4005+1G>A, c.3120 +1G >A, p.G27R, p.W277R, and c.622-2A>G). Login to comment
117 Other most signiWcant diVerences were that in Buenos Aires, besides the p.F508del, only Wve mutations showed frequencies higher than 1%, being their percentages the following ones: p.F508del 58.64%, p.G542X 4.1%, p.W1282X 2.73%, p.N1303K 2.73%, and the last two ones p.R334W and c.1717-1G > A with 1.14%. Login to comment
121 In addition, it is important to denote that in our series the most frequent mutations found were p.F508del, p.N1303K, p.G542X, p.R334W, p.R1066C, and c.2789+5G>A, however, the last two ones were rare in Buenos Aires series (p.R1066C, 0.23%) and others were not found (p.S589I, c.3272-26A>G, c.1898+1G>A, c.711+1G>T, c.3199_ 3204delATAGTG, p.W1089X, p.R1283M, p.Y913C, c.4005+1G>A, c.3120 +1G >A, p.G27R, p.W277R, and c.622-2A>G). Login to comment

PMID: 16581722 [PubMed] Bertuzzo CS et al: "Molecular screening of CFTR gene in Brazilian men with bilateral agenesis of the vas deferens."

No. Sentence Comment

57 When we compared the mutations detected by the present study with those found in fibrocystic patients in our region, we verify that among fibrocystics the most frequent mutations are: DF508, G542X, G551D, R553X and N1303K (Bernardino et al., 2000; Martins et al., 1993; Raskin et al., 1999), while in the present study they were the DF508, IVS8-5T, R117H and N1303K. Login to comment

PMID: 16436643 [PubMed] Elahi E et al: "A haplotype framework for cystic fibrosis mutations in Iran."

No. Sentence Comment

32 Only four (p.G542X, p.N1303K, p.G551D, and p.W1282X) have overall frequencies greater than 1%.12 Intriguingly, p.G542X and p.N1303K are found on the same haplotype background as ⌬F508, suggesting that they arose in the same population.13 Two previous reports of CFTR mutations in Iran have been published. Login to comment
111 of Patients Total alleles* Associated haplotype Global distributionHom Het Exon 1 c.134TϾC M1T 1 1 Rare Exon 3 c.386GϾA G85E 1 1 Global Exon 4 c.460GϾC D110H 1 1 H2 Europe Exon 7 c.1132CϾT R334W 1 1 H2 Global Exon 7 c.1145CϾT T338I 1 1 Europe Intron 9 c.1525-1GϾA Mis-splicing 1 1 H8 Pakistan Exon 10 c.1529CϾG S466X 1 2 H4 Germany Exon 10 c.1531CϾT L467F 1 1 Rare Exon 10 c.1649TϾC I506T 1 2 H8 Lebanon Exon 10 c.1652del3† ⌬F508 6 7 19 H5 Global Exon 10 c.1677delTA 515fs 4 1 9 H1 Europe Exon 11 c.1756GϾT G542X 1 1 H5 Global Exon 12 c.1821CϾA Y563X 2 2 Europe Exon 13 c.2183AAϾG 684fs 3 6 H3 Europe Exon 17a c.3170CϾT P1013L 1 1 Turkey Exon 19 c.3616CϾT R1162X 2 2 H2 Germany Exon 19 c.3661AϾT K1177X 1 1 3 H2 Bahrain Intron 20 c.4005ϩ1GϾA Mis-splicing 1 2 H2 Europe Exon 21 c.4041CϾG N1303K 3 1 7 H5 Global Exon 23 c.4363CϾT Q1412X 1 1 Rare *A total of 64 (53%) of the 120 expected alleles were observed. Login to comment
175 Specifically, the four most common Turkish mutations were found in Iran, including ⌬F508, c.1677delTA, p.G542X, and c.2183AAϾG.9,29 The p.G542X "Mediterranean mutation," purported to be of Phoenician origin, was found on only one Iranian chromosome, whereas it was relatively frequent (3.6%) among the Turkish CF chromosomes.6,51 Another common mutations in Iran, p.K1177X, was not found in Turkey but was reported in Bahrain.39 In contrast, three mutations commonly found in Europe, including p.W1282X, p.G551D, and c.1717-1GϾA,12 were not found in Iran. Login to comment

PMID: 16412743 [PubMed] Schulz S et al: "Increased frequency of cystic fibrosis transmembrane conductance regulator gene mutations in infertile males."

No. Sentence Comment

45 Mutations R117H, R347P, G542X, G551D, R553X, 3849ϩ10kbCϾT, and N1303K were analyzed by PCR and restriction enzyme cleavage. Login to comment
47 Among CFTR mutations detected in the German population, F508del, R117H, R347P, G542X, G551D, R553X, 3849ϩ10kbCϾT, N1303K, and CFTR2,3dele(21kb) occur with a frequency of 72%, 1%, 1.2%, 1.2%, 0.9%, 2%, 1%, 1.8%, and 1.2%, respectively (9-11). Login to comment

PMID: 16275171 [PubMed] Braun AT et al: "Cystic fibrosis mutations and genotype-pulmonary phenotype analysis."

No. Sentence Comment

80 Thereafter, the longitudinal patterns of WCXR and BCXR for the two patients with novel mutations (i.e., G1047R and 1525-2AYG) were superimposed on the Table 1 Summary of patient characteristics Characteristics F508del homozygote group (n =38) Pancreatic sufficiency groupa (n =19) Sex Male 25 8 Female 13 11 Center Madison 21 12 Milwaukee 17 7 Group Screened 38 3 Control 0 14 Other 0 2 Meconium ileus Yes 6 0 No 32 19 Mean age at diagnosis (weeks)TS.D. 7.15T2.4 193.1T192 Mean sweat Cl mEq/lTS.D. Login to comment
81 101.0T9.5 83.5T21.2 CXR scores at diagnosis WCXR 2.48T32b 4.68T71 BCXR 21.9T0.3 21.1T.48 Pulmonary function at 8 years FEV1 (%)c 97T4 104T2 FVC (%)c 103T3 103T2 FEV1/FVC% 0.92T0.03 0.98T.01 FEF25 - 75% 99T11 104T5 a Mild pancreatic phenotype mutations include: R117H occurring with F508del (n =5) and G542X (n =1); R117C with F508del (n =2); R347P with F508del (n =1), R1066H (n =1) and 2184insA (n À1), 2789+5G>A with F508del (n =3); 3272À26A>G with F508del (n =1); 3849+10kbC>T with F508del (n =1); L138ins with 3272À26A>G (n =1); R352Q with F508del (n =1); and 1336K with F508del (n =1). Login to comment

PMID: 15890513 [PubMed] Eaker S et al: "Detection of CFTR mutations using ARMS and low-density microarrays."

No. Sentence Comment

3 Mutations within the cystic fibrosis transmembrane regulator (CFTR) gene ( F508, 1717-1G>A, G542X, 621+1G>T, and N1303K) were detected by multiplex-ARMS-PCR, and fragments were post-PCR labeled with Cy5. Login to comment
88 Each mutation on the panel ( F508, 1717-1G>A, G542X, 621+1G>T, and N1303K) was tested individually (Fig. 1), and in a multiplex reaction containing all five primer pairs (Fig. 1B, lanes 8 and 9). Login to comment
97 PCR reactions containing various DNA templates to evaluate the performance of the ARMS reaction to detect the specific mutations are listed as follows: (A2) wild-type (wt); (A3) N1303K; (A4) wt; (A5) 621+1G>T; (A7) wt; (A8) G542X; (B1) wt; (B2) F508; (B3) wt; (B4) W1282X; (B6) wt; (B7) 1717-1G>A; (B8) wt; (B9) multiplex F508 and W1282X (using F508/W1282X compound heterozygous DNA template). Login to comment
98 Table 1 Probe sequences specific for each mutation, 5 -amine-modified with C6 spacers Mutant probe Sequence 621+1G>T TTT GAT TTA TAA GAA GTT AAT ACT TCC TTG CAC AGG F508 GGC ACC ATT AAA GAA AAT ATC ATT GGT GTT TCC TA 1717-1G>A CTA TTT TTG GTA ATA AGA CAT CTC CAA GTT TGC AG G542X ATA GTT CTT TGA GAA GGT GGA ATC ACA CTG N1303K TAG AAA AAA GTT GGA TCC CTA TGA ACA GTG G W1282X TTT GCA ACA GTG AAG GAA AGC CTT T To each array/glass slide, Cy5-labeled PCR products were hybridized to each array/glass slide, and the fluorescence measured by both a commercial scanner and an inexpensive detection device designed in-house (Fig. 2). Login to comment
101 Each spot is 1 mm in diameter and contains: (1) F508; (2) 1717-1G>A; (3) N1303K; (4) 621+1G>T; (5) W1282X; (6) G542X; and (R) reference spot containing amino-linked 15-mer with a terminal Cy5 label (seen as a smear in B and E due to bleaching of the scanner. Login to comment
102 Each box represents a separate hybridization with the PCR products from ARMS reactions containing known DNA: (A) wt; (B) 1717-1G>A; (C) N1303K; (D) 621+1G>T; (E) F508; (F) G542X. Login to comment
105 After establishing a baseline fluorescence for each slide, ARMS-products from F508, 1717-1G>A, G542X, 621+1G>T, and N1303K DNA templates were hybridized, and detection on each corresponding spot was achieved, leaving the other mutant spots unbound and unlabeled. Login to comment
107 Fig. 2F shows that the ARMS product from G542X DNA bound both to the G542X probe as well as the 1717-1G>A probe. Login to comment
108 This arose due to the fact that the G542X ARMS primers overlap the 1717-1G>A region. Login to comment
109 However, the 1717-1G>A ARMS primers do not overlap the G542X sequence, and does not produce a product which binds to the G542X probe (Fig. 2B). Login to comment
121 (A) and (B) show the readings (screen shots) using slides from Fig. 2(A) N1303K and (B), G542X. Login to comment
143 Multiple spots can be displayed as well, seen in Fig. 4B using the G542X slide from Fig. 2F (reference, blue bar; 1717-1G>A, green bar; G542X, yellow bar). Login to comment
142 Multiple spots can be displayed as well, seen in Fig. 4B using the G542X slide from Fig. 2F (reference, blue bar; 1717-1G>A, green bar; G542X, yellow bar). Login to comment

PMID: 16051530 [PubMed] Kinnunen S et al: "Spectrum of mutations in CFTR in Finland: 18 years follow-up study and identification of two novel mutations."

No. Sentence Comment

6 G542X, R1162X, R117H, 3732delA, 1898+3A>C, S1196X, S945L, W57R, 774insT and S589T were each identified in a number of chromosomes from one to three. Login to comment
22 Journal of Cystic Fibrosis 4 (2005) 233 - 237 www.elsevier.com/locate/jcf Only two other mutations, G542X (c.1624G>T, p.Gly542X) and 3732delA (c.3600delA, p.Asp1201fs), were each identified in one CF chromosome out of 40. Login to comment
36 The InnoLipa assay recognizes 36 mutations: E60X (c.178G>T, p.Glu60X), G85E (c.254G>A, p.Gly85- Glu), 394delTT, R117H (c.350G>A, p.Arg117His), I148T (c.443T>C, p.Ile148Thr), 621+1G>T (c.489+1G>T), 711+1G>T (c.579+1G>T), 711+5G>A (c.579+5G>A), 1078delT (c.948delT, p.Phe316fs), R334W (c.1000C>T, p.Arg334Trp), R347P (c.1040G>C, p.Arg347Pro), A455E (c.1364C>A, p.Ala455Glu), I507del (c.1519_1521delATC, p.Ile507del), F508del, 1717À1G>A (c.1585À1G>A), G542X, G551D (c.1652G >A, p.Gly551Asp), Q552X (c.1654C > T, p.Gln552X), R553X (c.1657C > T, p.Arg553X), R560T (1679G>vC, p.Arg560Thr), 1898+ 1G > A (c.1766 + 1G > A), 2143delT (c.2012delT, p.Leu671fs), 2183AA > G (c.2051_2052delAAinsG, p.Lys684fs), 2184delA (c.2052delA, p.Lys684fs), 2789+ 5G>A (c.2657+5G>A), 3120+1G>A (c.2988+1G>A), 3199del6 (c.3067_3072del, p.Ile1023_Val1024del), 3272À 26A > G (c.3140 À26A > G), R1162X (c.3484C > T, p.Arg1162X), 3849+10kbCYT, 3659delC (c.3528delC, p.Lys1177fs), S1251N (c.3752G > A, p.Ser1251Asn), 3905insT (c.3773dupT, p.Leu1258fs), W1282X (c.3846G> A, p.Trp1282X), N1303K (c.3909C>G, p.Asn1303Lys), CFTRdele2,3(21kb) and Tn-polymorphism on intron 8. Login to comment
94 394delTT has been suggested to have a Table 1 Spectrum of CFTR mutations in Finland Mutation Recommended nomenclature/nucleotide Recommended nomenclature/protein Exon/Intron N % F508del c.1520_1522delTCT p.Phe508del E 10 37 36 394delTT c.262_263delTT p.Leu88fs E 3 36 35 CFTRdele2,3(21kb) E2 and E3 6 5.9 3659delC c.3528delC p.Lys1177fs E 19 6 5.9 1898+3A>C c.1766+3A>C I 12 3 2.9 R117H c.350G>A p.Arg117His E 4 2 2 S945L c.2834C>T p.Ser945Leu E 15 2 2 W57R c.169T>C p.Trp57Arg E 3 1 1 774insT c.642_643insT p.Ile215fs E 6a 1 1 G542X c.1624G>T p.Gly542X E 11 1 1 S589T c.1766G>C p.Ser589Thr E 12 1 1 R1162X c.3484C>T p.Arg1162X E 19 1 1 S1196X c.3587C>G p.Ser1196X E 19 1 1 3732delA c.3600delA p.Asp1201fs E 19 1 1 Unknown 2.9 Total 102 100 Reference sequence is Genbank NM_000492.2. Login to comment
109 An exception is G542X, which is one of the five mutations that have relative world frequencies higher than 1%. Login to comment
23 Journal of Cystic Fibrosis 4 (2005) 233 - 237 www.elsevier.com/locate/jcf Only two other mutations, G542X (c.1624G>T, p.Gly542X) and 3732delA (c.3600delA, p.Asp1201fs), were each identified in one CF chromosome out of 40. Login to comment
37 The InnoLipa assay recognizes 36 mutations: E60X (c.178G>T, p.Glu60X), G85E (c.254G>A, p.Gly85Glu), 394delTT, R117H (c.350G>A, p.Arg117His), I148T (c.443T>C, p.Ile148Thr), 621+1G>T (c.489+1G>T), 711+1G>T (c.579+1G>T), 711+5G>A (c.579+5G>A), 1078delT (c.948delT, p.Phe316fs), R334W (c.1000C>T, p.Arg334Trp), R347P (c.1040G>C, p.Arg347Pro), A455E (c.1364C>A, p.Ala455Glu), I507del (c.1519_1521delATC, p.Ile507del), F508del, 1717 1G>A (c.1585 1G>A), G542X, G551D (c.1652G >A, p.Gly551Asp), Q552X (c.1654C > T, p.Gln552X), R553X (c.1657C > T, p.Arg553X), R560T (1679G>vC, p.Arg560Thr), 1898+ 1G > A (c.1766 + 1G > A), 2143delT (c.2012delT, p.Leu671fs), 2183AA > G (c.2051_2052delAAinsG, p.Lys684fs), 2184delA (c.2052delA, p.Lys684fs), 2789+ 5G>A (c.2657+5G>A), 3120+1G>A (c.2988+1G>A), 3199del6 (c.3067_3072del, p.Ile1023_Val1024del), 3272 26A > G (c.3140 26A > G), R1162X (c.3484C > T, p.Arg1162X), 3849+10kbCYT, 3659delC (c.3528delC, p.Lys1177fs), S1251N (c.3752G > A, p.Ser1251Asn), 3905insT (c.3773dupT, p.Leu1258fs), W1282X (c.3846G> A, p.Trp1282X), N1303K (c.3909C>G, p.Asn1303Lys), CFTRdele2,3(21kb) and Tn-polymorphism on intron 8. Login to comment
95 394delTT has been suggested to have a Table 1 Spectrum of CFTR mutations in Finland Mutation Recommended nomenclature/nucleotide Recommended nomenclature/protein Exon/Intron N % F508del c.1520_1522delTCT p.Phe508del E 10 37 36 394delTT c.262_263delTT p.Leu88fs E 3 36 35 CFTRdele2,3(21kb) E2 and E3 6 5.9 3659delC c.3528delC p.Lys1177fs E 19 6 5.9 1898+3A>C c.1766+3A>C I 12 3 2.9 R117H c.350G>A p.Arg117His E 4 2 2 S945L c.2834C>T p.Ser945Leu E 15 2 2 W57R c.169T>C p.Trp57Arg E 3 1 1 774insT c.642_643insT p.Ile215fs E 6a 1 1 G542X c.1624G>T p.Gly542X E 11 1 1 S589T c.1766G>C p.Ser589Thr E 12 1 1 R1162X c.3484C>T p.Arg1162X E 19 1 1 S1196X c.3587C>G p.Ser1196X E 19 1 1 3732delA c.3600delA p.Asp1201fs E 19 1 1 Unknown 3 2.9 Total 102 100 Reference sequence is Genbank NM_000492.2. Login to comment
110 An exception is G542X, which is one of the five mutations that have relative world frequencies higher than 1%. Login to comment

PMID: 16182611 [PubMed] Texereau J et al: "Reduced exhaled NO is related to impaired nasal potential difference in patients with cystic fibrosis."

No. Sentence Comment

65 Amongst the patients with normal BPD values, four were homozygous for DF508, one was compound heterozygous for DF508 and two were compound heterozygous 1717-1G-A/3272-26G-A and G542X/3849+10KbC-T. Login to comment

PMID: 16378926 [PubMed] Marcus-Soekarman D et al: "Hyperechogenic fetal bowel: counseling difficulties."

No. Sentence Comment

36 Routine CFTR-mutation analysis identified the G542X CFTR-mutation in fetal DNA and DNA from the mother (results available in the 21st week of pregnancy). Login to comment
45 Compound heterozygosity for the G542X and 1677delTA mutations was subsequently demonstrated in fetal DNA confirming the diagnosis of cystic fibrosis in the fetus. Login to comment
67 Routine CFTR-mutation analysis, using Table 1 CFTR-mutations screened for in the first step E60X 2143delT G542X G85E 2183AA-G G551D 394delTT 2184delA Q552X 621 + 1G-T 2789 + 5G-A R553X R117H 3849 + 10kbC-T R560T 711 + 5G-A R1162X S1251N 1078delT 3659delC 390insT R334W delta I507 W1282X R347P delta F508 N1303K A455E 1717-1G-A a panel of 29 CFTR-mutations, detects only 41.6% of CFTR-mutations in the Turkish population [1]. Login to comment
70 The G542X mutation, initially detected in this case, is commonly found in Mediterranean populations and is present on 3.6% of the CF chromosomes in the Turkish population [1]. Login to comment

PMID: 16046196 [PubMed] Trevisiol C et al: "MBL2 polymorphisms screening in a regional Italian CF Center."

No. Sentence Comment

42 Table 4 CFTR and MBL2 genotypes CFTR genotypes MBL2 genotypes AA A0 00 Severe/Severe CFTR genotype deltaF508/deltaF508 (20) 10 8 2 deltaF508/N1303K (1) 0 1 0 deltaF508/621+1GYT (3) 2 1 0 1717-1GYA/1717-1GYA (1) 1 0 0 deltaF508/1677delTA (1) 1 0 0 G542X/G542X (1) 0 1 0 deltaF508/1717-1GYA (1) 0 1 0 Total 28 14 12 2 Mild; unknown/unknown CFTR genotype R1162X/2789+5GYA (6) 3 3 0 2183 AAYG/4016insT (4) 2 2 0 R1162X/R1162X (3) 1 2 0 DI507/2183 AAYG (4) 2 1 0 S466X/R1070Q; T (2) 2 1 0 Total 19 10 9 0 C. Trevisiol et al. / Journal of Cystic Fibrosis 4 (2005) 189-191190 0/0 CF patients (6.29 years) when compared to A/A patients (11.24; p =0.037). Login to comment

PMID: 16049310 [PubMed] Schrijver I et al: "Genotyping microarray for the detection of more than 200 CFTR mutations in ethnically diverse populations."

No. Sentence Comment

51 Complete List of Mutations Detectable with the CF APEX Assay CFTR location Amino acid change Nucleotide change 1 E 1 Frameshift 175delC 2 E 2,3 Frameshift del E2, E3 3 E 2 W19C 189 GϾT 4 E 2 Q39X 247 CϾT 5 IVS 2 Possible splicing defect 296 ϩ 12 TϾC 6 E 3 Frameshift 359insT 7 E 3 Frameshift 394delTT 8 E 3 W57X (TAG) 302GϾA 9 E 3 W57X (TGA) 303GϾA 10 E 3 E60X 310GϾT 11 E 3 P67L 332CϾT 12 E 3 R74Q 353GϾA 13 E 3 R75X 355CϾT 14 E 3 G85E 386GϾA 15 E 3 G91R 403GϾA 16 IVS 3 Splicing defect 405 ϩ 1GϾA 17 IVS 3 Possible splicing defect 405 ϩ 3AϾC 18 IVS 3 Splicing defect 406 - 1GϾA 19 E 4 E92X 406GϾT 20 E 4 E92K 406GϾA 21 E 4 Q98R 425AϾG 22 E 4 Q98P 425AϾC 23 E 4 Frameshift 444delA 24 E 4 Frameshift 457TATϾG 25 E 4 R117C 481CϾT 26 E 4 R117H 482GϾA 27 E 4 R117P 482GϾC 28 E 4 R117L 482GϾT 29 E 4 Y122X 498TϾA 30 E 4 Frameshift 574delA 31 E 4 I148T 575TϾC 32 E 4 Splicing defect 621GϾA 33 IVS 4 Splicing defect 621 ϩ 1GϾT 34 IVS 4 Splicing defect 621 ϩ 3AϾG 35 E 5 Frameshift 624delT 36 E 5 Frameshift 663delT 37 E 5 G178R 664GϾA 38 E 5 Q179K 667CϾA 39 IVS 5 Splicing defect 711 ϩ 1GϾT 40 IVS 5 Splicing defect 711 ϩ 1GϾA 41 IVS 5 Splicing defect 712 - 1GϾT 42 E 6a H199Y 727CϾT 43 E 6a P205S 745CϾT 44 E 6a L206W 749TϾG 45 E 6a Q220X 790CϾT 46 E 6b Frameshift 935delA 47 E 6b Frameshift 936delTA 48 E 6b N287Y 991AϾT 49 IVS 6b Splicing defect 1002 - 3TϾG 50 E 7 ⌬F311 3-bp del between nucleotides 1059 and 1069 51 E 7 Frameshift 1078delT 52 E 7 Frameshift 1119delA 53 E 7 G330X 1120GϾT 54 E 7 R334W 1132CϾT 55 E 7 I336K 1139TϾA 56 E 7 T338I 1145CϾT 57 E 7 Frameshift 1154insTC 58 E 7 Frameshift 1161delC 59 E 7 L346P 1169TϾC 60 E 7 R347H 1172GϾA 61 E 7 R347P 1172GϾC 62 E 7 R347L 1172GϾT 63 E 7 R352Q 1187GϾA 64 E 7 Q359K/T360K 1207CϾA and 1211CϾA 65 E 7 S364P 1222TϾC 66 E 8 Frameshift 1259insA 67 E 8 W401X (TAG) 1334GϾA 68 E 8 W401X (TGA) 1335GϾA 69 IVS 8 Splicing changes 1342 - 6 poly(T) variants 5T/7T/9T 70 IVS 8 Splicing defect 1342 - 2AϾC Table 1. Continued CFTR location Amino acid change Nucleotide change 71 E 9 A455E 1496CϾA 72 E 9 Frameshift 1504delG 73 E 10 G480C 1570GϾT 74 E 10 Q493X 1609CϾT 75 E 10 Frameshift 1609delCA 76 E 10 ⌬I507 3-bp del between nucleotides 1648 and 1653 77 E 10 ⌬F508 3-bp del between nucleotides 1652 and 1655 78 E 10 Frameshift 1677delTA 79 E 10 V520F 1690GϾT 80 E 10 C524X 1704CϾA 81 IVS 10 Possible splicing defect 1717 - 8GϾA 82 IVS 10 Splicing defect 1717 - 1GϾA 83 E 11 G542X 1756GϾT 84 E 11 G551D 1784GϾA 85 E 11 Frameshift 1784delG 86 E 11 S549R (AϾC) 1777AϾC 87 E 11 S549I 1778GϾT 88 E 11 S549N 1778GϾA 89 E 11 S549R (TϾG) 1779TϾG 90 E 11 Q552X 1786CϾT 91 E 11 R553X 1789CϾT 92 E 11 R553G 1789CϾG 93 E 11 R553Q 1790GϾA 94 E 11 L558S 1805TϾC 95 E 11 A559T 1807GϾA 96 E 11 R560T 1811GϾC 97 E 11 R560K 1811GϾA 98 IVS 11 Splicing defect 1811 ϩ 1.6 kb AϾG 99 IVS 11 Splicing defect 1812 - 1GϾA 100 E 12 Y563D 1819TϾG 101 E 12 Y563N 1819TϾA 102 E 12 Frameshift 1833delT 103 E 12 D572N 1846GϾA 104 E 12 P574H 1853CϾA 105 E 12 T582R 1877CϾG 106 E 12 E585X 1885GϾT 107 IVS 12 Splicing defect 1898 ϩ 5GϾT 108 IVS 12 Splicing defect 1898 ϩ 1GϾA 109 IVS 12 Splicing defect 1898 ϩ 1GϾC 110 IVS 12 Splicing defect 1898 ϩ 1GϾT 111 E 13 Frameshift 1924del7 112 E 13 del of 28 amino acids 1949del84 113 E 13 I618T 1985TϾC 114 E 13 Frameshift 2183AAϾG 115 E 13 Frameshift 2043delG 116 E 13 Frameshift 2055del9ϾA 117 E 13 D648V 2075TϾA 118 E 13 Frameshift 2105-2117 del13insAGAA 119 E 13 Frameshift 2108delA 120 E 13 R668C 2134CϾT 121 E 13 Frameshift 2143delT 122 E 13 Frameshift 2176insC 123 E 13 Frameshift 2184delA 124 E 13 Frameshift 2184insA 125 E 13 Q685X 2185CϾT 126 E 13 R709X 2257CϾT 127 E 13 K710X 2260AϾT 128 E 13 Frameshift 2307insA 129 E 13 V754M 2392GϾA 130 E 13 R764X 2422CϾT 131 E 14a W846X 2670GϾA 132 E 14a Frameshift 2734delGinsAT 133 E 14b Frameshift 2766del8 134 IVS 14b Splicing defect 2789 ϩ 5GϾA 135 IVS 14b Splicing defect 2790 - 2AϾG 136 E 15 Q890X 2800CϾT 137 E 15 Frameshift 2869insG 138 E 15 S945L 2966CϾT 139 E 15 Frameshift 2991del32 140 E 16 Splicing defect 3120GϾA interrogation: ACCAACATGTTTTCTTTGATCTTAC 3121-2A3G,T S; 5Ј-ACCAACATGTTTTCTTTGATCTTAC A GTTGTTATTAATTGTGATTGGAGCTATAG-3Ј; CAACAA- TAATTAACACTAACCTCGA 3121-2A3G,T AS. Login to comment
73 Genomic DNA Samples Used for Mutation Evaluation on the APEX Array Mutations validated with native DNA CFTRdel 2,3 (21 kb) 394delTT G85E R75X 574delA Y122X R117C R117H 621 ϩ 1GϾT 621 ϩ 3AϾG 711 ϩ 1GϾT I336K R334W R347P IVS8-5T IVS8-7T IVS8-9T A455E ⌬F508 ⌬I507 1677delTA 1717 - 1GϾA G542X G551D R553X R560T S549N 1898 ϩ 1GϾA 1898 ϩ 1GϾC 2183AAϾG 2043delG R668C 2143delT 2184delA 2184insA 2789 ϩ 5GϾA S945L 3120 ϩ 1GϾA I1005R 3272 - 26AϾG R1066C G1069R Y1092X (CϾA) 3500 - 2AϾT R1158X R1162X 3659delC S1235R 3849 ϩ 10 kb CϾT W1282X primer. Login to comment

PMID: 15829248 [PubMed] Lee JE et al: "Gene SNPs and mutations in clinical genetic testing: haplotype-based testing and analysis."

No. Sentence Comment

713 Several mutations of the CFTR gene, such as F508del, G542X and N1303K are associated with the severe CF phenotypes and display a high disease penetrance [23]. Login to comment
749 It was observed that the three most common disease-causing mutations, F508del, G542X and N1303K are found in a specific haplotype background (haplotype IIIa by Cuppens et al. [23]). Login to comment
712 Several mutations of the CFTR gene, such as F508del, G542X and N1303K are associated with the severe CF phenotypes and display a high disease penetrance [23]. Login to comment
748 It was observed that the three most common disease-causing mutations, F508del, G542X and N1303K are found in a specific haplotype background (haplotype IIIa by Cuppens et al. [23]). Login to comment

PMID: 15858154 [PubMed] Schrijver I et al: "Diagnostic testing by CFTR gene mutation analysis in a large group of Hispanics: novel mutations and assessment of a population-specific mutation spectrum."

No. Sentence Comment

81 G542X, which is a common allele of European origin, occurred a total of 7 times (1%), including once in homozygosity, while R334W and R553X occurred twice each. Login to comment
83 While ⌬F508 was homozygous in six subjects, seven other less common alleles (G542X, W1204X, R75X, V232D, E116K, T501A, 3272-26 AϾG) were also seen in the homozygous state. Login to comment
85 1429del7bp A one-year-old Hispanic female has a novel 1429del7bp in combination with the well-established G542X mutation (exon 11). Login to comment
98 Spectrum of CFTR Sequence Variants in 257 Hispanic Patients Who Underwent Diagnostic DNA Testing for CF Mutations in 257 patients Allele counts of each mutation % of variant alleles (183) % of all alleles tested (514) ACMG/ACOG recommended 25 mutation panel* DeltaF508 53 28.96 10.31 G542X 7 3.83 1.36 R334W 2 1.09 0.39 R553X 2 1.09 0.39 DeltaI507 1 0.55 0.19 1717 - 1 GϾA 1 0.55 0.19 3120 ϩ 1 GϾA 1 0.55 0.19 7 different mutations 67 36.61 13.04 All mutations included ACMG/ACOG 1248 ϩ 1 GϾA 1 0.55 0.19 1249 - 29delAT 1 0.55 0.19 1288insTA1288insTA 1 0.55 0.19 1341 ϩ 80 GϾA1341 ϩ 80 GϾA 1 0.55 0.19 1429del71429del7 1 0.55 0.19 1525 - 42 GϾA1525 - 42 GϾA 1 0.55 0.19 1717 - 1 GϾA 1 0.55 0.19 1717 - 8 GϾA 2 1.09 0.39 1811 ϩ 1 GϾA1811 ϩ 1 GϾA 1 0.55 0.19 2055del9-ϾA 3 1.64 0.58 2105-2117del13insAGAAA 1 0.55 0.19 2215insG 1 0.55 0.19 2585delT2585delT 1 0.55 0.19 2752 - 6 TϾC 1 0.55 0.19 296 ϩ 28 AϾG 1 0.55 0.19 3120 ϩ 1 GϾ A 1 0.55 0.19 3271 ϩ 8 AϾG3271 ϩ 8 AϾG 1 0.55 0.19 3271delGG 1 0.55 0.19 3272 - 26 AϾG 2 1.09 0.39 3876delA 2 1.09 0.39 4016insT 1 0.55 0.19 406 - 1 GϾA 6 3.28 1.17 406 - 6 TϾC 1 0.55 0.19 4374 ϩ 13 A ϾG 1 0.55 0.19 663delT 1 0.55 0.19 874insTACA874insTACA 1 0.55 0.19 A1009T 2 1.09 0.39 A559T 1 0.55 0.19 D1152H 1 0.55 0.19 D1270N 3 1.64 0.58 D1445N 2 1.09 0.39 D836Y 1 0.55 0.19 DeltaF311 1 0.55 0.19 DeltaF508 53 28.96 10.31 DeltaI507 1 0.55 0.19 E116K 2 1.09 0.39 E585X 1 0.55 0.19 E588VE588V 2 1.09 0.39 E831X 1 0.55 0.19 F311L 1 0.55 0.19 F693L 1 0.55 0.19 G1244E 1 0.55 0.19 G542X 7 3.83 1.36 G576A 1 0.55 0.19 H199Y 3 1.64 0.58 I1027T 3 1.64 0.58 I285FI285F 1 0.55 0.19 L206W 3 1.64 0.58 L320V 1 0.55 0.19 L967S 1 0.55 0.19 L997F 3 1.64 0.58 P1372LP1372L 1 0.55 0.19 P205S 1 0.55 0.19 P439SP439S 1 0.55 0.19 Q1313X 1 0.55 0.19 Q890X 2 1.09 0.39 Q98R 1 0.55 0.19 R1066C 1 0.55 0.19 R1066H 1 0.55 0.19 (Table continues) missense variant, I1027T (3212TϾC), in exon 17a.25 Family studies have not been performed to identify which allele carries two mutations. Login to comment
102 Novel Variants Detected in 257 Hispanic Patients Patient Novel variant 1 Other variants Age and symptoms 1 1429del7bp G542X Newborn with intestinal blockage 2 S573C None 9 years old, pancreatitis, limited clinical history 3 Y913X deltaF508/I1027T 1 month old, vomiting, weight loss, diarrhea 4 E588V deltaF508/R1438W Identified one time in a family, family studies revealed deltaF508 and R1438W are in cis 5 E588V G542X Newborn with pneumonia and sweat chloride of 59 mmol/L 6 P439S R668C 10 years old with mild CF symptoms; another patient with CBAVD has P439S/R334W 7 T604S deltaF508 1 month old 8 874insTACA deltaF508 Newborn with meconium ileus and IUGR 9 2585delT deltaF508/I1027T 13 years old with CF 10 1811 ϩ 1 G to A None 44 years old with positive sweat chloride; also seen in 5-year-old CF patient with 3821delT mutation 11 I285F None 1 year old with chronic respiratory problems, also carries a silent mutation at A455 12 P1372L None 1 month old, rule out CF 13 3271 ϩ 8 A to G None 16 years old, borderline sweat test 14 1341 ϩ 80 G to A None Recurrent sinusitis 15 1525 - 42 G to A None Two patients, one 9 years old with FTT, and one 18 months old with chronic lung disease, pulmonary hypotension, hypoxia CBAVD, congenital bilateral absence of the vas deference; IUGR, intrauterine growth retardation. Login to comment
114 This was a newborn with pneumonia and a borderline sweat chloride result of 59 mmol/L, who also carried a G542X mutation. Login to comment
170 Mutations G542X and 406-1GϾA accounted for 3.8% and 2.5% respectively, and 3849 ϩ 10kbCϾT was present at 1.6%. Login to comment
173 Of the 22 mutations present at a relative frequency of 1% or more, only eight are currently included in the standard 25 mutation panel recommended (I148T, R334W, ⌬F508, G542X, R553X, 1717-1GϾA, 3120 ϩ 1GϾA, and 3849 ϩ 10kbCϾT), although a recent ACMG revision will remove variant I148T.13 The California Department of Health Services is also tracking Hispanic mutations.15 However, these may duplicate some of those described in the other reports and therefore are not included in this analysis. Login to comment
176 In comprehensive non-U.S. studies from Brazil, Colombia, and Spain, 420 mutations were identified (231, 117, and 72, respectively).33-35 Only seven occurred with a relative frequency Ͼ1%: ⌬F508 (67.4%), G542X (9%), N1303K (2.4%), R1162X (2.4%), R334W (2.1%), W1282X (1.2%), and S549R (1%). Login to comment
187 CFTR Sequence Variants Identified in Five Comprehensive CFTR Studies in US Hispanics CFTR mutations Alleles Relative mutation frequency (%) (of 317) deltaF508 123 38.80 3876delA 15 4.70 G542X 12 3.80 406 - 1GϾA 8 2.50 3849 ϩ 10kbCϾT 5 1.60 R75X 4 1.30 935delA 4 1.30 S549N 4 1.30 W1204X 4 1.30 R334W 4 1.30 2055del9ϾA 3 1 R74W 3 1 H199Y 3 1 L206W 3 1 663delT 3 1 3120 ϩ 1GϾA 3 1 L997F 3 1 I1027T 3 1 R1066C 3 1 W1089X 3 1 D1270N 3 1 2105del13insAGAAA 3 1 Q98R 2 Ͻ1 E116K 2 Ͻ1 I148T 2 Ͻ1 R668C 2 Ͻ1 P205S 2 Ͻ1 V232D 2 Ͻ1 S492F 2 Ͻ1 T501A 2 Ͻ1 1949del84 2 Ͻ1 Q890X 2 Ͻ1 3271delGG 2 Ͻ1 3272 - 26AϾG 2 Ͻ1 G1244E 2 Ͻ1 D1445N 2 Ͻ1 R553X 2 Ͻ1 E588V 2 Ͻ1 1717 - 8GϾA 2 Ͻ1 A1009T 2 Ͻ1 S1235R 2 Ͻ1 G85E 1 Ͻ1 296 ϩ 28AϾG 1 Ͻ1 406 - 6TϾC 1 Ͻ1 V11I 1 Ͻ1 Q179K 1 Ͻ1 V201 mol/L 1 Ͻ1 874insTACA 1 Ͻ1 I285F 1 Ͻ1 deltaF311 1 Ͻ1 F311L 1 Ͻ1 L320V 1 Ͻ1 T351S 1 Ͻ1 R352W 1 Ͻ1 1248 ϩ 1GϾA 1 Ͻ1 1249 - 29delAT 1 Ͻ1 1288insTA 1 Ͻ1 1341 ϩ 80GϾA 1 Ͻ1 1429del7 1 Ͻ1 1525 - 42GϾA 1 Ͻ1 P439S 1 Ͻ1 1717 - 1GϾA 1 Ͻ1 1811 ϩ 1GϾA 1 Ͻ1 deltaI507 1 Ͻ1 G551D 1 Ͻ1 A559T 1 Ͻ1 Y563N 1 Ͻ1 (Table continues) In this study, we used temporal temperature gradient gel electrophoresis (TTGE) and direct DNA sequencing to increase the sensitivity of mutation detection in U.S. Hispanics, and to determine whether additional mutations are recurrent. Login to comment
199 The pooled data set demonstrates that the most frequently seen mutations are: ⌬F508, G542X, 406-1GϾA, W1204X, R75X, 2055del9ϾA, 3876delA, ⌬I507, S549N, I148T, N1303K, 935delA, and 3849 ϩ 10kbCϾT. Login to comment
201 Comparison of Relative Frequencies of CFTR Sequence Variants in Comprehensive CFTR Studies in US and Mexican Hispanics This study % Orozco 2000 % US/ Mexican % deltaF508 28.96 54.48 43.72 G542X 3.83 8.28 5.19 406 - 1GϾA 3.28 2.07 2.38 W1204X 2.19 Ͻ1 1.08 R74W 1.64 Ͻ1 R75X 1.64 2.07 1.51 H199Y 1.64 Ͻ1 Ͻ1 L206W 1.64 Ͻ1 L997F 1.64 Ͻ1 I1027T 1.64 Ͻ1 2055del9ϾA 1.64 1.38 1.27 D1270N 1.64 Ͻ1 E116K 1.09 Ͻ1 V232D 1.09 Ͻ1 R334W 1.09 Ͻ1 S492F 1.09 Ͻ1 T501A 1.09 Ͻ1 R553X 1.09 Ͻ1 Ͻ1 E588V 1.09 Ͻ1 R668C 1.09 Ͻ1 Q890X 1.09 Ͻ1 W1089X 1.09 Ͻ1 S1235R 1.09 Ͻ1 D1445N 1.09 Ͻ1 3876delA 1.09 3.24 1717 - 8GϾA 1.09 Ͻ1 3272 - 26AϾG 1.09 Ͻ1 A1009T 1.09 Ͻ1 deltaI507 Ͻ1 3.45 1.30 S549N Ͻ1 3.45 1.95 G567A Ͻ1 Ͻ1 I148T 2.07 1.08 I506T 1.38 Ͻ1 N1303K 2.76 1.08 935delA 1.38 1.30 2183AAϾG 1.38 Ͻ1 3199del6 1.38 Ͻ1 3849 ϩ 10kbCϾT Ͻ1 1.30 ACMG/ACOG italicized. Login to comment
202 which occur with a relative frequency above 1% in the pooled data set, only six (⌬F508, G542X, ⌬I507, I148T, N1303K, and 3849 ϩ 10kbCϾT) were included in the ACMG/ACOG 25-mutation screening panel12 and in the recent revision exclusion of I148T has been recommended.13 The most frequently seen mutations in the U.S. and Mexican studies combined (n ϭ 462 identified mutations) include the 10 most frequent mutations observed in the Mexican study.36 They also include all but one mutation (R334W) occurring with a relative frequency above 1% in the five combined studies performed in the U.S. In that group, only ⌬I507, N1303K and I148T were present at a relative frequency below 1%. Login to comment

PMID: 15681482 [PubMed] Chou LS et al: "Complete gene scanning by temperature gradient capillary electrophoresis using the cystic fibrosis transmembrane conductance regulator gene as a model."

No. Sentence Comment

75 Mutation Samples with Known Genotypes Scanned by TGCE* Exon Mutation† Amplicon size (bp) Location of mutation from 5Ј end (bp) Base change Detection‡ 3 G85E 234 124 G to A 1/1 3 394delTT 234 132 del TT 1/1 4 R117H 270 83 G to T 2/2 4 I148T 270 176 T to C 3/3 Intron 4 621 ϩ 1 G/T 270 233 G to T 1/1 5 663delT/663delT 186 75 del T 0/1 Intron 5 711 ϩ 1 G/T 186 124 G to T 1/1 7 R334W 345 208 C to T 1/1 7 R347P 345 248 G to C 1/1 9 A455E 263 155 C to A 2/2 10 I506V 292 168 A to G 1/1 10 ⌬I507 292 171 del ATC 2/2 10 ⌬F508 292 174 del TTT 2/2 10 ⌬F508/⌬F508 292 174 del TTT 0/1 10 F508C 292 175 T to G 1/1 10 V520F 292 210 G to T 1/1 Intron 10 1717-1 G/A 175 50 G to A 1/1 11 G542X 175 90 G to T 2/2 11 G542X/G542X 175 90 G to T 0/1 11 G551D 175 118 G to A 3/3 11 R553X 175 123 C to T 3/3 11 R560T 175 145 G to C 2/2 13 2184delA 834 356 del A 1/1 Intron 14b 2789 ϩ 5G/A 192 102 G to A 1/1 Intron 16 3120 ϩ 1G/A 216 111 G to A 1/1 19 R1162X 322 68 C to T 1/1 19 3659delC 322 111 del C 1/1 20 W1282X 206 154 G to A 1/1 21 N1303K 250 175 C to G 2/2 Total exon/intron Overall accuracy 17 93% *Samples were compared with their respective wild-type control (confirmed by sequencing). Login to comment
76 † All genotypes were heterozygous except homozygous sample 663delT/663delT, ⌬F508/ ⌬F508, and G542X/G542X. Login to comment
135 In our study, homozygous mutants 663 delT (exon 5), ⌬F508 (exon 10), and G542X (exon 11) were not initially detected. Login to comment
179 Discussion More than 1000 mutations have been reported since the CFTR gene was cloned and characterized in 1989.23,25 Of these mutations, ⌬F508 (a 3-base deletion) is the most frequent mutation and results in a defective cAMP-regulated chloride transport in epithelial cells.26 Other mutations in the CFTR gene such as G542X, G551D, and N1303K occur in greater than 1% in the CF population and are associated with severe pancreatic insufficiency.23,27 Recently, carriers of the I148T mutation have received more attention because I148T has been found in association with the 3199del6 mutation, which may be necessary for the classic CF phenotype.28 Because of the complexity of both the mutations and the phenotypes, a high-throughput mutation scanning method to screen the entire coding region of the CFTR gene may provide valuable clinical information regarding CF genotypes and respective phenotypes. Login to comment

PMID: 16156102 [PubMed] Dunbar SA et al: "Rapid screening for 31 mutations and polymorphisms in the cystic fibrosis transmembrane conductance regulator gene by Lminex xMAP suspension array."

No. Sentence Comment

25 A 635-nm 10-mW red diode laser excites the two fluo- 148 Dunbar and Jacobson xMAP™ 149 Table 1 Recommended Core Mutation Panel for General Population Cystic Fibrosis (CF) Carrier Screening Standard mutation panel ΔF508 ΔI507 G542X G551D W1282X N1303K R553X 621+1G→T R117H 1717-1G→A A455E R560T R1162X G85E R334W R347P 711+1G→T 1898+1G→A 2184delA 1078delT 3849+10kbC→T 2789+5G→A 3659delC 1148T 3120+1G→A Reflex tests I506Va I507Va F508Ca 5T/7T/9Tb a Benign variants. Login to comment
94 Methods The methods described below include: (1) design of oligonucleotide capture probes, (2) design of PCR amplification primers and multiplexed PCR reactions, (3) preparation of the probe-conjugated microsphere sets, (4) verification 150 Dunbar and Jacobson xMAPTM Table 2 Oligonucleotide Capture Probesa Target Microsphere Probe sequence Modificationb Sequence 5' → 3' set Standard mutation panel 1c I507 & F508 5'-AmMC12 AACACCAAAGATGATATTTT 006 2B DI507 5'-AmMC12 ACACCAAAGATATTTTCTT 008 3B DF508 5'-AmMC12 AAACACCAATGATATTTTC 015 4B W1282 5'-AmMC12 CAACAGTGGAGGAAAGCC 012 5B W1282X 5'-AmMC12 CAACAGTGAAGGAAAGCC 020 6 1717-1G 5'-AmMC12 TTGGTAATAGGACATCTCCA 017 7 1717-1GÆA 5'-AmMC12 TTGGTAATAAGACATCTCCA 019 8B G542 5'-AmMC12 TATAGTTCTTGGAGAAGGTGGA 026 9B G542X 5'-AmMC12 TATAGTTCTTTGAGAAGGTGGA 028 10C G551 & R553 5'-AmMC12 AGTGGAGGTCAACGAGCAA 038 11B G551D 5'-AmMC12 GTGGAGATCAACGAGCAA 030 12C R553X 5'-AmMC12 GTGGAGGTCAATGAGCAA 032 13 R560 5'-AmMC12 CTTTAGCAAGGTGAATAACT 035 14 R560T 5'-AmMC12 CTTTAGCAACGTGAATAACT 039 15 R117 5'-AmMC12 AGGAGGAACGCTCTATCGCG 042 16 R117H 5'-AmMC12 AGGAGGAACACTCTATCGCG 025 17B I148 5'-AmMC12 CTTCATCACATTGGAATGCAGA 034 18B I148T 5'-AmMC12 CTTCATCACACTGGAATGCAGA 045 19C 621+1G 5'-AmMC12 TTTATAAGAAGGTAATACTTCCT 046 20E 621+1G→T 5'-AmMC12 ATTTATAAGAAGTTAATACTTCCTT 048 21 N1303 5'-AmMC12 GGGATCCAAGTTTTTTCTAA 051 22 N1303K 5'-AmMC12 GGGATCCAACTTTTTTCTAA 052 23B 1078T 5'-AmMC12 CACCACAAAGAACCCTGA 054 24C 1078delT 5'-AmMC12 ACACCACAAGAACCCTGA 061 25 R334 5'-AmMC12 ATATTTTCCGGAGGATGATT 063 26 R334W 5'-AmMC12 ATATTTTCCAGAGGATGATT 064 27B R347 5'-AmMC12 ACCGCCATGCGCAGAACAA 067 28B R347P 5'-AmMC12 ACCGCCATGGGCAGAACAA 053 29C 711+1G 5'-AmMC12 ATTTGATGAAGTATGTACCTAT 059 30C 711+1G→T 5'-AmMC12 ATTTGATGAATTATGTACCTAT 071 31 G85 5'-AmMC12 TGTTCTATGGAATCTTTTTA 066 32B G85E 5'-AmMC12 ATGTTCTATGAAATCTTTTTA 073 33 3849+10kbC 5'-AmMC12 GTCTTACTCGCCATTTTAAT 077 34 3849+10kbC→T 5'-AmMC12 GTCTTACTCACCATTTTAAT 075 35 A455 5'-AmMC12 CCAGCAACCGCCAACAACTG 011 36D A455E 5'-AmMC12 TCCAGCAACCTCCAACAACTG 036 37 R1162 5'-AmMC12 TAAAGACTCGGCTCACAGAT 060 38 R1162X 5'-AmMC12 TAAAGACTCAGCTCACAGAT 068 39B 3659C 5'-AmMC12 TTGACTTGGTAGGTTTAC 022 40C 3659delC 5'-AmMC12 TTGACTTGTAGGTTTACC 079 41B 2789+5G 5'-AmMC12 TGGAAAGTGAGTATTCCATGTC 074 42D 2789+5G→A 5'-AmMC12 TTGGAAAGTGAATATTCCATGTC 014 43E 2184A 5'-AmMC12 GAAACAAAAAAACAATC 007 44E 2184delA 5'-AmMC12 AGAAACAAAAAACAATC 018 45B 1898+1G 5'-AmMC12 TATTTGAAAGGTATGTTCTTTG 013 (Continued) of microsphere coupling, (5) direct hybridization of biotinylated PCR amplification products to the multiplexed probe-coupled microsphere sets, and (6) results and data analysis. Login to comment
106 Table 3 Reverse Complementary Oligonucleotide Targetsa Target Target sequence Modification Sequence 5' → 3' Standard mutation panel C1b I507 & F508 5'-Biotin AAAATATCATCTTTGGTGTT C2 ΔI507 5'-Biotin AAAGAAAATATCTTTGGTGT C3 ΔF508 5'-Biotin AGAAAATATCATTGGTGTTT C4 W1282 5'-Biotin GGCTTTCCTCCACTGTTGC C5 W1282X 5'-Biotin GGCTTTCCTTCACTGTTGC C6 1717-1G 5'-Biotin TGGAGATGTCCTATTACCAA C7 1717-1G→A 5'-Biotin TGGAGATGTCTTATTACCAA C8 G542 5'-Biotin CCACCTTCTCCAAGAACTAT C9 G542X 5'-Biotin CCACCTTCTCAAAGAACTAT C10 G551 & R553 5'-Biotin CTTGCTCGTTGACCTCCACT C11 G551D 5'-Biotin CTTGCTCGTTGATCTCCACT C12 R553X 5'-Biotin CTTGCTCATTGACCTCCACT C13 R560 5'-Biotin AGTTATTCACCTTGATAAAG C14 R560T 5'-Biotin AGTTATTCACGTTGCTAAAG C15 R117 5'-Biotin CGCGATAGAGCGTTCCTCCT C16 R117H 5'-Biotin CGCGATAGAGTGTTCCTCCT C17 I148 5'-Biotin CTGCATTCCAATGTGATGAA C18 I148T 5'-Biotin CTGCATTCCAGTGTGATGAA C19 621+1G 5'-Biotin GGAAGTATTACCTTCTTATA C20 621+1G→T 5'-Biotin GGAAGTATTAACTTCTTATA C21 N1303 5'-Biotin TTAGAAAAAACTTGGATCCC C22 N1303K 5'-Biotin TTAGAAAAAAGTTGGATCCC C23 1078T 5'-Biotin CTCAGGGTTCTTTGTGGTGT C24 1078delT 5'-Biotin TCTCAGGGTTCTTGTGGTGT C25 R334 5'-Biotin AATCATCCTCCGGAAAATAT C26 R334W 5'-Biotin AATCATCCTCTGGAAAATAT C27 R347 5'-Biotin ATTGTTCTGCGCATGGCGGT C28 R347P 5'-Biotin ATTGTTCTGCCCATGGCGGT C29 711+1G 5'-Biotin TAGGTACATACTTCATCAAA C30 711+1G→T 5'-Biotin TAGGTACATAATTCATCAAA C31 G85 5'-Biotin TAAAAAGATTCCATAGAACA C32 G85E 5'-Biotin TAAAAAGATTTCATAGAACA C33 3849+10kbC 5'-Biotin ATTAAAATGGCGAGTAAGAC C34 3849+10kbC→T 5'-Biotin ATTAAAATGGTGAGTAAGAC C35 A455 5'-Biotin CAGTTGTTGGCGGTTGCTGG C36 A455E 5'-Biotin CAGTTGTTGGAGGTTGCTGG C37 R1162 5'-Biotin ATCTGTGAGCCGAGTCTTTA C38 R1162X 5'-Biotin ATCTGTGAGCTGAGTCTTTA (Continued) Rapid CF Screening by xMAPTM 153 Table 3 (Continued) Target Target sequence Modification Sequence 5' → 3' C39 3659C 5'-Biotin GGTAAACCTACCAAGTCAAC C40 3659delC 5'-Biotin AGGTAAACCTACAAGTCAAC C41 2789+5G 5'-Biotin ACATGGAATACTCACTTTCC C42 2789+5G→A 5'-Biotin ACATGGAATATTCACTTTCC C43 2184A 5'-Biotin AAGATTGTTTTTTTGTTTCT C44 2184delA 5'-Biotin AAGATTGTTTTTTGTTTCTG C45 1898+1G 5'-Biotin AAAGAACATACCTTTCAAAT C46 1898+1G→A 5'-Biotin AAAGAACATATCTTTCAAAT C47 3120+1G 5'-Biotin TTTTTACATACCTGGATGAA C48 3120+1G→A 5'-Biotin TTTTTACATATCTGGATGAA Reflex panel CR2 I506V 5'-Biotin GAAAATGTCATCTTTGGTGT CR3 I507V 5'-Biotin GAAAATATCGTCTTTGGTGT CR4 F508C 5'-Biotin AAAATATCATCTGTGGTGTT CR5 5T 5'-Biotin TCCCTGTTAAAAACACACAC CR6 7T 5'-Biotin CCCTGTTAAAAAAACACACA CR7 9T 5'-Biotin CCTGTTAAAAAAAAACACAC a The position and sequence of the mutation or variation is indicated in bold type. b Target C1 (I507 & F508) is also used in the reflex panel. Login to comment
114 Using a small target DNA (approx 100-300 bp) minimizes the potential for steric hindrance to affect the xMAPTM Table 4 PCR Amplification Primers Size CFTR target Mutation(s) Primer 5' Modification Sequence 5' → 3' (bp) Exon 10 ΔI507, ΔF508, BE10U 5'-Biotin TTCTGTTCTCAGTTTTCCTGG 107 I506V, I507V, E10D None TTGGCATGCTTTGATGACG F508C Exon 20 W1282X E20U None TTGAGACTACTGAACACTGAAGG 126 BE20D 5'-Biotin TTCTGGCTAAGTCCTTTTGC Intron 10 1717-1G→A E11U None TCAGATTGAGCATACTAAAAGTGAC 89 BE11D2 5'-Biotin GAACTATATTGTCTTTCTCTGCAAAC Exon 11 G542X, G551D, E11U2 None AAGTTTGCAGAGAAAGACAATATAG 135 R553X, R560T BE11D 5'-Biotin GAATGACATTTACAGCAAATGC Exon 4 R117H E4U None TTTGTAGGAAGTCACCAAAGC 145 BE4D2 5'-Biotin GAGCAGTGTCCTCACAATAAAGAG Exon 4/intron 4 I148T, E4U2 None CTTCTCTTTATTGTGAGGACACTGC 169 621+1G→T BE4D 5'-Biotin ATGACATTAAAACATGTACGATACAG Exon 21 N1303K BE21U 5'-Biotin TGCTATAGAAAGTATTTATTTTTTCTGG 106 E21D None AGCCTTACCTCATCTGCAAC Exon 7 1078delT, BE7U 5'-Biotin GAACAGAACTGAAACTGACTCG 199 R334W, R347P E7D3 None CAGGGAAATTGCCGAGTG Intron 5 711+1G→T I5U None CAACTTGTTAGTCTCCTTTCC 99 BI5D2 5'-Biotin AGTTGTATAATTTATAACAATAGTGC Exon 3 G85E E3U None CTGGCTTCAAAGAAAAATCC 117 BE3D2 5'-Biotin TGAATGTACAAATGAGATCCTTACC Chromosome 7 3849+10kbC→T BC7U 5'-Biotin GACTTGTCATCTTGATTTCTGG 148 C7D None TTTGGTGCTAGCTGTAATTGC Exon 9 A455E BE9U 5'-Biotin TCACTTCTTGGTACTCCTGTCC 105 E9D None CAAAAGAACTACCTTGCCTGC Exon 19-I R1162X BE19U 5'-Biotin ATTGTGAAATTGTCTGCCATTC 167 E19Da None CAATAATCATAACTTTCGAGAGTTG Exon 19-II 3659delC BE19U2 5'-Biotin TTTAAGTTCATTGACATGCCAAC 91 E19Da None CAATAATCATAACTTTCGAGAGTTG Intron 14B 2789+5G→A I14BU None GTGTCTTGTTCCATTCCAGG 147 BI14BD 5'-Biotin TGGATTACAATACATACAAACATAGTGG Exon 13 2184delA E13U None AGATGCTCCTGTCTCCTGG 126 BE13D 5'-Biotin TGCACAATGGAAAATTTTCGTATAG Intron 12 1898+1G→A I12U None TTAGACTCTCCTTTTGGATACC 110 BI12D 5'-Biotin GTCTTTCTTTTATTTTAGCATGAGC Intron 16 3120+1G→A I16U None ATGACCTTCTGCCTCTTACC 118 BI16D 5'-Biotin ATGAAAACAAAATCACATTTGC Intron 8 5T/7T/9T I8U None TAATGGATCATGGGCCATGTGC 212 BI8D 5'-Biotin ACTGAAGAAGAGGCTGTCATCACC CFTR, cystic fibrosis transmembrane conductance regulator gene. Login to comment
118 Table 5 Genomic DNA Samples CFTR genotype Sourcea Normal/normal Sigma, D6537 ΔF508/normal Patient sample ΔF508/ΔF508 Coriell Cell Repositories, NA04540 ΔI507/normal Coriell Cell Repositories, NA11277 W1282/normal Coriell Cell Repositories, NA11723 1717-1G→A/normal Coriell Cell Repositories, NA12444 G542X/G542X Coriell Cell Repositories, NA11496B G542X/normal Coriell Cell Repositories, NA11497B ΔF508/G551D Coriell Cell Repositories, NA11274 ΔF508/R553X Coriell Cell Repositories, NA07469 G551D/R553X Coriell Cell Repositories, NA11761 ΔF508/R560T Coriell Cell Repositories, NA11284 ΔF508/R117H Coriell Cell Repositories, NA13591 I148T/normal Patient sample ΔF508/621+1G→T Coriell Cell Repositories, NA11281 N1303K/G1349D Coriell Cell Repositories, NA11472A ΔF508/1078delT Patient sample R334W/? Login to comment
276 At higher concentrations of M2, the hybridization efficiency of the exon 11 target was decreased, with a concomitant drop in reporter signal on the G542X-, G551D-, and R553X-specific microsphere sets. Login to comment

PMID: 15698946 [PubMed] des Georges M et al: "High heterogeneity of CFTR mutations and unexpected low incidence of cystic fibrosis in the Mediterranean France."

No. Sentence Comment

2 The frequency of p.F508del was 60.23% in L-R versus 67.18% in the whole country and only five other mutations (p.G542X, p.N1303K, p.R334W, c.1717-1GNA, c.711+1GNT) had a frequency higher than 1%. Login to comment
38 The 20 most common mutations responsible for CF worldwide were investigated by amplification refractory mutation system (ARMS) and migration on agarose gel (Kit Elucigene CF20, including mutations c.1717-1GNA, p.G542X, p.W1282X, p.N1303K, p.F508del, c.3849+10kbCNT, c.621+1GNT, p.R553X, p.G551D, p.R117H, p.R1162X, p.R334W, p.A455E, c.2183AANG, c.3659delC, c.1078delT, p.I507del, p.R347P, p.S1251N, p.E60X). Login to comment
55 Five other mutations were found with a relative frequency higher than 1%: p.G542X (5.35%), p.N1303K (3.%), p.R334W (1.63%), c.1717-1GNA (1.40%) and c.711+1GNT (1.16%) (Table 1). Login to comment
56 From Fig. 1, it can be seen that mutations p.G542X, p.N1303K, p.R334W and c.711+1GNT are more common in Mediterranean areas than in the whole country. Login to comment
68 of chromosomes (frequency %) p.M1V 1 1 (0.23) p.M1K 1 1 (0.23) c.300delA 3 1 (0.23) p.P67L 3 1 (0.23) c.359insT 3 1 (0.23) p.G85E 3 3 (0.70) c.394delTT 3 1 (0.23) p.Q98R 4 1 (0.23) p.R117H 4 2 (0.47) p.Y122X 4 2 (0.47) p.Y161N 4 1 (0.23) c.621+1GNT intron 4 1 (0.23) c.621+2TNG intron 4 1 (0.23) p.I175V 5 2 (0.47) c.711+1GNT intron 5 5 (1.16) p.L206W 6 3 (0.70) p.Q220X 6 1 (0.23) p.L227R 6 1 (0.23) c.1078delT 7 2 (0.47) p.R334W 7 7 (1.63) p.R347P 7 2 (0.47) c.1215delG 7 1 (0.23) c.T5 intron 8 1 (0.23) p.D443Y 9 1 (0.23) p.I506T 10 1 (0.23) p.I507del 10 4 (0.93) p.F508del 10 259 (60.23) p.F508C 10 1 (0.23) c.1677delTA 10 1 (0.23) c.1717-8GNA intron 10 1 (0.23) c.1717-1GNA intron 10 6 (1.40) p.G542X 11 23 (5.35) p.S549R 11 1 (0.23) p.G551D 11 2 (0.47) p.R553X 11 1 (0.23) c1811+1.6kbANG intron 11 4 (0.93) c.1812-1GNA intron 11 1 (0.23) p.T582I 12 1 (0.23) p.E585X 12 2 (0,47) c.1898+1GNA intron 12 1 (0.23) [c.1898+5GNA ;p.E725K] intron 12 1 (0.23) c.1898+73TNG intron 12 1 (0.23) c.2183AANG 13 4 (0.93) c.2184insA 13 1 (0.23) p.K710X 13 4 (0.93) c.2423delG 13 1 (0.23) p.S776X 13 1 (0.23) c.2493ins8 13 1 (0.23) p.R792X 13 1 (0.23) p.K830X 13 1 (0.23) p.D836Y 14a 1 (0.23) p.W846X1 14a 1 (0.23) c.2711delT 14a 1 (0.23) c.2789+5GNA intron 14b 3 (0.70) p.S945L 15 3 (0.70) p.D993Y 16 1 (0.23) c.3129del4 17a 1 (0.23) c.3195del6 17a 1 (0.23) c.3272-26ANG intron 17a 1 (0.23) [c.3395insA ;pI148T] 17b/4 1 (0,23) p.Y1092X 17b 3 (0.70) Table 1 (continued) Mutation Location exon/intron No. Login to comment
83 Table 2 Genotypes identified by newborn screening in 19 affected babies IRT (ng/ml) Genotypes 118 [p.F508del]+[p.F508del]a 163 [p.F508del]+[p.F508del]a N130 [p.F508del]+[p.F508del]b N130 [p.F508del]+[p.F508del]b N130 [p.F508del]+[p.F508del]b 155 [p.F508del]+[p.F508del]a 166 [p.F508del]+[p.F508del]a 109 [p.F508del]+[p.F508del]a 110 [p.F508del]+[p.F508del]a 136 [p.F508del]+[c.3007delG]a 160 [p.F508del]+[c.2622+1GNA]a 129 [p.F508del]+[c.3850-1GNA]a 151 [p.G542X]+[c.2380del8]a 131 [c.1078delT]+[p.K710X]a N130 [p.I507del]+[p.R334W]b 75 [p.G542X]+[p.R117H ;c1342-6 T7]b MI [p.E1104X]+[p.E1104X]b 84 [p.R117H; c1342-6 T7]+[p.R117H; c1342-6 T7]a 99 [c.2183AANG]+[p.Q220X]a IRT: Immunoreactive trypsinogen (cutoff: 65 ng/ml). Login to comment
87 M. des Georges et al. / Journal of Cystic Fibrosis 3 (2004) 265-272268 in trans of p.G542X, p.K710X in trans of c.1078delT and p.Q220X in trans of c.2183AANG (Table 2). Login to comment
89 The mutation was p.F508del (n=47), p.G542X (n=5), p.N1303K (n=4), p.G551D (n=2), p.R334W (n=2), c.1717- 1NA (n=1), p.I507del (n=1), p.R1162X (n=1), [p.R117H;IVS8-T7] (n=8) or [p.R117H;IVS8-T5] (n=1). Login to comment
131 The panel of 30 mutations (c.1717-1GNA, p.G542X, p.W1282X, p.N1303K, p.F508del, c.3849+10kbCNT, c.621+1GNT, p.R553X, p.G551D, p.R117H, p.R1162X, p.R334W, p.A455E, c.2183AANG, c.3659delC, c.1078delT, p.I507del, p.R347P, p.S1251N, p.E60X, p.Y1092X, c.394delTT, c.1811+1.6kbANG, c.3272-26ANG, c.2789+5GNA, c.3120+1GNA, c.711+ 1GNT, p.G85E, p.Y122X, p.W846X) should account for 83.32% of the CF alleles in L-R and 84.25% in the whole country. Login to comment

PMID: 15507674 [PubMed] Hadd AG et al: "Microsphere bead arrays and sequence validation of 5/7/9T genotypes for multiplex screening of cystic fibrosis polymorphisms."

No. Sentence Comment

197 Intron 8 Genotype by Coriell Number, Characterized CF Mutation and Allele Fraction for 5/7/9T Intron 8 genotype Coriell sample Characterized mutation Allele fraction by probe 5T 7T 9T 7T/7T NA09947 Normal 0.04 0.93 0.03 NA11277 ⌬I507/normal 0.06 0.90 0.04 NA11761 G551D/R553X 0.06 0.92 0.02 NA11859 2789ϩ5GϾA/2789ϩ5GϾA 0.02 0.96 0.02 NA11860 3849ϩ10kbCϾT/3849ϩ10kbCϾT 0.03 0.94 0.03 NA12444 1717-1GϾT/normal 0.06 0.87 0.07 NA12585 R1162X/normal 0.07 0.86 0.08 NA12785 R347P/G551D 0.04 0.92 0.05 NA12960 R334W/normal 0.06 0.92 0.02 NA12961 V520F/normal 0.06 0.89 0.05 NA13033 F508C/normal 0.03 0.93 0.04 9T/9T NA01531 ⌬F508/⌬F508 0.14 0.04 0.82 NA11281 621ϩ1GϾT/⌬F508 0.14 0.04 0.82 NA11283 A455E/⌬F508 0.13 0.05 0.82 NA11290 A455E/621ϩ1GϾT 0.12 0.01 0.87 NA11496 G542X/G542X 0.14 0.05 0.81 5T/7T NA11723 W1282X/normal 0.53 0.44 0.03 NA13032 I506V/normal 0.58 0.39 0.03 5T/9T NA11279 129GϾC/⌬F508 0.51 0.00 0.49 NA13591 R117H/⌬F508 0.52 0.00 0.48 7T/9T NA07441 3120ϩ1GϾA/621ϩ1GϾA 0.08 0.41 0.51 NA07552 R553X/⌬F508 0.09 0.36 0.55 NA07830 556dA/⌬F508 0.11 0.37 0.52 NA11275 3659dC/⌬F508 0.10 0.37 0.53 NA11278 Q493X/⌬F508 0.09 0.38 0.53 NA11280 711ϩ1GϾT/621ϩ1GϾA 0.09 0.37 0.54 NA11282 G85E/621ϩ1GϾA 0.07 0.39 0.53 NA11284 R560T/⌬F508 0.08 0.39 0.52 NA11472 N1303K/G1349D 0.08 0.39 0.54 Figure 3. Login to comment

PMID: 15480987 [PubMed] Hirtz S et al: "CFTR Cl- channel function in native human colon correlates with the genotype and phenotype in cystic fibrosis."

No. Sentence Comment

78 Relationship Between the CFTR Genotype and Cl- Channel Function in Native Rectal Epithelia CFTR genotype Number of individuals Sweat Cl-concentration (mmol/L)a cAMP-mediated response Carbachol-induced plateau response or maximal lumen-negative response Isc-cAMP (␮A/cm2) Cl- secretion (% of control) Isc-carbachol (␮A/cm2) Cl- secretion (% of control) Cl- secretion absent R1162X/Q552X 1 71 17.1 0 0.7 0 W1282X/3121-2AϾG 1 112 1.9 0 0.6 0 1898 ϩ 1G Ͼ T/1609delCA 2b 114, 118 25.4, 13.4 0, 0 0, 0.7 0, 0 ⌬F508/Q39X 2b 127, 129 2.6, 4.4 0, 0 1.7, 3.7 0, 0 ⌬F508/G542X 1 102 29.0 0 6.6 0 ⌬F508/R553X 3 112, 102, 109 13.1, 4.5, 23.8 0, 0, 0 1.5, 4.4, 1.0 0, 0, 0 ⌬F508/E585X 1 115 1.4 0 1.1 0 ⌬F508/Q637X 1 100 2.9 0 1.2 0 ⌬F508/Y1092X 1 119 0.0 0 -0.3 0 ⌬F508/120del23c 1 72 20.1 0 3.3 0 ⌬F508/182delT 1 116 10.8 0 5.2 0 ⌬F508/3905insT 2 88, 96 8.4, 5.6 0, 0 2.3, -1.1 0, 1 ⌬F508/V520F 1 68 1.2 0 1.7 0 ⌬F508/A561E 3 113, 146, 100 17.0, 17.0, 16.0 0, 0, 0 2.1, 1.5, 3.7 0, 0, 0 ⌬F508/R1066C 1 138 0.0 0 0.0 0 ⌬F508/N1303K 3 100, 117, 94 1.7, 4.1, 1.5 0, 0, 0 -0.6, 2.2, 0.8 0, 0, 0 A561E/A561E 2 101, 116 6.6, 2.0 0, 0 7.3, 3.3 0, 0 Residual Cl- secretiond G542X/I148N 1 75 -50.1 54 -22.2 12 1898 ϩ 3A Ͼ G/1898 ϩ 3A Ͼ G 1 82 -36.8 39 -12.9 7 ⌬F508/3272-26A Ͼ G 1 116 -17.8 19 -27.2 14 ⌬F508/S108F 1 118 -15.8 17 -12.3 7 ⌬F508/R117H 1 90 -35.9 38 -207.7 109 ⌬F508/Y161Cc 1 44 -35.1 37 -45.9 25 ⌬F508/P205S 1 80 -23.3 25 -10.4 5 ⌬F508/V232D 1 120 -16.9 18 -26.9 14 ⌬F508/R334W 1 92 -22.1 23 -21.1 11 ⌬F508/R334W 1 101 -24.5 26 -37.4 20 ⌬F508/T338I 1 73 -44.4 47 -79.4 42 ⌬F508/G576A 1 40 -16.9 18 -115.5 61 ⌬F508/I1234V 1 113 -13.6 15 -8.6 5 G576A/G85E 1 95 -26.1 28 -61.6 32 F1052V/M1137R 1 47 -36.7 39 -146.6 77 M1101K/M1101K 1 94 -11.1 12 -4.8 3 S1159F/S1159F 1 67 -47.9 51 -38.7 21 N1303K/R334W 1 91 -30.3 32 -47.7 25 NOTE. CFTR Cl- channel function was determined in rectal epithelia from Cl- secretory responses induced by IBMX/forskolin (Isc-cAMP) and after co-activation with carbachol (Isc-carbachol). Login to comment
84 One patient had TG10-9T/TG11-5T with G542X/1148N; the second patient had TG10-9T/TG12-5T with ⌬F508/S108F. Login to comment
101 Functional Classification and Protein Location of CFTR Mutations Mutation type Severe mutations (protein location) Mild mutations (protein location) Missense V520F, A561E (NBD1) G85E (MSD1, TM1) R1066C (MSD2, CL4) S108F, R117H (MSD1, EL1) N1303K (NBD2) I148N, Y161Ca (MSD1, CL1) P205S (MSD1, TM3) V232D (MSD1, TM4) R334W, T338I (MSD1, TM6) G576A (NBD1) I1234V (NBD2) F1052V, M1101K (MSD2, CL4) M1137R (MSD2, TM12) S1159F (pre-NBD2) Splice 1898 ϩ 1G Ͼ T (R domain) 1898 ϩ 3A Ͼ G (R domain) 3121-2A Ͼ G (MSD2, TM9) 3272-26A Ͼ G (MSD2, TM10) Single amino acid deletion ⌬F508 (NBD1) Nonsense Q39X (N-terminus) G542X, Q552X, R553X, E585X (NBD1) Q637X (R domain) Y1092X (MSD2, CL4) R1162X (pre-NBD2) W1282X (NBD2) Frameshift 120del23a 182delT (N-terminus) 1609delCA (NBD1) 3905insT (NBD2) NOTE. Severe mutation, Cl- secretion absent; mild mutation, residual cAMP-mediated Cl- secretion. Login to comment

PMID: 15464445 [PubMed] Davis PB et al: "Some like it hot: curcumin and CFTR."

No. Sentence Comment

13 The best-studied therapy is gentamicin, which causes read-through of 'stop` codons and has been used to correct the defect for the W1282X, G542X and other similar CF mutations with some success in clinical trials [2]. Login to comment

PMID: 15463923 [PubMed] Mendes F et al: "Immunohistochemistry of CFTR in native tissues and primary epithelial cell cultures."

No. Sentence Comment

90 Furthermore, tissues from CF patients carrying two nonsense mutations, e.g., R553X, G542X, and W1282X, can represent the golden-standard negative control, as no full-length CFTR protein is produced in these cells. Login to comment
91 Furthermore, tissues from CF patients carrying two nonsense mutations, e.g., R553X, G542X, and W1282X, can represent the golden-standard negative control, as no full-length CFTR protein is produced in these cells. Login to comment

PMID: 15463906 [PubMed] Dugueperoux I et al: "Cystic fibrosis at the Reunion Island (France): spectrum of mutations and genotype-phenotype for the Y122X mutation."

No. Sentence Comment

67 A 7 (4.79) Y122X/Y122X 13 (19.40) G542X 2 (1.37) 3120 + 1G ! Login to comment
76 A 1 (0.68) DeltaF508/ D993Y 1 (1.49) 993del5 1 (0.68) DeltaF508/ G542X 1 (1.49) A455E 1 (0.68) DeltaF508/2183AA ! Login to comment

PMID: 15269305 [PubMed] Pont-Kingdon G et al: "Long-range (17.7 kb) allele-specific polymerase chain reaction method for direct haplotyping of R117H and IVS-8 mutations of the cystic fibrosis transmembrane regulator gene."

No. Sentence Comment

131 Genotypes and Haplotypes of R117H Samples Sample Genotype Haplotype Interpretation R chromosome (wild type) H chromosome (mutant) 1 R117H-5T/7T R-5T H-7T Trans 2 R117H-5T/7T R-7T H-5T Cis 3 R117H-5T/9T R-9T H-5T Cis 4 R117H-5T/7T R-5T H-7T Trans 5 R117H/Del F508-7T/9T R-9T H-5T Cis 6 R117H-7T/7T failed H-7T na 7 R117H-7T/7T R-7T H-7T na 8 R117H-7T/9T R-9T H-7T na 9 R117H-7T/7T R-7T H-7T na 10 R117H-7T/7T failed H-7T na 11 R117H-7T/7T R-7T H-7T na 12 R117H-7T/7T R-7T H-7T na 13 R117H-7T/7T R-7T H-7T na 14 R117H-7T/9T R-9T H-7T na 15 R117H-7T/9T R-9T H-7T na 16 R117H/DelF508-7T/9T R-9T H-7T na 17 R117H/G542X-7T/9T R-9T H-7T na na, not applicable. Login to comment

PMID: 15181620 [PubMed] Maisonneuve P et al: "Pancreatitis in hispanic patients with cystic fibrosis carrying the R334W mutation."

No. Sentence Comment

26 Of Ͼ1000 identified mutations in the CFTR gene, only 25 proven disease-causing mutant alleles (⌬F508, G551D, G542X, R553X, W1282X, R347P, NI303K, R560T, ⌬I507, 1717-1GϾA, A455E, 3120ϩ1GϾA, 621ϩ1GϾT, R117H, 711ϩ1GϾT, R1162X, 3849ϩ10kbCϾT, 2789ϩ5GϾT, R334W, G85E, 1078delT, 1898ϩ1GϾT, 2184delA, 3659delC, and I148T) are recommended by the American College of Medical Genetics for routine diagnostic and carrier testing.16 Most of these are routinely recorded in the CFF registry, but rarer mutations can be recorded if identified by more comprehensive testing. Login to comment
28 Patients were classified according to their genotype: those carrying 2 severe mutations (⌬F508, ⌬I507, G542X, G551D, N1303K, R553X, R560T, R1162X, W1282X, 621ϩ1GϾT, 711ϩ1GϾT, 1717-1GϾA, 2184delA, and 3659delC), which generally are associated with pancreas insufficiency (PI); and those carrying at least 1 mild mutation (3849ϩ10kbCϾT, R117H, 2789ϩ5GϾA, R347P, R334W, and A455E), which are generally associated with PS. Login to comment
67 aPatients with pancreas insufficiency (PI) carrying 2 PI mutations (⌬F508, ⌬I507, G542X, G551D, N1303K, R553X, R560T, R1162X, W1282X, 621ϩ1GϾT, 711ϩ1GϾT, 1717-1GϾA, 2184delA, 3659delC). Login to comment
73 Genotype Distribution of Patients With CF in Puerto Rico and Other States According to Ethnicity Genotypea Hispanics Non-Hispanics Puerto Rico United States United States ⌬F508/any 25 (66) 796 (83) 15,561 (92) R334W/any 13 (34) 25 (3) 41 (0.2) ⌬I507/any 4 (11) 78 (8) 436 (3) G542X/any 2 (5) 88 (9) 754 (4) R553X/any 1 (3) 15 (2) 324 (2) N1303K/any 1 (3) 28 (3) 424 (3) 621ϩ1GϾT/any 1 (3) 9 (1) 314 (2) Not identified/any 18 (47) 269 (28) 3137 (19) NOTE. Values expressed as number (percent). Login to comment
85 Characteristics of 15 Patients With CF Carrying an R334W Mutation Who Developed Pancreatitis Genotype Sex Race Ethnicity Age at CF (yr) CF diagnosis Age (yr)a R334W/⌬F508 Female White Non-Hispanic 4 Respiratory symptoms 38 R334W/⌬F508 Male White Non-Hispanic 23 Respiratory symptoms, nasal polyps 51 R334W/⌬F508 Female White Non-Hispanic 7 Respiratory symptoms 28 R334W/⌬F508 Female White Non-Hispanic 16 Electrolyte imbalance, respiratory symptoms 34 R334W/⌬F508 Male White Hispanic 13 Respiratory symptoms, electrolyte imbalance, failure to thrive Dead 18 R334W/⌬I507 Female White Hispanic 29 Respiratory symptoms, steatorrhea 31 R334W/G542X Female White Hispanic 7 Respiratory symptoms 10 R334W/R553X Female White Hispanic 10 Respiratory symptoms 21 R334W/G85E Female White Hispanic 0 Respiratory symptoms 8 R334W/G85E Female White Hispanic 4 Failure to thrive 10 R334W/R334W Male White Hispanic 4 Meconium ileus 10 R334W/R334W Female White Hispanic 0 Respiratory symptoms 41 R334W/? Login to comment

PMID: 15181619 [PubMed] Dray X et al: "Distal intestinal obstruction syndrome in adults with cystic fibrosis."

No. Sentence Comment

110 CFTR Genotypes of Patients With a History of DIOS CFTR mutations Observations Frequency Mutation classes CFTR genotype ⌬F508/⌬F508 15 55.6% II/II Severe ⌬F508/non-⌬F508 9 33.3% ⌬F508/E60X 1 II/I Severe ⌬F508/G542X 1 II/I Severe ⌬F508/W846X 1 II/I Severe ⌬F508/R851X 1 II/I Severe ⌬F508/2894insAG 2 II/I Severe ⌬F508/⌬I507 1 II/II Severe ⌬F508/G551D 1 II/III Severe ⌬F508/2789ϩ5GϾA 1 II/V Mild Non-⌬F508/non-⌬F508 3 11.1% G542X/G542X 1 I/I Severe W1282X/W1282X 1 I/I Severe 1811ϩ1.6kb AϾG/ni 1 I/undetermined Undetermined Total 27 100.0% ni, not identified. Login to comment

PMID: 12584532 [PubMed] Solomon MP et al: "Glucose intolerance in children with cystic fibrosis."

No. Sentence Comment

118 of patients with IGT 2 10 2 0 0 1/1 16 No of patients with CFRD without FH 0 4 0 0 0 0 4 *Genotype class based on mutation with ∆F508: Class I, 621+1G→T, G542X, 441delA, R553X, W1282X, 3120+1G→A, 4016insT, 1154insTC, I1027T; Class II, ∆F508; Class III, G551D, G85E, S549N, L1077P, H199R; Class IV, Class V, 3849+10kbC→T, 5T; Unknown, G85E/-, ∆F508/-; Other, G551D/R506T, W1282X/W1282X. Login to comment

PMID: 12458151 [PubMed] Powell K et al: "Therapeutic approaches to repair defects in deltaF508 CFTR folding and cellular targeting."

No. Sentence Comment

88 These authors [34] immunoprecipitated G542X, R553X, 621 1 1 G → T, 1717-1 G → A, the immature bands A and B of mutant DF508 CFTR and 3905insT. Login to comment
89 These authors [34] immunoprecipitated G542X, R553X, 621 1 1 G ࢐ T, 1717-1 G ࢐ A, the immature bands A and B of mutant DF508 CFTR and 3905insT. Login to comment

PMID: 12454843 [PubMed] Durno C et al: "Genotype and phenotype correlations in patients with cystic fibrosis and pancreatitis."

No. Sentence Comment

105 CFTR Genotypes Among CF Patients With PS With and Without Pancreatitis Two mutations (n) ⌬F508/R117H (9) ⌬F508/(5T) (6) ⌬F508/3272-26A 3 G (4) ⌬F508/R347H (2) ⌬F508/P574H (2) ⌬F508/875 ϩ 1G Ͼ C (2) ⌬F508/3849 ϩ 10kb C 3 T (1) ⌬F508/A455E (1) ⌬F508/D614G (1) ⌬F508/G85E (1) ⌬F508/R347P (1) ⌬F508/S1251N (1) ⌬F508/⌬F508a (1) ⌬F508/3120G Ͼ A (1) ⌬F508/G551Da (1) G542X/R117H (1) R560T/L206W (1) R117H/R117H (1) R31L/P67L (1) 1461ins4 (AGAT)/G85E (1) G551D/(5T) (1) R1066C/3849 ϩ 10kb C Ͼ T (1) G551D/3849 ϩ 10kb C Ͼ T (1) R334W/R334W (1) R334W/681delC (1) W1282X/3489 ϩ 10kb C Ͼ T (1) One mutation (n) ⌬F508/- (18) L1077P/- (1) W1282X/- (1) M1137V/- (1) G551D/- (1) R347H/- (1) Q30X1/- (1) G1244E/- (1) R117H/- (1) 621 ϩ 2G621 ϩ 1G 3 T/- (1) NOTE. Login to comment
124 of episodes of pancreatitis Genotype 1 0.3 12 21.7 2 ⌬F508/S1251N 2 0.3 34 30.0 1 ⌬F508/R347H 3 4.4 13 42.5 3 / 4 4.4 21 36.5 1 ⌬F508/ 5 7.3 26 40.8 10 ⌬F508/P67L 6 9.6 29 29.9 (D) 1 ⌬F508/ 7 12.0 18 39.9 1 ⌬F508/R347P 8 12.9 37 40.9 2 G542X/D1152H 9 13.0 30 50.3 1 ⌬F508/3849 ϩ 10Kbc Ͼ T 10 14.7 13 21.5 1 DF508/R117H 11 15.6 34 40.8 1 ⌬F508/2789ϩ5G Ͼ T 12 15.6 10 26.0 10 ⌬F508/R117H 13 16.0 10 22.0 14 ⌬F/508/3849 ϩ 10kbC Ͼ T 14 16.0 18 21.2 (D) 1 R1066C/3849 ϩ 10kbC Ͼ T 15 19.9 15 40.8 5 No DNA 16 23.2 19 23.2 15 ⌬F508/11234V 17 24.1 40 47.6 (D) 1 No DNA 18 26.9 25 43.3 12 No DNA 19 27.4 35 50.3 (D) 2 ⌬F508/A455E NOTE. Login to comment

PMID: 12079272 [PubMed] Naruse S et al: "Cystic fibrosis and related diseases of the pancreas."

No. Sentence Comment

29 These include regulations of (1) the outwardly rectifying ClÀ channel, a separate class of ClÀ channel regulated by cAMP-dependent PKA and PKC, (2) the epithelial Na channel, (3) the inwardly rectifying K channel, (4) vesicle tracking, and (5) intracellular compartment acidi®cation and protein processing.8 CFTR GENE MUTATIONS Approximately 70% of the mutations in CF patients in Caucasian populations correspond to a speci®c deletion of three base pairs which results in the loss of a phenylalanine at position 508 (DF508) in the CFTR protein.4 Other mutations are rare and vary considerably among dierent ethnic groups.5 The most common 10 mutations are DF508 (66%), G542X (2.4%), G551D (1.6%), N1303K (1.3%), W1282X (1.2%), R553X (0.7%), 621 1G 4 T (0.7%), 1717-1G 4 A (0.6%), R117H (0.3%) and R1162X (0.3%).9 It is not clear how many dierent CF mutations exist in the CFTR gene. Login to comment
62 is observed only when normal CFTR function is less than 1%.13 In general, patients with pancreatic insuciency are homozygous or compound heterozygous for two severe mutations (class I, II or III in Figure 3), such as DF508, DI507, Q493X, G542X, R553X, W1282X, 621 1G 4 T, 1717-1G 4 A, 556delA, 3659delC, I148T, G480C, V520F, G551D, and R560T, whereas the PS phenotype occurs in patients who have one or two mild CFTR mutations, such as R117H, R334W, R347P, A455E, and P574H (class IV or V).5,20 EXOCRINE PANCREAS IN CYSTIC FIBROSIS Pathology of the pancreas in CF There is a spectrum of pancreatic abnormalities in CF irrespective of age.21,22 Pancreatic lesions may be absent in an individual case, but in long-standing CF the pancreas is small, hard and nodular with increased fat and multiple cysts; hence the name `cystic ®brosis of the pancreas'. Login to comment
27 These include regulations of (1) the outwardly rectifying Cl channel, a separate class of Cl channel regulated by cAMP-dependent PKA and PKC, (2) the epithelial NaW channel, (3) the inwardly rectifying KW channel, (4) vesicle traQcking, and (5) intracellular compartment acidi&#ae;cation and protein processing.8 CFTR GENE MUTATIONS Approximately 70% of the mutations in CF patients in Caucasian populations correspond to a speci&#ae;c deletion of three base pairs which results in the loss of a phenylalanine at position 508 (DF508) in the CFTR protein.4 Other mutations are rare and vary considerably among diPerent ethnic groups.5 The most common 10 mutations are DF508 (66%), G542X (2.4%), G551D (1.6%), N1303K (1.3%), W1282X (1.2%), R553X (0.7%), 621 W 1G 4 T (0.7%), 1717-1G 4 A (0.6%), R117H (0.3%) and R1162X (0.3%).9 It is not clear how many diPerent CF mutations exist in the CFTR gene. Login to comment
64 is observed only when normal CFTR function is less than 1%.13 In general, patients with pancreatic insuQciency are homozygous or compound heterozygous for two severe mutations (class I, II or III in Figure 3), such as DF508, DI507, Q493X, G542X, R553X, W1282X, 621 W 1G 4 T, 1717-1G 4 A, 556delA, 3659delC, I148T, G480C, V520F, G551D, and R560T, whereas the PS phenotype occurs in patients who have one or two mild CFTR mutations, such as R117H, R334W, R347P, A455E, and P574H (class IV or V).5,20 EXOCRINE PANCREAS IN CYSTIC FIBROSIS Pathology of the pancreas in CF There is a spectrum of pancreatic abnormalities in CF irrespective of age.21,22 Pancreatic lesions may be absent in an individual case, but in long-standing CF the pancreas is small, hard and nodular with increased fat and multiple cysts; hence the name `cystic &#ae;brosis of the pancreas'. Login to comment

PMID: 12009340 [PubMed] Robert F et al: "Relation between the anatomical genital phenotype and cystic fibrosis transmembrane conductance regulator gene mutations in the absence of the vas deferens."

No. Sentence Comment

60 In 950 unrelated chromosomes, the incidences of ⌬F508, G542X and N1303K mutations were 69%, 4.6% and 2.7% respectively (15, 16; unpublished data). Login to comment
65 Methods used to detect these mutations were [1] heteroduplex formation followed by polyacrylamide gel electrophoresis (⌬F508, ⌬I507, 508C, and 1612delTT in exon 10 and 2183AA3G, 2184delA, and 2347delG in exon 13), [2] digestion with appropriate restriction enzymes, that is, MnlI for W1282X (exon 20) and SspI for 2789ϩ5G3A (exon 14b), and [3] PCR with the modified primers MvaI for G542X (exon 11) and N1303K (exon 21), AvaII for 1717-1G3A (exon 11), and HaII for R117H (exon 4) to create a new restriction site. Login to comment
135 The fetuses had the ⌬F508/⌬F508 and ⌬F508/G542X genetic mutations. Login to comment

PMID: 11713719 [PubMed] Mateu E et al: "Can a place of origin of the main cystic fibrosis mutations be identified?"

No. Sentence Comment

20 Only four other mutations (G542X, N1303K, G551D, and W1282X) have overall frequencies 11% among the CF chromosomes. Login to comment
22 G542X is common in Mediterranean countries and is present in most of Europe, being most frequent (16.7%) in the Balearic Islands (Estivill et al. 1997). Login to comment
26 In addition, 17 other mutations have frequencies of 0.1%-0.9% (Estiv- Figure 1 Polymorphisms in the CFTR region (IVS1CA, IVS6aGATT, IVS8CA, T854, IVS17bTA, and TUB20), and location of the five most common CF mutations (DF508, G542X, N1303K, G551D, and W1282X). Login to comment
48 OF REPEATS FREQUENCY OF DF508 (n p 148) G542X (n p 56) N1303K (n p 17) 21 .993 1 .941 22 0 0 .059 23 .007 0 0 NOTE.-Numbers of chromosomes studied appear in parentheses. Login to comment
51 Because no disease chromosomes had yet been typed for the more recently described IVS1CA marker, a total of 126 patients (252 chromosomes), who carried the DF508, G542X, and/or N1303K mutations, were typed for this locus. Login to comment
56 IVS6aGATT, IVS8CA, T854, IVS17bTA, and TUB20 allele frequencies for CF chromosomes (with DF508, G542X, N1303K, G551D, and W1282X mutations) were obtained from the literature (Morral et al. 1994, 1996). Login to comment
58 Allele frequencies for the intron 1 CA repeat in CF Table 2 Most Frequent CFTR Haplotype(s) for the Five Most Common CF Mutations CF MUTATION HAPLOTYPE(S) AT MARKER a IVS1CA IVS6aGATT IVS8CA T854 IVS17bTA TUB20 DF508 21 6 23/17 1 31/32 2 G542X 21 6 23 1 33/32 2 N1303K 21 6 23/22/24 1 31 2 G551D NA 7 16 2 7 1 W1282X NA 7 17 2 7 1 a IVS1CA was typed in the present study. Login to comment
62 Table 3 Frequencies, in Normal Chromosomes, of Haplotypes Associated with CF Mutations DF508, G542X, and N1303K POPULATION MEAN FREQUENCY (SE) IN HAPLOTYPE (%)a A B C D Druze 2.4 ‫ע‬ 1.4 0 4 ‫ע‬ 1.7 0 Basque 0 0 4.2 ‫ע‬ 1.4 0 Catalan 0 0 1.4 ‫ע‬ .9 .6 ‫ע‬ .6 Finnish 0 1.6 ‫ע‬ 1.6 3.2 ‫ע‬ 2.2 1.6 ‫ע‬ 1.6 Russian 0 0 1.7 ‫ע‬ 1.7 1.7 ‫ע‬ 1.7 Adygei 0 0 2.0 ‫ע‬ 1.4 0 Japanese 0 0 0 1.2 ‫ע‬ 1.2 NOTE.-The frequency in the populations not listed is zero. Login to comment
66 When all six markers are considered in their chromosomal order (i.e., IVS1CA, IVS6aGATT, IVS8CA, T854, IVS17bTA, and TUB20), these haplotype background groups are: (1) 21-6-(17/22/23/24)-1-(31/32/33)-2, of which the most frequent are 21-6-23-1-31-2 (for DF508 and N1303K mutations) and 21-6-23-1-33-2 (for the G542X mutation) it is evident that these three different CF mutations (which have independent origins) are found in very closely related haplotypes, since they differ only by a few repeat units at the fast-evolving STRP sites; and (2) 7-(16/17)-2-7-1, in which G551D and W1282X are found. Login to comment
72 Haplotypes associated with CF mutations G542X and N1303K are closely related to those of DF508, and the situation is therefore similar. Login to comment
77 Thus, haplotypes found at frequencies of the same order Figure 3 Maximum-likelihood tree of allele frequencies of five loci (IVS6aGATT, IVS8CA, T854, IVS17bTA and TUB20) among normal chromosomes, from worldwide populations, and among CF chromosomes (DF508, G542X, N1303K, G551D and W1282X chromosomes). Login to comment
90 Thus, it appears that DF508, G542X, and N1303K are closely related to each other, as are G551D and W1282X, independently of the population from which chromosomes were sampled. Login to comment
94 Although no population has them in frequencies high enough to suggest a likely place of origin, it should be kept in mind that mutations DF508, G542X, and N1303K are independent unique events and that their occurrence in a similar background gives support to the hypothesis that the three mutations arose in a single population in which these haplotypes were frequent. Login to comment

PMID: 11265322 [PubMed] Cuppens H et al: "Solid phase fluorescent sequencing of the CFTR gene."

No. Sentence Comment

17 Depending on the ethnic origin, five to ten mutations, such as 1717-1G A, G542X, G551D, R553X, W1282X, and N1303K, reach rather high frequencies (4). Login to comment

PMID: 10766983 [PubMed] Restrepo CM et al: "CFTR mutations in three Latin American countries."

No. Sentence Comment

5 Among them, the G542X, N1303K, and 3849+10kb C>T were the most common. Login to comment
7 Two of these mutations, G542X and 3849+10kb C>T, that were relevant in this analysis, have a particularly high incidence in Spanish communities. Login to comment
34 The isolated DNA from each patient was amplified by polymerase chain reaction (PCR) using a kit for reverse dot blot detection of 16 common CF mutations: ⌬F508, R553X, G542X, G551D, N1303K, W1282X, R117H, R334W, R347P, A455E, ⌬I507, 1717-1 G>A, R560T, 3849+10kb C>T, 621+1 G>T, S549N [Villalobos-Torres et al., 1997]. Login to comment
43 The next three most common alleles determined in the present study were G542X (4.7% present in the three countries studied), N1303K (1% present in Mexico and Colombia), and 3849+10kb C>T (1% present only in two Mexican CF chromosomes). Login to comment
44 Besides ⌬F508 and G542X, no other CF alleles were detected in the Venezuelan sample. Login to comment
54 G542X mutation, the second most common allele worldwide, has a higher prevalence in Colombia (6.3%). Login to comment
59 Besides the differences in ⌬F508 occurrence, the allele frequencies of G542X and N1303K mutations are similar for Mexico and Colombia, but differ from those found in Venezuela. Login to comment
62 Frequencies and (Chromosome Number) of CF Mutations Detected in Three Latin American Countries CF mutation Mexico % (90) Colombia % (48) Venezuela % (54) Total % (192) ⌬F508 47.8 (43) 35.4 (17) 29.6 (16) 39.6 (76) G542X 4.4 (4) 6.3 (3) 3.7 (2) 4.7 (9) N1303K 1.1 (1) 2.1 (1) 0.0 (0) 1.0 (2) 3849 + 10kb C > T 2.2 (2) 0.0 (0) 0.0 (0) 1.0 (2) W1282X 0.0 (0) 2.1 (1) 0.0 (0) 0.5 (1) 621 + 1 G > T 1.1 (1) 0.0 (0) 0.0 (0) 0.5 (1) S549N 1.1 (1) 0.0 (0) 0.0 (0) 0.5 (1) Non-⌬F508a 10.0 (9) 10.4 (5) 3.7 (2) 8.3 (16) Unknown 42.2 (38) 54.2 (26) 66.7 (36) 52.1 (100) a Detected with the 16 CF mutation panel in this study. Login to comment

PMID: 10639207 [PubMed] Mussaffi H et al: "Severe allergic bronchopulmonary aspergillosis in an infant with cystic fibrosis and her asthmatic father."

No. Sentence Comment

22 Sweat chloride was 101 mEq/L, and her gene mutations were W1282X and G542X. Login to comment

PMID: 10767489 [PubMed] Kostuch M et al: "Detection of CFTR gene mutations in patients suffering from chronic bronchitis."

No. Sentence Comment

6 Patients were analyzed for the eight most common mutations of the CFTR gene (⌬F508, G542X, N1303K, 1717-1(GoA)), W1282X, G551D, R553X, and ⌬I507 by the reverse-hybridization method. Login to comment
57 These mutations include the following: ⌬F508; G542X; N1303K; 1717-1(GoA); W1282X; G551D; R553X, and ⌬I507. Login to comment
92 Other rare CFTR gene mutations (R553X, G542X, G551D, N1303K, and 621ϩ1G(T)) were excluded in their study. Login to comment
7 Patients were analyzed for the eight most common mutations of the CFTR gene (èc;F508, G542X, N1303K, 1717-1(GoA)), W1282X, G551D, R553X, and èc;I507 by the reverse-hybridization method. Login to comment
91 Other rare CFTR gene mutations (R553X, G542X, G551D, N1303K, and 621af9;1G(T)) were excluded in their study. Login to comment

PMID: 10923036 [PubMed] Claustres M et al: "Spectrum of CFTR mutations in cystic fibrosis and in congenital absence of the vas deferens in France."

No. Sentence Comment

2 The most common were F508del (67.18%; range 61-80), G542X (2.86%; range 1-6.7%), N1303K (2.10%; range 0.75-4.6%), and 1717-1G>A (1.31%; range 0-2.8%). Login to comment
32 Analysis of more than 43,000 CF chromosomes from different continents has shown that only five mutations have relative world frequencies higher than 1% [F508del (66%), G542X (2.4%), G551D (1.6%), N1303K (1.3%), and W1282X (1.2%)] [The Cystic Fibrosis Genetic Analysis Consortium, 1994]. Login to comment
74 Only three other mutations had relative frequencies ≥1%, G542X (2.86%), N1303K (2.10%), 1717-1G>A (1.31%). Login to comment
80 A trend of decreasing frequency of F508del from Northwest (70%) to Southeast (61%) was generally observed; the second most common mutation was G542X in the Southwest (6.7%) or in the South (5.6%), whereas it was I507del in Normandy (2.7%). Login to comment
84 The most common mutations in this group were F508del (31.01%), 711+1G>T (11.39%), W1282X (6.33%), N1303K (5.7%), G542X (5.06%), and R1162X (3.8%), a distribution which seems different from the global French population. Login to comment
88 Five genotypes are responsible for 57.31% of cases of CF in France: F508del/F508del (47.75 %), F508del/G542X (3.4%), F508del/N1303K (2.7%), F508del/1717-1G>A (2.02%), and F508del/2789+5G>A (1.43%). Login to comment
102 Distribution of 310 CF Mutations in France With Respect to Relative Frequencies (Total Number of CF Chromosomes = 7,420) Group Mutations Number of alleles % Cum. % A F508del 4,985 67.18 G542X 212 2.86 N1303K 156 2.10 73.45 1717-1G>A 97 1.31 B G551D 73 0.98 2789+5G>A 72 0.97 W1282X 68 0.91 R553X 66 0.89 I507del 52 0.70 1078delT 49 0.66 7.47 2183AA>G 48 0.64 711+1G>T 33 0.44 R1162X 33 0.44 Y1092X 30 0.40 3849+10kbC>T 30 0.40 C 12 mutationsa 29 to 15 (239) 0.39-0.20 19 mutationsb 14 to 8 (190) 0.19-0.10 11 mutationsc 7 to 6 (71) 0.09-0.08 11 mutationsd 5 (55) 0.06 10.57 15 mutationse 4 (60) 0.05 23 mutationsf 3 (69) 0.04 50 mutationsg 2 (100) 0.02 D 154 mutationsh 1 (154) 0.01 2.07 6,942 93.56 a 3659delC, R347P, 3272-26A>G, R334W, W846X, 621+1G>T, G85E, R1066C, L206W, 394delTT, 4055+1G>A, R347H. Login to comment
140 Non-F508del Mutations Found as Homozygous in a Sample of 3,710 Patients With Cystic Fibrosis Mutation n 711+1G>T 8 G542X 7 N1303K 7 2183delAA>G 5 W1282X 4 G551D 3 3905insT 3 R334W 2 R347P 2 1078delT 2 1811+1.6kbA>G 2 2113delA 2 Y1092X 2 R1162X 2 306insA 1 E92K 1 G178R 1 L227R 1 1677delTA 1 1717-1G>A 1 1717-8G>A 1 R553X 1 S549R(T>G) 1 R560S 1 V562I 1 Y569D 1 2711delT 1 S945L 1 R1158X 1 I1234V 1 3849+10kbC>T 1 Q1313X 1 del25kb 1 E831X 1 I175V 1 G314V 1 L1077P 1 produce a small quantity of functional protein as a result of a variable proportion of normal CFTR mRNA transcripts in addition to the abnormal ones (class V); 3) they are located in sites known to generate less severe mutants (external loops, residues lining the pore); and/or 4) they have been observed in CF with pancreatic sufficiency, CBAVD, and/or CF-related attenuated phenotypes only. Login to comment
152 Twenty-four non F508del mutations were found associated with the 9T allele: 394delTT, L90S, D110H, R117G, 621+1G>T, V232D, A455E, G542X, R851L, T908N, 2789+5G>A, 2896insAG, H939R, 3007delG, I980K, I1027T, R1066H, A1067T, D1154G, 3737delA, R74W+D1270N, N1303I, N1303K, D1377H. Login to comment
158 Distribution of Mutations Within the CFTR Gene Due to the high frequencies of F508del and G542X, 75.22% of French CF alleles were mutated in exons 10 and 11, encoding for the first nucleotide binding domain of CFTR (NBD1) or their flanking intronic sequences (Fig. 5). Login to comment
171 CFTR Mutation Genotypes Identified Both in Cystic Fibrosis (CF) and in Congenital Bilateral Absence of the Vas Deferens (CBAVD) CF CBAVD F508del/5T 3 143 F508del/2789+5G>A 53 1 F508del/3272-26A>G 17 4 F508del/R117H* 10 39 F508del/R117C 2 2 F508del/L206W 12 4 F508del/R347H 10 5 F508del/R347L 1 1 F508del/D443Y 1 5 F508del/Y569C 1 1 F508del/P574H 3 1 F508del/G628R(G>A) 2 1 F508del/V920M 1 1 F508del/R1070W 2 3 F508del/D1152H 6 8 F508del/S1235R 3 1 F508del/T1246I 1 1 F508del/D1270N+R74W 2 3 F508delN1303I 1 1 3659delC/R347H 1 1 G542X/T338I 2 2 R347H/R1066H 1 1 *The only case with CF whose alleles at IVS8(T)n were reported had mutation R117H associated with a 5T allele. Login to comment
175 1.6kbA>G) is markedly different from the rest of France whereas the Mediterranean coast (G542X) shows similarity between the western and eastern parts,withsomedifferencefromthecentralpart.This study demonstrates that even within one country, wide variations exist among the frequencies of spe- cificmutations.OtherEuropeancountriesshowmore substantial genetic homogeneity than France [Cuppensetal.,1993;Bonizzatoetal.,1995;Schwarz et al., 1995; Tümmler et al., 1996]. Login to comment

PMID: 10862085 [PubMed] Ellis LA et al: "A comparison of fluorescent SSCP and denaturing HPLC for high throughput mutation scanning."

No. Sentence Comment

97 Comparison of F-SSCP and DHPLC Using a Panel of ABCC7 Mutations Gel condition Location Location 49:1 49:1 49:1 49:1 MDE MDE MDE Capillary DHPLC °C from 5' (bp) from 3' (bp) 15 20 25 35 20 25 35 35 N/A Exon 3 (320bp) E60X 128 192 + + + + + + + + - P67L 150 170 + + + - + + + - + R75X 173 147 + + + + + + + + + R75Q 174 146 + + + - + + + + + G85E 204 116 + + + - + + + + + L88S 213 107 + + + + + + + + + Exon 4 (400bp) 441delA 135 265 + + + + + + + + + D110H 154 246 + + + + + + - + + R117H/H 176 224 + + + + + + + + N/A R117R/H 176 224 + + + + + + + + + L137H 236 164 + + + + + + + + + I148T 261 139 + + + + + + + + + 621+1 (G>T) 309 91 + + + + + + + + + Exon 7 (360bp) R334W 180 180 + + + + + + + - + 1058delC 105 255 + + + + + + + + + 1078delT 125 235 + + + - + + + + + 1138insG 226 134 - + + - + + + + + 1154insTC 202 158 + + + + + + + + + 1161delC 209 151 + + + + + + + + + R347H 220 140 + + + + + + - + + R347P 220 140 + + + - + + + - + A349V 226 134 + + + + + + + + + W356X 248 112 + + + + + + + + + Exon 10 (365bp) M470V 143 222 + + + + + + + + + Q493X 212 153 + + + + + + - + - DelF508 255 110 + + + + + + + + - Del I507 253 112 + + + + + + + + + V520F 293 72 + + - + + - + - + Exon 11 (190bp) 1717-1 (G>A) 54 136 + + + - + + - + + G542X 94 96 + + + - + + - + + S549N 116 74 + + + + + + + + - S549R 117 73 + + + + - - - + + G551D 122 68 + - - - + + + - + R553X 127 63 + + + + + + + + + G551D/R553X + + + + + + + + + R560T 149 41 + + + - - - - - + R560K 149 41 + + + - + + + - + 1811+1 (G>C) 150 40 + + + + + + + + + Exon 12 (250bp) 1898+1(G>A) 167 83 + + + + + + - + + Exon 13a (290bp) C590W 87 203 + + - - + - - + + Exon 13b (405bp) 2184insA 148 257 + + + + + + + - + R709X 220 185 - + - - - - - - + V754M 453 52 + + + + + + + - - Exon 13c (345bp) V754M 65 280 + + + + + + - - + R785X 158 187 + + - - + + - - + Exon 19 (370bp) 3601-17 (T>C) 29 341 - + + - + + + - + R1162X 61 309 + + - - + - - + + 3659delC 105 265 - - - + + + + + + Y1182X 123 247 - + + - + + + - + Exon 20 (370bp) W1282X 186 184 + + + + + + + + + % detected 90 96 86 66 94 88 74 72 90 remainder were detected using DGGE. Login to comment
135 Effect of Amplicon Size on Mutation Detection Rate in ABCC7 Exon 11 SSCP slab gels SSCP 310 DHPLC 49:1, 20°C MDE, 20°C 35°C Exon 11 ABCC7 190bp 490bp 190bp 490bp 190bp 490bp 190bp 490bp 1717-1G>A - - + + + + + + G542X + + + + + - + + S549N + + + + + + - - S549R + + - + + + + - G551D - + + + - - + - R553X + + + + + + + - G551D/R553X + + + + + + + - R560T + - - + - - + + R560K + + + + - - + + 1811+1G>C + + + + + + + + Sensitivity 9/10 8/10 8/10 10/10 7/10 6/10 9/10 5/10 ammonium acetate as an ion-pairing agent has the unintended consequence of modifying the stability of GC and AT base pairs in a similar manner to the effects of tetra-alkyl ammonium salts, tetraethyl ammonium chloride and tetramenthyl ammonium chloride. Login to comment

PMID: 10571016 [PubMed] Scanlin TF et al: "Terminal glycosylation in cystic fibrosis."

No. Sentence Comment

650 Some mutations (e.g., G542X) produce a truncated transcript and no protein, while other mutations (e.g., R117H) produce a protein that has impaired conduction properties. Login to comment

PMID: 10445602 [PubMed] Puechal X et al: "Increased frequency of cystic fibrosis deltaF508 mutation in bronchiectasis associated with rheumatoid arthritis."

No. Sentence Comment

129 In the DB group, two patients carried mutations: one was compound heterozygous (G542X/3849+ 10Kb CRT) and was diagnosed as suffering from an atypical CF with a normal sweat chloride concentration, while the other was heterozygous for the missense mutation G239R with normal values of both sweat chloride concentrations and nasal potential differences. Login to comment
128 In the DB group, two patients carried mutations: one was compound heterozygous (G542X/3849+ 10Kb CRT) and was diagnosed as suffering from an atypical CF with a normal sweat chloride concentration, while the other was heterozygous for the missense mutation G239R with normal values of both sweat chloride concentrations and nasal potential differences. Login to comment

PMID: 10445601 [PubMed] Danner I et al: "Respiratory epithelial ion transport in patients with disseminated bronchiectasis."

No. Sentence Comment

36 This method allowed the detection of seven common mutations: 621+1GRT, DF508, G542X, N1303K, G551D, 1717-1GRA, and 3659delC [23]. Login to comment

PMID: 10228103 [PubMed] Jorissen MB et al: "Genotype-phenotype correlations for the paranasal sinuses in cystic fibrosis."

No. Sentence Comment

94 The fourth patient had undergone sinus surgery and was ⌬F508 negative (G542X/unidentified). Login to comment
120 of Patients in Surgical Group ⌬F508 Genotype Homozygosity 69 61 22 Compound heterozygosity 33 29 5 Negative 11 10 1 Mutations ⌬F508 171 75.7 27 Non-⌬F508 55 24.3 6 R117H (4) C276X (1) 394delT (1) W401X (2,† ) A455E (1) G542X (4,‡ ) G551D (1) R553X (1) G628R(G→C) (1) Y1092X (1) D1152H (1) S1251N (1) W1282X (3) N1303K (8) W1310X (1) 1717-1G→A (3,† ) 1898ϩ1G→C (1) 2183AA-G (3,†† ) 3659delC (2) 3272-26A→G (2,† ) 4218-insT (2) unknown (11,‡ ) * The genotype and mutations are given for the 113 patients with CF. Login to comment
95 The fourth patient had undergone sinus surgery and was DF508 negative (G542X/unidentified). Login to comment
121 of Patients in Surgical Group DF508 Genotype Homozygosity 69 61 22 Compound heterozygosity 33 29 5 Negative 11 10 1 Mutations DF508 171 75.7 27 Non-DF508 55 24.3 6 R117H (4) C276X (1) 394delT (1) W401X (2,ߤ ) A455E (1) G542X (4,ߥ ) G551D (1) R553X (1) G628R(G࢐C) (1) Y1092X (1) D1152H (1) S1251N (1) W1282X (3) N1303K (8) W1310X (1) 1717-1G࢐A (3,ߤ ) 189811G࢐C (1) 2183AA-G (3,ߤߤ ) 3659delC (2) 3272-26A࢐G (2,ߤ ) 4218-insT (2) unknown (11,ߥ ) * The genotype and mutations are given for the 113 patients with CF. Login to comment

PMID: 10232317 [PubMed] Johnson DW et al: "Sunshine, sweating, and main d'accoucheur."

No. Sentence Comment

16 Screening for ten of the common cystic fibrosis transmembrane conductance regulator gene (CFTR) mutations (⌬F508, G551D, R553X, G542X, N1303K, A455E, 621+1, Delta I507 and R117H), showed a single delta F508 mutation. Login to comment

PMID: 9915972 [PubMed] Castellani C et al: "Cystic fibrosis mutations in heterozygous newborns with hypertrypsinemia and low sweat chloride."

No. Sentence Comment

16 Am. J. Hum. Genet. 64:303-304, 1999 Table 1 Sweat Chloride Concentration and CFTR Genotypes CASE SWEAT CHLORIDE (mEq/liter) MUTATION Allele 1a Allele 2b 1 10 R1162X 3041-71G/C,c 4002A/Gc 2 14 DF508 3 30 R1162X R117H 4 21 DF508 E527G 5 8 DF508 6 12 N1303K, 2622ϩ14G/Ad 7 6 DF508 8 20 DF508 1716G/Ac 9 16 DF508 10 10 DF508 11 19 R1162X 12 19 N1303K 13 12 G542X 1716G/Ac 14 32 DF508 15 14 DF508 16 26 N1303K 2622ϩ14G/Ac 17 18 DF508 Y301C 18 18 2183AArG a First mutation found, assigned to one gene. Login to comment

PMID: 10571949 [PubMed] Lazaro C et al: "Missense mutations in the cystic fibrosis gene in adult patients with asthma."

No. Sentence Comment

57 TheCFTR gene was analyzed for the two most common mutations in the Spanish population (∆F508 and G542X) and for a DNA variant located in intron 8 of the CFTR gene, IVS8-6(5T) [Chu et al., 1991]. Login to comment

PMID: 10502783 [PubMed] Paz-y-Mino C et al: "The DeltaF508 mutation in Ecuador, South America."

No. Sentence Comment

17 In the affecteds who did not show any ∆F508 allele, we searched for the presence of the eight most common "European" mutations (∆F508, G542X, N1303K, 1717-1, W1282X, G551D, R553X, ∆1507) with the test INNO-Lipa. Login to comment
31 However, in this study the G542X and N1303K mutations were found [Villalobos-Torres et al., 1997], although these were not found in Ecuador. Login to comment

PMID: 10447267 [PubMed] Telleria JJ et al: "Spectrum of CFTR mutations in the Middle North of Spain and identification of a novel mutation (1341G-->A). Mutation in brief no. 252. Online."

No. Sentence Comment

33 Spectrum of CFTR Mutations Table 1 Spectrum of CFTR mutations identified in the present study compared with data published by Casals et al. (Casals et al. 1997) This study Casals et al. Mutation Exon/Intron n % n % ∆F508 E 10 51 65.4 681 53.2 711+1G→T I 5 3 3.8 22 1.7 G542X E 11 3 3.8 108 8.43 1213delT E 7 2 2.6 0 0 1341G→A E 8 2 2.6 0 0 R1066C E 17b 2 2.6 14 1.09 1717-1G→A I 10 1 1.3 1 0.08 S549R E 11 1 1.3 0 0 V562I E 12 1 1.3 0 0 G576A E 12 1 1.3 0 0 2183AA→G E13 1 1.3 5 0.39 2789+5G→A I 14b 1 1.3 11 0.86 Q890X E 15 1 1.3 13 1.01 3849+1G→A I 19 1 1.3 0 0 N1303K E 21 1 1.3 34 2.65 Other 0 0 391 30.5 Known mutations 72 92.3 1155 90.23 Unknown mutations 6 7.7 125 9.7 DISCUSSION The knowledge of the spectrum of mutations causing CF in any specific geographic region provide useful information to design the best approach in pre and postnatal diagnosis of CF; for the screening of mutations in the population at risk; to stimate the genetic risk etc. Moreover, the response to different therapeutic approaches could vary depending on the CF mutations in any case. Login to comment

PMID: 9949435 [PubMed] Kim ED et al: "Genetic concerns for the subfertile male in the era of ICSI."

No. Sentence Comment

93 Because these previous series had relied only on delta F508 mutations, Scobie et al. (1996) demonstrated the detection of G551D, R553X, G542X, 621+1G>T and delta F508 CFTR gene mutations using a rapid and specific differential amplification system. Login to comment

PMID: 9797105 [PubMed] Jarvi K et al: "Heterogeneity of reproductive tract abnormalities in men with absence of the vas deferens: role of cystic fibrosis transmembrane conductance regulator gene mutations."

No. Sentence Comment

60 of men Single mutation 5T /Unknown 13 ⌬F508 /Unknown 8 R117H /Unknown 2 W1282X /Unknown 1 4016insT /Unknown 1 N1303K /Unknown 1 Total 26 Two mutations ⌬F508 /5T 4 ⌬F508 /R117H 2 ⌬F508 /R75Q 1 5T /2183AA3G 1 5T /N1303K 1 5T /G542X 1 R117H /G551A 1 R117H /2184insA 1 A455E /3849ϩ10KbC 1 3T Total 13 No mutations 7 Total no. Login to comment

PMID: 9683582 [PubMed] Dork T et al: "Evidence for a common ethnic origin of cystic fibrosis mutation 3120+1G-->A in diverse populations."

No. Sentence Comment

63 This study demonstrates that the 3120ϩ1GrA mutation shares the same extragenic CS.7-KM.19 "risk" haplotype with the other frequent and ancient CF mutations-DF508, N1303K, and G542X (Do¨rk et al. 1992; Morral et al. 1993)-but that it differs from these latter mutations with respect to intragenic CFTR markers. Login to comment

PMID: 9674722 [PubMed] Schwiebert EM et al: "Cystic fibrosis: a multiple exocrinopathy caused by dysfunctions in a multifunctional transport protein."

No. Sentence Comment

218 The number of missense or point mutations (frequent examples are R117H and G551D), nonsense (frequent examples are G542X and W1282X), and frameshift mutations within CFTR has reached more than 700, according to the CF Genetic Analysis Consortium. Login to comment
223 They include another deletion mutation at amino acid position 507 (⌬I507), several missense mutations (F508C, G551D, G551S, A455E, R553Q, P574H, S549N, A559T), and some nonsense mutations (G542X, R553X, Q493X). Login to comment
299 Examples of such nonsense mutations are G542X in NBF1, W1282X in NBF2, and S1455X in the C-terminus of the CFTR protein. Login to comment

PMID: 9591500 [PubMed] Tuerlings JH et al: "Mutation frequency of cystic fibrosis transmembrane regulator is not increased in oligozoospermic male candidates for intracytoplasmic sperm injection."

No. Sentence Comment

2 The three most frequent cystic fibrosis (CF)-causing CFTR mutations in the Dutch population (⌬F508, A455E, and G542X) and the three most frequent CFTR mutations potentially causing congenital bilateral absence of the vas deferens (CBAVD) in the Dutch population (⌬F508, R117H, and IVS8-5T) were analyzed. Login to comment
65 The three most frequent CFTR mutations causing CF in the Dutch population (⌬F508, A455E, and G542X) and the three most frequent CFTR mutations potentially causing congenital bilateral absence of the vas deferens in the Dutch population (⌬F508, R117H, and IVS8-5T) were analyzed. Login to comment
68 Detection of R117H, A455E, and G542X mutations was performed with the use of allele-specific amplification tests, as described by Ferrie et al. (12) for G542X and R117H. Login to comment
92 For the A455E, G542X, and ⌬I507 mutations, the frequency in the normal population was based on the 3.3% carrier frequency and the locally derived relative frequencies of mutations in CF patients (H.S., unpublished data). Login to comment
132 Mutation General population* (95% CI) Patients with OAT† (95% CI) Patients with CBAVD‡ Patients with CF§ ⌬F508 0.013 (0.011-0.015) 0.013 (0.0037-0.047) 0.169 0.777 R117H 0.009 (0.0027-0.030) 0.006 (0.0012-0.037) 0.305 Ͻ0.001 IVS8-5T 0.037 (0.019-0.073) 0.006 (0.0012-0.037) 0.055 ND A455E Ͻ0.001 (ND) 0 (ND) Ͻ0.001 0.026 G542X Ͻ0.001 (ND) 0 (ND) Ͻ0.001 0.015 ⌬I507 Ͻ0.001 (ND) 0 (ND) Ͻ0.001 Ͻ0.001 Total 0.005 (ND)࿣ 0.027 (0.010-0.067) 0.529 0.818 Note: OAT ϭ oligoasthenoteratozoospermia; CBAVD ϭ congenital bilateral absence of the vas deferens; ND ϭ not done. Login to comment
133 * Locally derived frequencies for ⌬F508, R117H, and IVS8-5T (n ϭ 21,544 chromosomes, n ϭ 232 chromosomes, and n ϭ 212 chromosomes, respectively); and theoretical estimates for A455E, G542X, and ⌬I507 based on a 3.3% carrier frequency and regionally derived mutation frequencies (H.S., unpublished data). Login to comment
136 § H.S., unpublished data (n ϭ 726 for ⌬F508, A455E, and G542X; n ϭ 272 for R117H; IVS8-5T not determined). Login to comment

PMID: 9499426 [PubMed] Mickle JE et al: "A mutation in the cystic fibrosis transmembrane conductance regulator gene associated with elevated sweat chloride concentrations in the absence of cystic fibrosis."

No. Sentence Comment

151 Mutation analysis Total genomic DNA was assayed for 16 common CFTR mutations (R117H, 621+1G→T, R334W, R349P, A455E, 1717-1G→A, ∆I507, ∆F508, G542X, S549N, G551D, R553X, R560T, 3849+10 kb C→T, W1282X, N1303K) by reverse dot-blot hybridization (46). Login to comment
152 Mutation analysis Total genomic DNA was assayed for 16 common CFTR mutations (R117H, 621+1G࢐T, R334W, R349P, A455E, 1717-1G࢐A, ࢞I507, ࢞F508, G542X, S549N, G551D, R553X, R560T, 3849+10 kb C࢐T, W1282X, N1303K) by reverse dot-blot hybridization (46). Login to comment

PMID: 9559222 [PubMed] De Braekeleer M et al: "Correlation of sweat chloride concentration with genotypes in cystic fibrosis patients in Saguenay Lac-Saint-Jean, Quebec, Canada."

No. Sentence Comment

69 Simone Aubin, Claudette La- rochelle and Suzanne Mignault from the Clinique de TABLE 2 Distribution of the Mean Sweat Chloride Concentration by Genotype Genotype No. of CF Patients Mean Chloride Concentration (mmol/L) (SD) Pancreatic Status References G542X/⌬F508 128 109 (23) Pl 18 R553X/⌬F508 46 105 (18) Pl 18 N1303K/⌬F508 56 104 (24) Pl 18 W1282X/⌬F508 13 110 (18) Pl 18 1717-1G3A/⌬F508 26 107 (36) Pl 18 621ϩ1G3T/⌬F508 22 100 (20) Pl 18 R117H/⌬F508 20 82 (19) PS 18 ⌬F508/⌬F508 328 106 (22) Pl 18 3849ϩ10kb C3T/⌬F508 6 61 (11) PS 19 3849ϩ10kb C3T/⌬F508 9 41 (12) PS (6) 20 R347P/⌬F508 5 100 (26) Pl 21 R334W/⌬F508 10 108 (19) Pl (6) 22 1811ϩ1.6kb A3C/⌬F508a 17 98 (12) Pl 23 3905insT/⌬F508 7 124 Pl 24 W1282X/W1282X 16 113 (12) Pl 25 W1282X/⌬F508 22 109 (11) Pl 25 G551D/⌬F508 58 101 (16) Pl 26 R1162X/R1162X 9 99 (13) Pl 27 1949del84/⌬F508 4 105 (20) Pl 28 ⌬F508/⌬F508 47 103 (8) Pl This study 621ϩ1G3T/⌬F508 28 103 (7) Pl This study 621ϩ1G3T/A455E 6 94 (11) Pl/PS This study A455E/⌬F508 12 77 (18) Pl/PS This study a Or other 'severe` mutations. Login to comment
71 Simone Aubin, Claudette Larochelle and Suzanne Mignault from the Clinique de TABLE 2 Distribution of the Mean Sweat Chloride Concentration by Genotype Genotype No. of CF Patients Mean Chloride Concentration (mmol/L) (SD) Pancreatic Status References G542X/DF508 128 109 (23) Pl 18 R553X/DF508 46 105 (18) Pl 18 N1303K/DF508 56 104 (24) Pl 18 W1282X/DF508 13 110 (18) Pl 18 1717-1G3A/DF508 26 107 (36) Pl 18 62111G3T/DF508 22 100 (20) Pl 18 R117H/DF508 20 82 (19) PS 18 DF508/DF508 328 106 (22) Pl 18 3849110kb C3T/DF508 6 61 (11) PS 19 3849110kb C3T/DF508 9 41 (12) PS (6) 20 R347P/DF508 5 100 (26) Pl 21 R334W/DF508 10 108 (19) Pl (6) 22 181111.6kb A3C/DF508a 17 98 (12) Pl 23 3905insT/DF508 7 124 Pl 24 W1282X/W1282X 16 113 (12) Pl 25 W1282X/DF508 22 109 (11) Pl 25 G551D/DF508 58 101 (16) Pl 26 R1162X/R1162X 9 99 (13) Pl 27 1949del84/DF508 4 105 (20) Pl 28 DF508/DF508 47 103 (8) Pl This study 62111G3T/DF508 28 103 (7) Pl This study 62111G3T/A455E 6 94 (11) Pl/PS This study A455E/DF508 12 77 (18) Pl/PS This study a Or other 'severe` mutations. Login to comment

PMID: 9521595 [PubMed] Onay T et al: "Analysis of the CFTR gene in Turkish cystic fibrosis patients: identification of three novel mutations (3172delAC, P1013L and M1028I)."

No. Sentence Comment

3 The second most common mutation was 1677delTA, with a frequency of 7.3%, followed by G542X and 2183AA→G mutations, with frequencies of 4.9%. Login to comment
26 Other frequent mutations, namely G542X, R560T, S549N or S549I and G551D or R553X, were analysed by the multiplex ARMS method combined with restriction enzyme analysis (Dean et al. 1990; Cutting et al. 1990; Ferrie et al. 1992). Login to comment
41 Three other mutations, namely G542X, N1303K and W1282X, were found on 10 chromosomes and screening of exon 10 by DGGE resulted in the identification of the homozygous presence of 1525-1 G→A in one affected child with a sweat test score of 109 mEq/l. Login to comment
67 Mutations 1677delTA, G542X and 2183AA→G have frequencies greater or equal to approximately 5%, whereas F1052V, 2043delG, D110H, N1303K, L571S and 296+9 A→T have frequencies of 2%. Login to comment
69 Nine homozygous CF genotypes, for mutations ∆F508, 1677delTA, 2183AA→G, G542X, L571S, N1303K, W1282X, 1525-1 G→A and 2043 delG, were observed in 26.0% of cases. Login to comment
75 G542X 11 Gly→Stop at 542 G→T at 1756 6 (4.91) Kerem et al. 1990 5. Login to comment
115 This study reveals the presence of mutations G542X and 2182AA→G with the same frequency (4.9%) in the Turkish population. Login to comment
117 The frequency of G542X is 8.1% in Spain (Cassals et al. 1993), 4% in Italy, 5% in Greece (Nunes et al. 1991) and 13.5% in the Jewish population of Israel (Lerer et al. 1991). Login to comment
140 Nine homozygous CF genotypes, for mutations ∆F508, 1677delTA, 2183AA→G, G542X, L571S, N1303K, W1282X, 1525-1 G→A and 2043delG, were observed in 26.0% of cases, whereas consanguinity was noted in approximately 9.6% of patients. Login to comment

PMID: 9755815 [PubMed] Meschede D et al: "Genetic diseases of the seminal ducts."

No. Sentence Comment

39 This is the case in homozygotes and compound heterozygotes for AF508 and other common "severe" mutations such as 17 171 G + A, G542X, G55lD, R553X, W1282X or Nl303K. Login to comment
40 This is the case in homozygotes and compound heterozygotes for AF508 and other common "severe" mutations such as 17 171 G + A, G542X, G55lD, R553X, W1282X or Nl303K. Login to comment

PMID: 10200050 [PubMed] de Meeus A et al: "Genetic findings in congenital bilateral aplasia of vas deferens patients and identification of six novel mutatations. Mutations in brief no. 138. Online."

No. Sentence Comment

83 Phenotype CFTRamutations Intron 8, Poly(T) tract 1 3 crisis of acute pancreatitis F508 / L206W 9/7 2 F508 / L206W 9/9 3 frequent bronchitis F508 / R347H 9/9 4 F508 / R347H 9/9 5 F508 / M244K 9/7 6 F508 / A1364V 9/7 7 F508 / D1152H 9/7 8 chronic sinusitis and bronchitis F508 / D1152H 9/7 9 F508 / R117H 9/7 10 F508 / R117H 9/7 11 F508 / M952I 9/7 12 D443Y / G542X 7/9 13 D443Y / G542X 7/9 14 2184delA / D443Y 7/7 15 2184delA / D443Y 7/7 16 R347H / D443Y 9/7 17 seminal vesicles agenesia R117H / G1349D 7/7 18 R117H / G1244E 7/7 19 N1303K / P111L 9/7 20 chronic sinusitis, nasal polyps W1282X / D1152H 7/7 21 chronic sinusitis R347H / Y1092X 7/7 22 seminal vesicles agnesia 297-3C-GTT / 4279insA 7/7 23 G544V / F508C 7/7 24 D1152H / 2896insAG 7-9 25 F508 / - 9/5 26 F508 / - 9/5 27 F508 / - 9/5 28 F508 / - 9/5 29 F508 / - 9/5 30 chronic sinusitis, bronchitis F508 / - 9/5 31 sinusitis and allergy F508 / - 9/5 32 allergy F508 / - 9/5 33 F508 / - 9/5 34 F508 / - 9/5 35 F508 / - 9/5 36 F508 / - 9/5 37 bronchitis, asthma F508 / - 9/5 38 chronic sinusitis F508+A1067T / - 9/5 39 chronic sinusitis D1152H / - 7/5 40 2184delA / - 7/5 41 R764X / - 7/5 42 711+1G-GTT / - 7/5 43 F508 / - 9/7 44 F508 / - 9/7 45 F508 / - 9/7 46 F508 / - 9/9 47 R553X / - 7/7 48 -33G-GTA / - 7/7 49 K710X / - 7/7 50 - / - 5/5 51 - / - 5/7 52 - / - 5/7 53 - / - 7/7 54 - / - 7/7 55 - / - 7/7 56 - / - 7/7 57 - / - 7/7 58 - / - 7/7 59 - / - 7/7 60 - / - 7/7 61 - / - 7/9 62 - / - 7/9 63 NIDDb - / - 7/9 64 - / - 7/9 a : Cystic Fibrosis Transmembrane Regulator gene b : Non Insulino-Dependant Diabetis References Anguiano A, Oates RD, Amos JA, Dean M, Gerrard B, Stewart C, Maher TA, White MB, Milunsky A (1992) Congenital absence of the vas deferens: a primarily genital form of cystic fibrosis. Login to comment

PMID: 9439669 [PubMed] Casals T et al: "High heterogeneity for cystic fibrosis in Spanish families: 75 mutations account for 90% of chromosomes."

No. Sentence Comment

21 The ∆F508 (Rommens et al. 1990) and G542X (Kerem et al. 1990; Gasparini et al. 1992) mutations were analysed in all patients as they are the most common mutations in the population, 50.6% and 8.0%, re- Teresa Casals · Maria D. Ramos · Javier Giménez · Sara Larriba · Virginia Nunes · Xavier Estivill High heterogeneity for cystic fibrosis in Spanish families: 75 mutations account for 90% of chromosomes Hum Genet (1997) 101:365-370 (c) Springer-Verlag 1997 Received: 3 July 1997 / Accepted: 20 August 1997 ORIGINAL INVESTIGATION T. Casals · M. D. Ramos · J. Giménez · S. Larriba · V. Nunes · X. Login to comment
31 Only ten mutations have a frequency of 1% and above: ∆F508 (53.2%), G542X (8.4%), N1303K (2.6%), 1811+1.6kbA→G (1.8%), 711+1G→T (1.7%), R1162X and R334W (1.6%), R1066C, 1609delCA and Q890X (1.0%). Login to comment
33 Eight mutations have frequencies 366 Table 1 Seventy-five CFTR mutations identified in 640 Spanish families with cystic fibrosis (CF) Mutation Exon/intron CF alleles % ∆F508 E.10 681 53.20 G542X E.11 108 8.43 N1303K E.21 34 2.65 1811+1.6kbA→Ga I.11 24 1.87 711+1G→T I.5 22 1.71 R1162Xa E.19 21 1.64 R334Wa E.7 21 1.64 R1066C E.17b 14 1.09 1609delCAa E.10 13 1.01 Q890X E.15 13 1.01 G85E E.3 12 0.94 712-1G→Ta I.5 11 0.86 2789+5G→A I.14b 11 0.86 ∆I507 E.10 10 0.78 W1282X E.20 10 0.78 2869insGa E.15 9 0.70 L206W E.6a 7 0.54 R709X E.13 7 0.54 621+1G→T I.4 6 0.47 3272-26A→G I.17a 6 0.47 R347H E.7 5 0.39 2183AA→G E.13 5 0.39 K710X E.13 5 0.39 2176insC E.13 5 0.39 3849+10kbC→T I.19 5 0.39 P205Sa E.6a 4 0.31 1078delT E.7 4 0.31 R553X E.11 4 0.31 G551D E.11 4 0.31 1812-1G→Aa I.11 4 0.31 CFdel#1a E.4-7/11-18 4 0.31 V232D E.6a 3 0.23 936delTAa E.6b 3 0.23 1717-8G→A I.10 3 0.23 1949del84 E.13 3 0.23 W1089X E.17b 3 0.23 R347P E.7 3 0.23 del E.3a E.3 2 0.16 R117H E.4 2 0.16 L558S E.11 2 0.16 A561E E.12 2 0.16 2603delT E.13 2 0.16 Y1092X E.17b 2 0.16 Q1100Pa E.17b 2 0.16 M1101K E.17b 2 0.16 delE.19a E.19 2 0.16 G1244E E.20 2 0.16 P5La E.1 1 0.08 Q30Xa E.2 1 0.08 G85Va E.3 1 0.08 E92Ka E.4 1 0.08 A120Ta E.4 1 0.08 I148T E.4 1 0.08 711+3A→Ta I.5 1 0.08 H199Y E.6a 1 0.08 875+1G→A I.6a 1 0.08 Table 1 (continued) Mutation Exon/intron CF alleles % 1717-1G→A I.10 1 0.08 L571S E.12 1 0.08 T582Ra E.12 1 0.08 E585X E.12 1 0.08 1898+3A→G I.12 1 0.08 G673X E.13 1 0.08 E692Xa E.13 1 0.08 R851X E.14a 1 0.08 R851La E.14a 1 0.08 A1006E E.17a 1 0.08 L1065Ra E.17b 1 0.08 F1074La E.17b 1 0.08 R1158X E.19 1 0.08 3667del4a E.19 1 0.08 3860ins31a E.20 1 0.08 3905insT E.20 1 0.08 4005+1G→A I.20 1 0.08 Q1281Xa E.20 1 0.08 Q1313X E.21 1 0.08 Known mutations (75) 1155 90.23 Unknown mutations 125 9.77 a Mutations discovered by the CF group of the Medical and Molecular Genetics Centre - IRO, Barcelona, Spain that range between 0.5% and 0.9%, representing 6.0% of the CF chromosomes. Login to comment
43 The G85V mutation was identified in a patient who carries the G542X mutation on the maternal CF allele. Login to comment

PMID: 9429141 [PubMed] el-Harith EA et al: "Novel and characteristic CFTR mutations in Saudi Arab children with severe cystic fibrosis."

No. Sentence Comment

26 Deletions of two or more base pairs were screened for by electrophoresis using a native 12% polyacrylamide gel. The 20 common CFTR mutations that were screened for were AF508, AI507, 1677delTA, R347P, R347H, R553X, G551D, G542X, N1303K, 3849+1OKbC-8'T, R334W, I336K, 2789+5G-A, 1717-1G-A, 3272- 26A- G, Y1092X, 2143delT, W1282X, RI 17H, and the 5T allele. Login to comment
49 For direct mutation analyses, PCR products were digested with the respective restriction enzyme and the fragments were separated by electrophoresis using a 3% NuSieve/i % SeaKem agarose gel. Mutagenesis primers were designed for some mutations (Ri17H, 1717-lG-A, G542X, 2143delT, 3272-26A-.G, and N1303K) to create artifi- shown). Login to comment

PMID: 9345100 [PubMed] Meschede D et al: "CFTR gene mutations in men with bilateral ejaculatory-duct obstruction and anomalies of the seminal vesicles."

No. Sentence Comment

23 Direct testing by allele-specific amplification, heteroduplex analysis, or by restriction analysis was performed in all patients, for detection of the following CFTR gene mutations: R117H, R347P, DI507, DF508, 1717-1 GrA, G542X, G551D, R553X, 3849ϩ10 kB, W1282X, and N1303K. Login to comment
22 DNA was isolated from peripheral lymphocytes, and target sequences were amplified by PCR. Direct testing by allele-specific amplification, heteroduplex analysis, or by restriction analysis was performed in all patients, for detection of the following CFTR gene mutations: R117H, R347P, DI507, DF508, 1717-1 GrA, G542X, G551D, R553X, 3849af9;10 kB, W1282X, and N1303K. Login to comment

PMID: 9511934 [PubMed] Brown CR et al: "Strategies for correcting the delta F508 CFTR protein-folding defect."

No. Sentence Comment

37 Howard and his colleagues have shown that treatment of cells expressing some of these truncation mutants (e.g., G542X and R553X) with different aminoglycoside antibiotics results in "translational read-through" and the production of low levels of a full-length and functional CFTR protein (Howard et al., 1996). Login to comment

PMID: 9272157 [PubMed] Dork T et al: "Distinct spectrum of CFTR gene mutations in congenital absence of vas deferens."

No. Sentence Comment

43 This initial screening included the mutations ∆F508, G542X, R553X, G551D, N1303K, 1717-1 G→A, 3272-26 A→G, Y1092X, 2143delT, R347P, R347H, R334W, I336K, R117H, R117C, 2789+5 G→A, 3849+10kB C→T and the "5T" allele, the latter two splice variants being tested according to the instructions of Highsmith et al. (1994) and Chillón et al. (1995). Login to comment
69 Only four other common CF mutations were found in more than one family by this initial screening: 2789+5 G→A on 4 alleles, R347H on 3 alleles, G542X and 3272-26 A→G each on 2 alleles (Table 1). Login to comment
86 The V938G substitution was identified in two unrelated patients, one homozygote with unilateral ab- 368 Table 1A Frequency distribution and haplotypes of CFTR mutations in 106 CAVD patients Mutationa Nucleotide changesb Locationc Frequencyd Haplotypee Referencef 174delA deletion of A at 174 exon 1 1 D3 This study E56K G→A at 298 exon 3 1 B3 This study D58N G→A at 304 exon 3 1 C2 This study D110H G→A at 460 exon 4 2 C2 Dean et al. (1990) R117H G→A at 482 exon 4 24 B6 Dean et al. (1990) A120T G→A at 490 exon 4 1 n.p. Chillón et al. (1994) ̃L138 insertion of CTA after 546 exon 4 1 A2 This study L206W T→G at 749 exon 6a 1 B8 Claustres et al. (1993) M265R T→G at 926 exon 6b 1 A2 Schwarz et al. (pers. comm.) R297W C→T at 1021 exon 7 1 C2 This study 1078delT deletion of T at 1078 exon 7 1 C2 Claustres et al. (1992) R334W C→T at 1132 exon 7 1 B1 Gasparini et al. (1991) R334L G→T at 1133 exon 7 1 D3 This study I336K T→A at 1139 exon 7 1 A2 Cuppens et al. (1993) R347H G→A at 1172 exon 7 3 D1 Cremonesi et al. (1992) L375F A→C at 1257 exon 8 1 B3 Jézéquel et al. (1996) ∆F508 deletion of 3 bp between 1652-1655 exon 10 57 B1 Kerem et al. (1989) G542X G→T at 1756 exon 11 2 B1 Kerem et al. (1990) R553X C→T at 1789 exon 11 1 A4 Cutting et al. (1990) L568F G→T at 1836 exon 12 1 B3 This study 2184insA insertion of A at 2184 exon 13 1 D3 Dörk et al. (1994b) 2789+5 G→A G→A at 2789+5 intron 14b 4 D3 Highsmith et al. (1997) R933S A→T at 2931 exon 15 1 n.p. Login to comment
137 Complex alleles are indicated a One CF allele with R75X and 125G→C b One CBAVD allele with R75Q and R933S c One CBAVD allele with 5T and Q1352H d Two CF alleles with F508C and S1251N e One CF allele with 1716G→A and L619S f G576A and R668C were linked on two CBAVD and three CF alleles, whereas two additional CF alleles carried R668C together with the 3849+10kB C→T mutation (Dörk and Stuhrmann 1995) 371 Table 3 CFTR mutation genotypes in 106 males with CAVD Genotype PolyT Frequency Ethnic descent Diagnosis ∆F508/R117H 9/7 21 German, Austrian 20 CBAVD, 1 CUAVD ∆F508/5T 9/5 9 German, Austrian 8 CBAVD, 1 CUAVD ∆F508/F508C 9/7 3 German CBAVD ∆F508/R347H 9/9 2 German CBAVD ∆F508/1716 G→A 9/7 2 German CBAVD ∆F508/3272-26 A→G 9/7 2 German CBAVD ∆F508/E56K 9/7 1 German CBAVD ∆F508/M265R 9/7 1 German-Portuguese CBAVD ∆F508/R334W 9/9 1 German CBAVD ∆F508/T351S 9/9 1 German CBAVD ∆F508/L375F 9/7 1 Volga German CBAVD ∆F508/G576A & R668C 9/7 1 German CBAVD ∆F508/R933S 9/7 1 German CBAVD ∆F508/L997F 9/9 1 German CBAVD ∆F508/Y1032C 9/7 1 German CBAVD ∆F508/D1152H 9/7 1 German CBAVD ∆F508/K1351E 9/7 1 German CBAVD ∆F508/D1377H 9/7 1 Portuguese CBAVD ∆F508/L1388Q 9/7 1 German CBAVD ∆F508/unknown 9/7 4 German 3 CBAVD, 1 CUAVD 5T/5T 5/5 2 German CBAVD 5T/G542X 5/9 2 German, Turkish CBAVD 5T/D58N 5/7 1 Lebanese CBAVD 5T/̃L138 5/7 1 German-Polish CBAVD 5T/1078delT 5/7 1 German CBAVD 5T/R553X 5/7 1 German CBAVD 5T/2184insA 5/7 1 Turkish CBAVD 5T/D979A 5/7 1 Vietnamese CBAVD 5T/D1152H 5/7 1 Turkish CBAVD 5T/3659delC 5/7 1 German CBAVD 5T/S1235R 5/7 1 Greek CBAVD 5T/W1282X 5/7 1 German CBAVD 5T & Q1352H/ R297W & Q1352H 5/7 1 Vietnamese CBAVD 5T/unknown 5/7 1 German CBAVD R117H/L206W 7/9 1 German CBAVD R117H/2789+5 G→A 7/7 1 German CBAVD R117H/unknown 7/7 1 German CBAVD 2789+5 G→A/2789+5 G→A 7/7 1 Lebanese CBAVD 2789+5 G→A/L973F 7/7 1 German CBAVD V938G/V938G 7/7 1 Greek CBAVD V938G/174delA 7/7 1 German CBAVD D110H/D110H 7/7 1 Turkish CBAVD R334L/I336K 7/7 1 German CBAVD R347H/N1303K 9/9 1 German CBAVD L568F/D1152H 7/7 1 Turkish CBAVD 3272-26 A→G/V1153E 7/7 1 German CBAVD R75Q/unknown 7/7 1 German CBAVD A120T/unknown 9/7 1 German CBAVD 1716G→A/unknown 7/7 1 German CBAVD G576A & R668C/unknown 7/7 1 German CBAVD 2752-15 C→G/unknown 7/7 1 Iranian CBAVD Unknown/unknown 17 German, Turkish 7 CBAVD and 1 CUAVD without observed renal agenesis, 9 CBAVD with renal agenesis allele and the R297W mutation on a homozygous Q1352H background may then reduce CFTR function to a disease-causing level. Login to comment
145 Maldigestion 13 25 5T/D58N 184 99 55 - 14 34 5T/̃L138 177 80 53 - 15 33 5T/1078delT 187 87 56 Recurrent bronchitis 16 31 5T/G542X 181 85 79 - 17 31 5T/2184insA n.d. n.d. 60 Borderline pancreatic sufficiency 18 31 5T/D979A n.d. n.d. 55 Recurrent infections, FEVI 76% 19 29 5T/D1152H n.d. n.d. 57 - 20 32 5T/W1282X 180 76 n.d. Recurrent infections, nasal polyposis 21 37 5T/unknown 180 74 n.d. Nasal polyposis 22 28 D110H/D110H 175 80 n.d Asthma bronchiale, obstipation 23 33 R334L/I336K 170 65 n.d. Recurrent infections, nasal polyposis, maldigestion, salt depletion episodes 24 35 N1303K/R347H 167 77 93 - 25 30 V938G/174delA n.d. n.d. 42 - 26 29 V938G/V938G 197 115 n.d. Asthma bronchiale Fig.2 Spectrum of CFTR mutation genotypes in CF patients (left) and in patients with congenital absence of the vas deferens (right). Login to comment

PMID: 9363704 [PubMed] Pauer HU et al: "Relevance of genetic counselling in couples prior to intracytoplasmic sperm injection."

No. Sentence Comment

25 Patients whose history or physical examination showed a possible diagnosis of CBAVD were typed for 19 additional CFTR mutations (e.g. R117H, Introduction R347P, 1717-1, G542X, G551D, R553X, W1282X and N1303K), including an intronic polymorphism (5T allele) which leads to reducedThe development of intracytoplasmic sperm injection (ICSI) for splicing efficiency of the CFTR mRNA (Chillo´n et al., 1995). Login to comment
24 Patients whose history or physical examination showed a possible diagnosis of CBAVD were typed for 19 additional CFTR mutations (e.g. R117H, Introduction R347P, 1717-1, G542X, G551D, R553X, W1282X and N1303K), including an intronic polymorphism (5T allele) which leads to reduced The development of intracytoplasmic sperm injection (ICSI) for splicing efficiency of the CFTR mRNA (Chillo &#b4;n et al., 1995). Login to comment

PMID: 9271620 [PubMed] Kerem E et al: "A missense cystic fibrosis transmembrane conductance regulator mutation with variable phenotype."

No. Sentence Comment

126 Several genotype-phenotype studies including the CF genotype-phenotype consortium have shown that there are mutations like the ⌬F508,2,6,11 W1282X,3,6 G542X,6 N1303K,4,6 and R533X5,6 in which Ͼ95% of the patients had PI2-10 whereas others like the 3849ϩ10kb C-ϾT,7,8 A455E15 Fig 1. Login to comment

PMID: 9254853 [PubMed] Hergersberg M et al: "A new mutation, 3905insT, accounts for 4.8% of 1173 CF chromosomes in Switzerland and causes a severe phenotype."

No. Sentence Comment

17 Martin Hergersberg · Jaya Balakrishnan · Thomas Bettecken · Francoise Chevalier-Porst · Christian Brägger · René Burger · Inge Einschenk · Sabina Liechti-Gallati · Michael Morris · Daniel Schorderet · Francine Thonney · Hans Moser · Naseem Malik A new mutation, 3905insT, accounts for 4.8% of 1173 CF chromosomes in Switzerland and causes a severe phenotype Hum Genet (1997) 100:220-223 (c) Springer-Verlag 1997 Received: 17 February 1997 / Accepted: 26 March 1977 ORIGINAL INVESTIGATION M. Hergersberg (౧) · J. Balakrishnan · I. Einschenk Institut für Medizinische Genetik, Universität Zürich, Rämistrasse 74, CH-8001 Zurich, Switzerland Tel.: +411 257 25 35; Fax: +411 262 04 70; e-mail hergie@medgen.unizh.ch T. Bettecken · S. Liechti-Gallati · H. Moser Universitäts-Kinderklinik, Bern, Switzerland F. Chevalier-Porst Hôpital Debrousse, Lyon, France C. Brägger · R. Burger Universitäts-Kinderklinik, Zurich, Switzerland M. Morris Division de Génétique Médicale, Gèneve, Switzerland D. Schorderet · F. Thonney Division Autonome de Génétique Médicale, Lausanne, Switzerland N. Malik Abteilung für Medizinische Genetik, Universitätskinderklinik, Basel, Switzerland Materials and methods Patients and families All blood samples received by the five Swiss University Centres of medical genetics for mutation analysis in the CFTR gene were screened for the eight mutations ∆F508, R553X, 1717-1G→A, G542X, N1303K, W1282X, R347P and 3905insT (Table 1). Login to comment
42 Using this method, the 3905insT mutation was found on 56 (4.8%) of "Swiss" CF chromosomes, but was not detected in more than 400 normal chromosomes, in more than 200 CF chromosomes with the ∆F508 mutation and in numerous CF chromosomes 221 Table 1 The frequency of eight common cystic fibrosis (CF) mutations among 1173 CF mutations in Switzerland Mutation Number of CF Frequency chromosomes (%) ∆F508 841 71.7 3905insT 56 4.8 R553X 43 3.7 1717-1G→A 39 3.3 G542X 23 2.0 N1303K 17 1.4 W1282X 13 1.1 R347P 7 0.6 Other mutations 21 1.9 Total 1060 90.4 Unidentified mutations 113 9. Login to comment

PMID: 9216450 [PubMed] Braun A et al: "Detecting CFTR gene mutations by using primer oligo base extension and mass spectrometry."

No. Sentence Comment

74 PROBE was also used for simultaneous (biplex) detection of the CFTR gene exon 11 G542X and R553X mutations in two patients. Login to comment
111 a, heterozygous G542X; homozygous wild-type at codon 553. b, homozygous wild-type at codon 542; heterozygous R53X. Login to comment

PMID: 9216449 [PubMed] Heinonen P et al: "Simple triple-label detection of seven cystic fibrosis mutations by time-resolved fluorometry."

No. Sentence Comment

20 We utilized triple-label time-resolved fluorometry and short, allele-specific oligonucleotide probes to detect ⌬F508, G1717 3A, G542X, R553X, 3905 insertion T 1 Department of Biotechnology, University of Turku, FIN-20520 Turku, Finland. Login to comment
55 of hybridization wells Detection probe 5؅-3؅ sequence and label5؅-Primer 3؅-Primer ⌬F508 w 1 AAGCACAGTGGAAGAATTTC BioCTCTTCTAGTTGGCATGCT 2 Tb-(modC)20ATCATCTTTGGT m 3 Sm-(modC)20TATCAT∧TGGTGT w 1 BioGAGCATACTAAAAGTGACTC BioCATGAATGACATTTACAGCAA 1 Eu-(modC)20ATGTCCTATTAC G1717 3A m 3 Tb-(modC)20TAATAAGACATCT G542X w 1 BioGAGCATACTAAAAGTGACTC BioCATGAATGACATTTACAGCAA 2 Eu-(modC)20GGTCTTGGAGAA m 1 Tb-(modC)20GGTCTTTGAGAA R553X w 1 BioGAGCATACTAAAAGTGACTC BioCATGAATGACATTTACAGCAA 2 Sm-(modC)20GTCAACGAGCAA m 3 Eu-(modC)20TTGCTCATTGAC 3905insT w 2 BioCCTTATAGGTGGGCCTCT BioGCTAAGTCCTTTTGCTCAC 4 Tb-(modC)20AGCTTTTTT*GAG m 5 Sm-(modC)20CTCAAAAAAAGC W1282X w 2 BioCCTTATAGGTGGGCCTCT BioGCTAAGTCCTTTTGCTCAC 4 Eu-(modC)20TTCCTCCACTGT m 5 Eu-(modC)20CAGTGAAGGAAA N1303K w 2 AAGTATTTATTTTTTCTGGAACA BioTTCTTGATCACTCCACTGTT 4 Sm-(modC)20AAAACTTGGATC m 5 Tb-(modC)20AAAAAGTTGGAT Sequences, labels, and design of hybridization wells for wild-type specific (w) and mutant specific (m) detection probes for seven CFTR mutations. Login to comment
85 and type of label Optimal hybridization temperature,b,d °C Optimal probe conc.,b ng/well Hybridization sensitivity (target molecules/well)c,d Cross-reactivity,b,d % Maximal hybridization efficiency,b % ⌬F508 w 19Tb 31 2 4.1 ϫ 107 0.0 6.5 m 19Sm 24 5 1.2 ϫ 108 1.0 13.5 G1717 3A w 18Eu 17 5 5.9 ϫ 107 0.2 10.5 m 19Tb Ͻ10 5 5.6 ϫ 107 0.1 8.0 G542X w 18Eu 18-27 5 6.7 ϫ 107 0.4 5.5 m 19Tb 20 10 8.1 ϫ 107 0.5 2.5 R553X w 9Sm 32 2 3.2 ϫ 108 1.0 8.5 m 16Eu 22 1 2.2 ϫ 107 0.2 14.5 3905insT w 18Tb 25 5 1.8 ϫ 107 2.9 10.5 m 19Sm 22 2 1.8 ϫ 107 6.5 38.0 W1282X w 19Eu 22 1 3.2 ϫ 107 0.4 14.0 m 19Eu 20 2 1.7 ϫ 107 0.5 21.0 N1303K w 9Sm 31 10 6.4 ϫ 107 0.6 8.0 m 13Tb 27 2 3.1 ϫ 107 0.0 11.0 a For sequences, see Table 1. b Determined using 1 ϫ 1011 target molecules/well. Login to comment
88 probes specific for ⌬F508, G1717 3A, G542X, and R553X in wells 1-3, and the fragments amplified in PCR2 with probes specific for 3905insT, W1282X, and N1303K in wells 4 and 5 (Fig. 1). Login to comment
97 The mutations of interest were ⌬F508 in exon 10, G1717 3A, G542X, and R553X in exon 11, 3905insT and W1282X in exon 20, and N1303K in exon 21. Login to comment
110 The hybridization reactions were distributed as follows: wild-type G1717 3A probe and mutant G542X probe were hybridized in well 1, wild-type probes for ⌬F508, G542X, and R553X in well 2, and mutant probes for ⌬F508, G1717 3A, and R553X in well 3. Login to comment
132 The maximal efficiency varied from probe to probe between 2.5% (the mutant G542X probe) and 38% (the mutant 3905insT probe) (Table 2). Login to comment
148 A typical calibration curve for the wild-type G542X probe is shown in Fig. 4. Login to comment
155 Fig. 4 illustrates the cross-reactivity of the wild-type G542X probe with different target concentrations. Login to comment
162 Calibration curve and cross-reaction of wild-type G542X probe. Login to comment
163 Hybridization signals of wild-type G542X probe hybridized with different concentrations of wild-type specific synthetic target (F) and cross-reaction signals with mutant specific synthetic target (ࡗ) (background subtracted). Login to comment
167 Signal-to-noise ratio for wild/mutant ⌬F508 G1717 3A G542X R553X 3905insT W1282X N1303K w m w m w m w m w m w m w m Diagnosis Purified DNA samples 293 1.2 255 1.1 65 1.4 64 2.3 82 1.2 20 1.0 23 1.2 Normal 120 77 218 1.2 57 1.5 57 2.2 76 1.3 24 1.4 18 1.4 ⌬F508/unknown 2.2 166 236 1.1 73 2.7 62 3.0 78 1.4 25 1.6 15 2.0 ⌬F508/⌬F508 141 91 132 17 79 1.5 69 3.0 79 1.4 22 1.7 19 1.6 ⌬F508/G1717 3A 286 1.4 2.5 31 61 2.4 59 2.5 81 1.3 23 1.4 25 1.7 G1717 3A/G1717 3A 280 1.4 61 14 18 13 29 2.8 82 1.2 25 1.0 16 1.5 G1717 3A/G542X 220 1.8 265 1.5 73 1.6 40 36 78 1.3 19 1.4 13 2.0 ⌬F508/R553X 284 2.0 176 1.7 75 4.0 3.0 60 87 1.4 21 1.7 20 1.8 R553X/R553X 264 1.8 226 1.7 76 3.5 37 32 44 17 23 1.1 20 1.5 R553X/3905insT 104 67 214 2.3 46 2.3 48 3.5 44 16 22 1.6 15 1.9 ⌬F508/3905insT 154 97 268 1.5 68 1.5 62 3.2 74 1.8 11 33 21 0.9 ⌬F508/W1282X 310 1.2 294 1.1 83 2.5 73 2.4 78 1.3 18 1.5 6.4 40 N1303K/N1303K Blood spot samples 250 1.2 265 0.9 75 0.9 73 1.3 69 1.3 31 2.2 12 2.7 Normal 69 40 213 1.1 63 1.1 54 1.9 58 1.2 17 55 18 2.4 ⌬F508/W1282X 1.5 138 256 1.2 62 1.1 74 3.7 76 1.5 32 2.1 11 2.7 ⌬F508/⌬F508 96 48 304 1.0 96 12 76 2.2 82 1.5 31 2.9 13 3.2 ⌬F508/G542X Boldface numbers indicate signal-to-noise ratios considered positive. Login to comment
201 Results of DNA samples analyzed for seven CFTR mutations: 16 amplified samples, each plotted for seven mutations, ⌬F508 (ࡗ), G1717 3A (छ), G542X (f), R553X (Ⅺ), 3905insT (F), W1282X (E), and N1303K (‫. Login to comment

PMID: 9191467 [PubMed] Davies JC et al: "CFTR gene transfer reduces the binding of Pseudomonas aeruginosa to cystic fibrosis respiratory epithelium."

No. Sentence Comment

95 Twelve patients were homozygous for the dF508 mutation, six were compound heterozygotes with two identified mutations (d/G542X X 3, d/R347P, d/R117H, d/1717), 11 were heterozygous for dF508 with an unknown mutation, and in 3, the genotype was unknown. Login to comment

PMID: 9196095 [PubMed] Kerem E et al: "A cystic fibrosis transmembrane conductance regulator splice variant with partial penetrance associated with variable cystic fibrosis presentations."

No. Sentence Comment

70 The frequency of the 5T allele among normal chromosomes was significantly lower than its frequency among chromosomes carried by CF patients and patients with atypical TABLE 1 MUTATIONS AND POLYTHYMIDINE VARIANTS ON THE OTHER CHROMOSOME OF UNRELATED PATIENTS WITH 5T ALLELE Mutation CF and Atypical CF CBAVD Total AF508 4 8 12 W1282X 1 6 7 N1303K 0 2 2 G85E 1 1 2 D1152H 1 0 1 W 1089X 1 0 1 G542X 0 1 1 ST 0 3 3 7T' 7 9 16 9T* 2 2 4 Total 17 32 49 Definition of abbreviations: CF = cystic fibrosis; CBAVD = congenital bilateral aplasia of the vas deferens. Login to comment

PMID: 9164776 [PubMed] Gregg RG et al: "Newborn screening for cystic fibrosis in Wisconsin: comparison of biochemical and molecular methods."

No. Sentence Comment

52 Polyacrylamide gel electrophoresis of PCR-amplified DNA served to identify the ⌬F508 mutation.14 Mutations S549N, R553X, and G551D were screened by PCR amplification of exon 11, followed by restriction enzyme digests that are diagnostic of each mutation. Login to comment
57 Mutations, G542X, W1282X, R117H, R553X, N1303K, 1717-1G3A, R560T, and 621ϩ1G3T were analyzed by the ARMS procedure using published primers and conditions.18 A total of 360 patients were studied by multimutation analysis (80% of the Wisconsin CF population). Login to comment
123 Tested) Frequency (%) Theoretical Cumulative Detection† (%) Patients Missed in One Year‡ ⌬F508§ 513/720 71.25 91.74 1.32 G542X 17/162 3.02 93.38 1.05 W1282X 7/102 1.97 94.36 0.90 R117H 6/101 1.71 95.14 0.77 R553X 11/197 1.61 95.82 0.66 G551D 9/195 1.33 96.35 0.58 N1303K 3/100 0.86 96.67 0.53 1717 - 1G 3 A 2/99 0.58 96.88 0.49 R560T 2/106 0.54 97.06 0.47 621 ϩ 1G 3 T 3/163 0.53 97.25 0.44 S549N 0/196 0.0 97.25 0.44 * Chromosomes were analyzed on blood or cheek cell specimens obtained from 360 patients (80% of the total Wisconsin CF population), all of whom had a positive sweat test. Login to comment
140 They report results of adding DNA testing for the ⌬F508 mutation, and Ranieri et al15 also investigated adding three other CFTR mutations (G542X, R553X, and G551D) to the screen. Login to comment
152 DNA Analysis of Genotyped CF Patients in the US* n Percent ⌬F508 12701 67.7 G542X 403 2.2 G551D 357 1.9 W1282X 240 1.3 N1303K 223 1.2 R553X 157 0.8 3849 ϩ 10kbC 3 T 102 0.5 621 ϩ 1G 3 T 147 0.8 1717 - 1G 3 A 101 0.5 R117H 101 0.5 R334W 36 0.2 ⌬I507 42 0.2 R347P 37 0.2 R560T 23 0.1 R1162X 44 0.2 2789 ϩ 5G 3 A 25 0.1 A455E 16 0.1 3120 ϩ IG 3 A 14 0.0 S549N 12 0.0 711 ϩ IG 3 T 9 0.0 Other 178 0.9 Unidentified 3814 20.3 Total 18782 99.7† Patient Genotypes Allele 1/Allele 2 n % of Genotype ⌬F508/⌬F508 4573 48.7 ⌬F508/Known 1511 16.1 ⌬F508/Unknown 2044 21.8 Known/unknown 310 3.3 Known/known 223 2.4 Unknown/unknown 730 7.8 Total 9391 100.0 *Data from Cystic Fibrosis Registry, 1995; Annual Report. Login to comment
118 Tested) Frequency (%) Theoretical Cumulative Detectionߤ (%) Patients Missed in One Yearߥ DF508&#a7; 513/720 71.25 91.74 1.32 G542X 17/162 3.02 93.38 1.05 W1282X 7/102 1.97 94.36 0.90 R117H 6/101 1.71 95.14 0.77 R553X 11/197 1.61 95.82 0.66 G551D 9/195 1.33 96.35 0.58 N1303K 3/100 0.86 96.67 0.53 1717 2 1G 3 A 2/99 0.58 96.88 0.49 R560T 2/106 0.54 97.06 0.47 621 1 1G 3 T 3/163 0.53 97.25 0.44 S549N 0/196 0.0 97.25 0.44 * Chromosomes were analyzed on blood or cheek cell specimens obtained from 360 patients (80% of the total Wisconsin CF population), all of whom had a positive sweat test. Login to comment
135 They report results of adding DNA testing for the DF508 mutation, and Ranieri et al15 also investigated adding three other CFTR mutations (G542X, R553X, and G551D) to the screen. Login to comment
147 DNA Analysis of Genotyped CF Patients in the US* n Percent DF508 12701 67.7 G542X 403 2.2 G551D 357 1.9 W1282X 240 1.3 N1303K 223 1.2 R553X 157 0.8 3849 1 10kbC 3 T 102 0.5 621 1 1G 3 T 147 0.8 1717 2 1G 3 A 101 0.5 R117H 101 0.5 R334W 36 0.2 DI507 42 0.2 R347P 37 0.2 R560T 23 0.1 R1162X 44 0.2 2789 1 5G 3 A 25 0.1 A455E 16 0.1 3120 1 IG 3 A 14 0.0 S549N 12 0.0 711 1 IG 3 T 9 0.0 Other 178 0.9 Unidentified 3814 20.3 Total 18782 99.7ߤ Patient Genotypes Allele 1/Allele 2 n % of Genotype DF508/DF508 4573 48.7 DF508/Known 1511 16.1 DF508/Unknown 2044 21.8 Known/unknown 310 3.3 Known/known 223 2.4 Unknown/unknown 730 7.8 Total 9391 100.0 *Data from Cystic Fibrosis Registry, 1995; Annual Report. Login to comment

PMID: 9150159 [PubMed] Macek M Jr et al: "Identification of common cystic fibrosis mutations in African-Americans with cystic fibrosis increases the detection rate to 75%."

No. Sentence Comment

39 Mutation Analysis All patients were screened for the AF508 mutation and 15 common Caucasian CF mutations using a reverse dot strip hybridization system (Kawasaki et al. 1993) (R117H, 621+1G--T, R334W, R347P, A455E, A1507, 1717-1G-+A, G542X, S549N, GSS1D, R553X, R560T, 3849+10kbC-+T, W1282X, and N1303K) (Welsh et al. 1995) and a deep intron 11 splice-site mutation, 1811+1.6kbA-+G (Chillon et al. 1995). Login to comment
70 Finally, 13 mutations found in one patient each had been previously reported in Caucasian patients (Q98R, R352Q, V520F, 1812-1G--A, G542X, S549N, and Y913C) (Romey et al. 1995; Welsh et al. 1995) or in African-American patients (444delA, G480C, 1342-2delAG [originally reported as 1342-1G--+C], 2307insA, 3662delA, and W1316X) (Cutting et al. 1990b; White et al. 1991; Zielenski et al. Login to comment
86 The most common muta- Table 2 Distribution of CF Mutations in African-American and U.S.-Caucasian CF Patients African-American U.S. Caucasiana Mutation (n= 148) % (n = 8,714) % Caucasian mutations: AF508 71 48 5,769 66.2 R117H 0 0 47 .5 621+1 G--T 0 0 68 .8 R334W 1 .7 7 .1 R347P 0 0 24 .3 A455E 0 0 5 .1 AI507 1 .7 10 .1 1717-1 G-IA 1 .7 39 .5 G542X 1 .7 204 2.3 S549N 1 .7 4 .1 GS51D 1 .7 173 2.0 R553X (Caucasian)b 0 0 87 1.0 R560T 0 0 16 .2 3849+10kb C-T 0 0 51 .6 W1282X 0 0 235 2.7 N1303K 0 0 116 1.3 Subtotal 77 52 6,855 78.7 African-American mutations: 405+3 A-C 2 1.4 ... ... 444delA 1 .7 ... ... G480C 2 1.4 ... ... R553X (African)b 3 2.0 ... ... A559T 3 2.0 ... ... 2307insA 3 2.0 ... ... 3120+1 GC-A 18 12.2 ... ... S1255X 2 1.4 ... ... Subtotal 34 23 ... ... Total 111 75.0 6,855 78.7 NOTE.-Percentages are rounded. Login to comment
40 Mutation Analysis All patients were screened for the AF508 mutation and 15 common Caucasian CF mutations using a reverse dot strip hybridization system (Kawasaki et al. 1993) (R117H, 621+1G--T, R334W, R347P, A455E, A1507, 1717-1G-+A, G542X, S549N, GSS1D, R553X, R560T, 3849+10kbC-+T, W1282X, and N1303K) (Welsh et al. 1995) and a deep intron 11 splice-site mutation, 1811+1.6kbA-+G (Chillon et al. 1995). Login to comment
71 Finally, 13 mutations found in one patient each had been previously reported in Caucasian patients (Q98R, R352Q, V520F, 1812-1G--A, G542X, S549N, and Y913C) (Romey et al. 1995; Welsh et al. 1995) or in African-American patients (444delA, G480C, 1342-2delAG [originally reported as 1342-1G--+C], 2307insA, 3662delA, and W1316X) (Cutting et al. 1990b; White et al. 1991; Zielenski et al. Login to comment
87 The most common muta- Table 2 Distribution of CF Mutations in African-American and U.S.-Caucasian CF Patients African-American U.S. Caucasiana Mutation (n= 148) % (n = 8,714) % Caucasian mutations: AF508 71 48 5,769 66.2 R117H 0 0 47 .5 621+1 G--T 0 0 68 .8 R334W 1 .7 7 .1 R347P 0 0 24 .3 A455E 0 0 5 .1 AI507 1 .7 10 .1 1717-1 G-IA 1 .7 39 .5 G542X 1 .7 204 2.3 S549N 1 .7 4 .1 GS51D 1 .7 173 2.0 R553X (Caucasian)b 0 0 87 1.0 R560T 0 0 16 .2 3849+10kb C-T 0 0 51 .6 W1282X 0 0 235 2.7 N1303K 0 0 116 1.3 Subtotal 77 52 6,855 78.7 African-American mutations: 405+3 A-C 2 1.4 ... ... 444delA 1 .7 ... ... G480C 2 1.4 ... ... R553X (African)b 3 2.0 ... ... A559T 3 2.0 ... ... 2307insA 3 2.0 ... ... 3120+1 GC-A 18 12.2 ... ... S1255X 2 1.4 ... ... Subtotal 34 23 ... ... Total 111 75.0 6,855 78.7 NOTE.-Percentages are rounded. Login to comment

PMID: 9154877 [PubMed] Walker LC et al: "Relationship between airway ion transport and a mild pulmonary disease mutation in CFTR."

No. Sentence Comment

2 We also evaluated five patients possessing premature truncation mutations (G542X and R553X) for which an association with mild pulmonary disease has not been as well established. Login to comment
20 As a control, we measured airway ion transport in patients with the common R553X and G542X truncation mutations. Login to comment
25 The clinical features of the A455E, R553X, and G542X CF patients we studied are given in Table 1. Login to comment
31 Age (yr) Sex Genotype Pseudomonas Colonization % Predicted FVC 96 Predicted FEV, Sweat C1 (meq/L) PS versus PI* 1 121/2 F A455E/621 + 1G-T + 113 106 106 P1 2 111/2 F A455E/621 + 1G-*T - 109 101 97 PI 3 16 M AF508/A455E - 77 63 84 PS 4 16 F AF508/A455E - 123 120 59 PS 5 151/2 F AF508/A455E + 101 94 54 PS 6 21 M G551D/G542X + 56 26 84 PI 7 18 M AF508/G542X + 90 80 80 PI 8 16 M AF508/G542X + 121 110 132 PI 9 16 F R553X/G542X + 68 46 78 PI 10 18 M AF508/G542X + 51 41 100 PI 1685 * PS = pancreatic sufficient; PI = pancreatic insufficient terfly needle filled with a 4% agar/lactated Ringer's solution) was inserted subcutaneously in the dorsal aspect of the distal forearm or hand. Login to comment
59 RESULTS Table 1 summarizes clinical features of the A455E, G542X, and R553X CF patients we studied. Login to comment
67 Decisions regard- -10 26t5 mV -39*9 mVtt -57±5 mVtt -43*9 mVtt Control G542X or R553X A544E AF508 B 50 40 • C A PD 30 • (mV) • 20 • •• 10 ' • • o - t----------------------------- aj J0 mVtt -27±8 mVtt Control G542X or R553X A455E AF508 C -40 -30 1686 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL. 155 1997 A -60 -50 • t 1 ' PD max -40 I (mV) • • • -30 • • s-20 to mV L - - i--- --- - -- -------loses A Amilo,id Amilonde Amiloride Low CI' Low Cl* fenol lomV L l0 Sea --------------^--------- --------t- - --- -- - --------- l0 mV L ------^--- --------Y- -^ t t lOmV L 10Sa. Login to comment
71 Genotypes of the patients shown include B:A455E/621 + 1 G-*T; C:AF508/A455E; and D:R553X/G542X. Login to comment
77 The remainder of patients with the A455E mutation exhibited no response to low Cl- /isoproterenol, as in the tracing in Figure I.C. Figure 1D shows a tracing from a patient homozygous for truncation mutations within CFTR (G542X/R553X). Login to comment
80 Figure 2 shows a summary of the data from patients and healthy controls in the study, and describes the baseline PD during perfusion with lactated Ringer's solution (Figure 2A), -20 APD (mv) • -10 tl • 0•------'------------------s---------------------------------- --- 10 12t7 mV -2:4 rVtt -4t8 mVtt -5)mVtt Control G542X or R553X A455E AF508 Figure 2. Login to comment
93 In the A455E patients, the maximal PD during perfusion with lactated Ringer's solution and the change after amiloride were well within the range anticipated for the general CF population (Figure 2A and B; [6-21]). Login to comment
94 In the patients with CFTR truncations G542X or R553X, the magnitude of the amiloride-sensitive PD (Figure 2B) was less than in A455E or AF508 patients, although these measurements were still highly useful in discriminating all CF patient groups from individuals without CF (p < 0.01). Login to comment
19 As a control, we measured airway ion transport in patients with the common R553X and G542X truncation mutations. Login to comment
24 The clinical features of the A455E, R553X, and G542X CF patients we studied are given in Table 1. Login to comment
30 Age (yr) Sex Genotype Pseudomonas Colonization % Predicted FVC 96 Predicted FEV, Sweat C1 (meq/L) PS versus PI* 1 121/2 F A455E/621 + 1G-T + 113 106 106 P1 2 111/2 F A455E/621 + 1G-*T - 109 101 97 PI 3 16 M AF508/A455E - 77 63 84 PS 4 16 F AF508/A455E - 123 120 59 PS 5 151/2 F AF508/A455E + 101 94 54 PS 6 21 M G551D/G542X + 56 26 84 PI 7 18 M AF508/G542X + 90 80 80 PI 8 16 M AF508/G542X + 121 110 132 PI 9 16 F R553X/G542X + 68 46 78 PI 10 18 M AF508/G542X + 51 41 100 PI 1685 * PS = pancreatic sufficient; PI = pancreatic insufficient terfly needle filled with a 4% agar/lactated Ringer's solution) was inserted subcutaneously in the dorsal aspect of the distal forearm or hand. Login to comment
58 RESULTS Table 1 summarizes clinical features of the A455E, G542X, and R553X CF patients we studied. Login to comment
66 Decisions regard- -10 26t5 mV -39*9 mVtt -57&#b1;5 mVtt -43*9 mVtt Control G542X or R553X A544E AF508 B 50 40 ߦ C A PD 30 ߦ (mV) ߦ 20 ߦ ߦ ߦ 10 ' ߦ ߦ o - t---------------------------- - aj J0 mVtt -27&#b1;8 mVtt Control G542X or R553X A455E AF508 C -40 -30 1686 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL. 155 1997 A -60 -50 ߦ t 1 ' PD max -40 I (mV) ߦ ߦ ߦ -30 ߦ ߦ s -20 to mV L - - i--- --- - -- -------loses A Amilo,id Amilonde Amiloride Low CI' Low Cl* fenol lomV L l0 Sea --------------^--------- --------t- - --- -- - --------- l0 mV L ------^--- --------Y- -^ t t lOmV L 10Sa. Login to comment
70 Genotypes of the patients shown include B:A455E/621 + 1 G-*T; C:AF508/A455E; and D:R553X/G542X. Login to comment
76 The remainder of patients with the A455E mutation exhibited no response to low Cl- /isoproterenol, as in the tracing in Figure I.C. Figure 1D shows a tracing from a patient homozygous for truncation mutations within CFTR (G542X/R553X). Login to comment
79 Figure 2 shows a summary of the data from patients and healthy controls in the study, and describes the baseline PD during perfusion with lactated Ringer's solution (Figure 2A), -20 APD (mv) ߦ -10 tl ߦ 0ߦ------' ------------------s---------------------------------- --- 10 12t7 mV -2:4 rVtt -4t8 mVtt -5)mVtt Control G542X or R553X A455E AF508 Figure 2. Login to comment

PMID: 9194642 [PubMed] Mau UA et al: "Chromosomal findings in 150 couples referred for genetic counselling prior to intracytoplasmic sperm injection."

No. Sentence Comment

21 Mutation screening included δI507, δF508, in combination with other abnormalities of the semen 1717-1(G→A), G542X, G551D, R553X, W1282X, N1303K, R347P, (Bourrouillou et al., 1992). Login to comment

PMID: 9098486 [PubMed] Villalobos-Torres C et al: "Analysis of 16 cystic fibrosis mutations in Mexican patients."

No. Sentence Comment

14 According to data from the Cystic Fibrosis Genetic Analysis Consortium [1994] (CFGAC), the most frequent non-⌬F508 mutations are the following: G542X (2.4%), G551D (1.6%), N1303K (1.3%), W1282X (1.2%), R553X (0.7%), 621 + 1 G→T (0.7%), 1717 - 1 G→T (0.6%), R117H (0.3%), R1162X (0.3%), G85E (0.2%), R347P (0.2%), ⌬I507 (0.2%), and 3849 + 10 kb C→T (0.2%). Login to comment
44 All patients with two severe mutations suffered PI (⌬F508/G542X, G542X/S549N, and ⌬F508/⌬F508). Login to comment
47 Of the two G542X/unknown heterozygotes, one had PI and the other had pancreatic sufficiency (PS). Login to comment
54 The G542X mutation is second in frequency after ⌬F508, as has been reported worldwide and for Spain, where it has a frequency of 8.0% [Casals et al., 1993]; this is similar to the 4.8% value reported for Southern Europeans, specifically Italians [Nunes et al., 1991]. Login to comment
60 Mutation Frequency Data and Geographic Distribution of the Mutations Found in 80 Chromosomes From Mexican CF Patients Mutation Northeast n ‫ס‬ 54 Central n ‫ס‬ 16 Western n ‫ס‬ 10 Total n ‫ס‬ 80 CFGAC [1994] (%)n (%) n (%) n (%) n (%) ⌬F508 27 (50) 2 (12.5) 7 (70) 36 (45) 66 G542X 2 (3.7) 2 (12.5) 0 4 (5) 2.4 3849 + 10 kb C→T 1 (1.9) 0 1 (10) 2 (2.5) 0.2 N1303K 0 1 (6.25) 0 1 (1.25) 1.3 S549N 0 1 (6.25) 0 1 (1.25) 0.1 621 + 1 G→T 0 0 1 (10) 1 (1.25) 0.7 Othera 24 (44.4) 10 (62.5) 1 (10) 35 (43.7) Detected 30 (55.6) 6 (37.5) 9 (90) 45 (56.3) a Different from W1282X, R117H, R334W, R347P, A455E, ⌬I507, 1717 - 1 G→T, G551D, R553X, and R560T. Login to comment

PMID: 9138152 [PubMed] Castellani C et al: "CFTR mutations and IVS8-5T variant in newborns with hypertrypsinaemia and normal sweat test."

No. Sentence Comment

21 Initially we tested for AF508, Rl 162X, and N1303K, estimated by a cohort study7 to cover 61 % of CF chromosomes in our area; from March 1995 10 other mutations were included (2183AAG, 3849+1OKbCT, G542X, 1717-1GA, R553X, Q552X, G85E, 711+5GA, 3132delTG, Cystic Fibrosis Centre, Ospedale Civile Maggiore, Piazzale Stefani, 37126 Verona, Italy C Castellani A Bonizzato G Mastella Correspondence to: Dr Castellani. Login to comment
62 Sweat IRT Meconium chloride PolyT IRT retest Weight Z Subject Sex (ugll) lactase (Ulg) (mEqlkg) CFTR mutation genotype (pgll) score 1 F 134 0 6 AF508 7/9 67 1.47 2 M 95 0 28 AF508 7/9 3 F 408 0 7 2183AA-*G 7/7 14 -0.29 4 M 150 0.72 16 N1303K 7/9 19 -0.47 5 F 106 Unknown 18 R1162X 7/7 -6.38 6 M 131 0 22 N1303K 9/9 27 -0.54 7 M 106 0 21 AF508 7/9 34 0.11 8 F 100 0 15 AF508 5/9 37 -0.01 9 F 105 0 25 AF508 5/9 51 -0.15 10 F 100 0 24 R1162X 7/7 11 M 266 0 14 AF508 7/9 5 0.20 12 F 103 0 9 AF508 7/9 13 F 105 0 32 AF508 7/9 14 F 268 0 22 AF508 7/9 30 15 M 110 Unknown 33 R1162X 7/7 16 M 174 0 12 AF508 7/9 52 1.87 17 F 100 0 15 AF508 7/9 18 M 140 0 9 AF508 7/9 19 M 98 0 30 AF508 5/9 20 M 110 1.2 10 AF508 7/9 11 0.26 21 F 102 0 20 G542X 7/9 45 0.77 22 F 111 0 16 N1303K 7/9 23 F 100 0 16 AF508 7/9 54 -0.44 24 F 95 0 18 R553X 7/9 25 F 285 0 16 AF508 7/9 20 0.28 26 M 117 0 23 AF508 7/9 101 27 M 115 0 24 AF508 5/9 12 -0.4 28 F 236 0 8 AF508 7/9 21 0.26 29 M 192 0 19 N1303K 7/9 73 0.04 30 M 103 0 39 AF508 5/9 69 31 M 133 0 10 AF508 7/9 65 1.17 32 M 144 0 30 R1162X 7/7 74 -0.83 33 F 123 0 20 AF508 7/9 66 -0.02 34 F 100 Unknown 30 AF508 5/9 65 35 M 134 0 28 AF508 7/9 36 M 294 0.8 12 R553X 7/7 37 M 102 Unknown 32 2789+5G-9A 7/7 38 F 114 0 36 AF508 7/9 39 M 123 0 9 R1162X 7/7 51 -0.36 40 F 118 0 33 AF508 5/9 16 0.18 41 M 134 0 10 AF508 7/9 15 1.36 42 M 97 0 9 AF508 7/9 43 M 98 1.71 31 AF508 7/9 44 F 122 Unknown 23 AF508 7/9 45 F 101 0 23 AF508 9/9 show mild biological abnormalities as early as the first days of life. Login to comment
61 Sweat IRT Meconium chloride PolyT IRT retest Weight Z Subject Sex (ugll) lactase (Ulg) (mEqlkg) CFTR mutation genotype (pgll) score 1 F 134 0 6 AF508 7/9 67 1.47 2 M 95 0 28 AF508 7/9 3 F 408 0 7 2183AA-*G 7/7 14 -0.29 4 M 150 0.72 16 N1303K 7/9 19 -0.47 5 F 106 Unknown 18 R1162X 7/7 -6.38 6 M 131 0 22 N1303K 9/9 27 -0.54 7 M 106 0 21 AF508 7/9 34 0.11 8 F 100 0 15 AF508 5/9 37 -0.01 9 F 105 0 25 AF508 5/9 51 -0.15 10 F 100 0 24 R1162X 7/7 11 M 266 0 14 AF508 7/9 5 0.20 12 F 103 0 9 AF508 7/9 13 F 105 0 32 AF508 7/9 14 F 268 0 22 AF508 7/9 30 15 M 110 Unknown 33 R1162X 7/7 16 M 174 0 12 AF508 7/9 52 1.87 17 F 100 0 15 AF508 7/9 18 M 140 0 9 AF508 7/9 19 M 98 0 30 AF508 5/9 20 M 110 1.2 10 AF508 7/9 11 0.26 21 F 102 0 20 G542X 7/9 45 0.77 22 F 111 0 16 N1303K 7/9 23 F 100 0 16 AF508 7/9 54 -0.44 24 F 95 0 18 R553X 7/9 25 F 285 0 16 AF508 7/9 20 0.28 26 M 117 0 23 AF508 7/9 101 27 M 115 0 24 AF508 5/9 12 -0.4 28 F 236 0 8 AF508 7/9 21 0.26 29 M 192 0 19 N1303K 7/9 73 0.04 30 M 103 0 39 AF508 5/9 69 31 M 133 0 10 AF508 7/9 65 1.17 32 M 144 0 30 R1162X 7/7 74 -0.83 33 F 123 0 20 AF508 7/9 66 -0.02 34 F 100 Unknown 30 AF508 5/9 65 35 M 134 0 28 AF508 7/9 36 M 294 0.8 12 R553X 7/7 37 M 102 Unknown 32 2789+5G-9A 7/7 38 F 114 0 36 AF508 7/9 39 M 123 0 9 R1162X 7/7 51 -0.36 40 F 118 0 33 AF508 5/9 16 0.18 41 M 134 0 10 AF508 7/9 15 1.36 42 M 97 0 9 AF508 7/9 43 M 98 1.71 31 AF508 7/9 44 F 122 Unknown 23 AF508 7/9 45 F 101 0 23 AF508 9/9 show mild biological abnormalities as early as the first days of life. Login to comment

PMID: 9012419 [PubMed] Slatkin M et al: "Estimating the age of alleles by use of intraallelic variability."

No. Sentence Comment

5 The method is applied to two alleles at the cystic fibrosis (CFTR) locus, AF508 and G542X, for which intraallelic variability at three intronic microsatellite loci has been examined. Login to comment
6 Our results indicate that G542X is somewhat older than AF508. Although absolute estimates depend on the mutation rates at the microsatellite loci, our results support the hypothesis that AF508 arose <500 generations (- 10,000 years) ago. Login to comment
46 Finally, we apply this method to estimate the ages of two alleles of the cystic fibrosis (CF) locus, AF508 and G542X. Login to comment
79 Figure 2c shows 1 as a function of t1 with parameters appropriate for a second allele of cystic fibrosis, G542X. Login to comment
83 Solely on the basis of on the observed frequencies of the two alleles, AF508 then appears to be somewhat older than G542X. Login to comment
84 The estimated population frequency of AF508 is higher than that of G542X, and this conclusion agrees with the general view that more frequent alleles are likely to be older. Login to comment
91 With mutation rate g, the number of segregating sites within the allelic class, S is a Poisson distributed random variable with mean pT, where T is the total length of the intraallelic gene genealogy (see, -8 -8.25 -8.5 -8.75 _9 -9.25 -9.5 -9.75 a 2000 2200 2400 2600 2800 3000 -5 -5.25 -5.5 -5.75 e -6 -6.25 -6.5 -6.75 1200 1400 1600 1800 2000 tl 350 400 450 500 550 600 650 tl Figure 2 Log-likelihood (1) of the observed number of copies of the AF508 and G542X mutations of the CF gene as a function of the time of origin of each mutation (tj) measured in units of generations. Login to comment
96 Panel c shows I as a function of t1 for the G542X allele with 4 = 0.005, N = 3 X 108, and f = 0.00014. Login to comment
98 Panel d shows I as a function of t1 for the G542X allele with 4 = 0.02 and the other parameters as given above. Login to comment
223 We can apply our method to another mutation of CFTR, G542X, a nonsense mutation in exon 11, that has been assessed by Casals et al. Login to comment
229 The frequency of G542X is much smaller than AF508, making up 8% of the CF alleles found in a survey of Spain. Login to comment
230 The frequency of G542X varies with location in Spain (Casals et al. 1993), but for the purposes of our analysis we will assume a frequency of .03 x .08 = .0024 in a random sample of the Spanish population. Login to comment
233 (1993) suggest the geographic distribution supports the introduction of G542X from North Africa between 2,000 and 3,000 years ago, which implies that the appropriate population for analysis may be much larger. Login to comment
236 Figure 4 shows the likelihood curves for four combinations of parameter values for G542X. Login to comment
237 These figures, and others not shown, indicate that G542X is somewhat -70 -75 -80 -85 -90 -95 e e - - --L- -13 -14 -15 -16 -17 e a -14r -16 -18 -20 -22 -24 0 100 200 300 400 b 0 50 100 150 200 50 100 150 200 250 tl tl Figure 4 Log-likelihood (1) of the observed number of copies (i = 62) and segregating sites (S = 5) for the G542X allele of CF. Login to comment
246 older than AF508. Although many fewer copies were examined for the G542X allele, the relative amount of intraallelic variability is slightly larger than that found for the AF508 allele. Login to comment
247 The ratio of estimated ages depends on the values of unknown parameters, but, if we assume the same value of 4 for both alleles, then G542X appears to be -1.5-3 times older than AF508. Login to comment
248 If we assume that the value of 4 for G542X is lower than for AF508, reflecting the possibility that AF508 may have a heterozygote advantage that G542X lacks, then the ratio of the ages would be even greater. Login to comment
250 Because G542X is in much lower frequency than AF508, (8) implies that it is younger. Login to comment
80 Figure 2c shows 1 as a function of t1 with parameters appropriate for a second allele of cystic fibrosis, G542X. Login to comment
85 The estimated population frequency of AF508 is higher than that of G542X, and this conclusion agrees with the general view that more frequent alleles are likely to be older. Login to comment
92 With mutation rate g, the number of segregating sites within the allelic class, S is a Poisson distributed random variable with mean pT, where T is the total length of the intraallelic gene genealogy (see, -8 -8.25 -8.5 -8.75 _9 -9.25 -9.5 -9.75 a 2000 2200 2400 2600 2800 3000 -5 -5.25 -5.5 -5.75 e -6 -6.25 -6.5 -6.75 1200 1400 1600 1800 2000 tl 350 400 450 500 550 600 650 tl Figure 2 Log-likelihood (1) of the observed number of copies of the AF508 and G542X mutations of the CF gene as a function of the time of origin of each mutation (tj) measured in units of generations. Login to comment
97 Panel c shows I as a function of t1 for the G542X allele with 4 = 0.005, N = 3 X 108, and f = 0.00014. Login to comment
99 Panel d shows I as a function of t1 for the G542X allele with 4 = 0.02 and the other parameters as given above. Login to comment
224 We can apply our method to another mutation of CFTR, G542X, a nonsense mutation in exon 11, that has been assessed by Casals et al. Login to comment
231 The frequency of G542X varies with location in Spain (Casals et al. 1993), but for the purposes of our analysis we will assume a frequency of .03 x .08 = .0024 in a random sample of the Spanish population. Login to comment
234 (1993) suggest the geographic distribution supports the introduction of G542X from North Africa between 2,000 and 3,000 years ago, which implies that the appropriate population for analysis may be much larger. Login to comment
238 These figures, and others not shown, indicate that G542X is somewhat -70 -75 -80 -85 -90 -95 e e - - - -L- -13 -14 -15 -16 -17 e a -14r -16 -18 -20 -22 -24 0 100 200 300 400 b 0 50 100 150 200 50 100 150 200 250 tl tl Figure 4 Log-likelihood (1) of the observed number of copies (i = 62) and segregating sites (S = 5) for the G542X allele of CF. Login to comment
249 If we assume that the value of 4 for G542X is lower than for AF508, reflecting the possibility that AF508 may have a heterozygote advantage that G542X lacks, then the ratio of the ages would be even greater. Login to comment
251 Because G542X is in much lower frequency than AF508, (8) implies that it is younger. Login to comment

PMID: 9039981 [PubMed] Antinolo G et al: "Genotype-phenotype relationship in 12 patients carrying cystic fibrosis mutation R334W."

No. Sentence Comment

19 Patients were diagnosed as either pancreatic sufficient group.bmj.comon October 25, 2012 - Published byjmg.bmj.comDownloaded from Antinolo, Borrego, Gili, Dapena, Alfageme, Reina Table 1 Clinical characteristics of 12 patients with R334Wmutation Patients 1 2 3 4 5 6 7 8 9 10 11 12 Genotype Sex Current age Age at diagnosis Age at first clinical symptoms First clinical symptoms Sweat ClF mEq/l Weight* (%) Chrispin-Norman Schwachman-Kulcycki FEV1 % predicted FVC % predicted Lung colonisation (LC) Age of onset of LC Meconium ileus Dehydration Pancreatic insufficiency (PI) Age of onset ofPI Sterility R334W/ AF508 F 3 y 7 mth 5 mth 3 mth Pulmonary/ pancreatic 90 100 4 90 No R334W/ AF508 M 27 y R334W/ AF508 F 2 y 5 mth 15y 5mth I y 4 mth 5 mth R334W/ AF508 M R334W/ AF508 F R334W/ AF508 M R334W/ R334W/ G542X R1 162X F F 25y 17y 59y 1Oy9 23y mth 20y 2y 49y 5y6mth 15y 4y 3mth 35y 8y I y R334W/ del84 F 3 y 3 mth R334W/ R334W/ R334W/ G542X G542X G542X F F F 27 y 25y 23y 15mth 25y 24y 21y 4mth 5y 17y Pulmonary Dehydration Dehydration Pulmonary Pancreatic Pulmonary Dehydration Dehydration Pulmonary Pulmonary Asymptomatic 90 80 100 105 110 110 100 85 100 100 100 100 100 115 90 89 95 76 89 116 115 121 20 2 23 65 100 95 65 70 95 50 95 85 90 95 24 82 41 44 27 74 85 91 43 91 51 60 43 82 84 97 Yes No No Yes Yes No Yes No No No No - 15y No No Yes Yes Yes Yes 3 mth - - 17y 58y - 14y - - - - No No Yes No No No No No No No Yes Yes Yes No No Yes Yes No No No No No No Yes No No No No Yes No 26y - - - - Yes - Yes - Yes - - - 24y - - - No No No * Weight expressed as a percentage of ideal weight for height. Login to comment
24 Six patients were compound heterozygotes for R334W and AF508, four for R334W and G542X, one for R334W and 1949del84, and one for R334W and R1162X. Login to comment

PMID: 9401006 [PubMed] Shrimpton AE et al: "Cystic fibrosis mutation frequencies in upstate New York."

No. Sentence Comment

84 % Comment 3 G85E 1 1 0.5 4 R117H 1 1 0.5 i4 621 + 1,G>T 1 2 3 1.5 5 711 + 1,G>T 1 1 0.5 6b N287Y 1 1 0.5 Novel 7 1154insTC 2 2 1.0 8 1259insA 1 1 0.5 Novel 9 A455E 1 1 0.5 10 Delta F508 109 39 148 74.0 10 1609delCA 1 1 0.5 Spanish i10 1717-1,G>A 3 3 1.5 11 G542X 2 1 3 1.5 11 G551D 3 3 1.5 11 R553X 4 4 2.0 i12 1898+1,G>A 2 2 1.0 13 2143delT 1 1 0.5 13 2184delA+G>A 1 1 0.5 i14 2789+5,G>A 2 2 1.0 17b R1070P 1 1 0.5 Novel 17b Y1092X(C>A) 2 2 1.0 French Canadian (Rozen et al., 1992) 17b CF?20kbdel 14b-18 1 1 0.5 Novel (Shrimpton and Borowitz, 1997) i19 3849+10kb,C>T 1 1 0.5 20 W1282X 2 2 0.5 Ashkenazi 21 N1303K 3 3 6 3.0 Unknown 4/144 4/56 8/200 4.0 AL. 75 and 81 mMol/L. Login to comment

PMID: 9375855 [PubMed] Casals T et al: "Missense mutation R1066C in the second transmembrane domain of CFTR causes a severe cystic fibrosis phenotype: study of 19 heterozygous and 2 homozygous patients."

No. Sentence Comment

46 Nine patients were heterozygous for five different mutations: R334W, G542X (1 sib deceased), 712-1G→T (1 sib deceased), 711+1G→T (2 sibs deceased), and 3905insT (only one patient for each one of these five mutations is included in Table 1). Login to comment
59 of patients 21 82 Sex: female/male 10/11 36/46 Mean ± SD (no. studied) Mean ± SD (no. studied) Current age-year 11.05 ± 6.93 (21) P < 0.01 7.72 ± 5.26 (82) Age at diagnosis-year 2.57 ± 4.63 (21) 2.22 ± 2.91 (82) Sweat Cl-mEq/l 112.44 ± 28.80 (18) 104.40 ± 15.70 (80) %ile-height 32.19 ± 35.03 (18) 30.70 ± 26.04 (80) %ile-weight 33.68 ± 35.95 (19) 27.99 ± 24.19 (80) Chrispin-Norman 12.50 ± 8.07 (12) P < 0.005 6.60 ± 6.26 (63) Shwachman-Kulcycki 69.46 ± 17.88 (15) P < 0.0004 83.11 ± 11.79 (72) FEV1-% predicted 64.06 ± 22.81 (15) 74.80 ± 23.06 (41) FVC-% predicted 72.20 ± 20.26 (15) 82.31 ± 20.03 (41) No. positive/no. studied (%) No. positive/no. studied (%) Lung colonization with 14/20 (70.0) 46/80 (57.5) bacterial pathogens Meconium ileus 1/21 (4.7) 9/81 (11.1) Dehydration 2/19 (10.5) 10/68 (14.7) Pancreatic insufficiency 21/21 (100.0) 79/81 (97.5) Other clinical features 13/21 (61.9) P < 0.02 29/82 (35.4) a Mutations were: ∆F508 (14 cases), R1066C (2), R334W (1), G542X (1), 712-1G>T (1), 711+1G>T (1), and 3905insT (1); FEV1, forced expiratory volume in 1 sec; FVC, forced vital capacity. Login to comment
73 In all the patients heterozygous for mutation R1066C, the second CF mutation can be considered as severe (∆F508, G542X, 712-1G→T, 711+1G→T, 3905insT, and R334W). Login to comment
93 Brancolini et al. (1995) found three heterozygous patients: R1066H/1717-1G→A, R1066H/ G542X and R1066C/∆F508 all PS. Login to comment

PMID: 9222768 [PubMed] Gouya L et al: "Novel mutation (A141D) in exon 4 of the CFTR gene identified in an Algerian patient."

No. Sentence Comment

3 More than 500 mutations have now been identified, but only five mutations have a frequency > 1% worldwide (i.e., ∆F508, G542X, G551D, W1282X, and N1303K) (CFGAC, 1994). Login to comment

PMID: 9101301 [PubMed] Clavel C et al: "Identification of four novel mutations in the cystic fibrosis transmembrane conductance regulator gene: E664X, 2113delA, 306delTAGA, and delta M1140."

No. Sentence Comment

9 In this group, the a508 represents 66%, other common mutations, such as aI507, G542X, R553X, G551D), 1717-lGÃA, R1162X, W1282X, and N1303K, were screened by restriction enzyme assay and account for 11%. Login to comment

PMID: 9067754 [PubMed] Macek M Jr et al: "Sensitivity of the denaturing gradient gel electrophoresis technique in detection of known mutations and novel Asian mutations in the CFTR gene."

No. Sentence Comment

42 621 + 1 GÃT, R334W, R347P, A455E, aI507, aF508, 1717-1 GÃA, G542X, S549N, G551D, R553X, R560T, 3849 + 10kb CÃT, W1282X, and N1303K) was performed using the rapid multiplex reverse dot hybridization system, under conditions provided by Roche Molecular Systems (Alameda, CA) (Kawasaki et al., 1993; Welsh et al., 1995). Login to comment

PMID: 8947061 [PubMed] Hubert D et al: "Genotype-phenotype relationships in a cohort of adult cystic fibrosis patients."

No. Sentence Comment

32 Only three patients had a normal sweat test: two related patients, who were compound heterozygotes for the G542X and 3849+10 kb cytosine (C)→thymine (T) mutations, and one patient who was compound heterozygote for the R1070Q and D1152H mutations. Login to comment
65 The ∆F508 mutation was found in 134 chromosomes (61%), the mutation G542X in nine (4%), whereas all the other mutations were rare, since they were found in no more than 1% of the cohort. Login to comment
77 - Genotype of the 110 CF patients: details of the CF mutations and classification into four groups Genotype Genotype Pts groups n 1 ∆F508/∆F508 48* 2 ∆F508/G542X 6 ∆F508/E827X 3† ∆F508/R553X 2 ∆F508/W1282X 2 ∆F508/E595X 1 ∆F508/E60X 1 ∆F508/W846X 1 ∆F508/1078delT 1 ∆F508/2143delT 1 ∆F508/2347delG 1 ∆F508/3659delC 1 ∆F508/4382delA 1 ∆F508/2183 AA→G 1 ∆F508/1717-1 G→A 1 ∆F508/1811+1.6 kb A→G 1 E595X/Y1092X 1 1717-1 G→A/1078delT 1 3 ∆F508/I336K 1 ∆F508/G27E 1 ∆F508/D192N 1 ∆F508//I980K 1 ∆F508/P205S 1 ∆F508/2789+5 G→A 1 ∆F508/3272-26 A→G 1 G542X/3849+10 kb C→T 2‡ G542X/2789+5 G→A 1 W361R/297-3 C→T 1 G551D/1717-1 G→A 1 N1303H/2183 AA→G 1 2789+5 G→A/2183 AA→G 1 R1070Q/D1152H 1 R1070Q/unidentified 1 S1251N/unidentified 1 4 ∆F508/unidentified 7 ∆I507/unidentified 2 1811+1.6 kb A→G/unidentified 1 1161delC/unidentified 1 unidentified/unidentified 8 *: two patients are brothers; †: three brothers; ‡: two sisters. Login to comment
105 - Characteristics of patients with pancreatic sufficiency and FEV1 <30% of predicted value Age at P. aeruginosa Genotype Age diagnosis FVC FEV1 colonization yrs yrs % pred % pred Group 2 ∆F508/4382del A 27 18 43 21 Yes Group 3 ∆F508/3272-26 G→A 21 8 32 28 Yes G542X/3849+10kb C→T 35 32 53 25 Yes W361R/297-3 C→T 45 25 25 12 Yes Group 4 unid/unid 30 15 38 27 Yes unid: unidentified. For further definitions see legends to tables 1 and 3. Login to comment
107 - Characteristics of patients with FEV1 >70% of predicted value Age at P. aeruginosa PI Hepatic Genotype Age diagnosis FVC FEV1 colonization cirrhosis yrs yrs % pred % pred Group 1 ∆F508/∆F508 18 <1 83 75 Yes Yes No ∆F508/∆F508 19 8 88 72 Yes Yes Yes ∆F508/∆F508 24 <1 87 84 Yes Yes No ∆F508/∆F508 25 13 85 82 Yes Yes No ∆F508/∆F508 37 34 90 83 No Yes No Group 2 ∆F508/E827X 18 <1 82 76 Yes Yes Yes ∆F508/W846X 29 27 101 95 No Yes No ∆F508/W1282X 31 28 91 77 No Yes No Group 3 2789+5 G→A/G542X 18 2 107 103 No No No 2789+5 G→A/2183 AA→G 36 34 93 87 No No No ∆F508/G27E 39 28 115 78 No No No Group 4 ∆I507/unid 18 <1 103 103 No Yes No unid/unid 26 5 89 77 No Yes No unid/unid 39 38 96 87 No No No unid/unid 40 38 110 106 No No No PI: pancreatic insufficiency; unid: unidentified. For further definitions see legend to tables 1 and 3. and the nature of pulmonary infection are very different among patients. Login to comment
116 In the latter study, most of the compound heterozygotes for ∆F508 were associated with another mutation (G542X, R553X, W1282X, 1717- 1G→A, 621+1G→T) that corresponded to Group 2. Login to comment

PMID: 8863168 [PubMed] Parad RB et al: "Heterogeneity of phenotype in two cystic fibrosis patients homozygous for the CFTR exon 11 mutation G551D."

No. Sentence Comment

10 R B Parad Received 27 December 1995 Revised version accepted for publication 15 March 1996 Methods Cheekbrush DNA for CFTR mutation analysis was collected and prepared according to Richards et al.1 CFTR mutation analysis was performed for 12 mutations (AF508, G551D, G542X, 621 + 1G->T, AI507, 1717-1G-4A, R117H, N1303K, W1282X, R560T, R553X, 3849 + 1Okb C-+T). Login to comment
53 Lanes are paired to show both normal and abnormal alleles con; mutations 621 + JG-*T (normal band lane 1, abnormal band lane 2), G551D (abnormal band lane 1, normal band lane 2), G542X (abnormal band lane 1, n band lane 2), and AF508 (normal band lane 1, abnormal band lane 2) at these first pair oflanes shows the ARMS pattern ofa GSSJDIN heterozygote. Login to comment
60 Recent studies have shown present (but diminished) chloride conduct- iction for ance, and absent CFTR inhibitory regulation G542X of the outwardly rectifying chloride channel. Login to comment

PMID: 8869353 [PubMed] Alton EW et al: "A mild variant of cystic fibrosis."

No. Sentence Comment

41 Examples include G542X, a mutation with a frequency of around 3% worldwide. Login to comment

PMID: 8659542 [PubMed] Miller PW et al: "Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations in allergic bronchopulmonary aspergillosis."

No. Sentence Comment

62 Mutation Analysis Genomic DNA samples from both patient groups were screened for six of the most common CF mutations-AF508, G542X, GS51D, R553X, W1282X, and N1303K-by using reverse allele-specific oligonucleotide (ASO) analysis (Erlich et al. 1991). Login to comment
85 One patient with normal sweat electrolytes and pseudomonas colonization had the G542X mutation on one allele. Login to comment

PMID: 8967432 [PubMed] Zhang Y et al: "In vivo analysis of fluid transport in cystic fibrosis airway epithelia of bronchial xenografts."

No. Sentence Comment

77 Genotypes for CF tissues included l-AF50NAF508, l-AF508/ G542X, 2-AF508/unknown, l-R553X/unknown, and Reservoir (7oQN Fluid Apparatus Subcutaneous Buffer A graded scale Buffer B (mm) detachment detachment perfusion point 1 Pump subcutaneous Potential Difference Apparatus Fig. 2. Login to comment
83 1-G542X/G%lD. Login to comment

PMID: 8644747 [PubMed] Witt DR et al: "Cystic fibrosis heterozygote screening in 5,161 pregnant women."

No. Sentence Comment

69 Lab group A was screened for the 6 most common mutations (F508, G542X, G551D, R553X, W1282X, and N1303K); lab group B was screened for 12 mutations, including the 6 most common and an additional 6 less common alleles (R117H, 621+1, I507, 1717G-A, R560T, and S549N). Login to comment
142 Table 7 CFTR Mutations in Screened Women NUMBER (%) wITH MUTATIONa GROUP ETHNiciTY F508 G542X GS5lD R553X W1282X N1303K R117H 621+1 1507 1717G-A R560T S549N TOTAL A Caucasian 26 (81) 5 (16) 1 (3) NA NA NA NA NA NA 32 Hispanic 2 (100) NA NA NA NA NA NA 2 B Caucasian 63b (65) 4 (4) 2 (3) 1 (1) 2 (2) 4 (4) 16b (16) 4 (4) 1 (1) 97b Hispanic 7 (88) 1 (12) 8 Caucasian/ Hispanic 2 (50) 1 (25) 1 (25) 4 'NA = not applicable. Login to comment
172 Factors that potentially contributed to the high rate of acceptance in this study included incorporation of pretest education into an ex- Table 8 Results of Prenatal Diagnosis in High-Risk Pregnancies CFTR MUTATIONSa COUPLE PRENATAL DIAGNOSIS Mother Father Fetus 1 No (miscarriage) GSS1D R117H N/GSS1D (abortus) 2 No (miscarriage) F508 1717G-A NA 3 No (miscarriage) F508 RS60T NA Yes (second pregnancy) N/N 4 Yes G542X F508 N/N S Yes F508 F508 N/F508 6 Yes (twins) F508 F508 F508/F508, F508/F508 7 Yes F508 F508 N/N 8b Yes F508 NA N/F508 9b Yes N1303K NA N/N1303K a NA = not available; and N = normal. Login to comment

PMID: 8617131 [PubMed] McGill JM et al: "Survey of cystic fibrosis transmembrane conductance regulator genotypes in primary sclerosing cholangitis."

No. Sentence Comment

33 In total, 32 mutations were evaluated, which represent 90% of the most common mutations (t4): AF508 G542X G551D W1282X 3905insT NI303K 3849+ 10kbC--~T R553X 621+ IG--*T 1717- IG--,A lt)78delT 2789+5G---~A 3849+4A--~G 711+ IG---oT R1162X 1898+IG----~A R117H 3659delC G85E 2184delA A1507 R347P Y1092X R560T A455E R334W Y122X S549R(T---~G) Q493X V520F $549N R347H Patient Selection. Login to comment

PMID: 9238680 [PubMed] Scobie G et al: "Identification of the five most common cystic fibrosis mutations in single cells using a rapid and specific differential amplification system."

No. Sentence Comment

2 In the first round of the polymerase chain reaction (PCR), regions of exons 4, 10 and 11 of the cystic fibrosis transmembrane conductance regulator (CFTR) gene containing the mutations AF508, G551D, R553X, G542X and 621 + 1 O T were co-amplified in a single multiplex PCR. Login to comment
11 Although this mutation accounts for ~50-80% of cases (CF Genetic Analysis Consortium, 1990), depending on the population being studied, in the UK around 10% of the remainder present with one or two of the four other most common mutations, these being the G551D Gly-Asp, R553X Arg-Stop (Cutting et al, 1990), the G542X Gly-Stop (Kerem et al, 1990) and the G-T splice mutation 621 + 1 O T (the first intronic base in the splice donor site flanking the 3' end of exon 4) (Zielenski et al, 1991). Login to comment
22 Using this procedure, we have shown it is possible to genotype a single cell for any of the five most common mutations responsible for CF, which when used in parallel 621 + IOT AFSOS A B G551D0U53X) G542X Cystic fibrosis diagnosis in single cells 200 bp 4S 4AS S21 + 10 >T 10S 11S 10AS AFSOS 11 AS R553X QS51D L G54ZX Figure 2. Login to comment
23 Schematic diagram of external CFTR primers for exons 4, 10 and 11 and the relative positions of the cystic fibrosis mutations 621 + 1 O T , AF508, G542X, R553D and G551X. Login to comment
36 CF cell lines Four lymphoblastoid cell lines with genotypes AF5O8/AF5O8, G542X/ G542X, G551D/R553X and 621+ l>G/AF508 were purchased from Coriell Cell Repositories (Camden, NJ, USA) and one cell line with genotype 621 + lG>T/normal was purchased from European Collection of Animal Cell Cultures (Porton Down, UK). Login to comment
54 Table I. Sequences of pnmary and secondary polymerase chain reaction (PCR) primers including ARMS kit primers and their relevant uM concentrations (compared to a standard concentration of 0.86 nM per reaction) CFTR Exon Sequence Size (bp) Primary PCR primers Exon 4 Exon 10 Exon II HUMTH01 5'- CAAGTCTTATTTCAAAGTACCAAG 5'- CAGCTCACTACCTAATTTATGACA 5'- AAGTGAATCCTGAGCGTGATTTGATAATGA 5'- CACAGTAGCTTACCCATAGAGGAAACATAA 5'- TATTTAATGATCATTCATGACATTT 5'- TAAAGCAATAGAGAAATGTCTGTA 5'- ATTCAAAGGGTATCTGGGCTCTGG 5'- GTGGGCTGAAAAGCTCCCGATTAT 479 380 425 179-203 Mutation and sequence Size (bp) Tube Concentration Secondary PCR primers AF508 C: 5'- GACTTCACTTCTAATGATGATTATGGGAGA N: 5'- GTATCTATATTCATCATAGGAAACACCAC M: 5'- GTATCTATATTCATCATAGGAAACACCATT Exon II C: 5'- TAAAATTTCAGCAATGTTGTTTTTGACC G551D/R553X N: 5'- GCTAAAGAAATTCTTGCTCGTTGCC M: 5'- AGCTAAAGAAATTCTTGCTCGTTGCT G542X N: 5'- ACTCAGTGTGATTCCACCTTCTAC M: 5'- CACTCAGTGTGATTCCACCTTCTCA 621 + 1 O T C: 5'- TCACATATGGTATGACCCTCTATATAAACT N: 5'- TGCCATGGGGCCTGTGCAAGGAAGTATTCC M: 5'- TGCCATGGGGCCTGTGCAAGGAAGTATTCA HUMTHOI 5'- TGATTCCCATTGGCCTGTTCCTCC 5'- TGGCCCACACAGTCCCCTGTACAC 160 157 285 286 256 257 380 380 123-147 A/B A B A/B I A B A A/B A B 1.0 1.0 2.0 2.0 2.0 1.0 1.0 1.0 0.5 0.5 0.5 C = common primer, N = normal primer, M = mutant primer. Login to comment
56 Figure 3 shows the detection of individual AF508, G551D, R553X and G542X, 621 + 1 O T mutations using the CF ARMS kit after primary amplification of individual CFTR exons containing these mutations, and the corresponding fingerprint from the same cells (Figure 4). Login to comment
63 One drawback of using single exon 1 2 3 4 5 6 7 8 9 10 0 X 621+1G>T G551D/R553X G542X AF508 Figure 3. Login to comment
65 Tubes A and B for a normal genotype (lanes I and 2), then tubes A and B for the mutations: AF5O8/AF5O8 (lanes 3 and 4), 621 + lOT/normal (lanes 5 and 6), G551D/R553X (lanes 7 and 8), and G542X/G542X (lanes 9 and 10). Login to comment
69 Lanes 1-5 are cells containing the mutations AF508/AF508, 621 + lG>T/normal, G551D/R553X, G542X/G542X and 621 + 1OT/AF508 respectively. Login to comment
71 1 2 3 4 5 6 7 8 9 10 11 12 621+1G>T G551D/R553X G542X AF508 Figure 5. Login to comment
72 Detection of the same five mutations using a multiplex containing external primers for exons 4, 10 and 11, and subsequent genotyping using the ARMS kit Tubes A and B for a normal genotype (lanes 1 and 2), then tubes A and B for the mutations AF5O8/AF5O8 (lanes 3 and 4), 621+ lG>17normal (lanes 5 and 6), G551D/R553X (lanes 7 and 8), G542X/G542X (lanes 9 and 10) and 621 + 1OT/AF508 (lanes 11 and 12). Login to comment
86 The ARMS procedure used here has this advantage in that it is capable of detecting the 621 + 1 O T , AF508, G551D, R553X and the G542X mutations within 6-8 h from a single cell. Login to comment

PMID: 8956039 [PubMed] Hughes DJ et al: "Mutation characterization of CFTR gene in 206 Northern Irish CF families: thirty mutations, including two novel, account for approximately 94% of CF chromosomes."

No. Sentence Comment

45 Prior to the DGGE study a variety of methods (see Tables 1 and 2) were used to screen for CFTR mutations, including single mutation assaysfor AF508, AI507, G55lD, G542X, R553X, R117H, R560T, 621+lG>T, and 3849+10kbC>T. Login to comment
53 35%) PAGE (278) Kerem et al.. 1989AF508 G551D R117H R560T G542X 621+1G>T A1507 E60X 3659delC R553X 3120G>A 1l54insTC 2789+5G>A N1303K MlI(G>T) QW P67L 557delT 711+3A>G L206W R297Q V520F V562L Y563N Y917C R1162X 3849G>A 3849 +10kbC>T 3850-1GBA W1282X 280 21 17 12 9 9 7 3 2 1 68.0 5.1 4.1 2.9 2.2 2.2 1.7 0.7 0.5 0.24 17-32-13 (38;27%j 17-31-13(24,17%) 16-07-17 16-30-13 plus14 rare haplotypes (29) 16-07-17 23-33-13 (4) 22-31-13 (2) 21-31-13 17-07-17 (5) 16-31-13 16-35-13 17-58-13 17-35-13 16-07-17 17-07-17 23-29-13 (1) 23-31-13 (1) 16-07-17 16-31-13 16-07-17 15-29-13 16-33-13 16-07-17 17-07-17 16-07-17 16-07-17 16-30-13 16-32-17 17-31-13 16-31-14 16-46-13 16-30-14 17-07-17 DGGE(2) ' RD ASO's (11) DGGE(6) RD AR (8) DGGE (1) RD PAGE (5) DGGE (2) SEQ SEQ (2) DGGE (1) RD DGGE DGGE DGGE SEQ DGGE DGGE DGGE SEQ DGGE DGGE SEQ DGGE DGGE DGGE DGGE DGGE SEQ RD DGGE DGGE Cutting et al.. 1990 Dean et al.. 1990 Kerem et al., 1990 Kerem et al.. 1990 Zielenski et al., 1991 Kerem et al.. 1990 Malone et al., CFGAC Kerem et al., 1990 Cutting et al., 1990 Zielenski et al., CFGAC lannuzzi et al., 1991 Highsmith et al., 1990 Osborne et al., 1991 this study Savov et al., 1994 Hamosh et al., CFGAC Graham et al., 1992 Petreska et al., CFGAC Claustres et al., 1993 Graham et al., 1991 Jones et al.. 1992 this study Kerem et al.. 1990 Edkins & Creegan, CFGAC Gasparini et al., 1991 Cutting et al.. 1992 Highsmith et al., 1994 Audriizet et al., 1993 Vidaud et al., 1990 "Numbers in parentheses after the microsatellite haplotypes refer to the number of alleles haplotyped when not all of the available chromosomeswere typed. Login to comment
77 R553X, G542X. Login to comment
99 G542X (2.2%), 621+1G>T (2.2%), and A1507 (1.7%); the next seven mutations were found in two or three chromosomes, with the remaining 16 mutations being identified only once. Login to comment
108 There were four mutations, R117H, AF508, AI507, and G542X, on 11 CF alleles that were missed due to poor PCR amplification in their original screening methods (Table 1) but were detected using DGGE. Login to comment
120 A commercially available reverse dotblot assay (Innogenetics) is presently used in our laboratory for routine screening of eight CF mutations, of which seven are found in this population; AF508, AI507, G551D, G542X, R553X, N1303K, and W1282X and account for 78% of CFTR defects with additional mutations R560T, 621+1G>T and Rl17H screened using individual assays. Login to comment

PMID: 8889582 [PubMed] Hughes D et al: "Fluorescent multiplex microsatellites used to define haplotypes associated with 75 CFTR mutations from the UK on 437 CF chromosomes."

No. Sentence Comment

6 Ancient mutations, AF508, G542X, N1303K, were associated with several related haplotypes due to slippage during replication, whereas other common mutations were associated with the one respective haplotype (e.g., G551D and R560T with 16-7-17, R117H with 16-30-13,621+1G>T with 21-31-13,3659delC with 16-35-13). Login to comment
43 AF508, G542X, and N1303K are ancient CFTR mutations that are the first, second, and fourth most prevalent in Northern Europe, with respective frequenciesof -70%, 2%, and 1% (CFGAC, 1994). Login to comment
50 There are six associated haplotypes with G542X whose ancestral haplotype probably is 23-33-13, as it is found most frequentlyhere and in Spain (Morral et al., 1993). Login to comment
74 CF 8CA-17bTA-17bCA Mutation chromosomes % Normal Laboratoryb Reference' HaplotVpe 1)15-29-13 557delT Nl Graham et al.. 1992 21 16-07-17 MU (G>T) 3) 16-24-13 4) 16-25-13 5) 16-29-13 6) 16-30-13 7) 16-30-14 8) 16-31-13 9) 16-31-14 10) 16-32-13 12) 16-33-13 13) 16-34-13 14) 16-35-13 11)16-32-17 15)1645-13 16) 1646-13 17) 1646-14 19) 17-07-17 18)16-53-13 20)17-29-14 21) 17-31-13 22) 17-32-13 23) 17-35-13 24) 17-51-11 25) 17-55-13 27) 17-58-13 28) 21-31-13 29) 22-31-13 31)23-22-17 26) 17-56-13 30) 22-33-13 32) 23-29-13 33)23-31-13 34)23-32-13 35)23-33-13 36)23-34-13 37) 23-36-13 38)24-22-17 39) 24-31-13 182delT P67L R75X L206W 1154insTC 146linsAGAT Q493x V520F 1717-1G>A G551D R560T V562L R709X S1196X L1254X R1283M G85E 2184insA 711+lG>T 3495delA 4279insA SlOR L88S R117C R117H G178R 1717-1G>A Y563N W1098R G1123R 3850- 1G>A E6OX %%deIT 1138insG R34P 2183AA>G 2184delA R1158X 1078delT R1162X 3849G>A Q141W R347P Y917C G2iX 711+3A>G 441delA 3130de115 3659delC 1898+1G>A R709X 2711delT R1158X E92K 3849+lOkbC>T 2118delAACT 4048insCC 296+1 2 T S Q22OX R297Q A1507 2789+5G>A 3120+1G>A W128W 1811+lG>C AF508 E831X R116W AF508 W846X1 3120G>A R785X R553X R553X R553X 621+1G>T G542X G542X Y1182X N1303K AF508 G54W 3041delG 1525-1G>A N1303K G542X G542X G542X 394delTT R709X N1303K 1 1 1 2 1 1 4 2 3 4 2 26 8 1 1 1 1 1 8 1 1 1 1 1 1 1 19 1 2 1 1 1 1 7 1 1 2 1 1 2 1 1 1 1 1 1 1 1 2 1 1 7 4 1 2 1 1 2 1 1 4 Asian 1 2 1Asian 5 4 i Afro-Caribbean 5 1 42 (19%) 1 1 57 (26%) 1 2 1 1 1 2 12 2 11.4 0.4 4.9 16.3 1.1 3.8 1.9 10.6 2.3 1.5 2.3 1.5 2.7 4.5 0.4 0.8 0.8 0.4 0.8 0.4 1 2 1 7 1 1 1Asian 1 1.5 0.8 0.8 NI G NI, M M NI NI. Login to comment
82 MicrosatelliteHaplotypesfor 16 Most Common CFTR Mutations in UK Population Mutation frequency(%)b Haplotype chromosomes Normal Laboratory" AF508 75 23-31-13 81 0.4 NI,M, G, C 17-32-13 57 0.8 NI,M, G, C 17-31-13 42 0.8 N1,M, G, C G551D 3 16-07-17 26 11.4 NI,M, G, C G542X 2 23-33-13 7 1.5 NI,C ApproximateUK 8CA-17bTA-17bCA No.CF % 22-31-13 1 NI 22-33-13 1 G 23-31-13 1 G 23-32-13 1 N1 23-34-13 1 0.8 C 621+1G>T 1 21-31-13 12 NI N1303K 0.5 23-29-13 2 NI. Login to comment

PMID: 8844213 [PubMed] Morral N et al: "Haplotype analysis of 94 cystic fibrosis mutations with seven polymorphic CFTR DNA markers."

No. Sentence Comment

9 Only four other mutations, G542X, G551D, N1303K, and W1282X, are rel- ativelyfrequent in the world Caucasoid population, and each has an overall frequency of 1-2.5% (CFGAC, 1994).Another 19mutations are found in 0.1-0.7% of chromosomes, but their distribution is variable, and in many cases they are only present in some populations (CFGAC, 1994). Login to comment
34 The high number of haplotypes associated with mutations AF508, G542X, and N1303K suggests that they are the most ancient CF mutations in the population. Login to comment
85 Other haplotypes that were less commonon normal chromosomes(16-44-13, 16-35-13, 16-33-13, and 16-29-13)were each associatedwith only one CF mutation. Several mutations were associated with more than one haplotype apparentlyas the result of slippage at one of the microsatellites IVS8CA, IVS17BTA, and IVS17BCA: AF508, G542X, N1303K, R553X, Q552X, 2869insG, L1077P, 7H, and R1162X (Table 3). Login to comment
90 Mutations AF508, G542X, and N1303K were associated with severalmicrosatellite haplotypes as the result of slippage at one of the three microsat- Y R334W, 1811+1.6kbA+G, 711+IG-T, R34- ellites, giving additional support to an ancient origin of these mutations (Morral et al., 1993a, 1994a). Login to comment
106 (1992) Dork et al. (1994a) Malone et al. (personal communication) Claustreset al. (1992) Ferec et al. (1992) Fanen et al. (1992) lvaschenko et al. (1991) T. Dork (personal communication) Dean et al. (1990) Dork et al. (1994a) Ferec et al. (1992) Bozon et al. (1994) Costes et al. (personal communication) Fanen et al. (1992) Audrezet et al. (personal communication) Zielenski et al. (1991a) Zielenski et al. (1991a) Granell et al. (1992) Highsmith et al. (1990) Mercier et al. (1993b) Vidaud et al. (1990) Fanen et al. (1992) Fanen et al. (1992) Dork et al. (1994b) (continued) HAPLOTYPESFOR 94 CF MUTATIONS TABLE2. CFTR HaplotvpesforDiallelic and Multiallelic DNA Markers for 94 CF Mutations"(Continued) ~~ ~ J44-GAIT- 8CA-17BTA- No. of TSU-TUB20 17BCA Mutation chromosomes % Normal Laboratory Reference 1-6-1-2 (9.1%) 1-6-2-2 (8.9%) 1-7-1-2 (3.4%) 1-7-2-2 (2.6%) 2-7-1-1 (1.2%) 2-7-2-2 (0.7%) 17-7-16 16-7-18 16-7-17 15-7-17 24-31-13 23-52-13 23-34-13 23-33-14 23-33-13 23-32-13 23-31-13 23-30-13 23-21-19 23-18-13 22-35-13 22-31-13 22-30-13 21-31-13 19-33-13 18-45-13 18-37-13 18-35-13 17-57-11 17-55-13 17-55-11 17-54-11 17-53-11 17-52-11 17-51-11 17-33-13 16-46-13 16-45-13 16-44-13 16-42-13 16-35-13 16-30-13 16-30-13 16-7-17 16-21-19 L107% L1077P 24ldelAT L719X A1507 3849+10kbC-T 2184insA 2991de132 G551D 1154insTC V520F R560T 4114ATA+lT 3667de14 435insA Q414X C225R Q39X N1303K R1162X H199Y G542X G542X w1204x R347H G542X AF50gb N1303K 2143delT 3849f 10kbC-T N1303K 681delC R347H A455E N1303K A120T 621+1 h T 574delA 1221delCT F311L R560K R553X R533X R553X Q552X R553X Q552X R116W R553X 1898+5 h T 3272-26A-G 1717-1hA 1342-2A-C A1507 2869insG 2869insG E92X 4374+1 h T 2183AA-G R117H 1609delCA I336K W1063X 1 1 1 1 6 1 3 1 1 22 17 1 1 1 1 1 1 1 1 1 1 1 1 1 17 1 1 4 157 7 1 2 2 1 1 2 2 1 9 1 1 1 1 1 1 6 1 1 1 2 1 3 2 1 3 1 1 1 4 2 4 1 1 - - 10.33 1.45 - - 0.48 1.45 - 0.24 1.45 0.24 - - - - 0.24 0.48 - - - - - - 0.49 0.48 - 0.24 0.24 0.24 - - - - - 0.72 0.24 0.72 - t h fP h b.fb,fP h b,fp.t t h b.fb.fp,h,t b.fb.fp,h,t t t t h b h h fP h fP fb b fP b.fb,fP,h.t fP fb b,fP,t b.fb,fp,h,t b.fb,h h h h,t t fb t b b b.fb.t fP fb fb tb h fP h h t t b h t h b b h h b,fb,h fP.h b h fP fP Bozon et al. (1994) Fanen et al. (1992) Dork et al. (1994a) Kerem et al. (1990) Dork et al. (1994~) Cutting et al. (1990) Kerem et al. (1990) lannuui et d. Login to comment
131 Data based on the evolution of two other common mutations G542X and N1303K have shown that they could also be very ancient (more than 30,000 years old) (Morral et al., 1993a). Login to comment
133 Therefore, on normal and on AF508, G542X and N1303K chromosomes, a large microsatellite haplotype variability has been generated, supporting a very ancient origin for these chromosomes. Login to comment

PMID: 8829658 [PubMed] Cronin MT et al: "Cystic fibrosis mutation detection by hybridization to light-generated DNA probe arrays."

No. Sentence Comment

203 Figure 5 shows a typical image from this experiment made from CHO sample nine which had two exon 11 mutations, G542X and G551D. Login to comment
238 Cystic Fibrosis Mutation-Specific DNA Probe Array" Mutation Exon and column Tested Subarrayhow G85E R117H I148T 621 -+ l(G+T) 711 + 1(G+T) R334W R347H R347P 1078 delT A455E G480C Q493X A1507 F508C AF508 V520F G542X S549R(T-+ G) G551D Q552X R553X A559T R560T 1898 + l(G-,A) 2184 del A 2789 + 5(G+ A) R1066C L1077P Y1092X R1162X 3659 del C 1717-1(& A) 3272 - 26(A+ G) 3 4 4 in 4 in 5 7 7 7 7 9 10 10 10 10 10 10 in 10 11 11 11 11 11 11 11 in 12 13 in 14b in 17a 17b 17b 17b 19 19 * * * * * * * * * * * * * * * * * * * * * * * * * * * * 3849 + lOkb C-, T in 19 9,3 W1282X 20 994 3905insT 20 10.1 * N1303K 21 10,2 * * * "Row and column locations for each of the mutation specific,40 probe sets included in the specialized probe array design. Login to comment
248 Results From Unknown Patient Sample CFTR Genotyping" Sample CHO 1 CHO 2 CHO 3 CHO 4 CHO 5 CHO 6 CHO 7 CHO 8 CHO 9 CHO 10 Exon 10 genotype Wild-type AF508 Wild-type Wild-type AF508 Wild-type Wild-type AF508 Wild-type Wild-type Exon 11genotype Wild-type G542X Wild-Type Wild-Type G551D R553X G542X R553X G542WG551D Wild-type "Results summary from blind analysis of ten patient samples for CFTR exon 10and 11 mutations. Login to comment
265 Image of a specialized mutation array hybridized with exon lO/exon 11targets prepared from a compound heterozygote for exon 11 mutations G542X and G551D (Children`s Hospital of Oakland, Sample 9). Login to comment
268 G542X: 5'TAGTTClTTGAGAAGGT3`.Wild type: 5'GAGTGGAGGTCAACGAG3`. Login to comment
280 All except G542X and G551D display homozygous wild-type hybridization patterns. Other hybridization signals that appear as incomplete hybridization patterns compared with examples in Figure 3result from cross-hybridization with probes partially complementary to the target. Login to comment

PMID: 8723695 [PubMed] Bienvenu T et al: "Identification of three novel mutations in the cystic fibrosis transmembrane conductance regulator gene in Argentinian CF patients."

No. Sentence Comment

42 In addition, none of the most common CF mutations (G542X, G551D, W1282X, N1303K, R553X, 1717-1G>A, R1162X, 81507) were present in this series. Login to comment

PMID: 8803789 [PubMed] Nemeth K et al: "Analysis of five CFTR mutations in Hungarian cystic fibrosis patients."

No. Sentence Comment

5 Budapest; 3Children's Hospital Helm Pill, Budapest, Hungary *Correspondence Four hundred and fifty-eight cystic fibrosis (CF; McKusick 219700) patients, aged 6 months to 19 years old were screened for mutations AF508, G542X, G551D, R553X and N1303K. Login to comment
14 Mutation G542X was identified in 14 (3.0%), mutation R553X in 6 probands (1.3%); 7 patients (1.5%) were heterozygous for mutation N1303K. Login to comment

PMID: 21374513 [PubMed] Schwarz M et al: "Methods for screening in cystic fibrosis."

No. Sentence Comment

10 Molecular D/agnoss of GenetIc Diseases Edlted by R Elles Humana Press Inc , Totowa, NJ 99 Table1 RelativeFrequenciesoftheCommonCFMutationsintheUnitedKingdom(S),NorthAmerica, andNorthernandSouthernEurope(7)" NorthNorthernSouthern UKAmericaEuropeEurope MutationExonNo.%No.%No.%No%References AF508 G551D G542X 621+l(G>T) 1717-l(G>A) sR117H =R553x 1898+l(G>A) N1303K R560T AI507 G85E 1154insTC V520F W1282X E60X 3659delC 1078delT 10738775.32690066.114,86670.28400755.033 113023.082061.973561.68370.518 111651.682342.244392.082593.569 intron4910.931541.48970.46370.51IO intron10560.57440.421600.76650.899 4450.46610.586202930.04II 11450.46960.921650.7844068 intron12450.4620.02410.191001412 21450.461301.252090.991792.4613 11410.42240.2340019009 10300.31200.19570.2750.079,14 3210.211601530014140.19II 7190.19n/an/an/an/an/an/a15 10170.17n/an/an/an/an/an/a16 20170.172452.351200.57430.5917 3160.16n/an/an/an/an/an/aMaloneb 19140.14140.133901810.019 790.0910.015302520.318 S549N1180.0850.051800920038 Q493X1070.07n/an/adan/adan/a9 R347P760.06260.25550.26240.3311 3849+10kb(C>T)intron1950.05570.55230.1180.1119 A455E930.03270.26350.17009 %/a,Datanotavadable. Login to comment
82 For example the mutations AEl15 and K1060T, aswell asAF508, G542X, and RI 17H have been seenm CBAVD (29). Login to comment
193 Odd-numbered tracks contain the ARMS products for the normal alleles of 621 + l(G > T) and AF508, plus the mutant alleles of G55 1D and G542X. Login to comment
194 Even-numbered tracks contain products for the normal alleles of G55 1D and G542X and the mutant alleles of 62 1 + 1(G > T) and AF508. Tracks 1 and 2 are from an individual who is negative for all four mutations, as are tracks 3 and 4. Login to comment
198 Tracks 13 and 14 are from a compound heterozygote of G542X and AF508. Tracks 15 and 16 are a negative (no DNA) control and track 17 is DNA molecular weight marker VI (Boehringer Mannheim). Login to comment

PMID: 8522333 [PubMed] Desgeorges M et al: "Four adult patients with the missense mutation L206W and a mild cystic fibrosis phenotype."

No. Sentence Comment

24 Open symbols, and J~ 0 halJ:filled symbols, healthy individuals filled symbols, CF (cystic fibrosis) G542X G542X G542X G542X L206W 1.,206W AI507 S L206W L206W A1507 O L206W AF508 AF508 V #, g g g AF508 L206W L206W AF508 AF508 while working in the sun in the hot and arid climate of southern France, he presented with two severe acute dehydration episodes, with excessive sweating and salt crystals on the skin. Login to comment
58 The alleles AF508 and AI507, located in NBD1, affect the processing of the CFTR, which fails to translocate to the correct cellular location at the apical membrane; the nonsense mutation G542X produces premature termination of translation, resulting in an unstable mRNA and no detectable protein (Welsh and Smith 1993). Login to comment
61 The CFTR protein with 206W might retain some residual function in respiratory and digestive tissues, exercising a "dominant" effect on the null alleles G542X, AI507 or AF508 and allowing the occurrence of mild phenotypes of CE In the two male patients reported here clinical expression of CF occurs only when the need for heat dissipation is tremendously increased and depends on evaporative heat loss. Login to comment

PMID: 8825927 [PubMed] Cashman SM et al: "The Irish cystic fibrosis database."

No. Sentence Comment

39 Care Table 2 Haplotypes associated with the most common CF mutations in Ireland, as well as with Irish CF chromosomes with unidentified mutations and non-CF chromosomes Mutation NmlNcf % X/Kt Mt Microsatellite§ No chrsll AF508 367/506 72-5 A 1 See table 3 2 B 2 116 C - 0 D 2 2 G551D 35/506 6-9 B 2 16-7-17 20 R117H 10/506 2-0 C 1 16-30-13 5 C 1 16-31-13 1 G542X 5/506 1-0 B 2 17-32-13 2 621 + 1G-T 4/506 0-8 B 2 21-7-17 2 B 2 21-31-13 2 R560T 4/506 0-8 D 2 16-7-17 1 D 2 16-31-17 1 1717-1G-A 3/506 0-6 C 1 16-32-13 2 A 2 17-32-13 1 N1303K 2/506 0-4 B 2 23-29-13 2 3659delC 2/506 0-4 C 1 16-35-13 2 AI507 2/506 0-4 ND ND R352Q 1/506 0-2 C 1 16-31-13 1 R553X 0/506 0 0 ND ND 1078delT 0/506 0.0 ND ND Total identified 435/506 85-6 Unidentified 71/506 14-4 A 1 See table 3 3 A 2 5 B 2 17 C 1 5 D 2 8 Normal A 1 See table 3 16 A 2 1 B 2 3 C 1 13 C 2 1 D 2 2 * Nm = number of chromosomes bearing the mutation. Login to comment
69 For instance, table 2 shows that mutations G542X, 621 + 1G-T, N1303K, 3659delC, R560T, and Ri 17H are associated with the same haplotypes, or with haplotypes probably derived from these by slippage of the DNA polymerase, as has been seen in patients from other European populations.7'0 Since those haplotypes are relatively rare in normal chromosomes (table 3), the constancy of the association has been explained as suggesting identity by descent of all chromosomes bearing the same mutations.9 Haplotype 16-7-17 is found in CF non-AF508 chromosomes more frequently than would be expected from its frequency in normal chromosomes (p<0 01, table 3), suggesting perhaps that another fairly common CF mutation may be associated with this haplotype in Ireland. Login to comment
38 Care Table 2 Haplotypes associated with the most common CF mutations in Ireland, as well as with Irish CF chromosomes with unidentified mutations and non-CF chromosomes Mutation NmlNcf % X/Kt Mt Microsatellite&#a7; No chrsll AF508 367/506 72-5 A 1 See table 3 2 B 2 116 C - 0 D 2 2 G551D 35/506 6-9 B 2 16-7-17 20 R117H 10/506 2-0 C 1 16-30-13 5 C 1 16-31-13 1 G542X 5/506 1-0 B 2 17-32-13 2 621 + 1G-T 4/506 0-8 B 2 21-7-17 2 B 2 21-31-13 2 R560T 4/506 0-8 D 2 16-7-17 1 D 2 16-31-17 1 1717-1G-A 3/506 0-6 C 1 16-32-13 2 A 2 17-32-13 1 N1303K 2/506 0-4 B 2 23-29-13 2 3659delC 2/506 0-4 C 1 16-35-13 2 AI507 2/506 0-4 ND ND R352Q 1/506 0-2 C 1 16-31-13 1 R553X 0/506 0 0 ND ND 1078delT 0/506 0.0 ND ND Total identified 435/506 85-6 Unidentified 71/506 14-4 A 1 See table 3 3 A 2 5 B 2 17 C 1 5 D 2 8 Normal A 1 See table 3 16 A 2 1 B 2 3 C 1 13 C 2 1 D 2 2 * Nm = number of chromosomes bearing the mutation. Login to comment

PMID: 8553305 [PubMed] Gan KH et al: "Genetic and clinical features of patients with cystic fibrosis diagnosed after the age of 16 years."

No. Sentence Comment

41 DNA was analysed for the following mutations: E60X, R117H, A455E, AI507, AF508, G542X, S549N, G550X, G551D, R553X, R560T, R1162X, S1251N, W1282X, N1303K, 621 + 1G-+T, 1717-1G--+A. These mutations represent 80% ofthe expected cystic fibrosis mutations in The Netherlands. Login to comment
65 Table 3 CFTR mutations in 278 chromosomes of adult cystic fibrosis patients Early diagnosis Late diagnosis (n= 118) (n=25) n % n % AF508s 175 74-2 18 36-0 A455Em 12 5-1 14 28-0 1717-15 6 2-5 1 2-0 G542X' 4 1-7 - W1282X1 3 1-3 - R553X' 1 04 1 2-0 S1251N 2 0-8 - N1303K' 1 0 4 - E60X 1 0-4 3 6-0 Not identified 31 13-2 13 26-0 Total 236 50 Mutations not found: RI 17H, AI507, S549N, G550X, G551D, R560T, R1162X, 621+1G-+T. Login to comment

PMID: 8530001 [PubMed] Ferec C et al: "Neonatal screening for cystic fibrosis: result of a pilot study using both immunoreactive trypsinogen and cystic fibrosis gene mutation analyses."

No. Sentence Comment

82 {17bi DI507 [ Y569X W846X 2789+5G->A ,' $492F i ] i I G551D 2622+1 G->A Y1092X 1717-1 G->A E827X A1067T G542X 2183 AA->G R1066H R560K 2184 ins A 3320,ins 5 R553G R1070W 1806 del A & 4005+1G->A W1282X ] i "- Exons Fig.2 Distribution of the different mutations (except AF508) of the CFTR gene in Brittany Table 1 Mutations and genotypes in newborns Genotypes of newborns Number Sweat test AF508/AF508 7 + > 90 AF508/1806 del A 1 + > 90 R553G/G551D 1 Borderline (60) AF508/G551D 1 + > 90 AF508/R1070W 1 40 AF508/G542X 1 + > 90 AF508/G149R 1 45 Total 13 Mutations found in heterozygote newborns AF508 31 R560K 1 1078 del T 1 G544S l G542X 1 V317A 1 R347H 1 V322A 1 Total 38 gene. Login to comment

PMID: 7472820 [PubMed] Wilschanski M et al: "Correlation of sweat chloride concentration with classes of the cystic fibrosis transmembrane conductance regulator gene mutations."

No. Sentence Comment

13 Abnormal function of the channel results in aber- cAMP CF CFTR NBF PI PS RT-PCR Cyclicadenosinemonophosphate Cysticfibrosis Cysticfibrosistransmembraneconductance regulator Nucleotidebindingfold Pancreaticinsufficiency Pancreaticsufficiency Restrictiontransferasepolymerasechainreaction rant chloride conductance across the apical membrane of epithelial cells in a variety of organs.l-5 Approximately 70% of the CF chromosomes harbor a three base-pair deletionre- 705 0 Wilschanski et al. The Journal of Pediatrics November 1995 I II Ill IV V Normal Nonsense Missense G542X Missense Missense Missense A455E Frameshift AA deletion G551D R117H Alternative 394delTT AF508 splicing Splice junction 3849+10kbC~T 1717-1G~A (a) (b) (c) (d) (e) (f) Figure. Login to comment
43 Defined mutations (each mutation cited in references 8, 23, and 24; numerals in parentheses indicate number of patients): Nonsense mutations-----class I: Frameshift mutations---class I: Splice site mutations-class I: Missense mutations---class HI: Missense mutations---class IV: Partially defective processing---class V: Alternative spficing-----classV: R1162X (3), Y1092X (3), G542X (21), Q552X (2), Q493X (2), w1282x (2), E1104X (1), R553X (6), E585X (l), (all PI) 3659delC (5), 2184delA (4), 4010de14 (1), 556delA (1), 3002delG (1) 3905insT (1), 4016insT (3), 1154insTC (l), 441delA (1), 2184insA (2), 1078delT (1), 4326delTC (3) (all PI) I717-1G--~A (4), 621+lG--*T (10), 711+IG--~T (3), 875+1G-+C (2), 3120+IG-~A (1) (18 PI, 2 PS) G551D (25), N1303K (7), R560T (8), I148T (1), G85E (3), A559T (1), L1077P (2), T1234V (1), (47 PI, 1 PS) R117H (10), R347H (3), R347P (1), D614G (1), S1251N (2), (all PS) P574H (2), A455E (2), (all PS) 3272-26A-+G (4), 3849+10KbC---~T (2), 3120G-+A (1), (all PS) analysis, we further grouped the patients according to the molecular consequences conferred by the CFTR alleles. Login to comment
109 More recently, a multicenter study reported no significant differences in sweat chloride levels in 79 compound heterozygotes carrying the mutations G55ID with AF508 (class III), in comparison with those homozygous for AF508.21 In addition, no significantdifferences in sweat chloride values could be detected between those who were homozygous for AF508 and those who had other common "severe" mutations, including the nonsense mutations (G542X, R553X, and W1282X), missense mutation (N1303K), and splice site mutations (621 + 1G--->Tand 1717 - 1G--~A).22 In the latter study there was a significant difference in sweat chloride concentration between a group heterozygous for the mild missense mutation (AF508/R117H) and the reference group (AF508/AF508).22 These data were limited by the range of mutations and were defined by genotype rather than functional class, but the results are in complete agreement with the findings of the present study. Login to comment
12 Abnormal function of the channel results in aber- cAMP CF CFTR NBF PI PS RT-PCR Cyclicadenosinemonophosphate Cysticfibrosis Cysticfibrosistransmembraneconductance regulator Nucleotidebindingfold Pancreaticinsufficiency Pancreaticsufficiency Restrictiontransferasepolymerasechainreaction rant chloride conductance across the apical membrane of epithelial cells in a variety of organs.l-5 Approximately 70% of the CF chromosomes harbor a three base-pair deletionre- 705 0 Wilschanski et al. The Journal of Pediatrics November 1995 I II Ill IV V Normal Nonsense Missense G542X Missense Missense Missense A455E Frameshift AA deletion G551D R117H Alternative 394delTT AF508 splicing Splice junction 3849+10kbC~T 1717-1G~A (a) (b) (c) (d) (e) (f) Figure. Login to comment

PMID: 7573058 [PubMed] Zielenski J et al: "CFTR gene variant for patients with congenital absence of vas deferens."

No. Sentence Comment

21 More recently, CFTR alleles Letters to the Editor Table I CFTR Mutations Detected in the CBAVD Patients Number of Percentage Genotype Patients of Total AF508 IVS8/ST 16 W1282X IVS8/5T 9 AF508 R117H(7T) 4 N1303K IVS8/5T 2 IVS8/ST IVS8/5T 2 AF508 R117C 1 AF508 D1152H 1............ 1 58.6 AF508 S50Y 1 R553X R117H(7T) 1 R117H(7T) R117H(7T) 1 G542X IVS8/5T 1 1717-1G-+A IVS8/ST 1 1525-1G-A IVS8/5T 1 IVS8/5T Unknown 4 AF508 Unknown 4. Login to comment
22 W1282X Unknown 2 R553X Unknown ............ 20.0 4173delC Unknown1 1 D614G Unknown 1 1716+12T- C Unknown 1 J Unknown Unknown ............ .15 21.4 NOTE.-The known CFTR mutations screened included AF508, G542X, GSS1D, N1303K, R553X, W1282X, AI507, 1717-1G-A, R560T, S549N, 621+1G--T, and R117H. Login to comment

PMID: 7551394 [PubMed] Friedman KJ et al: "Screening Young syndrome patients for CFTR mutations."

No. Sentence Comment

78 Of the 13 Young syndrome patients, we identified one (Patient 5) who was het- CBAVD Dl152H D1270N G576A* R75Q* P67L Rl17H 3849 + 10 KB C > T G551S Rl17H Pancreatic Sufficient, Moderate Pulmonary Symptoms, Normal Sweat Chloride Concentrations Pancreatic Sufficient, Moderate Pulmonary Symptoms R347P 2789 + 5 G > A R334W G85E R347H R347L Rl17H G91R A455E S945L Y563N Q1291H R297Q R352Q L1065P 3850-3 T > G F1286S 3849 + 10 KB C > T TABLE 1 CFTR MUTATION SCREENING PANEL Severe M508 G551D R553X N1303K W1282X G542X 1717-1 G > A ~1507 R560T 3659deiC 621 + 1 G > T S549N TABLE 2 CLINICAL FEATURES OF YOUNG SYNDROME PATIENTS Patient Age Sweat CI- FEV, Paranasal Sputum No. Login to comment

PMID: 7544320 [PubMed] Kanavakis E et al: "Mutation analysis of ten exons of the CFTR gene in Greek cystic fibrosis patients: characterization of 74.5% of CF alleles including one novel mutation."

No. Sentence Comment

0 Hum Genet (1995) 96:364-366 9 Springer-Verlag 1995 Emmanuel Kanavakis 9Maria Tzetis 9Thalia Antoniadi Joanne Traeger-Synodinos - Stavros Doudounakis George Adam 9Nikos Matsaniotis 9Christos Kattamis Mutation analysis of ten exons of the CFTR gene in Greek cystic fibrosis patients: characterization of 74.5% of CF alleles including one novel mutation Received: 15 November 1994 / Revised: 20 February 1995 Abstract To initiate the complete characterization of mutations in the CFTR gene in Greek cystic fibrosis (CF) patients, we screened 184 patients for six relatively common mutations (zXF 508, G542X, G551D, 621+1 G-)T, N 1303K, W 1282X) using allele-specific hybridization and, in addition, analyzed exons 4, 5, 7, 8, 10, 11, 17b, 19, 20 and 21 using the method of denaturing gradient gel electrophoresis (DGGE). Login to comment
10 Allele-specific hybridization (ASO) The regions encompassing the mutations of interest (AF 508, G542X, G551D, 621+1 G ~ T, N1303K and WI282X) were amplified by the polymerase chain reaction (PCR) as described in Zielenski et al. (1991). Login to comment
15 Results and discussion Studies in southern European populations disclosed that the most frequent CF alleles are AF 508, G542X, G551 D, Fig. 1 Sequencing of the region of the cystic fibrosis transmembrane conductance regulator (CFTR)gene showing the A---~Gtran- sition in intron 17a, 4 bp 5" to the acceptor splice site (3272-4A--*G) 621+1 G-+T, W1282X, and N1303K (Tsui 1992; Abeliovich et al. 1992; Casals et al. 1993; Kazazian 1994). Login to comment
26 (ASO allele-specific hybridization, DGGE denaturing gradient gel electrophoresis, Seq direct genomic sequencing) Mutation Method Number of Percentage positive alleles AF 508 621+lG---~T G542X N1303K Rll7H R334W 574delA 3272-26A---~G R1158X 1677delTA R1070Q G551D G 1244V R553X 444delA 3849+4A---)G 457-TAT--)G 4010delTATT 4040delA W361R 3272-4A--)Ga Known Unknown Total number alleles ASO, DGGE ASO, DGGE ASO, DGGE ASO, DGGE DGGE, Seq DGGE, Seq DGGE, Seq DGGE, Seq DGGE, Seq DGGE DGGE, Seq ASO, DGGE DGGE, Sec DGGE, Sec DGGE, Sec DGGE, Sec DGGE, Sec DGGE, Sec DGGE, Sec DGGE, Sec DGGE, Sec 194 52.7 17 4.6 16 4.3 14 3.8 4 1.1 4 1.1 3 0.8 3 0.8 3 0.8 3 0.8 2 0.5 2 0.5 1 0.3 1 O.3 1 0.3 1 0.3 1 0.3 1 0.3 1 0.3 1 0.3 1 0.3 274 74.5% 94 25.5% 368 aNovel mRNA splicing mutations Acknowledgements This work was supported by the Greek Ministry of Health, the Hellenic Cystic Fibrosis Association and the Bodosakis Foundation. Login to comment

PMID: 7544319 [PubMed] Brancolini V et al: "Search for mutations in pancreatic sufficient cystic fibrosis Italian patients: detection of 90% of molecular defects and identification of three novel mutations."

No. Sentence Comment

21 We have studied a cohort of 31 Italian patients with PS using firstly traditional methods to screen for mutations which predominate in the Italian population [AF508, G542X (Kerem et al. 1990b), N1303K (Osborne et al. 1991), 1717-1G--~A (Guillermit et al. 1990) and W1282X (Vidaud et al. 1990)], secondly denaturing gradient gel electrophoresis (DGGE) analysis of the entire coding part of the CFTR gene, thirdly testing for the presence of the two mutations [1811+ 1.2kbA--+G (Chillon et al., personal communication to the CF Genetic Analysis Consortium) and 3849+10kbC-+T (Highsmith et al. 1994)] located in non-coding portions of the gene, which were not detectable by DGGE, and finally intragenic microsatellites [IVS8/GT (Morral et al. 1991), IVS17b/TA and IVS17b/CA (Zielenski et al. 1991b)] mapping. Login to comment
33 Mutation detection Screening for mutations which predominate in our population: AF508, G542X, N1303K, 1717-1G---~A,W1282X, and of the two intronic mutations 3849+10kbC--+T and 1811+l.2kbA---~G was carried out as previously described (Ballabio et al. 1990;Friedman et al. 1991; Cremonesi et al. 1991; Vidaud et al. 1990; Highsmith et al. 1994; Chillon et al., personal communication to the CF Genetic Analysis Consortium). Login to comment
38 Table 1 PCR primers and conditions for denaturing gradient gel electrophoresis analysis of exons 1 and 9 (for exon 9 two different PCR products were analyzed under different conditions in order to detect all possible base changes) Exon PCR primers 5"---~3" Annealing Denaturing Electrophoresis temperature (~C) range time (h) 1 TAGGTCTTTGGCATTAGGAG 54 40%-90% 6 (55GC)CCAAACCCAACCCATA CACAC (35GC)TGAAAATATCTGACAA 45 10%-60% 6 ACTC CCTTCCAGCACTACAAACTA (37GC)AACAGGGATTTGGGG 50 10%-60% 6 AATTA AACTAGAAAAAAAAAGAGA Results Screening for predominant mutations A preliminary screening for mutations being predominant in our population was carried out in our series of patients showing PS, revealing the presence of AF508 on 19 (30.6%) chromosomes, 1717-1G---~A and G542X on 2 (3.22%). Login to comment
39 In a previous study the overall frequencies of mutations in the whole sample population referring to our Center had been evaluated on a sample of 1018 CF chromosomes having the following frequencies: AF508:516 (50.7%) chromosomes, G542X: 52 (5.1%), 1717-1G--->A: 41 (4.0%), N1303K: 35 (3.4%), WI282X: 14 (1.4%) (our unpublished results). Login to comment
70 (UN yet unidentified mutation) Patient Genotype after Genotype at the end number preliminary screening of the analysis UN/UN M1V/4382delA 1717-1G---~A/UN 1717-1G---~A/R1066H AF508/UN AF508/D579G UN/UN M1V/UN AF508/UN AF508/UN UN/UN T338I/R1158X UN/UN G85E/71 I+5G---~A UN/UN D1152H/UN AF508/UN AF508/UN AF508/UN AF508/3849+ 10kbC---~T UN/UN 711+3A---~G/UN AF508/UN AF508/F1052V UN/UN R352Q/W57G UN/UN 1898+3A----~G/UN AF508/UN AF508/711+5G--~A G542X/UN G542X/DI 152H AF508/UN AF508/E193K 1717-1G---~A/UN 1717-1G---~A/2789+5A---)G AF508/UN AF508/G1349D AF508/UN AF508/G85E AF508/UN AF508/R347P AF508/UN AF508/R352Q AF508/UN AF508/R352Q AF508/UN AF508/S549N G542X/UN G542X/R1066H AF508/UN AF508/T338I AF508/UN AF508/R334W AF508/UN AF508/R334W AF508/UN AF508/S1251N AF508/UN AF508/R1066C AF508/UN AF508/D579G results) while the remaining three haplotypes had been found in association with other rare mutations, which were excluded by DGGE analysis in these patients (Table 3). Login to comment
85 In total, among the mutations detected in our PS patients, 17 (D579G, E193K, F1052V, 711+5G---~A, G1349D, G85E, R347R R352Q, $549N, 2789+5A---~G, D1152H, R1066H, R334W, T338I, 3849+10kbC---~T, S1251N, R1066C) have been detected in compound heterozygosity with a mutation already classified as severe (AF508, 1717-1G--~A, G542X) and thus can be considered as presumably mild. Login to comment
89 The results of this search showed, as expected, a different distribution of classical severe mutations (AF508, G542X, 1717-1G-+A, N1303K, W1282X) in patients with PS as compared to the overall CF population (37.1% against 67.4%). Login to comment
93 Screening for only eight presumed mild mutations (R352Q, R1066H, G85E, Dl152H, 711+5G---~A, T338I, R334W and D579G) in addition to the predominant four severe mutations (AF508, G542X, 1717-1G-+A and N1303K), would have allowed the identification of 64.5% of the molecular defects in our patients having PS. Login to comment

PMID: 7477025 [PubMed] Tzetis M et al: "Identification of two novel mutations (296 + 1G-C and A46D) in exon 2 of the CFTR gene in Greek cystic fibrosis patients."

No. Sentence Comment

4 Since the identification of the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) protein and the initial characterization of the predominant mutation in the Caucasian population, AF508,'-~ more than 400 other mutations have been reported.4 Mutations have been described in all of the exons and neighbouring intronic sequences of the CFTR gene, with highest concentration of the more common mutations occuring in exons coding for NBF1.s To determine the type and frequency of cystic fibrosis (CF) mutations in the Greek population we screened 184 patientsfor the most common mutations (,4F508, G542X, G551D, 621 +IG>T, N1303K and W1282X) by ASO hybridization and then proceeded to analyseexons2, 4, 5, 6a, 6b, 7, 8, 9, 10, 11,17b, 19, 20, and 21 by denaturing gradient gel electrophoresis (DGGE) asdescribed.6The DNA sequence of samples showing a shift in mobility was determined after as- symetric PCR as describedZ The six most common mutations accounted for 66-9% of the CF alleles in Greek patients, of which /IF508 had a frequency of 52.7%. Login to comment
8 One was a compound heterozygote A46D/G542X and the other a compound heterozygote with the 621 +IG-T mutation. Login to comment
12 1 2 3 CFTR genotype A46D/G542X A46D/621 +IG-T 296+1G-C/ unknown Sex Female Female Male Date of birth 1983 1965 1967 Age at diagnosis 4 years 4.5 years 26 years Sweat test chloride conc. Login to comment

PMID: 7539891 [PubMed] Gan KH et al: "A cystic fibrosis mutation associated with mild lung disease."

No. Sentence Comment

34 Among the patients screened, 151 were found to be homozygous for the ⌬F508 mutation and 39 were found to have compound heterozygosity for the A455E mutation. Login to comment
35 In the A455E compound heterozygotes, the following mutations were found on the other allele: ⌬F508 (27 patients), 1717-1G→A (4 patients), E60X (4 patients), G542X (2 patients), R553X (1 patient), and an unknown mutation (1 patient). Login to comment
69 †The following genotypes were identified: A455E/⌬F508 (25 patients), A455E/E60X (4), A455E/G542X (2), A455E/R553X (1), and A455E/1717-1G→A (1). Login to comment
70 ߤThe following genotypes were identified: A455E/F508 (25 patients), A455E/E60X (4), A455E/G542X (2), A455E/R553X (1), and A455E/1717-1G࢐A (1). Login to comment

PMID: 8528204 [PubMed] Savov A et al: "Double mutant alleles: are they rare?"

No. Sentence Comment

44 S912L and G1244V A C->T transition at nucleotide position 2867 in exon 15 and a G->T transversion at position 3863 in exon 20 of the CFTR gene were found in a patient who also carries G542X. Login to comment

PMID: 7562977 [PubMed] Mittre H et al: "High incidence of delta I507 mutation of the CFTR gene in a limited area of the north west of France."

No. Sentence Comment

5 The other most common mutations observed in our study with a frequency higher than 1% were: G551D (2 4%), G542X (2-4%), 574delA (1-2%), 3659delC (1-2%), and N1303K (1-2%). Login to comment

PMID: 7562966 [PubMed] Balnaves ME et al: "The impact of newborn screening on cystic fibrosis testing in Victoria, Australia."

No. Sentence Comment

121 Three hundred and fifty six people (to 30.9.93) have been tested for AF508 and three exon 11 mutations: G542X, G551D, and R553X. Login to comment

PMID: 7540706 [PubMed] Jarvi K et al: "Cystic fibrosis transmembrane conductance regulator and obstructive azoospermia."

No. Sentence Comment

18 We screened for 6 CF mutations (AF508, G551D, G542X, W1283X, N1303K, R117H), representing the most common mutations detected previously in men with CBAVD, and determined the CFTR gene variants of R75Q and T tract length of intron 8. Login to comment

PMID: 7539210 [PubMed] Rave-Harel N et al: "CFTR haplotype analysis reveals genetic heterogeneity in the etiology of congenital bilateral aplasia of the vas deferens."

No. Sentence Comment

38 The entire studied group of males with CBAVD was tested for 16 CFTR mutations, using DNA-PCR amplification (Saiki et al. 1985, 1988), followed by specific tests as described elsewhere: AF508 (Rommens et al. 1990); W1282X (Shoshani et al. 1992a); G542X, S549R, S549I, and 1717-1G-+A, by direct sequencing of exon 11, using oligonucleotide primers (Zielenski et al. 1991b); N1303K (Osborne et al. 1991); 3849+10Kb C&-T (Highsmith et al. 1994); W1089X and 4010delTATT (Shoshani et al. Login to comment
58 Mutation Analysis Fourteen CF-R mutations that were elsewhere identified among the Israeli CF patient population (Kerem et al. 1994) were analyzed: W1282X, AF508, N1303K, G542X, 3849+10Kb C--T, S549R, S549I, W1089X, 4010delTATT, G85E, 1717-1G--A, D1152H, 405+1G--A, and Q359K1T360K. Login to comment
59 Mutation Analysis Fourteen CF-R mutations that were elsewhere identified among the Israeli CF patient population (Kerem et al. 1994) were analyzed: W1282X, AF508, N1303K, G542X, 3849+10Kb C--T, S549R, S549I, W1089X, 4010delTATT, G85E, 1717-1G--A, D1152H, 405+1G--A, and Q359K1T360K. Login to comment

PMID: 7539342 [PubMed] Jezequel P et al: "Structural analysis of CFTR gene in congenital bilateral absence of vas deferens."

No. Sentence Comment

46 SF508/ SF508 SF508 / N1303K AF508/ G551D SF508 / 3272-26G--*A SF508 / 1078 delT F508/Y1092X SF508 / Ai507 F5O8 / G542X SF508 / 621+1G-T F508 / 3898 insC SF508 / 574 delA AF508 / G85E SF508 / W1282X N1303K/F311L G551D/F311L R553X I? Login to comment
47 N1303K/? Login to comment
72 However, none of the most frequent mutations described in our CF population (G551D, N1303K, 3272-26G--A, G542X) was identified in our CBAVD cohort. Login to comment
73 However, none of the most frequent mutations described in our CF population (G551D, N1303K, 3272-26G--A, G542X) was identified in our CBAVD cohort. Login to comment

PMID: 7739684 [PubMed] Chillon M et al: "Mutations in the cystic fibrosis gene in patients with congenital absence of the vas deferens."

No. Sentence Comment

74 OF PATIENTS POLYT GENOTYPE† ⌬F508/R668C ⌬F508/D1152H ⌬F508/D1270N ⌬F508/R75L ⌬F508/R117H ⌬F508/L206W ⌬F508/R258G ⌬F508/S1235R ⌬F508/R347H ⌬F508/R347H R117H/G1349D R117H/712-1G192;T G149R/R668C R347H/R1066H R553X/R668C R1070W/2869insG ⌬F508/- G542X/- W1282X/- R334W/- K1060T/- R1162X/- N1303K/- A800G/- ⌬F508/- ⌬F508/- ⌬F508/- ⌬E115/- R117H/- R347H/- G542X/- R553X/- 1677delTA/- 2184delA/- 2789ϩ5G→Α/- S1235R/- W1282X/- -/- -/- -/- -/- 2 2 2 1 1 1 1 1 1 1 1 1 1 1 1 1 22 4 3 1 1 1 1 1 7 1 1 1 1 2 1 1 1 1 1 1 1 3 3 1 19 9T/7T 9T/7T 9T/7T 9T/7T 9T/7T 9T/9T 9T/7T 9T/7T 9T/7T 9T/9T 7T/7T 7T/9T 9T/7T 9T/7T 7T/7T 7T/7T 9T/5T 9T/5T 7T/5T 7T/5T 7T/5T 7T/5T 9T/5T 5T/5T 9T/7T 9T/9T 7T/7T 7T/7T 7T/7T 9T/7T 9T/7T 7T/7T 7T/7T 7T/7T 7T/7T 7T/9T 7T/7T 9T/5T 7T/5T 5T/5T 7T/7T -/- 3 7T/9T *Data were obtained from the Spanish population analyzed in this study. Login to comment
101 Four fathers who were carriers of cystic fibrosis had one CFTR gene with the 5T allele and the other with a severe cystic fibrosis mutation (G542X, N1303K, 1812-1G→A, or 936delTA). Login to comment

PMID: 7578402 [PubMed] Crystal RG et al: "Evaluation of repeat administration of a replication deficient, recombinant adenovirus containing the normal cystic fibrosis transmembrane conductance regulator cDNA to the airways of individuals with cystic fibrosis."

No. Sentence Comment

112 G55 ID, S5491, A455E, and G542X account for 10-20% of ttie non-delta F508 mutations (33). Login to comment
116 "NuU" mutations, including frameshift, nonsense, and splicing mutations, have been found in compound heterozygotes [e.g., G542X/S1255X or R553X/W1316X]. Login to comment

PMID: 7535745 [PubMed] Hughes D et al: "Fluorescent multiplex microsatellites used to identify haplotype associations with 15 CFTR mutations in 124 Northern Irish CF families."

No. Sentence Comment

23 Each mutation that has been found more than once is linked to a single haplotype, except AF508 and G542X. Login to comment
25 Nine haplotypes having specific CF mutations are not present in normal chromosomes Mutation Alleles tested (%) AF508 41 (34.2) 32 (26.7) 22 (18.3) G551D 16 R560T 08 621 + 1G > T 08 Rll7H 05 G542X 03 02 E60X 02 M507 02 R297Q 01 R553X 01 3849 G > A 01 N1303K 01 3659delC 01 557delT 01 Q2X 01 Frequency Haplotype of mutation in % 8AC 17AT 17AC 463 % in normal chromosomes 58.0 23 31 13 - 17 32 13 01 17 31 13 - 4.0 16 07 17 03 2.5 16 07 17 03 1.7 21 31 13 - 2.1 16 30 13 16 1.7 23 33 13 01 22 31 13 - 0.6 16 31 13 03 0.8 17 07 17 08 0.2 17 07 17 08 0.2 17 58 13 - 0.2 16 31 14 - 0.4 23 31 13 - 0.2 16 35 13 03 0.2 15 29 13 - 0.2 23 34 13 01 Table 2 Frequent haplotypes generated from normal and uncharacterised CF chromosomes in N. Ireland. Login to comment

PMID: 7535742 [PubMed] Bonizzato A et al: "Analysis of the complete coding region of the CFTR gene in a cohort of CF patients from north-eastern Italy: identification of 90% of the mutations."

No. Sentence Comment

35 Table 1 CF mutations identified in this cohort study (225 chromosomes from Veneto and Trentino Alto-Adige) n Number of CF chromosomes, Cum fi cumulative fraction, wnovel mutation identified during this study " Cystic Fibrosis Genetic Analysis Consortium, personal comunication Table 2 DNA sequence variations identified in this cohort study (w Novel sequence variation identified during this study a Cystic Fibrosis Genetic Analysis Consortium, personal comunication Mutation Exon n % Cure fr References AF508 l0 107 47.56 47.56 Kerem et al. 1989 R1162X 19 22 9.78 57.33 Gasparini et al. 1991 2183AA----~G 13 21 9.33 66.67 Bozon et al. 1994 N1303K 21 9 4.00 70.67 Osborne et al. t991 G542X 11 6 2.67 73.33 Kerem et al. 1990 711+5G--~A intron 5 6 2.67 76.00 w 1717 1G--~A intron 10 5 2.22 78.22 Kerem et al. 1990 G85E 3 3 1.33 79.56 Zielenski et al. 1991~' R553X 11 3 1.33 80.89 Cutting et al. 1990 2789+5G--~A intron 14b 3 1.33 82.22 Highsmith* Q552X 11 3 1.33 83.56 Devoto et al. 1991 621+lG---~T intron 4 2 0.89 84.44 Zielenski et al. 1991b W1282X 20 2 0.89 85.33 Vidaud et al. 1990 3132delTG 17a 2 0.89 86.22 w 2790-2A---~G intron 14b 2 0.89 87.11 w 457TAT--)G 4 1 0.44 87.56 Ravnik-Glavac et al. 1993 R347P 7 1 0.44 88.00 Dean et al. 1990 G551D 11 .1 0.44 88.44 Cutting et al. 1990 1717-8G-+A intron 10 1 0.44 88.89 Savov et al. 1994 3849+ 10KbC--)T intron 19 1 0.44 89.33 Highsmith* R709X 13 1 0.44 89.78 w 1898+3A---~G intron 12 1 0.44 90.22 Cremonesi et al. 1992 Identified 203 90.22 Unidentified 22 9.78 Variatioh Exon References 1540 A orG Met or Val at 470 10 Kerem et al. 1990 1898+152 T or A intron 12 Chillon et al. 1991 2134 C or T Arg or Cys at 668 13 Fanen et al. 1992 2694 T or G No change Thr at 854 14a Zielenski et al. 199 lb 2752-22 A or G intron 14a w 3601-65 C or A intron 18 Dork et al. 199l 4029 A or G No change Thr at 1299 21 Fanen et al. 1992 4404 C or T No change Tyr at 1424 24 ShoshanP 711 +5G--+A This mutation was found in the splice donor site flanking the 3' end of exon 5. Login to comment

PMID: 7543317 [PubMed] Pignatti PF et al: "Increased incidence of cystic fibrosis gene mutations in adults with disseminated bronchiectasis."

No. Sentence Comment

25 RESULTS Common CF mutations All the study subjects were initially typed with respect to some CFTR mutations known to be present in CF patients in the North East Italian population: AF508, R1162X, 2183AA->G, NI303K, G542X, 711 + 5G->A, 1717-1 G^>A, 1717-8G->A, G85E, R553X, 2789 + 5 G->A, Q552X, 621 + 1 G->T, W1282X, 3132delTG, 2790-2A->G, 457 TAT->G, R347P, G551D, 1898 + 3A->G and 3849 + 10 kbC^T. Login to comment
31 List of CFTR gene mutations and DNA polymorphisms screened Mutations R75Q/X/L, G85E, 394deITT 457TAT->G, R117H 621 + 1G->T 711 + 5G->A L206W 875 + 40 A->G 936 del TA 1001 + 11C->T R334W, R347 P/H/L, 1154insTC A455E, V456F DF5O8 1717-IG->A, 1717-8G->A G542X, G551D, Q552X, R553X P574H 1898 + 3A->G 2183 AA->G, 2184delA, R709X D836Y, 2694 T/G 2752-22 A/G 2789 + 5 G->A, 2790-2 A-»G Q890X 3041-71 G/C 3132delTG 3271 + 18 C-»T, 3272-26 A->G H1054D, G1061R, R1066C/H, A1067T, H1085R, Y1092X, 3320 ins5 D1152H R1162X, 3667ins4, 3737delA, 11234V 3849 + 10 kb C-»T, 3850-1 G-»A SI25IN, S1255P, 3905insT, 3898insC, D127ON, W1282X, R1283M, 4002 A/G 4005 + 1 G-»A N1303 K/H, 4029 A/G D1377H Q1411 X 4404 C/T, 4521 G/A Location e 3 e 4 i 4 i 5 e 6a i 6a e 6b i 6b e 7 e 9 e 10 i 10 e 11 e 12 i 12 e 13 e 14a i 14a i 14b e 15 i 15 e 17a i 17a e 17b e 18 e 19 i 19 e 20 i 20 e2l e 22 e 23 e24 Listing is in order of location along the CFTR gene, e = exon; i = intron. Login to comment
124 Reverse dot blot analysis was used for detecting the following mutations: A F508, G542X, G55ID, R553X, R1162X, W1282X, N1303K (Roche Molecular Systems, kindly provided by Dr R.Saiki). Login to comment

PMID: 7534040 [PubMed] Chillon M et al: "A novel donor splice site in intron 11 of the CFTR gene, created by mutation 1811+1.6kbA-->G, produces a new exon: high frequency in Spanish cystic fibrosis chromosomes and association with severe phenotype."

No. Sentence Comment

67 To test this hypothesis, mRNA studies were performed in one Spanish CF patient (heterozygous for G542X and 3601-11G/C) and one German CF patient (heterozygous for SF508 and 3601-11lG/C). Login to comment
70 However, an extra band was detected between exons 10 and 12 in the G542X/3601-11lG/C patient. Login to comment
76 In the initial cDNA analysis of the G542X/1811+1.6kbA--G patient, we detected both the 49-bp insertion and the G542X allele, while in the AF508/1811+l.6kbA-oG patient, we mainly detected the AF508 allele, since RNA from the 1811 +1.6kbA-*G allele was 5-10-fold less abundant than the AF508 allele (fig. 3). Login to comment
111 Three CF patients carried mutation P205S on the other chromosome, which is associated with a mild CF phenotype and pancreatic sufficiency (Chillon et al. 1993). Login to comment
112 Seventeen other patients were carriers of a known severe CF mutation (AI507, AF508, 1609delCA, G542X, K71OX, or N1303K) on the other chromosome. Login to comment
125 of patients ...................... 17 3 82 Age (years) ...................... 9.1 ± 5.8 12 ± 5.3 7.8 ± 5.2 Age at diagnosis (years) ............... 2.8 ± 4.0 7.1 ± 5.2 2.2 ± 2.8 Sweat chloride (mmolIL) ............. 98 ± 11.7 100 ± 10 104.4 ± 15.7 FEV1 (% predicted)d .................... 65 ± 24.8 70.8 ± 12.8 74.8 ± 23.1 Shwachman score' ...................... 74.5 ± 12.3 86.6 ± 2.3 83.1 ± 11.8 Pancreatic sufficiency ................... 0/19 (0%) 3/3 (100%) 1/82 (1.2%) a A1507, AF508, 1609delCA, G542X, K710X, and N1303K. Login to comment
150 We could detect the two mRNA species in the G542X/1811 +1.6kbA-+G patient, since both mutations lead to a reduction in levels of mRNA. Login to comment
124 of patients ...................... 17 3 82 Age (years) ...................... 9.1 &#b1; 5.8 12 &#b1; 5.3 7.8 &#b1; 5.2 Age at diagnosis (years) ............... 2.8 &#b1; 4.0 7.1 &#b1; 5.2 2.2 &#b1; 2.8 Sweat chloride (mmolIL) ............. 98 &#b1; 11.7 100 &#b1; 10 104.4 &#b1; 15.7 FEV1 (% predicted)d .................... 65 &#b1; 24.8 70.8 &#b1; 12.8 74.8 &#b1; 23.1 Shwachman score' ...................... 74.5 &#b1; 12.3 86.6 &#b1; 2.3 83.1 &#b1; 11.8 Pancreatic sufficiency ................... 0/19 (0%) 3/3 (100%) 1/82 (1.2%) a A1507, AF508, 1609delCA, G542X, K710X, and N1303K. Login to comment
149 We could detect the two mRNA species in the G542X/1811 +1.6kbA-+G patient, since both mutations lead to a reduction in levels of mRNA. Login to comment

PMID: 7532152 [PubMed] Artlich A et al: "Common CFTR mutations are not likely to predispose to chronic bronchitis in northern Germany."

No. Sentence Comment

2 R553X, G542X, G551D, N1303K and 621 + 1G--->T were not detected. Login to comment
10 We have analyzed CF carrier frequency and the frequency of the more common CFTR mutations AF508, R553X, G551D, G542D, G542X, N1303K and 621 + 1G--+T by examination of 100 patients with chronic bronchitis. Login to comment
20 Sequences from exons 4, 10, l l and 21 were amplified by the polymerase chain reaction (PCR) according to the published protocols in order to search for mutations AF508, G542X, R553X, G551D, N1303K and 621 +IG---~T (Rommens et al. 1990; Cutting et al. 1990; Kerem et al. 1990;Osborne et al. 1991; Zielenski et al. 1991). Login to comment
22 Primers F: TTGCAGAGAAAGA- CAATATAGTTCCT and R: GCACAGATTCTGAGTAACCAT- AATC generate a 296 bp product with a BstI site destroyed by G542X. Login to comment

PMID: 7532150 [PubMed] Casals T et al: "Extensive analysis of 40 infertile patients with congenital absence of the vas deferens: in 50% of cases only one CFTR allele could be detected."

No. Sentence Comment

41 Genomic DNA from CBAVD and CUAVD subjects was first analyzed for the two most common mutations in the Spanish population, viz., AF508 and G542X (Casals et al. 1993). Login to comment
56 The two most frequent CF mutations in the Spanish population (AF508 and G542X) were found on 14 chromosomes (10 AF508 and 4 G542X). Login to comment
59 Direct sequencing of these two abnormal fragments identified mutation R ll7H, a known Table 1 Semen analysis of patients with CAVD, given as the mean (range) CBAVD CUAVD (n = 27) (n = 10) Sperm (x 106/ml) 0 10.6 (0-90) Seminal volume (ml) 0.9 (0.2-3.1) 2.5 (0.4 5.4) pH 6.7 (6.0-8.0) 7.3 (6.4-7.7) Fructose (retool/l) 2.6 (0-9) 10.3 (3-) '~Citrate (mmol/l) 77.5 (11-188) 48.6 (36-88) ~Reference values: fructose, 8 28 retool/l; citrate, 10 35 retool/1 Table 2 CFTR mutation analysis in 30 CBAVD and 10 CUAVD patients (CBAVD congenital bilateral absence of the vas deferens, CUAVD congenital unilateral absence of the vas deferens, ND not determined, - absence of mutations, RRI recurrent respiratory infection, R rhinitis, RS rhino-sinusitis, BR.ASTH bronchitis asthmatic) Table 3 Congenital malformations associated with CAVD in 40 patients 207 Patient Age Phenotype Sweat test Mutation Other clinical (years) (mEq/l) features 1 37 CBAVD 108 1677delTA 2 28 CBAVD 50 G542X 3 28 CBAVD 118 - 4 33 CBAVD 90 AF508/L206W RRI, R 5 26 CBAVD 118 R117H/712-1G-+T 6 42 CBAVD 66 - RS 7 31 CBAVD 170 AF508 R 8 27 CBAVD 100 AF508/R74W + D1270N RRI, R 9 32 CBAVD 74 AE115 RS 10 35 CBAVD 90 - Nasal polyps 11 33 CBAVD 78 KI060T RI, family history 12 45 CBAVD 150 R334W RS 13 42 CBAVD 60 - 14 40 CBAVD 110 R 1070W RS 15 29 CBAVD 110 G542X 16 37 CBAVD 80 R117H RI, RS, BR.ASTH 17 37 CBAVD 85 - Asthma 18 46 CBAVD 15 R1162X 19 37 CBAVD 110 AF508 RS, diarrhoea 20 42 CBAVD 45 2789+5G--)A RI 21 49 CBAVD 95 AF508 22 36 CBAVD 70 AF508 RRI, RS 23 42 CBAVD 90 - 24 15 CBAVD 150 AF508 25 26 CBAVD 60 - 26 39 CBAVD 100 AF508 RRI, RS 27 33 CBAVD 57 AF508 RRI 28 33 CBAVD 80 G542X 29 34 CBAVD 78 - 30 32 CBAVD 113 G542X 31 33 CUAVD ND AF508 RS, pancreatitis 32 37 CUAVD ND - 33 31 CUAVD 77 - BR.ASTH 34 39 CUAVD ND - 35 40 CUAVD 40 - 36 33 CUAVD 59 - 37 40 CUAVD 90 - 38 47 CUAVD 40 - RRI 39 39 CUAVD 50 - 40 35 CUAVD 100 - No. Login to comment
103 In 13 cases, the mutations are known to be associated with severe CF (AF508, G542X, Rl162X and 1677delTA), whereas in five cases, the phenotypic effect of the mutation is still unknown (AEll5, K1060T, R334W, R1070W, and 2789 + 5G---)A); in one case (Rll7H), the mutation is known to result in mild CE Of these mutations, R334W seems to cause pancreatic insufficiency with a variable age of onset (X. Estivill, in press), whereas mutation 2789 + 5G--)A (W. E. Jr. High- smith, personal communication to the CFGAC) has frequently been found in adult CF patients and is probably involved in a mild phenotype (T. Casals et al. unpublished). Login to comment
141 In: Striver CR, Beaudet AL, Sly WS, Valle D (eds) The metabolic basis of inherited disease, 6th edn. McGraw-Hill, New York, pp 2649-2680 Casals T, Nunes V, Palacio A, Gimdnez J, Gaona A, Ibfifiez N, Morral N, Estivill X (1993) Cystic fibrosis in Spain: high frequency o1"mutation G542X in the Mediterranean coastal area. Login to comment

PMID: 7539080 [PubMed] Cheadle JP et al: "Two CF patients, one homozygous for the 621 + 1G > T splice mutation, the other homozygous for the 1898 + 1G > A splice mutation."

No. Sentence Comment

5 To date, investigators have described homozygotes for G542X,2 R553X,3 G85E,4 S549N,5 Rl17H,6 2184delA,7 R1162X,8 and W128X.9 We report here two patients, one homozygous for 621 + 1G>T, the other homozygous for 1898 + 1G>A. Login to comment

PMID: 7531240 [PubMed] Zar H et al: "Binding of Pseudomonas aeruginosa to respiratory epithelial cells from patients with various mutations in the cystic fibrosis transmembrane regulator."

No. Sentence Comment

50 (yr) Sex Genotype Mutation defect disease* Kulczycki score (%) 1 13 F AF508/AF508 Processing Mild 80 35 2 21 F AF508/2xF508 Processing Mild 83 33 3 13 M 2xF508/AF508 Processing Mild 87 26 4 15 M AF508/AF508 Processing Mild 87 22 5 15 F AF508/AF508 Processing Moderate 60 21 6 28 M AF508/AF508 Processing Moderate 50 17 7 15 F AF508/AF508 Processing Moderate 60 12 8 29 M AF508/3849 + 10 Processing/protein synthesis Moderate 55 7 9 43 F WI282X/W1282X Protein synthesis Moderate 60 3 10 13 F 2xF508/W1282X Processing/protein synthesis Mild 88 13 11 16 M Unknown Unknown Mild 82 6 12 22 F AF508/G551D Processing/regulation Mild 80 4 13 19 M AF508/G551D Processing/regulation Mild 80 18 14 12 M G542X/3849 + 10 Protein synthesis Mild 87 18 15 60 M W1282X/unknown Protein synthesis Moderate 75 5 *Severityofpulmonarydiseasewasmeasuredwiththe Shwachman-Kulczyckiscoringsystem. binding, there was no significant correlation between pulmonary status and the quantity of adherent bacteria. Login to comment

PMID: 7529962 [PubMed] Mercier B et al: "Is congenital bilateral absence of vas deferens a primary form of cystic fibrosis? Analyses of the CFTR gene in 67 patients."

No. Sentence Comment

63 We identified 28 AF508, 5 W1282X, 1 G542X, 1 R553X, and 2 N1303K mutations. Login to comment
77 of Patients Genotypea 1 AF508 + (G628R + S1235R) 1 AF508 + (R74W + D1270N) 2 AF508 + R668C 4 AF508 + R117H 1 AF508 + R258G 1 AF508 + R75L 1 E193K + N1303K 1 R347H + R1066H 1 R117C + W1282X 1 R553X + R668C 1 G149R + R668C 1 R117H+R117H 18 AF508/unidentified 4 W1282X/unidentified 1 G542X/unidentified 1 N1303K/unidentified 1 S1235R/unidentified 1 R347H/unidentified 1 A800G/unidentified 1 F1052V/unidentified 23 unidentified/unidentified a In parentheses are the two mutations located on the same haplotype. Login to comment

PMID: 8825494 [PubMed] Zielenski J et al: "Cystic fibrosis: genotypic and phenotypic variations."

No. Sentence Comment

545 Even the second most common mutation (G542X) has only a relative frequency of about 2.4% (Table 1). Login to comment
580 For example, many different microsatellite alleles have been found associated with AF508, G542X, and N1303K (123). Login to comment
628 This strategy may also be applied to patients with other Normal II III IV V No synthesis Block in Block in Altered Reduced processing regulation conductance synthesis Nonsense Missense G542X Missense Missense Missense A455E Frameshift N1303K G551D R117H 394deiTT AA deletion Alternative L1F508 R347P splicing Splice junction 1717-1G-->A 3849+1OkbC-->T Figure 3 Molecular consequence of different classes ofCF mutations. Login to comment
679 Table 3 Atypical (non-CF) diseases associated with the CFTR gene Common manifestations Disease shared with CF CBAVD absence of vas deferens (bilateral CUAVD absence of vas deferens (unilateral) Obstructive azoospermia azoosperma Diffuse bronchiectasis abnormal dilatation of bronchi Bronchiectasis with elevated abnormal dilatation of bronchi and sweat CI- high levels of sweat chloride Allergic bronchopulmonary allergic asthma, tenacious sputum, aspergillosis mucus plugs Chronic pseudomonas bron- chronic sinusitis, nasal polyposis chitis Chronic bronchial abnormal mucous secretion hypersecretion Nasal polyposis nasal polyps Neonatal transitory hyper- high levels of immunoreactive tryp- trypsinemia sin (IRT) Fraction of patients with at least one CFTR mutation (%) Reference 80/\02 (78)" 31 51168 (75)' 207a 6/14 (43)b 1 1 8 8/17 (47)' 93 6/10 (6W 13 6/48 (l2.5)e 161 9/28 (32)" 136 5/16 (3 1)1 78 6/1 1 (54)e 1 19 2/10 (20)e 1 1 9 6/65 (9.2)f 65 7/1 12 (6.2)g 22 9/149 (6)f 106 • The numbers are based on comprehensive screening of CFfR mutations (including IVS8 : 5T) by a variety of methods; btesting of three mutations (�F508, RI I7H and R75Q; '-�F508, G55 1O, G542X, W1282X, N1303K, RI 17H and IVS8 : 5T;d direct sequencing of exons encoding NBFI; ' the most common CFTR mutations (unspecified); f �F508 only: "eight mutations (�F508, �I507, DlIOH, RII7H, 621 + IG .... T, N1303K, G5SID, and R553X). Login to comment
993 CFTR nonsense mutations G542X and WI282X associated with severe reduction of CFTR mRNA in nasal epithelial cells. Hum. Mol. Genet. 1 :542-44 85. Hamosh A, Trapnell BC, Zeitlin PL, Montrose RC, Rosenstein BJ, et aI. 1991. Login to comment
1376 A cystic fibrosis patient with 6F508, G542X and a deletion at the D7S8 locus. Login to comment

PMID: 7527370 [PubMed] Mercier B et al: "Complete detection of mutations in cystic fibrosis patients of Native American origin."

No. Sentence Comment

2 As the most common mutation found in Caucasians (AF508) was absent and only one chromosome carried the G542X mutation, we decided to analyze the entire coding sequence of the CFTR gene in eight Pueblo CF patients. Login to comment
3 We have identified four different mutations: G542X, Rl162X, 3849+10kbC---~T, and D648V that account for these 16 haplotypes. Login to comment
18 The other mutations most frequently found in Caucasians, such as G551D, R553X, N1303K, or W1282X, were also excluded and only one patient was found to carry the G542X. Login to comment
47 First, the change to valine instead of aspartic acid would introduce a conformational change in the R domain, a region of the protein that plays a major Table 1 Clinical and mutations data of these Native American cystic fibrosis (CF) patients Patient Nation Pancreatic Weight Height Haplosufficient (PS) (%ile) (%ile) type Pancreatic insufficient (PI) Mutations 021-l Pueblo PI 20 10 CC Zuni 022-1 Pueblo P1 7.5 20 CC Zuni 023-1 Pueblo PI 75 50 CC Zuni 024-1 Pueblo PI 40 10 CC Zuni 028-1 Pueblo PI 7.7 5 CC Zuni 029-1 Pueblo PS 2 17.5 AC Zuni 006-1 Pueblo PS 8.5 45 AC Jemez 008-1 Pueblo Santo PS > 95 > 95 AB Domingo R1162X R1162X R1162X R1162X R1162X R1162X D648V G542X R1162X R1162X R1162X R1162X R1162X 3849+ 10kbC---~T 3849+ I0kbC----~T 3849+ 10kbC--)T Fig. 1 Sequencing data of the D648V. Login to comment
66 The fourth mutation, G542X, was present on a single chromosome. Login to comment

PMID: 7881429 [PubMed] Teng H et al: "Identification of seven rather infrequent and one novel CFTR mutation in the Belgian population."

No. Sentence Comment

3 Five mutations had a frequency higher than 1%: AF508 (72.5%), G542X (5.5%), N1303K (3.5%), 1717-1G-A (2.5%) and S1251N (2.0%). Login to comment

PMID: 7526685 [PubMed] Morral N et al: "Independent origins of cystic fibrosis mutations R334W, R347P, R1162X, and 3849 + 10kbC-->T provide evidence of mutation recurrence in the CFTR gene."

No. Sentence Comment

16 Of all the other mutations, only G542X (Kerem et al. 1990), G551D (Cutting et al. 1990), N1303K (Osborne et al. 1991), and W1282X (Vidaud et al. 1990) have a frequency of 1%-2.5% in the worldwide population (Cystic Fibrosis Genetic Analysis Consortium, in press). Login to comment
105 Mutations that have a relatively high worldwide frequency (AF508, G542X, and N1303K) and that are also ancient have a small proportion of chromosomes associated with haplotypes different from the original, which can be explained by slippage of the DNA polymerase at one microsatellite during replication. Login to comment

PMID: 7525450 [PubMed] Dork T et al: "Detection of more than 50 different CFTR mutations in a large group of German cystic fibrosis patients."

No. Sentence Comment

49 A few other mutations known to be frequent (e.g. NI303K, R553X, G542X, G551D, 2789+5 G-+A and 3849+10 kB C--+T) were then screened by specific direct methods as previously described (D6rk et al. 1992 a). Login to comment
77 Table 1 Frequency distribution and haplotypes of CFTR mutations in 700 German CF chromosomes Mutation~ Nucleotide changesb Locationc Frequencyd Haplotype~ Referencef Q39x C--~T at 247 Exon 2 1 (0.1%) D3 Cutting et al. (1992) E60X G-+T at 310 Exon 3 1 (0.1%) A2 Malone et al. (*) R75X C--+T at 355 Exon 3 1 (0.1%) C2 This study 405+1 G---~A G-+A at 405+1 Intron 3 1 (0.1%) C2 D6rk et al. (1993c) E92X G--~T at 406 Exon 4 2 (0.3%) B2 Will et al. (1994) R117C C---~Tat 481 Exon 4 1 (0.1%) C2 This study R117H G--+A at 482 Exon 4 2 (0.3%) B6 Dean et al. (1990) 621+1 G--+T G--+T at 621+1 Intron 4 1 (0.1%) B1 Zielenski et al. (1991b) H199Y C--+T at 727 Exon 6a 1 (0.1%) A2 This study (*) 1078delT Deletion of T at 1078 Exon 7 4 (0.6%) C2 Claustres et al. (1992) R334W C-~T at 1132 Exon 7 2 (0.3%) BI Gasparini et al. (1991) 1336K T-->A at 1139 Exon 7 3 (0.4%) A2 Cuppens et al. (1993) R347P G--+C at 1172 Exon 7 11 (1.6%) A2, C2 Dean et al. (1990) 1342-2 A--+C A--+C at 1342-2 Intron 8 3 (0.4%) A4 D/3rk et al. (1993b) Q414X C--+T at 1372 Exon 9 1 (0.1%) D3 D6rk et al. (1994a) A455E C-+A at 1496 Exon 9 1 (0.1%) BI Kerem et al. (1990) V456F G--~T at 1498 Exon 9 1 (0.1%) B3 D6rk et al. (1994a) A1507 Deletion of 3 bp between 1648-1653 Exon 10 1 (0.1%) D5 Kerem et al. (1990) AF508 Deletion of 3 bp between 1652-1655 Exon 10 504 (72.0%) B1, DI, B7 Kerem et al. (1989) 1717-1 G--+A G--+A at 1717-1 lntron 10 6 (0.9%) B3 Kerem et al. (1990) G542X G--+T at 1756 Exon 11 10 (1.4%) B1 Kerem et al. (1990) G551D G--+A at 1784 Exon 11 7 (l.0%) B3 Cutting et al. (1990) Q552X C-+T at 1786 Exon 11 1 (0.1%) A4 Devoto et al. (1991) R553X C--+T at 1789 Exon 11 16 (2.3%) A4, B4, D3 Cutting et al. (1990) L558S T--+C at 1805 Exon 11 1 (0.1%) C2 Maggio et al. (*) 1811+I.6kBA-+G A--+Gat 1811+l.6kB lntron 11 1 (0.1%) A2 Chillonetal. Login to comment
120 There are, however, only six additional CFTR mutations with a frequency of approximately 1% or more of the CF chromosomes; two nonsense mutations, G542X and R553X, and the missense mutations G551D and NI303K were predominantly seen in severely affected patients, whereas the transmembrane missense mutation R347P and the splice mutation 3849 + 10 kB C---~T Table 2 Rare sequence variants in the CFTR promoter and coding region Sequence variant Nucleotide change Location Frequency Associated mutatiow' Reference 125 G--+C G--~C at 125 Promoter 1 (0.1%) R75X F508C T--~G at 1655 Exon 10 2 (0.3%) S1251N 1716 G---)A G---~Aat 1716 Exon 10 1 (0.1%) L619S R553Q G-~A at 1790 Exon I 1 I (0.1%) * R668C C--~T at 2134 Exon 13 1 (0.1%) 3849+10 kB C--eT 3030 G---~A G--+A at 3030 Exon 15 1 (0.1%) 405+1 G--~A I1027 T T--~C at 3212 Exon 17a 2 (0.3%) * 3417 A-+T A--->Tat 3417 Exon 17b 1 (0.1%) Unknown 4002 A--eG A--~G at 4002 Exon 20 2 (0.3%) Unknown Cutting et al. (1992) Kobayashi et al. (1990) Kerem et al. (1990) D6rk et al. ( 1991) Fanen et al. (1992) Chillon et al. (1992) Fanen et al. (1992) This study Ferec et al. (1992) ~'Marked (*) sequence variations were present on AF508 chromosomes were the most frequent in pancreas-sufficient patients. Login to comment

PMID: 7526344 [PubMed] Grossman PD et al: "High-density multiplex detection of nucleic acid sequences: oligonucleotide ligation assay and sequence-coded separation."

No. Sentence Comment

50 These included GM07224 (normal), GM11496B (G542X homozygote), and GM11274 (D551/AF508). Login to comment
55 Probes for multiplex CF OLA assay CF Locus S549R2-WT S549R2-MUT S549R2-COM S549N WT S549N-MUT S549N-COM G542-WT G542-MUT G542X-COM R553-WT R553X-MUT R553-COM G551-WT G55ID-MUT G55ICOM W1282-WT W1282X-MUT W1282-COM R560T-WT R560T-MUT R560-COM 1717-WT 1717-MUT 1717-COM 3905-WT 39O51NST-MUT 3905-COM Sequence (5'-3') (HEO)2-TTGCTCGTTGACCTCCA (HEO)3-TTGCTCGTTGACCTCCC PO4-CTCAGTGTGATTCCACCT-FAM (HEO)4-TGCTCGTTGACCTCCAC (HEO)5-TGCTCGTTGACCTCCAT PO4-TCAGTGTGATTCCACCTTC-FAM (HEO)6-GTGATTCCACCTTCTCC (HEO)7-GTGATTCCACCTTCTCA PO4-AAGAACTATATTGTCTTTCTCT-FAM (HEO)8-TGCTAAAGAAATTCTTGCTCG (HEO)9-TTGCTAAAGAAATTCTTGCTCA PO4-TTGACCTCCACTCAGTGTGA-FAM (HEO)IO-TAAAGAAATTCTTGCTCGTTGAC (HEO)11-TAAAGAAATTCTTGCTCGTTGAT PO4-CTCCACTCAGTGTGATTCCA-FAM (HEO) 12-TATCACTCCAA AGGCTTTCCTC (HEO) 13-TATCACTCCAAAGGCTTTCCTT PO4-CACTGTTGCAAAGTTATTGAATCC-FAM (HEO)14-TAGACCAATAATTAGTTATTCACC (HEO)15-TAGACCAATAATTAGTTATTCACG PO4-TTGCTAAAGAAATTCTTGCTCG-FAM (HEO) 16-TCTGCAAACTTGG AGATGTCC (HEO) 17-TCTGCAAACTTGGAGATGTCT PO4-TATTACCAAAAATAGAAAATTAGAGA-FAM (HEO) 18-A AGAGTACTTTGTTATCAGCTTTTTT (HEO)19-AAGAGTACTnUTIATCAGCTnTnT PO4-GAGACTACTGAACACTGAAGGAG-FAM Oligonucleotide ligation assay kinetics study For the study of ligation reaction kinetics, probe concentrations were 5 nM, and oligonucleotide target concentration was 0.5 nM. Login to comment
157 Variations in OLA product yield seen in Figure 4 can more likely be attributed to the high degree of overlap of the probes used in the exon 11 mutational hotspot (G542X, S549N, S549R2, G551D, R553X, R560T). Login to comment

PMID: 7522998 [PubMed] Tsongalis GJ et al: "Association of pancreatic adenocarcinoma, mild lung disease, and delta F508 mutation in a cystic fibrosis patient."

No. Sentence Comment

44 CorrelatIon of phenotype and genotype of CFTR mutations Key phenotypic Lung disease SweatC1 Exocnne pancreas function Vasdeferens Associated CFTR mutations Pancreatic InsuffIcIent Pancreatic sufficient Normalsweat C1 Severe Less severe Relatively mild Elevated Elevated Normal Insufficient Sufficient Sufficient Absent Absent Absent SF508, G542X, R553X, G5510, Ni 303K, Wi 282X, RI 17H, and others 2789 + 5G>A, R117H, R334W, R347P, A455E, P574H, S945L, G85E, and others G551S, R117H, 3849 + 10kb C>T, and others Congenitalabsence of the vas deferens None Normal or elevated Sufficient Absent F508C, Ri 17H, Di D1152H, and others FIg. 2. Login to comment

PMID: 7529319 [PubMed] Mercier B et al: "A cluster of cystic fibrosis mutations in exon 17b of the CFTR gene: a site for rare mutations."

No. Sentence Comment

51 All the most frequent mutations reported are located in the exons encoding the NBFs: AF508 inexon 10, G542X, G551D, and 1717-1 G--A in exon 11, and R1162X in exon 19. Login to comment

PMID: 7519167 [PubMed] Grade K et al: "Identification of three novel mutations in the CFTR gene using temperature-optimized non-radioactive conditions for SSCP analysis."

No. Sentence Comment

7 A further 10% (approximately) are attributable to the presence of the mutations R347P, G542X, G551D and R553X (Coutelle et al. 1992). Login to comment
24 G542X G551D R553X G576A Splice rout. Login to comment
36 Lanes 1, 7, wild type; lane 2, G542X/normal; lane 3, G551D/normal; lane 4, G551D/ G551D; lane 5, R553X/normal; lane 6, 1717G--+A/normal Case history of the patient with the 317 linsC mutation Among the patients carrying one non-deltaFs0~mutation, we found one girl with the genotype 3171insC/deltaFs0s. Login to comment

PMID: 7517933 [PubMed] Fearon K et al: "Premature translation termination mutations are efficiently suppressed in a highly conserved region of yeast Ste6p, a member of the ATP-binding cassette (ABC) transporter family."

No. Sentence Comment

35 CFTR was identified as the protein that isdefective in thedisease cystic fibrosis (CF)(13-15).Currently, over 230 CFTR mutations havebeen found that cause CF (16).Among this largecollection of mutations aretwo that result in in-frameopal (UGA) termination codons at glycine codon 542 (G542X) andarginine codon 553 (R553X) of CFTR (see Fig. 1).Both of these mutationsoccur near a highly conserved LSGGQ sequence motif that is shared by all members of the ABC transporter family. Login to comment

PMID: 7526925 [PubMed] Hull J et al: "Analysis of mutations and alternative splicing patterns in the CFTR gene using mRNA derived from nasal epithelial cells."

No. Sentence Comment

33 Of the 13 known sequence changes, 9 (G85E (8), E92K (10), Q220X (11), AF508 (1), G542X (12), G551D (13), 3659delC (12), W1282X (14), 4271delC (11)) were readily identified by •To whom correspondence should be addressed A-6 \ B c ~~i r D t 1 F 1 2 3 4 5 Ga 6b 7 8 9 1 0 1 1 1 2 13 14i 14bl 516 17a 17bl S 19 202122 23 24 MSD 1 NBF 1 R domain MSD 2 NBF 2 Figure 1. Login to comment
37 Autoradiograph showing cleavage products for the 3659delC mutation (577 bases) in the E fragment AF5O8 (634 + 267 bases), G542X (164 bases) and G551D (136 bases) mutations in the B fragment. Login to comment
43 An autoradiograph showing the labeled cleavage products for the AF508, G542X, G551D, and 3659delC mutations is seen in Figure 2. Login to comment
137 They had been screened for the AF5O8, G542X, G551D, R553X and 621 + 1G-T mutations by the clinical genetics service at the Churchill Hospital, Oxford, and they did not carry these mutations. Login to comment

PMID: 7525964 [PubMed] Miedzybrodzka ZH et al: "Evaluation of laboratory methods for cystic fibrosis carrier screening: reliability, sensitivity, specificity, and costs."

No. Sentence Comment

8 Standard methods of CF mutation analysis include deletion detection using polyacrylamide gel electrophoresis (PAGE) of PCR product (for example, AF508 and AI507), restriction enzyme digestion ofPCR product (for example, G551D, R553X, 621 + 1(G-.T)), and probing of PCR product with labelled allele specific oligonucleotides (ASOs) (for example, G542X). Login to comment
12 Methods The Cellmark ARMS system tests simultaneously for the mutations AF508, G551D, G542X, and 621 + 1(G--T).5 PCR is performed in two tubes, one tube containing mutation specific primers for G551D, G542X, and normal site specific primers for AF508 and 621 + 1(G-+T), the second containing mutation specific primers for AF508 and 621 + 1(G-4T) and normal site specific primers for G551D and G542X. Login to comment
19 We chose to evaluate dot blotting by using the Inno-LiPA CF2 kit as an example (Innogenetics).9 This kit detects the mutations AF508, AI507, G551D, G542X, N1303K, W1282Xm 1717-1,G-A, and R553X.4 12"1 Mouthwash DNA preparation (5 p1) and Taq polymerase are added to the PCR reagents provided, with biotin dUTP incorporated into PCR product as a label. Login to comment
26 2A + B normal sample: lane A indicates normal sequence at AF508 and 621 + 1, G-T mutation sites, lane B indicates normal sequence at G542X and G551D mutation sites. Login to comment
30 8A + B G542X/621 + 1, G-T compound heterozygote. Login to comment
32 12A + B G542X carrier. Login to comment
39 Strip 12 is AF508/G542X compound heterozygote, 14 is AF508IG551D compound heterozygote, 15 is 1717-1,G--A carrier, 16 is A1507 carrier, 17 is W1282X carrier. Login to comment
84 The G542X mutation specific band appeared, although it was fainter than its control. Login to comment
85 When the test was repeated on two occasions, no mutation specific band was present and direct sequencing confirmed that DNA tested had the wild type sequence at the G542X site. Login to comment
97 About half of the reported failures occurred in the first two tests in a batch, with faint extra bands in the mutant G551D and G542X positions. Login to comment

PMID: 7525963 [PubMed] Chevalier-Porst F et al: "Mutation analysis in 600 French cystic fibrosis patients."

No. Sentence Comment

2 The most frequent mutations in this population after AF508 (69% of the CF chromosomes) are G542X (3-3%), N1303K (1P8%), W1282X (1P5%), 1717-lG-.A (1P3%), 2184delA+2183 A-+G (0 9%), and R553X (0-8%). Login to comment
23 The most frequent mutations after AF508 are G542X (33%), N1303K (1*8%), W1282X (1 5%), 1717-1G-+A (1 3%), 2184delA+ 2183A-4G (09%), and R553X (08%). Login to comment
57 For the other partner, who has an initial risk of being a carrier of 1 in 25, the screening ofthe seven mutations AF508, G542X, N1303K, W1282X, 1717-1G-+A, 2184delA+2183A-.G, and R553X allows a better estimation ofthis risk; it drops to 1 in 120 if this screening is negative. Login to comment

PMID: 7516305 [PubMed] Audrezet MP et al: "Identification of three novel mutations (457 TAT-->G, D192G, Q685X) in the Slovenian CF patients."

No. Sentence Comment

40 She carries the G542X mutation on the other chromosome (Table 1, CF-53). Login to comment
50 Some clinical data of patients with the three novel mutations Patient Exon Mutation Age of Age at Chloride sweat Pancreatic Lung Pseudomonas onset diagnostic test mmol/per 1 function disease aeruginosa CF-53 4 457 TAT--~G Birth 4 months 90.9-167.0 Insufficient Severe Yes 11 G542X CF-67 5 D192G 2 months 3 months 58.8-106.7 Insufficient Moderate No 10 AF508 CF-52 13 Q685X 3 months 6 years 113.4-177.2 Insufficient Severe Yes 10 AF508 Table 2. Login to comment
51 Mutations identified in the population of Slovenia Number of chromosomes Mutations 661 83 AF508 4 G542X 5 R1162X 2 3905 ins T 2 I148T 1 Q552X 1 Q685X 1 S4X 1 457 TAT---~G 1 D192G 1 R1066H 19 Unidentified 121 Exons Frequencies References 10 68.60% Kerem et al. (1989) 11 3.30% Kerem et al. (1990) 19 4.10% Gasparini et al. (1991) 20 1.65% Personal Communication 4 1.65% Personal Communication 11 0.85% Devoto et al. (1991) 13 0.85% This study 1 0.85% Glavac et al. (1993) 4 0.85% This study and Glavac et al. (1993) 5 0.85% This study 17b 0.85% Ftrec et al. (1992) 15.70% by 11 mutations, occurring in 9 exons of the gene (1, 4, 5, 10, 11, 13, 17b, 19, and 20). Login to comment
54 A study performed by Dabovic et al. (1992) in a cohort of 54 families, each with one living CF child, from Serbia, Montenegro, Bosnia, and Herzegovina showed that the AF508 accounts for 70% (76/108 CF chromosomes) of CFTR genes and the G542X, for 4% (4/108). Login to comment
63 The distribution of mutations in our study differs from that observed in other populations of the Mediterranean area where, besides the AF508, two mutations, G542X and R1162X, have a frequency greater than 1% (Nunes et al. 1991). Login to comment

PMID: 7513296 [PubMed] Boteva K et al: "Novel cystic fibrosis mutation associated with mild disease in Cypriot patients."

No. Sentence Comment

39 Those mutations were 621+lG>T, G542X, G551D, R553X, W1282X and R1283M, and the methodology used is the Amplification Refractory Mutation System (Newton et al. 1989). Login to comment

PMID: 7521710 [PubMed] Ravnik-Glavac M et al: "Sensitivity of single-strand conformation polymorphism and heteroduplex method for mutation detection in the cystic fibrosis gene."

No. Sentence Comment

121 1078delT (35), L327R (Ravnik-Glavac a al., unpublished), R334W (36), D36K (31), R347L (26), R347P (14), A349V (26), R352Q (30), 1221delCT (34); Exon 8: W401X (31), 1342-1G-C (25); Exon 9: G458V (37), 1525 -1G-A (38); Exon 10: S492F (34), Q493X (39), 1609delCA (40,17), deltaI507 (39,41), deltaF5O8 (3), 1717-1G-A (39,42); Exon 11: G542X (39), S549N, G551D, R553X (43), R553Q (44), A559T (43), R560K (Fine et al., pers. comm.), R560T (39); Exon 12: Y563N (39), 1833delT (Schwartz et al., pers. comm.), P574H (39), 1898 + 1G-C (31), 1898+3A-G (Ferrari et al., pers. comm.); Exon 13: G628R(G-C) (31), Q685X (Firec et al., pers. comm.), K716X (26), L719X (Dork etal., pers. comm.), 2522insC (15), 2556insAT (45), E827X (34); Exon 14a: E831X (Ffrec et al., pers. comm.), R851X (29), 2721delll (31), C866Y (Audrezet et al., pers. comm.); Exon 14b: 2789+5G-A (Highsmith et al., pers. comm.); Exon 15: 2907denT (21), 2991del32 (Dark and TQmmler, pers. comm.), G970R (31); Exon 16: S977P, 3100insA (D6rk et al., pers. comm.); Exon 17a: I1005R (Dork and TQmmler, pers. comm.), 3272-1G-A (46); Exon 17b: H1054D (F6rec et al., pers. comm.), G1061R (Fdrec et al., pers. comm.), 332Oins5, R1066H, A1067T (34), R1066L (Fe"rec etal., pers. comm.), R1070Q (46), E1104X (Zielenski el al., pers. comm.), 3359delCT (46), L1077P (Bozon « a/., pers. comm.), H1085R (46), Y1092X (Bozon etal., pers. comm.), W1098R, M1101K (Zielenski et al., pers. comm.); Exon 18: D1152H (Highsmith et al., pers. comm.); Exon 19:R1162X (36), 3659delC (39), 3662delA (25), 3667del4 (Chillon et al., pers. comm.), 3737ddA (35), 3821ddT (15), I1234V (35), S1235R (31), Q1238X (26), 3849G-A (25), 385O-3T-G (38); Exon20:3860ins31 (Chillon etal., pers. comm.), S1255X (47), 3898insC (26), 3905insT (Malik et al., pers. comm.), D127ON (48), W1282X (49), Q1291R (Dork et al., pers. comm.), Exon 21: N1303H (35), N13O3K (50), W1316X (43); Exon 22: 11328L/4116delA (Dork and TQmmler, pers. comm.), E1371X (25); Exon 23: 4374+ 1G-T (38); Exon 24: 4382delA (Claustres et al., pers. comm.). Login to comment

PMID: 7513294 [PubMed] Culard JF et al: "Analysis of the whole CFTR coding regions and splice junctions in azoospermic men with congenital bilateral aplasia of epididymis or vas deferens."

No. Sentence Comment

31 Two CFTR mutations were found in patients not described as CBAVD: the stop mutation G542X (Kerem et al. 1990) in a case with congenital unilateral epididymis and vas deferens aplasia (CUAVD) (patient no. 4), and the missense mutation S1235R (Cuppens et al. CF Consortium) in a patient with congenital bilateral aplasia of the tail of epididymis (CBAE) (patient no. 7). Login to comment
33 CFTR mutations identified in 12 patients lacking an epididymis or vas deferens Patient Age Mutations Exon XV2c/KM19 (years) haplotypesa CBAVD 1 43 Unknown B Unknown A CBAVD 6 33 p AF508/A1067T 10/17b B m Unknown A CBAVD 8 32 p Unknown A m AF508 10 B CBAVD 9 27 p R347H 7 C m AF508 10 B CBAVD 11 31 m Unknown D p 2184delA+A---~G at 2183 13 B CBAVD 12 30 Unknown B Unknown B CBAVD 13 32 p AF508 10 B m Unknown A CBAVD 14 AF508 10 B R347H 7 C CUAVD 4 35 m G542X 11 B p Unknown D CBAE 2 28 Unknown C Unknown D CBAE 7 34 p Unknown B m S1235R 19 A CBAE 10 30 Unknown B Unknown C CBAVD, Congenital bilateral aplasia of the vas deferens; CUAVD, congenital unilateral aplasia of the vas deferens; CBAE, congenital bilateral aplasia of the epididymis; p, paternal chromosome; m, maternal chromosome The four haplotypes defined by the CFTR-linked polymorphic restriction sites XV-2c and KM-19 are as follows: A, 1-1; B, -2; C, 2-1; D, 2-2 (the absence of the restriction site for each polymorphism is defined as allele "1", and the presence of the site as allele "2") Table . Login to comment

PMID: 7513293 [PubMed] Chillon M et al: "Analysis of the CFTR gene confirms the high genetic heterogeneity of the Spanish population: 43 mutations account for only 78% of CF chromosomes."

No. Sentence Comment

5 This indicates that, in the Spanish population, with the exception of AF508 (50.6%) and G542X (8%), the mutations are not concentrated in a few exons of the gene nor are there any predominating mutations. Login to comment
22 We have previously analysed the three most frequent mutations in our population (AF508, G542X and N1303K), and the association between CF Spanish chromosomes and their intragenic microsatellites IVSCA8-IVS17BTA-IVS 17BCA (Nunes et al. 1991; Casals et al. 1992; Morral et al. 1993; Chilldn et al. 1993). Login to comment
30 There are seven mutations with a frequency higher than 1%, viz. AF508 (50.6%), G542X (8.0%), N1303K (2.3%), 3601-111G---~C (1.9%), Rl162X (1.8%, 711+IG--+T (1.2%) and R334W (1.1%), whereas the other 36 mutations have a frequency lower than 1% and account for only about 11% of CF chromosomes. Login to comment
34 A non-uniform distribution had previously been observed in the Spanish population for the AF508 and G542X mutations (Casals et al. 1993) but this had not been shown for any other mutations. Login to comment
37 When we analysed the Spanish CF population in subsets (Fig. 1), we found typical mutations; in the Mediterranean subset, G542X and N1303K (11.8% and 4.5%, respectively); in the Arab-Andalusian subset, 3601-111G---~ C (5.6%); in the Gallician subset, Rl162X and 711+1 G---~T (8.5% and 6.4%, respectively); in the Canary islands, because of the founder effect, we observed only a few mutations but with high frequencies, whereas we only found the AF508 mutation and none of the other six most common mutations in the Basques. Login to comment
40 Frequencies of CF mutations in the Spanish population Mutation Exon/intron N~chro- % mosomes Known (43) 760 78.18 AF508 Exon 10 492 50.61 G542X Exon 11 78 8.02 N1303K Exon 21 23 2.36 3601-111 G---~C Intron 18 19 1.95 R1162X Exon 19 18 1.85 711+1 G---~T Exon 5 12 1.23 R334W Exon 7 11 1.13 1609 del CA Exon 10 9 0.92 G85E Exon 3 8 0.82 2789+5 G---~A Intron 14b 7 0.72 2869 ins G Exon 15 7 0.72 R1066C Exon 17b 7 0.72 W1282X Exon 20 6 0.62 AI507 Exon 10 5 0.51 3272-26 A---~G Intron 17a 5 0.51 G551D Exon 11 4 0.41 1812-1 G---~A Intron 11 4 0.41 2184 de! Login to comment
42 Thus, of the seven most common mutations, they only have the G542X 4/47=8.5% MUTATION )/39=0% N1303K 0/47=0% MUTATION D/39=0% 3601-111G>CMUTATION )/47=0% _oI~=O% 10/260:3.8% )4" 26/220=11.8% I~7/49=14.3%~Qr ~lP,m. Login to comment
43 5/260=1.9%41~4," p- I0/220=4,5% 1/49:2.0%CT !/248=1.2% 13/'232=5.6% ~=0% R1162XMUTATION t/47=8.S% ~I3/49--6.1%(I" f-it*" 711+1G>T 5/47=6A% MUTATION 0~9=0% <7" Fig.1.DistributionoftheG542X,N1303K,3601-111G---~C,R1162X,7tI+IG--)Tand R334WmutationsinthedifferentsubsetsoftheSpanishpopulation.Onlythe615chro- mosomesforwhichtheethnicorigincouldbeestablishedhavebeenincluded.Subsets withahighfrequencyforagivenmutationareshaded.TheMediterraneansubsethasa R334WMUTATION 1/47=2.1% highfrequencyforG542XandN1303K;theArab-Andalusiansubsetfor3601-111G---) C;theGalliciansubsetforG542X,R1162Xand711+1G---)C;theCanariansubsetfor G542X,RlI62XandR334W,whereasnoneofthesesixmutationsispresentinthe Basquesubset4~ ~D AF508 mutation (76.9% compared with 50.6% for the rest of Spain). Login to comment
46 The Mediterranean subset The Mediterranean subset shows high frequencies of the mutations G542X and N1303K. Login to comment
48 The G542X mutation has been postulated to have arisen in a population of Semitic origin (Phoenicians and Jews) in the Neolithic Age, and to have been introduced into Spain, via the Mediterranean Sea, by Phoenicians (Casals et al. 1993); this would explain its high frequency in this subset (11.8%) with respect to the rest of Spain (3.8%) (~2 = 10.1, P < 0.001). Login to comment
59 Thus, we have found AF508 (46.9%), G542X (14.3%), Rl162X (6.1%), R334W (4.0%) and N1303K (2.0%) but we have not found 3601-111G--->C, 711+IG-~T or any of the other 36 less frequent mutations. Login to comment
69 There are seven mutations with a frequency higher than 1% (AF508, G542X, N1303K, 3601-111G-->C, Rl162X, 711+IG---~T and R334W), whereas another 36 less frequent mutations account for only 11% of the CF chromosomes. Login to comment
70 These results show that the Spanish population [like other Southern and Mediterranean European populations (Nunes et al. 1991)] has a marked genetic heterogeneity, since the CF mutations are not confined to a few exons and there are no predominant mutations (except for AF508 and G542X). Login to comment
75 Thus, the Basque subset has the AF508 mutation but none of the other 6 mutations; the Mediterranean subset has a high frequency of G542X and N1303K (as in South European populations); the Arab-Andalusian subset has a high frequency of 3601-111G---~C, which we propose has an Arab origin; the Canarian Islands has a founder effect, where we find high frequencies of the G542X, Rl162X and R334W mutations, and the Gallician subset has a high frequency of G542X, R1162X and 711+1G---~C. Login to comment

PMID: 7513292 [PubMed] Verlingue C et al: "Retrospective study of the cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations in Guthrie cards from a large cohort of neonatal screening for cystic fibrosis."

No. Sentence Comment

68 CFI'R mutations characterized by denaturing gradient gel electrophoresis and DNA sequencing from Guthrie cards of 98 children with cystic fibrosis 431 Number of Mutations Exons Fre- References chromo- quencies somes 129 AF508 10 65.8 Kerem et al. 1989 5 G551D 11 2.8 Cutting et al. 1990 3 2183 AA---~G 13 1.7 unpublished data 3 N1303K 21 1.7 Osborne et al. 1991 3 G542X 11 1.7 Kerem et ai.1990 2 E92K 4 1.1 Nunes et al. 1993 2 I148T 4 1.1 unpublished data 2 574 del A 4 1.1 Fanen et a1.1992 2 1078 del T 7 1.1 Claustres et a1.1992 2 E585X 12 1.1 Cremonesi et al. 1992 2 2789 + 5 G--->A intron 14b 1.1 unpublisheddata 2 3659 del C 19 l. Login to comment

PMID: 7513291 [PubMed] Dean M et al: "Heterogeneity in the severity of cystic fibrosis and the role of CFTR gene mutations."

No. Sentence Comment

57 These studies found no significant differences in % FEV1 or age of onset of chronic sputum colonization by Pseudomonas aeruginosa between AF508/G551D, AF508/G542X, AF508/ R553X, AF508/W1282X, AF508/N1303K, AF508/1717- 1G-A, AF508/621+lG-T compound heterozygotes and AF508 homozygotes (Hamosh et al. 1991; Cystic Fibrosis Genotype Analysis Consortium 1990). Login to comment

PMID: 7520798 [PubMed] Shoshani T et al: "Two novel mutations in the CFTR gene: W1089X in exon 17B and 4010delTATT in exon 21."

No. Sentence Comment

7 Together with the AF5O8 mutation and three other less common mutations (G542X, N1303K and 3849 + 10 Kb C-T) CFFM Figure 1. Login to comment

PMID: 7520797 [PubMed] Cuppens H et al: "CFTR haplotype backgrounds on normal and mutant CFTR genes."

No. Sentence Comment

4 With exception of the D7S8 locus, the three most common mutations, AF508, G542X and N1303K, were found on an identical haplotype background. Login to comment
6 However, the G542X and N1303K mutations, which have been estimated to be at least 35000 years old, were found to be associated with a single allele at the D7S8 locus. Login to comment
34 Distribution of alleles at 10 polymorphic loci Locus Allele Normal Mutant Mutations XV2c KM19 D9 1 2 1 2 1 2 58 (0.492) 60 (0.508) 84 (0.622) 51 (0.378) 78 (0.586) 55 (0.414) 146 (0.918) 13 (0.082) 19(0.109) 156 (0.891) 15 (0.085) 161 (0.915) 1001 + llC/T Tn 115 (0.927) R 9 (0.073) 5 7 (0.057) 7 102 (0.836) 9 13 (0.107) M470V C 62 (0.496) R 63 (0.504) 1898+15 2T/A C 84(0.641) R 47 (0.359) T854T Q1463Q D7S8 C 82 (0.636) R 47 (0.364) C 90 (0.692) R 40 (0.308) 1 38 (0.317) 2 82 (0.683) 33 (0.192) 139 (0.808) 0 (0.000) 32 (0.190) 136 (0.810) 156 (0.902) 17 (0.098) 163 (0.926) 13 (0.074) 162 (0.926) 13 (0.074) 162 (0.931) 12 (0.069) 91 (0.569) 69 (0.431) E60X, 622-2A-C, A455E, AF508 (98.3%), 1717-1G-A, G542X, 0.479 63.54 G628R(G-C)/S1235R,2183AA-G, G970R, W1282X, N1303K p<10~ G458V, AI5O7, AF508 (1.7%), 1898 + 1G-C, E73OX, 3272-26A-G, W1310X, 4218insT, UA, UB, UC I336K, W401X, 2T2ldelll, Y1092X, 3659delC, S1251N: not included (5%) E60X, 622-2A-C, W401X, G458V, AF5O8 (1.6%), 1898+ 1G-C, -0.541 90.63 G628R(G-Q/S1235R, E730X, G970R, 3272-26A-G (50.0%), p<10" Y1092X, 3659delC, S1251N, W1310X, UB, UTC A455E, AI507, AF5O8 (98.4%), 1717- 1G-A, G542X, 2183AA-G, 3272-26A-G (50.0%), W1282X, N13O3K, 4218insT, UA 1336K, 2721delU: not included (1%) E60X, 622-2A-C, W401X, G458V, 1898 +1G-C, E730X, G970R, -0.541 90.46 Y1092X, 3659delC, S1251N, W1310X, UB, UC p<10" A455E, AI507, AF508, 1717- 1G-A, G542X, G628R(G-Q/S1235R, 2183AA-G, 3272-26A-G, W1282X, N13O3K, 4218insT, UA I336K, 2721delll: not included (1%) E60X, 622-2A-C, I336K, W401X, G458V, AI507, 1717- 1G-A, -0.726 155.94 1898 + 1G-C, G628R(G-C)/S1235R, 2183AA-G, E730X, 2721delll, p< 10" G970R, 3272-26A-G, Y1092X, 3659delC, S1251N, W1282X, W1310X, 4218insT, UA, UB, UC A455E, AF5O8, G542X, N13O3K E60X, 622-2A-C, I336K, W401X, G458V, AI507, 1717-1G-A, 1898 + 1G-C, G628R(G-C)/S1235R, 2183AA-G, E730X, 2721delll, G970R, 3272-26A-G, Y1092X, 3659delC, S1251N, W1282X, W1310X, 4218insT, UA, UB, UC A455E, AF5O8, G542X, N13O3K A455E, AI5O7, AF508, 1717-1G-A, G542X, G628R(G-Q/S1235R, 2183AA-G, 3272-26A-G, W1282X, N13O3K, 4218insT, UA E60X, 622-2A-C, W401X, G458V, 1898 + 1G-C, E730X, G970R, Y1092X, 3659delC, S1251N, W1310X, UB, UC 1336K, midclll: not included (1%) E60X, 622-2A-C, W401X, A455E, G458V, AF508 (99.2%), G542X, 1898 + 1G-C, 2183AA-G, E730X, G970R, Y1092X, 3659delC, S1251N, N1303K, W1310X, UB, UC AI507, AF5O8 (0.8%), 1717-1G-A, G628R(G-Q/S1235R, 3272-26A-G, W1282X, 4218insT, UA I336K, 2721delU: not included (1%) E60X, 622-2A-C, W401X, A455E, G458V, AF508 (99.2%), G542X, 1898+1G-C, 2183AA-G, E730X, G970R, Y1092X, 3659delC,S1251N, N13O3K, W1310X, UB, UC AI507, AF508 (0.8%), 1717-1G-A, G628R(G-C)/S1235R, 3272-26A-G, W1282X, 4218insT, UA 1336K, midelll: not included (1%) E60X, 622-2A-C, W401X, A455E, G458V, AF5O8 (99.2%), G542X, G628R(G-Q/S1235R, 2183AA-G, E730X, G970R, Y1092X, 3659delC, S1251N,N1303K, W1310X, UC AI507, AF5O8 (0.8%), 1717-1G-A, 1898 + 1G-C, 3272-26A-G, W1282X, 4218insT 1336K, 2721del11. Login to comment
35 UA, UB: not included (2%) A455E, AF508 (61.2%), 1717-1G-A (66.7%), G542X, G628R(G-C)/S1235R, 3272-26A-G, S1251N, W1282X, W1310X E60X, 622-2A-C, W401X, G458V, AJ507, AF5O8 (38.8%), 1717- 1G-A (33.3%), 1898 +1G-C, 2183AA-G, E730X, G970R, Y1092X, 3659delC, N13O3K, 4218insT, UA, UB, UC 1336K, 2721delll: not included (1%) -0.694 139.81 p<10~ 0.452 60.83 p<10" 0.355 38.77 p<10" 0.360 39.44 p<10~7 0.314 29.91 0.250 17.54 p<10"4 The observed CFTR genes associated with a particular allele are given, proportions are given between brackets. Not all the mutations were informative for each of the tested loci, which were therefore not included. For the Tn locus the standardized linkage disequilibrium coefficient was calculated for the group of the non-T9 alleles and the T9 alleles. Login to comment
37 Standardized linkage disequilibrium coefficient at ten polymorphic loci for all mutant CFTR genes and for individual AF5O8, G542X and N13O3K CFTR genes. Login to comment
45 At the D7S8 locus, a higher value of A was found for G542X CFTR genes than for AF508 CFTR genes. Login to comment
46 All G542X CFTR genes (9 genes studied) were associated with allele 1, while only about 60% of AF508 CFTR genes (116 genes studied) were associated with this allele. Login to comment
59 These mutations are also the most common mutations worldwide, such as the G542X, "N1303K, 1717- 1G-A and W1282X mutations. Login to comment
72 Extragenic (XV2c/KM19/D9) haplotypes Haplotype Normal Mutant Mutations 111 211 121 112 212 122 222 23 (0.204) 43 (0.381) 2 (0.018) 6 (0.053) 0 (0.000) 22 (0.195) 17 (0.150) 4 (0.026) E60X, 622-2A-C, G970R 6 (0.039) G458V, 1898+1G-C, E73OX, W1310X, UB, UC 0 (0.000) 3 (0.019) AF5O8 (1.7%), G628R(G-Q/S1235R 1 (0.006) 3272-26A-G (50.0%) 134 (0.870) A455E, AF508 (96.5%), 1717-1G-A, G542X, 2183AA-G, W1282X, N13O3K 6 (0.039) AI507, AF508 (1.8%), 3272-26A-G (50.0%), 4218insT, UA p<10"3 p<10"7 p<10~7 p<10"2 The observed CFTR genes associated with a particular haplotype are given, proportions are given between brackets. Login to comment
95 With the exception of the D7S8 locus, the three most common mutations AF508, G542X, and N1303K shared the same haplotype background. Login to comment
103 CFTR haplocypes I II ma mb rv V VI Haplotype C7RCCC 211C7RCCC1 111C7RCCC1 /11C7RCCC1 211C7RCCC2 111C7RCCC2 /11C7RCCC2 122C7RCCC2 121C7RCCC2 C5CRRR 122C5CRRR1 211C5CRRR2 222C5CRRR2 C7CRRR 122C7CRRR1 222C7CRRR1 212C7CRRR1 122C7CRRR2 222C7CRRR2 122C7CRRR/ C9CRRR 211C9CRRR1 R9CCCC 122R9CCCC1 222R9CCCC1 /22R9CCCC1 112R9CCCC1 122R9CCCC2 222R9CCCC2 112R9CCCC2 R9CRRR 122R9CRRR1 C7CRRC 112C7CRRC1 112C7CRRC2 C9CRRC 211C9CRRC1 C7CCCC 211C7CCCC1 222C7CCCC1 122C7CCCC2 C7RCCR 211C7RCCR2 Normal 0.524 (43) 0.085 0.073 0.195 0.146 0.012 0.012 0.049 (4) 0.012 0.024 0.012 0.220 (18) 0.024 0.073 0.000 0.073 0.049 0.012 (1) 0.012 0.073 (6) 0.000 0.000 0.000 0.061 0.012 0.000 0.000 (0) 0.000 0.061 (5) 0.000 0.061 0.012 (1) 0.012 0.037 (3) 0.012 0.024 0.000 0.012 (1) 0.012 Mutant 0.080 (IS) 0.005 0.000 0.020 0.015 0.020 0.020 0.000 0.000 0.000 (0) 0.000 0.000 0.000 Mutations p<10"7 W1310X S1251N G458V, E730X, UC E60X, 622-2A-C, G970R W401X, Y1092X, 3659delC 0.055 (9) p<10"2 0.017 0.005 0.005 0.008 0.010 0.010 0.000 (0) 0.000 1717-1G-A (66.7%) 50.0% of 3272-26A-G 50.0% of 3272-26A-G 1717-1G-A(33.3%) AI507, 4218insT W1282X 0.819 (130) p<10~7 0.466 0.007 0.010 0.007 0.312 0.007 0.007 0.005 (1) 0.005 0.005 (1) 0.005 0.000 0.000 (0) 0.000 0.010 (2) 0.000 0.000 0.010 0.005 (1) 0.005 56.7% of AF508, G542X 1% of AF5O8 A455E 1% of AF5O8 38.1% of AF508, N1303K 1.0% of AF5O8 1% of AF508 1% of AF508 G628R(G-Q/S1235R 2183AA-G 1898+1G-C The proportion of CFTR genes associated with a particular haplotype, and the mutations found to be associated with that haplotype are given. Login to comment
123 The three most common CFTR mutations share a similar haplotype background The 3 most common mutations, AF5O8, G542X, N1303K, shared a very similar haplotype background. Login to comment
127 A complete association of allele 1 with G542X CFTR genes (Fisher Exact Test, p < 10~4 ) was found. Login to comment
128 Given the facts that the Q1463Q and D7S8 loci are in linkage equilibrium (ANorma] = -0.032, AMua« = -0.018) and that the G542X mutation has been estimated to be at least 35000 years old (16), this complete association is surprising. Login to comment
131 Absence of recombination between the Q1463Q and D7S8 loci was also observed among particular normal CFTR genes: no normal CFTR genes having haplotype background Ilia (haplotype background ma was associated with the AF508, G542X and N1303K mutations), and certain genes with haplotype background IV (Table 4), carried allele 1 at the D7S8 locus. Login to comment

PMID: 7511817 [PubMed] Lishanski A et al: "Mutation detection by mismatch binding protein, MutS, in amplified DNA: application to the cystic fibrosis gene."

No. Sentence Comment

49 a Mutation Location PCR primers (5' 4 3') AF508 exon 10 (1) CTCAGTTTTCCTGGATTATGCC (2) TGGCATGCTTIGATGACG (1) CTCAG1TTICCTGGATTATGCC (3) CTAACCGATTGMTATGGAGCC (4) CMGTGMTCCTGAGCGTGA (3) CTAACCGATTGAATATGGAGCC (5) GCAGAGTACCTGAAACAGGA (6) CATrCACAGTAGCTrACCCA R553X exon 11 (7) GCCTTTCAAATCAGATTGAGC (9) GACA1TTACAGCAAATGCTTGC (10) CAACTGTGGTTAAAGCAATAGTGT (11) GCACAGATTCTGAGTAACCATMT G551 D exon 11 (7) GCC1TTCAAATTCAGATTGAGC (9) GACA1TUACAGCAAATGCTTGC G542X exon 11 (7) GCCTTTCAAATTCAGATTGAGC (8) TGCTCGTTGACCTCCACTC b Exon 10 490 bp I 340 bp 200 bp 100 bp 100 200 PCR Lesion Mismatches product formed size upon (bp) reannealing of PCR product 100 3 bp deletion CTT + GAA (Phe deletion) bulges 200 340 491 203 C 4 T (Arg m 4 Stop) 425 203 G 4 A (Gly 5544 Asp) 141 G 4 T (Gly 542 4 Stop) 300 C/A + T/G single-base mismatches G/T + A/C single-base mismatches G/A + T/C single-base mismatches 400 AF508 LExon11 100 200 300 400 425 bp L 203 bp 141 bp G542X G51 D R553X FIG. 1. Login to comment
111 Similar results were obtained with G542X and G551D, as described in Fig. la (data not shown). Login to comment
136 Similar results were also obtained forthe G542X and G551D point mutations using 141- and 203-bp PCR products, respectively (data not shown). Login to comment

PMID: 7509564 [PubMed] Grebe TA et al: "Genetic analysis of Hispanic individuals with cystic fibrosis."

No. Sentence Comment

45 The following CFTR gene mutations were identified by published methods: AF508 (Rommens et al. 1990); G542X (Kerem et al. 1990); GS51D and R553X (Cutting et al. 1990); R1162X (Gasparini et al. 1991); W1282X (Vidaud et al. 1990); N1303K (Osborne et al. 1991); 3849 +lOkbC- T (Highsmith et al., submitted); and R117H, Y122X, 1148T, 621+1G-*oT, 711+1G- T, G314E, 1078AT, R334W, R347P, Q493X, A1507, V520F, 1717 -1G-oA, R560T, and 3569AC (J. DeMarchi et al., submitted). Login to comment
46 Alternatively, the G542X, G551D, R553X, and N1303K mutations were assayed by the method of Ng et al. Login to comment
52 .................. 67.1 59/129 (46) G542X .................. 3.4 7/129 (5.4) 3849+10kbC--T ......... Unknown 3/129 (2.3) G551D .................. 2.4 0/129 (0) R553X .................. 1.3 1/129 (.8) R1162 .................. .85b 2/129 (1.6) R334W .................. <1 2/129 (1.6) W1282X ................. 2.1 1/129 (.8) Otherc .................. 65 0/129 (0) Undetected ............... 15 54/129 (42) a CF Consortium 1992, unpublished data. Login to comment
54 COther = A1507, 621+1G- T, R117H, N1303K, 711+1G-*.T, 1717-1G-.A, R560T, Y122X, 1148T, G314E, 1078AT, R347P, Q493X, V520F, and 3659AC. Login to comment
56 The G542X mutation was found in 5.4% of Hispanic CF chromosomes, similar to the 3% frequency in the general population. Login to comment
66 (%) OF HAPLOTYPES CHROMOSOME TYPE A B C D TOTAL CF: AF508 ............ 2 (4) 36 (72) 5 (10) 7 (14) 50 Non-AF508a ....... 12 (29) 14 (33) 14 (33) 2 (5) 42 Normal" ............. 22 (49) 5 (11) 16 (34) 4 (9) 47 a Includes chromosomes carrying either G542X, RI 162X, W1282X, R334W, R553X, 3849+10kbC-*oT, or an unidentified mutation." Login to comment
85 This has been observed elsewhere (European Working Group in CF Genetics 1990), and several mutations, including G542X and GSS1D, have been identified on chromosomes of this haplotype (Kerem et al. 1990). Login to comment
47 The following CFTR gene mutations were identified by published methods: AF508 (Rommens et al. 1990); G542X (Kerem et al. 1990); GS51D and R553X (Cutting et al. 1990); R1162X (Gasparini et al. 1991); W1282X (Vidaud et al. 1990); N1303K (Osborne et al. 1991); 3849 +lOkbC-T (Highsmith et al., submitted); and R117H, Y122X, 1148T, 621+1G-*oT, 711+1G-T, G314E, 1078AT, R334W, R347P, Q493X, A1507, V520F, 1717 -1G-oA, R560T, and 3569AC (J. DeMarchi et al., submitted). Login to comment
48 Alternatively, the G542X, G551D, R553X, and N1303K mutations were assayed by the method of Ng et al. Login to comment
58 The G542X mutation was found in 5.4% of Hispanic CF chromosomes, similar to the 3% frequency in the general population. Login to comment
68 (%) OF HAPLOTYPES CHROMOSOME TYPE A B C D TOTAL CF: AF508 ............ 2 (4) 36 (72) 5 (10) 7 (14) 50 Non-AF508a ....... 12 (29) 14 (33) 14 (33) 2 (5) 42 Normal" ............. 22 (49) 5 (11) 16 (34) 4 (9) 47 a Includes chromosomes carrying either G542X, RI 162X, W1282X, R334W, R553X, 3849+10kbC-*oT, or an unidentified mutation. " Login to comment
87 This has been observed elsewhere (European Working Group in CF Genetics 1990), and several mutations, including G542X and GSS1D, have been identified on chromosomes of this haplotype (Kerem et al. 1990). Login to comment

PMID: 7516777 [PubMed] Savov A et al: "G1244V: a novel missense mutation in exon 20 of the CFTR gene in a Bulgarian cystic fibrosis patient."

No. Sentence Comment

17 The male patient who carries this mutation is of Bulgarian ethnic origin and is a compound heterozygote for G1244V and G542X. Login to comment

PMID: 7509311 [PubMed] Kere J et al: "Cystic fibrosis in a low-incidence population: two major mutations in Finland."

No. Sentence Comment

29 The haplotype associations of AF508 an G542X are similar to those found in other European populations (Casals et al 1992, 1993; Mortal et al. 1993). Login to comment
30 G542X and 3732delA (Tsui et al. 1992) were each identified in one chromosome, and the remaining eight mutations were not identified. Login to comment
59 Cystic fibrosis mutations and associated haplotypes in Finnish CF families CF PI/PS metD metH PT-3 XV2c CS7 KM19 MP6d-9 Mutations Microsatellites H-80 J3.11 chromo- MI/N TaqI TaqI BanII TaqI Hhal Pstl MspI IVS8/IVS 17TA/ PstI Mspl some IVS 17CA 1 pat PI, N l 1 1 1 2 2 2 394delTT 23/36/13 ND 2 l mat PI, N 1 2 1 l 2 2 2 394delTT 23/36/13 ND 1 2 pat PI, MI 1 2 1, 2 1 2 2 2 394delTT 23136/13 1, 2 1 2 mat PI, MI 1 1 1, 2 1 2 2 2 AF508 17/31/13 1, 2 1 3 pat PI, MI 1 1 2 l 1 l 1 Unknown 16/33/13 2 2 3 mat PI, MI 1 1 2 1 2 2 2 AF508 17/31/13 2 2 4 pat PI, N l 2 2 1 2 2 2 AF508 17/3 l/13 2 1 4 mat PI, N 1 1 2 1 2 2 2 G542X 23/33/13 1 1 5 pat PI, N 1 1 2 1 2 2 2 AF508 -/-/- 2 2 5 mat PI, N 1 1 2 1 2 2 2 AF508 -/-/- 2 2 6 pat PI, MI 1 2 1 1 2 2 2 AF508 23/31/13 2 2 6 mat PI, MI 1 1 l 1 2 2 2 394delTT 23/36/13 1 2 7 pat PI, N 1 1 2 1 1 1 1 Unknown 16/33/13 2 2 7 mat PI, N 1 2 2 1 2 2 2 394delTT 23/36/13 l 1 8 pat P1, N 1 2 1 1 2 2 2 394delTT 23/36/13 1 1 8 mat P1, N 1 2 1 1 2 2 2 394delTT 23/36/13 1 1 9 pat P1, MI 1 1 2 1 1 1 l Unknown 16/33/13 2 2 9 mat PI, MI I 2 1 1 2 2 2 394delTT 23/36/13 l 1 10 pat P1, N 1 1 1 1 2 1 2 Unknown 17/31/11 2 2 10 mat P1, N 1 1 2 1 2 2 2 AF508 17/31/13 2 1 i 1 pat PI, N 2 1 1 1 2 2 2 AF508 23/30/13 2 2 11 mat P1, N 1 1 2 1 2 2 2 AF508 17/31/13 2 1 12 pat PI, N 2 1 2 1 1, 2 1, 2 1, 2 AF508 17/32/13 2 2 12 mat PI, N 1 1 2 1 1, 2 1, 2 1, 2 Unknown 16/07/17 1 1 13 pat PI, N 1 1 2 l, 2 1, 2 l, 2 l, 2 AF508 23/31/13 2 2 13 mat PI, N 2 1 2 1, 2 l, 2 l, 2 1, 2 Unknown 16/35/13 2 2 14 pat PI, MI 1 2 1 1 2 2 2 394delTT 23/36/13 1 1 14 mat PI, MI 1 l 2 1 2 2 2 AF508 17/31/13 2 1 15 pat PS, N 1, 2 1, 2 2 1, 2 2 2 2 Unknown 15/07/17 2 15 mat PS, N 1, 2 1, 2 2 1, 2 2 2 2 AF508 17/07/13 2 1,2 1,2 16 pat PI, N 1 1 2 1 2 2 2 AF508 17/31/13 2 1 16 mat PI, N 1 1 1 1 2 2 2 AF508 17/31/13 2 1 17 pat PI, N 1 2 1 1 2 2 2 394delTT 23/36/13 1 1 17 mat PI, N 1 2 1 1 2 2 2 394delTT 23/36/13 1 1 18 pat PI, N 1 1 2 1 2 2 2 AF508 17/31/13 2 1 18 mat PI, N 1 1 2 1 2 2 2 AF508 17/31/13 2 1 19 pat PI, N ND ND 2 1, 2 2 2 2 394delTT 23/36/13 ND 19 mat PI, N ND ND 2 l, 2 1 l 2 Unknown 16/31/13 ND 1,2 1,2 20 pat PI, N ND 1 ND ND ND ND ND AF508 23/31/13 ND 2 20 mat PI, N ND l ND ND ND ND ND 3732delA 17/35/13 ND 2 pat, Paternal allele; mat, maternal allele; PUPS, pancreatic insufficiency/sufficiency; MI/N, meconium ileus/normal; ND, not determined 9 AF508 ~) 394delTT (~ G542X (~ Unknown, same Io C) Unknown, different haplotypes r IO | A D '* | Oo .g 9 Fig.2. Login to comment
82 Am J Hum Genet 339:119-120 Casals T, Nunes V, Palacio A, Gimtnez J, Gaona A, Ib~fiez N, Morral N, Estivill X (1993) Cystic fibrosis in Spain: high frequency of mutation G542X in the Mediterranean coastal area. Login to comment

PMID: 7509310 [PubMed] Schwartz M et al: "394delTT: a Nordic cystic fibrosis mutation."

No. Sentence Comment

9 A few of the non-AF508 mutations are found in more than one population at a frequency of 1-5%, viz. W1282X (Abeliovich et al. 1992), G551D and G542X (Cutting et al. 1990, 1992) and N1303K (Osborne et al. 1991), but most of the others are rare or private mutations. Login to comment
10 Correspondence to: M. Schwartz, Section of Clinical Genetics, Rigshospitalet 4062, Blegdamsvej 9, DK-2100 Copenhagen, Denmark Screening for AF508 and a few other common mutations, i.e. G542X, N1303K, 621+lG--->T and G551D, in the Danish CF population showed that these mutations account for 90% of all CF disease genes (Schwartz et al. 1992), a fact that has been used in a recent screening programme for carriers of CF among pregnant women (Schwartz et al. 1993). Login to comment
70 Other CF mutations Very few of the previously reported most "common" mutations (G551D, G542X, R553X, N1303K, 1717-1G---~ T, and W1282X) were identified on the "Nordic" CF chro- Discussion More than 200 CF mutations have been reported (Ysui 1992a) since the cloning of the CFTR gene. Login to comment
88 394delTT should therefore be regarded as one of the most common CF mutations in these countries, as common as G542X, G551D and W1282X are in other populations. Login to comment

PMID: 7505767 [PubMed] Dork T et al: "Exon 9 of the CFTR gene: splice site haplotypes and cystic fibrosis mutations."

No. Sentence Comment

61 Association of (TG),Tm alleles with CFTR mutations (TG),Tm CFTR mutationsa (TG)llT7 E60X, E92X, R117C, 1078delT, R347P, R553X, 2184delA, 2184insA, I1005R, 3272-26A--~G, L1059X, Y1092X, R1162X, 3659delC, 3850-3T-oG, S1251N Q39X, R117H, Q414X, V456F, AI507, 1717-1G--~A, G551D, 2043delG, 2183AA---~G, 2184insA, 2789 + 5 G---~A,3272-26A---~G, R1066C, L1077P, 3849 + l0 kB C---~T,4374 + 1 G---~T 621 + 1 G---~T,R334W, A455E, AF508, G542X, 2143delT, 3849 + 10 kB C---~T,NI303K 405 + 1 G----~A,1342-2 A---~C,R553X (TG)IoT7 (TG)10T9 (TG)12T7 a References are compiled in Tsui (1992), except for 2143delT (Dtrk et al. 1992b), 3850-3 T---~G,4374 + 1 G---~T,1342-2 A---~C (Dtrk et al. 1993a, b), Q414X, V456F (this work), 405 + 1 G---~A, E92X, R117C, 2184delA, 2184insA, I1005R, L1059X (T. Login to comment
158 J Clin Invest 88:1880-1885 Hamosh A, Rosenstein BJ, Cutting GR (1992) CFTR nonsense mutations G542X and W1282X associated with severe reduction of CFTR mRNA in nasal epithelial cells. Login to comment

PMID: 7512860 [PubMed] Savov A et al: "Identification of six novel mutations in the CFTR gene of patients from Bulgaria by screening the twenty seven exons and exon/intron boundaries using DGGE and direct DNA sequencing."

No. Sentence Comment

22 Preliminary studies on the molecular basis of CF in Bulgaria have shown that AF5O8 accounts for about 55% of the mutant alleles (9) with the N13O3K accounting for 6% (10), the G542X for 5% and three additional mutations including 1677 del TA, R1070Q and R347P for about 8%. Login to comment
74 The most common mutations of the CFTR gene (AF508, N1303K, G542X, 1677 del TA, R347P, R1070Q) have been in a first step identified and in our ongoing effort to identify the other mutations, we have fully scanned the entire coding sequence of 35 CF patients. Login to comment

PMID: 7512145 [PubMed] Desgeorges M et al: "Severe pulmonary and digestive disease in a cystic fibrosis child homozygous for G542X."

No. Sentence Comment

43 Using the SSCP technique" to study the DNA extracted from the patient and her family, we detected then identified the stop mutation G542X in the two CFTR genes transmitted to the affected child. Login to comment
45 The stop mutation G542X is predicted to result in decreased levels of mutant messenger RNA"2 and in a truncated CFTR protein from NBD-1,' suppressing 63% of the molecule. Login to comment
46 However, the homozygous patients for G542X previously reported had mild pulmonary disease,""5'° which would imply alternative splicing mechanisms suppressing the effect of the stop mutation in some tissues. Login to comment
47 Contrasting with these reports, we present the second case ofa child homozygous for G542X with severe pancreatic and lung disease. Login to comment
98 Also the intrafamilial heterogeneity of cystic fibrosis, perhaps because of other modifying loci, makes it plausible that 85 group.bmj.comon October 25, 2012 - Published byjmg.bmj.comDownloaded from doi: 10.1136/jmg.31.1.84-a 1994 31: 84-85J Med Genet M Desgeorges, M Laussel, B Rollin, et al. cystic fibrosis child homozygous for G542X. Login to comment

PMID: 7508414 [PubMed] Cuppens H et al: "Detection of 98.5% of the mutations in 200 Belgian cystic fibrosis alleles by reverse dot-blot and sequencing of the complete coding region and exon/intron junctions of the CFTR gene."

No. Sentence Comment

14 Two of these CF alleles were derived from an individual homozygous for the G542X mutation, having a rather mild form of cystic fibrosis, in which only a limited number of exons of the CFTR gene had been analyzed (6). Login to comment
36 Five mutations had a frequency higher than 1% (Table 1) AF508 (72.5%), G542X (5.5%), N1303K (3.5%), 1717-1G --~ A (2.5%), and $1251N (2.0%). Login to comment
43 TABLE 1 Mutations (and Their Frequencies) Identified in This Study Predicted amino Mutation Nucleotide change~ acid change Location Frequencyb Reference E60X G --~ T at 310 (TAGATAGCT) Glu --~ Stop at 60 Malone et al. in (21); this study G --~ A at 482 (GAACACTCT) (8) A --~ C at 622-2 (TTTTCGACT) This study T --~ A at 1139 (AAAAAATTC) This study G --~ A at 1335 (TCTGAGAGG) This study C --~ A at 1496 (TTGGAGGTT) (14) G -~ T at 1505 (GCTGTATCC) (6) Deletion of ATC from 1651 (14); Schwarz et al. (TATC_TTTG) in (21) Deletion of CTT from 1653 145 (13) (TCAT_TGGT) G --~ A at 1717-1 (AATAAGACA) G --~ T at 1756 (TCTTTGAGA) G --~ C at 1898 + 1 (AAAGCTATG) G --~ C at 2014 (TTATCGGAC Deletion of A at 2184; A --~ G at 2183 (AAAAG CAAT) G --~ T at 2320 (TGATTAGCC Deletion of 11 nucleotides from 2721 (TGCT_TAGT) G --~ C at 3040 (AGCACGTAC A --~ G at 3272-26 (TGCAGTGTT) C --~ A at 3408 (TGTAACTGT) Deletion of C at 3659 (CCTA_CAAG) T --~ G at 3837 (TAAGGCCTG G --* A at 3884 (AAGAATACT G --~ A at 3978 (AGTGAAGGA' C --~ G at 4041 (AAAAGTTGG G -~ A at 4061 (CAGTAGAGT Insertion of T after 4218 (CAGTTAAGG) R117H 622-2A --~ C I336K W401X A455E G458V AI507 AF508 1717-1G -~ A G542X 1898+ 1G-~C G628R(G -~ C) 2184delA plus A -~ G at 2183 E730X 2721de111 G970R 3272-26A --~ G Y1092X 3659delc $1235R $1251N W1282X N1303K W1310X 4218insT Exon 3 2 (1.0%) Arg --~ His at 117 Exon 4 c 3' splice signal Intron 4 1 (0.5%) Ile -~ Lys at 336 Exon 7 1 (0.5%) Trp --~ Stop at 401 Exon 8 2 (1.0%) Ala --~ Glu at 455 Exon 9 2 (1.0%) Gly --* Val at 458 Exon 9 1 (0.5%) Deletion of Ile 507 Exon 10 1 (0.5%) Deletion of Phe 508 Exon 10 (72.5%) 3' splice signal Intron 10 5 (2.5%) Gly --* Stop at 542 Exon 11 11 (5.5%) 5' splice signal Intron 12 1 (0.5%) Gly -~ Arg at 628 Exon 13 1 (0.5%) Frameshift Exon 13 2 (1.0%) Glu --~ Stop at 730 Exon 13 1 (0.5%) Frameshift Exon 14a I (0.5%) Gly --~ Arg at 970 Exon 15 1 (0.5%) 5' splice signal? Login to comment
48 The G628R(G --~ C) and $1235R mutations were found on a single allele; the W1310X allele and one 2184delA (plus A --~ G at 2183) allele were found on a CFTR gene from Turkish descent. Login to comment
49 For each type mutation, at least one allele was completely sequenced: 14 for AF508, 3 for G542X, 2 for 1717-1G -~ A, 1 for A455E, 1 for G458V, 1 for AI507, 1 for W1282X, 1 for N1303K, and for the remainder, the total number of alleles that were found in this study. Login to comment
94 No additional mutations, except for some polymorphisms, in the CF patient homozygous for the G542X mutation, as well as in her CF cousin, who was a compound heterozygote for the G458V and G542X mutations (6), could be found. Login to comment
104 The G458V allele carried seven thymidines in its poly- (T) tract, which suggests that the proportion of 9- CFTR transcripts of this allele will not be very low. Login to comment
105 The fact that the G458V/G542X individual has CF suggests that the alternatively spliced 9- CFTR mRNA transcript cannot compensate for the basic defect of the CFTR protein in this CF patient. Login to comment
35 Five mutations had a frequency higher than 1% (Table 1) AF508 (72.5%), G542X (5.5%), N1303K (3.5%), 1717-1G --~ A (2.5%), and $1251N (2.0%). Login to comment
42 TABLE 1 Mutations (and Their Frequencies) Identified in This Study Predicted amino Mutation Nucleotide change~ acid change Location Frequencyb Reference E60X G --~ T at 310 (TAGATAGCT) Glu --~ Stop at 60 Malone et al. in (21); this study G --~ A at 482 (GAACACTCT) (8) A --~ C at 622-2 (TTTTCGACT) This study T --~ A at 1139 (AAAAAATTC) This study G --~ A at 1335 (TCTGAGAGG) This study C --~ A at 1496 (TTGGAGGTT) (14) G -~ T at 1505 (GCTGTATCC) (6) Deletion of ATC from 1651 (14); Schwarz et al. (TATC_TTTG) in (21) Deletion of CTT from 1653 145 (13) (TCAT_TGGT) G --~ A at 1717-1 (AATAAGACA) G --~ T at 1756 (TCTTTGAGA) G --~ C at 1898 + 1 (AAAGCTATG) G --~ C at 2014 (TTATCGGAC Deletion of A at 2184; A --~ G at 2183 (AAAAG CAAT) G --~ T at 2320 (TGATTAGCC Deletion of 11 nucleotides from 2721 (TGCT_TAGT) G --~ C at 3040 (AGCACGTAC A --~ G at 3272-26 (TGCAGTGTT) C --~ A at 3408 (TGTAACTGT) Deletion of C at 3659 (CCTA_CAAG) T --~ G at 3837 (TAAGGCCTG G --* A at 3884 (AAGAATACT G --~ A at 3978 (AGTGAAGGA' C --~ G at 4041 (AAAAGTTGG G -~ A at 4061 (CAGTAGAGT Insertion of T after 4218 (CAGTTAAGG) R117H 622-2A --~ C I336K W401X A455E G458V AI507 AF508 1717-1G -~ A G542X 1898+ 1G-~C G628R(G -~ C) 2184delA plus A -~ G at 2183 E730X 2721de111 G970R 3272-26A --~ G Y1092X 3659delc $1235R $1251N W1282X N1303K W1310X 4218insT Exon 3 2 (1.0%) Arg --~ His at 117 Exon 4 c 3' splice signal Intron 4 1 (0.5%) Ile -~ Lys at 336 Exon 7 1 (0.5%) Trp --~ Stop at 401 Exon 8 2 (1.0%) Ala --~ Glu at 455 Exon 9 2 (1.0%) Gly --* Val at 458 Exon 9 1 (0.5%) Deletion of Ile 507 Exon 10 1 (0.5%) Deletion of Phe 508 Exon 10 (72.5%) 3' splice signal Intron 10 5 (2.5%) Gly --* Stop at 542 Exon 11 11 (5.5%) 5' splice signal Intron 12 1 (0.5%) Gly -~ Arg at 628 Exon 13 1 (0.5%) Frameshift Exon 13 2 (1.0%) Glu --~ Stop at 730 Exon 13 1 (0.5%) Frameshift Exon 14a I (0.5%) Gly --~ Arg at 970 Exon 15 1 (0.5%) 5' splice signal? Login to comment
93 No additional mutations, except for some polymorphisms, in the CF patient homozygous for the G542X mutation, as well as in her CF cousin, who was a compound heterozygote for the G458V and G542X mutations (6), could be found. Login to comment

PMID: 7509232 [PubMed] Meitinger T et al: "In frame deletion (delta F311) within a short trinucleotide repeat of the first transmembrane region of the cystic fibrosis gene."

No. Sentence Comment

4 Analysing CF chromosomes in a sample of 227 CF patients from South Germany by screening for known mutations (AF5O8, G542X, G551D, R553X) and further investigation of samples with unresolved chromosomes by SSCP and direct sequencing, we identified a novel in-frame deletion occurring within a short trinucleotide repeat in exon 7 of the CFTR gene. Login to comment

PMID: 7691712 [PubMed] Sereth H et al: "Extended haplotype analysis of cystic fibrosis mutations and its implications for the selective advantage hypothesis."

No. Sentence Comment

43 The G542X, $5491, 549R and 1717- IG--+A, and N1303K mutations, were detected by PCR and subsequent allele-specific oligonucleotide (ASO) hybridization as previously described (Kerem et al. 1990; Osborne et al. 1991). Login to comment
51 Distribution of CF and normal chromosomes associated with the extended extra- and intragenic DNA polymorphic markers a 291 Mutation Haplotype 2.3A GATT TUB 18 JG2E1 24M Ethnic origin Ash- Non- Arab kena- Ash- zim kenazim AF508 Total: B 2 1 2 12 19 12 B 1 1 2 1 B (2) 1 2 4 B (2) (1) 2 1 B 2 (1) (2) 2 B 2 (1) 2 1 (B) 2 (1) 2 1 D 2 1 2 1 22 19 13 W1282X Total: B 1 2 1 40 B (1) 2 1 5 B 1 (2) 1 1 B 1 (2) (1) 3 B (1) (2) (1) 3 B 2 2 1 1 53 1 2 Q359K/T360K b Total: B 2 1 2 5 B (2) 1 2 1 B 1 1 2 1 7 N1303K Total: B 2 1 2 2 B 2 1 (2) 2 (B) (2) (1) (2) 1 3 2 G542X B 2 1 2 6 1 2 $549R B 2 1 2 2 1717-1G---)A B 1 2 1 1 $549I A 2 1 2 2 3849+10kb C--*T C 1 1 2 4 1 (C) 1 1 2 1 C 2 1 2 1 Total: 6 1 Unknown B 2 1 2 1 3 2 B (2) 1 2 1 B (2) (1) (2) 1 B 1 1 2 3 A 1 1 2 1 5 1 (A) (1) 1 2 1 C 1 1 2 2 8 2 (C) 1 (1) (2) 1 C 2 1 2 2 2 D 1 2 1 1 D 2 1 2 3 Total: 5 21 14 Total CF: 95 50 38 Table 2 (continued) Mutation Haplotype Ethnic origin 2.3A GATT TUBI8 24M Ash- Non- Arab JG2EI kena- Ash- zim kenazim Normal Total: B 2 1 2 2 1 1 B 1 l 2 3 1 B l 2 1 1 A 2 1 2 7 2 2 A I 1 2 12 8 6 A 2 2 l 1 A 1 2 2 1 A 1 2 1 I C 2 1 2 3 1 C 1 1 2 20 13 1I C 2 1 I 1 C 2 2 2 1 C 1 2 1 3 2 D 2 I 2 1 1 D 1 1 2 2 1 D 2 1 I I D 2 2 1 1 D 1 2 1 2 5 2 57 37 26 Alleles that could not be phased are shown in parentheses b All the chromosomes carrying the Q359K/T360K mutation are of Georgian origin in the respective flanking introns of the CF gene (Kerem et al. 1990; Zielenski et al. 1991). Login to comment
67 Eight additional mutations: WI282X, G542X, N1303K, 3849+10kb C---)T, Q359K/T360K, $549I, $549R, and 1717-1G-->A were identified among the studied chromosomes and have all been described elsewhere (Vidaud et al. 1990; Kerem et al. 1990; Osborne et al. 1991; Tsui 1992; Shoshani et al. 1992a, b). Login to comment
75 This extended haplotype analysis revealed that 75 of 77 (97%) of the chromosomes carrying five of the seven mutations associated with haplotype B, (F508, G542X, N1303K, Q359K/T360K, $549R) share the same intragenic haplotype, 212. Login to comment
84 The studied chromosomes included all the chromosomes carrying the Q359K/T360K, G542X, $549R, N1303K, and 1717-1G---~A mutations, 12 chromosomes carrying the W1282X mutations, and 14 chromosomes carrying the AF508 mutation. Login to comment
111 The F508, W1282X, G542X, N1303K, and 1717-1G--+A mutations were found to be associated with the same intragenic haplotype in both ethnic groups suggesting that chromosomes carrying these mutations derive from a common origin. Login to comment
121 In a previous study (Shoshani et al. 1992) we have shown that the identification of 92% of CF chromosomes of Ashkenazi origin is possible by detection of only 5 mutations (W1282X, F508, G542X, NI303K, and 1717-1G--~A). Login to comment

PMID: 7505692 [PubMed] Osborne LR et al: "Nasal epithelial ion transport and genetic analysis of infertile men with congenital bilateral absence of the vas deferens."

No. Sentence Comment

25 Nasal potential difference, sweat sodium concentration and CF genotype in subjects with CBAVD, CF patients and controls CF genotype Control cohort CBAVD cohort CF cohort N/N« AF5O8/R347H SM9N/R1070Q AF508/Other R553X/N*> Unknown/Unknowtf AF 5«/AF5O8 AFjQj/Other AF508/R347P AF50e/G542X AFjQg/RllTH AF5O8/G85E AF5Q8/R553X AFJO8/G551D AF5O8A^520F AFJO8/S549N AF^/DIjQ, N1303K/Other G542X/R117H AFJ08/R334W Other/Other Subjects 50 1 1 1 6 1 16 25 18 3 2 1 1 1 2 1 1 1 3 1 1 3 Mean (range) sweat Na+ concentration (mmol/1) 50 (27-78) 88 N/A 94 57 (47-70) 36 49 (32-76) 126(80-162) 99 (80-128) 108 (99-115) 128 (118-137) 95 107 130 122 (116-128) 90 80 118 96 (92-99) 84 123 108(83-130) Mean (range) nasal potential difference (-mV) 21 (8-30) 31 N/A 34 23 (13-29) -15 20 (-13-28) 45 (32-58) 41 (33-61) 50 (36-77) 43 (33-52) 51 42 39 60 (50-71) 32 37 41 38 (36-40) 32 34 44(31-57) N = non-CF chromosome Other = uncharacterised CF chromosome N/A not available • with CF carrier frequency of 1/20-1/25, it is likely that 2 or 3 of these individuals will be carriers. Login to comment
116 DNA studies Genomk DNA from subjects with CBAVD was extracted from whole blood and initially analysed for four common CFTR mutations (AFjog, G551D, G542X and 621 + 1 G-T) using the amplification refractory mutation system (ARMS, Cellmark Diagnostics UK)29 . Login to comment

PMID: 7505690 [PubMed] Ferec C et al: "Genotype analysis of adult cystic fibrosis patients."

No. Sentence Comment

4 All these patients are compound heterozygote, seven carrying the AF508 and one the G542X on one allele. Login to comment
57 '*'* < GENOTYPE * • • ;i^>"; ' ' FUJ34W/G542X Exon 7/ Exon 11 Arginine •-> Tryptophan AF508/I336K Exon 10/Exon 7 Isoleucine ••> Lysine AF5O8/H1054O Exon 10/Exon 17b Histidine --> Aspartc Acid AF508 Unknown AF508 / 2789+5 G->A Exon 10/ Exon 14b Splice mutation AF508/2789+5 G->A Exon 10/ Exon 14b Splice mutation AF5O8/R117H Exon 10/Exon 4 Arginine -->Histidine AF508/O36K Exon 10/Exon 7 Isoteucine ••> Lysine SEX 4 M F M M F F F M DIAGNOSiS 13 13 27 17 39 32 30 17 PROFESSIONAL; . Login to comment

PMID: 7505689 [PubMed] Cheadle JP et al: "Direct sequencing of the complete CFTR gene: the molecular characterisation of 99.5% of CF chromosomes in Wales."

No. Sentence Comment

115 Further ARMS tests are in development and in principle it should be possible to use a three tube ARMS test to assay rapidly for 13 mutations (delta F508, 621 + 1G-T, G551D, G542X, R1283M, W1282X, R553X, N13O3K, delta 1507, 1898+1G-A, R117H, R560T, and 1717-1G-A) (S.Little, personal comm.). Login to comment

PMID: 7693946 [PubMed] Will K et al: "CFTR transcripts are undetectable in lymphocytes and respiratory epithelial cells of a CF patient homozygous for the nonsense mutation R553X."

No. Sentence Comment

11 The most frequent mutation, AF508,6 located in the first nucleotide binding fold, is usually associated with severe CF,7 but in exceptional cases AF508 homozygotes are only mildly affected.8 Three nonsense mutations, G542X,9 R553X,'0 and W1282X," represent the second, fourth, and fifth most frequent CF mutations worldwide (Cystic Fibrosis Genetics Analysis Consortium, unpublished data). Login to comment
13 Two CF patients, homozygous for the G542X mutation, have been described as mildly affected."213 Cutting et al14 found two patients heterozygous for W1316X/R553X and S1255X/G542X, respectively, to exhibit severe pancreatic but only mild pulmonary disease. Login to comment

PMID: 7691344 [PubMed] Claustres M et al: "Analysis of the 27 exons and flanking regions of the cystic fibrosis gene: 40 different mutations account for 91.2% of the mutant alleles in southern France."

No. Sentence Comment

26 Mutations identified in a Southern french population mutation AF5O8 M1K 300delA P67L R74W G85E 394detTT 406-6 (T-C) Y122X I148T 621 + 1G-T 62/+2T-G L206W 1078deIT R334W R347H R347P AI507 1717-1G-A G542X R553X S549N G551D E585X 2184delA K710X R792X S945L Y1092X 3272-26A-G R1158X R1162X 3737delA 3659delC 11234V D1270N W1282X N13O3H N13O3K 4382delA Exon 10 1 3 3 3 3 3 intron 3 4 4 intron 4 intron 4 6a 7 7 7 7 10 intron 10 11 11 11 11 , 12 13 13 13 15 17b intron 17a 19 19 19 19 19 20 20 21 21 24 Amino acid change 3 bp deletion start-Lys at 1 frameshift Pro-Leu at67 Arg-Trp at 74 Gly-Glu at 85 frameshift splice mutation? Login to comment

PMID: 7691870 [PubMed] Patrizio P et al: "Cystic fibrosis mutations impair the fertilization rate of epididymal sperm from men with congenital absence of the vas deferens."

No. Sentence Comment

38 Briefly, genomic DNA extracted from peripheral lymphocytes was amplified by the polymerase chain reaction (PCR) and analysed for 12 mutations in the CFTR gene: Delta F508, G542X, G551D, R553X, W1282X, N1303K, Delta 1507, 1717G-A, R560T, S549N, R117H and 621 + 1. Login to comment
56 DF508/ DF508/R117H R117H/R553X R117H/R117H W1282X/ R553X/ N1303K/ G542X/ 1717G-A 21 4 Negative Table H. Login to comment
69 Four patients had other, rarer mutations (1717G-A, 1303K, G542X, R553X). Login to comment

PMID: 7687986 [PubMed] Ezquieta B et al: "CF2603/4delT, a new frameshift mutation in exon 13 of the cystic fibrosis transmembrane conductance regulator (CFTR) gene."

No. Sentence Comment

8 The most frequent of these mutations account for as much as 20% of the non-AF508 mutations in the Spanish CF population (e.g. G542X, RII62X, N1303K, W1282X, G551D; Nunes et al. 1991). Login to comment

PMID: 7689896 [PubMed] Morral N et al: "Microsatellite haplotypes for cystic fibrosis: mutation frameworks and evolutionary tracers."

No. Sentence Comment

6 The number of haplotype changes seen for two other common mutations, G542X (haplotype 23-33-13) and N1303K (23 - 31 -13), suggests that they originated at least 35,000 years ago. Login to comment
7 Microsatellite allele variability associated with AF508, G542X and N1303K demonstrates that slippage and mispairing is the main mechanism generating microsatellite alleles. Login to comment
19 Only 4 non-AF508 mutations (G542X, G551D, W1282X and N13O3K) are present in most geographical and ethnic subgroups with frequencies higher than 1% each, but with considerable variation (5-8). Login to comment
32 Only 5 mutations have frequencies of more than 1 % in the sample of chromosomes analysed (AF508, G542X, N1303K, 3601-111G-C, and R1162X), accounting for a total of 63.8% of CF chromosomes; 17 mutations have frequencies of less than 1% each, accounting for 5.4% of CF chromosomes; and 271 chromosomes (30.8%) have as yet uncharacterized mutations (Table 1 and Figure 1). Login to comment
58 CF mutations identified in the Spanish population Mutation AF5O8 G542X N13O3K 36O1-111G-C R1162X 1609delCA 2869insG W1282X AI507 G551D 1949del84 CF50KBdel tt 1 K710X 621 + 1G-T R334W 1078delT E92K 3667deM R1158X A120T I148T 386Oins31 Unknown Total N 437 73 18 18 14 8 6 6 5 4 3 3 3 2 2 1 1 1 1 1 1 1 271 880 % 49.7 8.3 2.1 2.1 1.6 0.9 0.7 0.7 0.6 0.5 0.3 0.3 0.3 0.2 0.2 0. Login to comment
79 CFTR microsateDite haplotypes for me three most common CF mutations (AF508, G542X and N13O3K) 16 16 16 16 16 16 16 16 16 17 16 16 16 16 17 23 23 23 4: 3: 30 31 32 29 33 25 35 28 31 31 46 44 45 7 7 33 30 31 18 35 13; 17 49 11: 13 13 13 13 13 13 13 13 14 13 13 13 13 17 17 13 13 13 A A B C 17 52 11: 16 34 83 52 37 26 12 12 11 7 7 6 16 10 6 75 15 12 6 6 16.0 10.0 7.1 5.0 2.3 2.3 2.1 1.3 1.3 1.1 3.0 1.9 1.1 14.5 2.8 2.3 1.1 1.1 15 7 17; 23 7 17; 23 22 17. Login to comment
83 Haplotypes 8CA 17BTA 17BCA Mutation NCF Chromosomes %CF %Normal 23 23 23 22 24 23 17 17 17 17 18 16 16 16 16 21 23 23 23 23 23 17 16 23 22 24 24 23 31 32 30 31 31 31 32 31 33 41 32 31 30 31 7 7 33 32 34 31 37 33 32 31 31 31 32 30 13 13 13 13 13 14 13 13 13 13 13 13 13 14 17 17 13 13 13 13 13 13 13 13 13 13 13 13 AF5O8 (49.7) Total G542X (8.396) Total N13O3K (2.1%) Total 106 2 2 2 2 1 34 29 2 3 1 1 1 1 1 2 190 36 18 4 1 1 1 1 62 10 3 2 1 1 17 55.7 1.1 1.1 1.1 1.1 0.5 17.9 15.3 1.1 1.5 0.5 0.5 0.5 0.5 0.5 1.1 100.0 58.0 29.0 6.5 1.6 1.6 1.6 1.6 100.0 58.8 17.6 11.8 5.9 5.9 100.0 1.1 0.4 1.1 - 0.2 - - 1.1 0.2 - - 10.0 16.0 1.3 14.5 0.2 31.4 2.3 0.4 0.6 1.1 - 0.2 7.1 11.7 1.1 - 0.2 0.2 1.1 2.6 N CF, number of CF chromosomes; CF, cystic fibrosis; (), frequency of CF mutations. Login to comment
103 The three most common CF mutations are associated with the same haplotype subgroup About 90% of G542X chromosomes are associated with haplotypes 23-33-13 or 23-32-13, which account for 2.3% and 0.4% of normal chromosomes, respectively. Login to comment
104 Haplotype distribution for each allelic system and the haplotype frequency G542X N1303K Figure 3. Login to comment
105 Parsimonious tree of evolution for haplotypes carrying mutations AF5O8, G542X and N13O3K. Login to comment
112 The most parsimonious tree for G542X would suggest a hypothetical haplotype 17-32-13 or 16-33-13, which would explain haplotype 17-33-13. Login to comment
113 However, these haplotypes probably each derive independently from the most common G542X haplotypes 23-33-13 and 23-32 - 13, respectively. Login to comment
115 show that G542X originally arose with allele 23 for the IVS8CA locus, and 13 for the IVS17BCA. Login to comment
116 IVS17BTA alleles 32 and 33 are found in two haplotypes each; the highfrequencyof haplotype 23-33-13 makes it most likely that this haplotype is the original wherein G542X arose. Login to comment
117 Haplotypes 16-32-13 or 17-33-13 could be derived independently from the two most common G542X haplotypes by a deletion of 6 and 7 dinucleotides respectively at the IVS8 locus (Table 3 and Figure 3). Login to comment
120 The only difference between haplotype 23-31 -13 (AF508 and N1303K) and 23-33-13 (G542X) is two TA repeats at the IVS17BTA locus. Login to comment
124 Age of mutations AF508, G542X and N1303K The current knowledge on mutations generating new alleles at microsatellite loci suggests a mutation rate of about 1 x 10~4 (ref. 26). Login to comment
131 For the G542X chromosomes the mean number of mutations of the three microsatellites, according to the reconstructed tree (Figure 3), is 0.451, representing about 1,350 generations or 34,000 years as the minimum age of G542X. Login to comment
132 For N13O3K there are 17 chromosomes that would give a result very similar to that of G542X (at least 35,000 years), which, nonetheless, must be considered with caution because of the low sample size. Login to comment
180 The variability observed for G542X and N1303K haplotypes also suggests an ancient origin of, more than 35,000 years ago, for these two mutations. Login to comment
188 Therefore, mutation analysis can be performed, firstly by screening only for the most common mutations (i.e. AF508 and G542X, in the case of the Spanish population); then, having the microsatellite haplotypes allows us to conduct a specific search for known mutations pertaining to each framework (i.e. 17-7-17 with mutations W1282X or Rl 158X, 14-31 -13 with 1949del84, etc); finally, the negative cases are analysed by searching for the unknown molecular defects. Login to comment
201 G542X was analysed by restriction site-generation PCR and digestion with ScrFl (36). Login to comment
213 As at the departure point the mutations AF508, G542X and N1303K occurred each in a single haplotype, all the mutations at the microsatellite loci have accumulated in the genealogy. Login to comment

PMID: 7692049 [PubMed] Bienvenu T et al: "Severe cystic fibrosis in a child homozygous for the G542 nonsense mutation in the CFTR gene."

No. Sentence Comment

48 Severe cystic fibrosis in a child homozygous for the G542 nonsense mutation in the CFTR gene Several homozygous nonsense mutations in the CFTR gene (S1255X/G542X, W1316X/ R553X, G542X/G542X, R553X/R553X, and RI 162X/R1 162X) have been reported. Login to comment
52 We present the clinical and molecular findings in a child homozygous for G542X with severe pancreatic and pulmonary disease. This Turkish boy was born at term (birth weight 3200 g) and presented with meconium ileus, successfully treated with enemas. Login to comment
59 A homozygous G542X mutation was found by DGGE and identified by exon 11 group.bmj.comon October 25, 2012 - Published byjmg.bmj.comDownloaded from Letters to the Editor amplification using a modified primer on the 5' side of codon 542 and subsequent digestion with BstNI.5 The mutation (G-'T at 1756) was characterised by direct sequencing using the Sequenase USB kit by standard methods. Login to comment
60 G542 is a nonsense mutation in which a glycine at codon 542 is replaced with a stop codon G542X in the cystic fibrosis transmembrane conductance regulator gene.' This boy has a severe lung involvement, meconium ileus, and pancreatic insufficiency, as indicated by the high degree of steatorrhoea. Login to comment

PMID: 7689013 [PubMed] Reiss J et al: "A comprehensive CFTR mutation analysis of German cystic fibrosis patients."

No. Sentence Comment

10 Of these patients, 8 were heterozygous for AF508, one was heterozygous for G542X and for one, no mutation was known. Login to comment
13 R117P (CGC-CCQ was found in the patient with the G542X allele and confirmed by family analysis. This mutation is the only novel one we have found in the 5' part of the CFTR gene and replaces the same nucleotide as the former described mutation R117H (10). Login to comment
56 Frequency of CFTR mutations checked routinely in German CF patients Mutation AF508 AI507 R553X G542X G551D R347P N1303K 1717 -lg-a S549R others in exon total Exon 10 10 11 11 11 7 21 llfb) 11 ll(c) Frequency 375/500 1/500 17/124(a) 13/124 7/124 6/124 6/124 5/124 2/124 0/124 % of total CF chromosomes 75.1 0.2 3.4 2.6 1.4 1.2 1.2 1.0 0.4 0.0 86.5 Reference (3) (17) (18) (17) (18) (10) (19) (17) (17) (20) (a) Non-AF508 chromosomes. Login to comment

PMID: 7684943 [PubMed] Costes B et al: "Psoralen-modified oligonucleotide primers improve detection of mutations by denaturing gradient gel electrophoresis and provide an alternative to GC-clamping."

No. Sentence Comment

62 DGGE analysis of the CF mutation G542X. Login to comment
64 Lanes 1 and 3: G542X heterozygote; Lanes 2 and 4: Normal controls, h: heteroduplexes. Login to comment
67 Figure 4 shows, as an example, the results obtained with a G542X (exon 11) heterozygote. Login to comment

PMID: 7681035 [PubMed] Reiss J et al: "Two cystic fibrosis patients with the genotype G542X/G551D."

No. Sentence Comment

1 Two adult sisters affected by cystic fibrosis were both shown to carry two different alterations within exon 11 of the CFTR gene, the nonsense mutation G542X and the missense mutation G551D. Login to comment
3 In the described patients, G542X functions as a "mild" allele and is, in this respect, dominant to the "severe" G551D. Login to comment
9 Among these are the nonsense mutation G542X and the missense mutation G551D, which account for 2.6% and 1.4%, respectively, of CF alleles in the German population. Login to comment
11 The phenotypic effects of Stop codon mutations are controversial, especially with regard to patients homozygous for G542X (Cuppens et al. 1990; Kalaydjieva 1991). Login to comment
12 We report here the phenotype of two adult patients with the genotype G551 D/G542X. Login to comment
34 The heterozygous signals reflecting the mutations G542X (left) and G551D (right) can be recognized by small peaks and are designated by N tion G551D. Login to comment
35 The exon 11 amplification product was then subjected to automated direct sequencing, which both confirmed the presence of a G551D mutation and detected heterozygosity for the Stop codon mutation G542X (Fig. Login to comment
42 (1991) have both reported patients homozygous for the mutation G542X. Login to comment
44 However, in the former study, two patients are described; the one assigned as having milder symptoms, was homozygous for G542X and was diagnosed earlier than her heterozygous nephew. Login to comment
46 The relatively mild cystic fibrosis in patients homozygous for G542X has been confirmed by the report of Bonduelle et al. Login to comment

PMID: 7681034 [PubMed] Ivaschenko TE et al: "Two new mutations detected by single-strand conformation polymorphism analysis in cystic fibrosis from Russia."

No. Sentence Comment

14 The AF508 mutation accounts for 30% - 80% of all CF chromosomes, and several others (G551D, R553X, G542X, N1303K, and W1282X) consitute as high as 5% of the CF chromosomes in some populations (Cutting et al. 1990; Kerem et al. 1990; Os- Correspondenceto: M. Dean borne et al. 1991; Vidaud et al. 1990). Login to comment

PMID: 7684637 [PubMed] Richards B et al: "Multiplex PCR amplification from the CFTR gene using DNA prepared from buccal brushes/swabs."

No. Sentence Comment

108 observed AF5O8 G542X G551D W1282X R553X R560T 1717-1 N1303K 621 + 1 R117H S549N 1507 280 7 16 2 4 2 2 5 6 11 1 •Includes affected individuals and known carriers. Login to comment

PMID: 7684636 [PubMed] Shuber AP et al: "Efficient 12-mutation testing in the CFTR gene: a general model for complex mutation analysis."

No. Sentence Comment

48 A diird was hybridized with a pool of ASOs for the five most frequent CFTR mutations after AF508: G551D, G542X, W1282X, N1303K, and R553X. Login to comment
50 Percent GC content of allele-speciik oligonucleotides GC Content/ASO Mutation G542X G551D R553X W1282X N1303K DI507 1717-1 G - A R560T S549N R117H 621 + 1 G - T 40 53 53 47 41 30 41 53 53 47 30 HS«3X W12»2X N1J0JK £507 H117M • 21 SS4tN RSOOT Table 2. Login to comment
53 1) Number of ASOs (N = 12) 2) Mutation Frequencies # ofCF Mutation Chromosomes Frequency A508 G551D G542X W1282X N1303K R553X 621 + 1 G - T R117H 1717-1 G - A R560T AI507 S549N unknown Total 548 15 13 13 12. Login to comment
54 9 9 '3 3 2 1 1 133 764 • Minimal Number of Independent Conclusion (4 hybridizations) Filter # 1 N(A5O8) 2 A5O8 72.0% 2.0% 1.7% 2.0% 1.5% 1.1% 1.1% 0.4% 0.4% 0.3% 0.1% 0.1% 17.0% Hybridizations 3 4 G551D 621 + 1 G - T G542X R117H W1282X 1717-1 G - A N13O3K R560T R553X A507 S549N with the remaining six mutations: 621 + 1 G^T, R117H, 1717-1 G - A , R560T, AI507, and S549N. Login to comment
72 Example of results obtained from hybridizing four identical filters with ASOs specific for N (the normal sequence at position 508), AF508 (a 3 bp deletion at position 508), pool 1 (G542X, G551D, R553X, W1282X, and N13O3K), and pool 2 (AI507, R117H, 621 + 1 G - T , S549N, R560T, 1717-1 G-A). Login to comment
73 Row A contains positive control samples with the following genotypes: 1A (AF508/AF508); 2A (AF508/G542X); 3A (AF5O8/G551D); 4A (N/R553X); 5A (NAV1282X); 6A (AF5O8/N13O3K); 7A (N/AI5O7); 8A (N/R117H); 9A (N/621 + 1 G-T); 10A (AF508/S549N); HA (AF508/R560T); and 12A (N/1717-1 G-A). Login to comment
79 Pool 1: lane 1 (G542X); lane 2 (G551D); lane 3 (R553X); lane 4 (W1282X); lane 5 (N1303K). Login to comment
86 Row A contains positive control samples: lane 2 (G542X); lane 3 (G551D); lane 4 (R553X); lane 5 (W1282X); lane 6 (N13O3K); lane 7 (AI507); lane 8 (R117H); lane 9 (621 +1 G-T)); lane 10 (S549N); lane 11 (R560T); lane 12 (1717-1 G-A)). Login to comment

PMID: 8473422 [PubMed] Patrizio P et al: "Aetiology of congenital absence of vas deferens: genetic study of three generations."

No. Sentence Comment

45 In six patients the mutation identified was W1282X, a nonsense mutation, localized on exon 20 and predicting the production of truncated polypeptides of CFTR; one patient was found to have the R553X mutation, a nonsense mutation of the CG to TG rule localized on exon 11; one patient had the mutation 1717G-A, localized on intron 10, which would cause defective RNA splicing; one patient was found to have the G542X mutation, a nonsense mutation in exon 11. Login to comment
51 Exon 4,10,11,20 and 21 were amplified in a multiplex reaction followed by allele specific oligonucleotide (ASO) probe analysis for the mutations Delta F508, G542X, G551D, R553X, W1282X, N13O3K, Delta 1507, 1717G-A, R560T, S549N, R117H and 621 + 1. Login to comment
85 DF5O8/ DF5O8/ DF5O8/ DF508/ DF508/ DF508/ DF508/ DF5O8/ DF5O8/ DF5O8/ DF508/ DF5O8/ DF508/ W1282X/ W1282X/ W1282X/ W1282X/ W1282X/ DF508/R117H DF508/R117H DF508/R117H R553X/R117H R553X/ 1717G-A/ G542X/ Neg. NA NA NA NA DF508 NA NA NA Neg. NA NA NA NA Neg. NA NA NA DF508 NA R117H NA NA 1717G-A NA DF508 Neg. NA NA NA Neg. NA NA NA DF508 NA NA NA NA W1282X NA NA NA R117H NA DF508 NA NA Neg. NA Neg. Neg. NA NA NA Neg. NA Neg. Neg. Neg. Neg. Neg. Neg. NA Neg. NA Neg. Neg. Neg. NA R117H NA NA NA Neg. (g) DF508 - ... - - (g) Neg. - ... _. - - - - (b) Neg. - ... - - (g) DF5O8 (b) DF508 - - - (b) Neg. - b = boy; g = girl; NA = data not available; -, no offspring; DF5O8 = Delta F508. Login to comment
127 However in the present study, we extended the genetic screening to the parents and the offspring of men with CAVD and moreover, by testing for 12 CF mutations, we demonstrated other rare CF mutations (R117H, G542X and 1717G-A) in patients with CAVD. Login to comment
144 The six CFTR mutations identified in this study occur on four exons plus one intron and represent deletion (Delta F508), nonsense (W1282X, 1717G-A and G542X) and amino acid substitution (R553X and R117H) mutations. Login to comment

PMID: 7680378 [PubMed] Curtis A et al: "Absence of cystic fibrosis mutations in a large Asian population sample and occurrence of a homozygous S549N mutation in an inbred Pakistani family."

No. Sentence Comment

81 A CFTR product cystic fibrosis patient with the nonsense mutation G542X zygous R553X and the splice site mutation 1717-1 J Med Genet*1991;28:878-80. in a substitution io Chalkley G, Harris A. Login to comment
84 A CFTR product cystic fibrosis patient with the nonsense mutation G542X zygous R553X and the splice site mutation 1717-1 J Med Genet *1991;28:878-80. in a substitution io Chalkley G, Harris A. Login to comment

PMID: 7678316 [PubMed] Kubesch P et al: "Genetic determinants of airways' colonisation with Pseudomonas aeruginosa in cystic fibrosis."

No. Sentence Comment

62 most rapidly in AF508 compound heterozygotes with a stop mutation (G542X, R553X, R1162X, W1282X) or another mutation in the NBF-encoding exons on the second disease allele: Risk factor* Compound heterozygote (95% Cl) p AF508/nonsense 2-47 (1-42-4-29) < O-(Xn AF508/missense 0-78 (0-43-1-41) NS AF508/frameshift 0-52(021-132) NS AF508/splice site 0.40 (0-19--()-S6) < 0-05 OF508/NBFl orNBF2 1-99 (1-22-3-25) <0-01 AF508/TM1 or TM2 0-62 (0-30-1-30) NS AF508/R domain 0-46 (0-17-1-29) NS *Relative to AF508 homozygous group. Login to comment

PMID: 7682803 [PubMed] Sferra TJ et al: "The molecular biology of cystic fibrosis."

No. Sentence Comment

75 AF508,G542X, G551D, R533X, W1282X, and Nl303K account for 84.5% ofCF chromosomes in the non-Askenazic, North AmericanCaucasian population (43). Login to comment

PMID: 7683952 [PubMed] Audrezet MP et al: "Identification of 12 novel mutations in the CFTR gene."

No. Sentence Comment

62 His genotype was G542X/Q1238X. Login to comment

PMID: 1281385 [PubMed] Ober C et al: "Ethnic heterogeneity and cystic fibrosis transmembrane regulator (CFTR) mutation frequencies in Chicago-area CF families."

No. Sentence Comment

7 When a panel of 10 mutations (AF508, AI507, G542X, G551D, R553X, S549N, R1162X, W1282X, N1303K, and 1717-1G--A) was used, detection rates ranged from 75% in non-Ashkenazi Caucasians to 40% in African-Americans. Login to comment
36 Mutation Analysis DNA from each subject was screened for the following mutations: AF508 (Kerem et al. 1989a), G542X (Kerem et al. 1990), GS51D (Cutting et al. 1990), R553X (Cutting et al. 1990), S549N (Cutting et al. 1990), R1162X (Gasparini et al. 1991), W1282X (Vidaud et al. 1990), N1303K (Osborne et al. 1991), and 1717-1G- A (Guillermit et al. 1990; Kerem et al. 1990). Login to comment
44 G542X. Login to comment
60 The fact that only approximately 60% of our Caucasian sample was of northern European ancestry may account for the relatively low frequency (.60) of AF508 in Chicago-area non-Ashkenazi Caucasians. The frequencies of the next two most common mutations, G542X and G551D, are also consistent with the ethnic composition of our sample. Login to comment
61 The G542X mutation is fairly common throughout Europe, particularly in southern Europe (Nunes et al. 1991). Login to comment
80 Among 20 Pueblo and Navajo CF chromosomes, only one mutation (G542X) was detected by a panel of six mutations (AF508, G542X, GSS1D, R553X, G542X, and N1303K). Login to comment

PMID: 1282898 [PubMed] Fortina P et al: "Non-radioactive detection of the most common mutations in the cystic fibrosis transmembrane conductance regulator gene by multiplex allele-specific polymerase chain reaction."

No. Sentence Comment

3 The strategy involves multiplex PCR of exons 10, 11, and 21 within the cystic fibrosis transmembrane conductance regulator (CFTR) gene in a single reaction containing three common oligoprimers and either the four normal or four mutant oligos corresponding to the AF508, G551D, G542X, and N1303K mutations. Login to comment
11 Five mutations have been identified (AF508, G551D, R553X, G542X, and N1303K), which account for 84% of all Caucasian CF chromosomes, and a rapid, reliable and cost-effective screening method is required that includes detection of these prevalent mutations. Login to comment
18 Oligonucleotide primers used for mutation detection by multiplex allele-specific polymerase chain reaction (MASPCR) Primers ~ Sequence b pMoV CF-W1468-N CF-508RP AF508 5' IVS-11 R553X-N R553X-M G551D-N G551D-M G542X-N G542X-M 5' IVS-2I N1303K-N N1303K-M 5'-GGCACCATTAAAGAAAATATCATCTT-3' l5 5'-TAGTGTGAAGGGTTCATATGCATAAT-3' 15 5'-GGCACCATTAAAGAAAATATCATTGG-3' 15 5'-CAACTGTGGTTAAAGCAATAGTGT-3' 20 5'-CTAAAGAAATTCTTGCTCG-3' 10 5'-CTAAAGAAATTCTTGCTCA-3' 10 5'-GAAATTCTTGCTCGTTGA C-3' 5 5'-GAAATTCTTGCTCGTTGAT-3 ' 5 5'-GTGTGATTCCACCTTCTCC-3' 2(1 5'-GTGTGATTCCACCTTCTCA-3' 20 5'-AAGAATGATACAAAGCAGACATG-3' 40 5'-CACTGTTCATAGGGATCCAAG-3' 40 5'-CACTGTTCATAGGGATCCAAC-3' 4(1 a Normal (N) and mutant (M) primers b Bold letters indicate single-base mutations c Amount (pMol) of each primer used in multiplex reactions single lane of a gel. Login to comment
22 DNA samples were obtained from CF patients with the AF508, G551D, R553X, and G542X mutations. Login to comment
30 Each reaction contained the three common primers (CF-508RP, 5' IVS-11, and 5' IVS-21) and either four normal or four mutant primer sets for the AF508, G551D, G542X, and NI303K sequences (Table 1). Login to comment
33 5' IVS-11 5' IVS-21 f,f A AA CF-W1468-N.--1~(139 bp) d'---- CF-508RP AFS08 .~1P.(136bp) <1~ CF-508RP ._~ (174 bp) ~ G542X (N or M) 5' IVS-11 (202 bp) ~ G551D (N or M) 5' IVS-21 ~ (240 bp) ~I~N1303K (N or M) Fig. 1. Login to comment
36 Multiplex amplification is accomplished using common primers (CF-508RP, 5' IVS-I1, and 5' IVS-21) and a mixture of either the four normal (CF-W1468-N, G551D-N, G542X-N, and N 1303K-N) or four mutant primer (AF508, G55 l DM, G542X-M, and NI303K-M) sets (Table 1) in each PeR reaction. Login to comment
47 All amplifications were done with either normal (N) or mutant (M) primers corresponding to the AF508, G551D, G542X, and N1303K regions of the human CFTR gene. Login to comment
48 Amplifications were done with DNA from normal controls using normal primers (lane 2 N1303K-N and 5' IVS-21; lane 4 G551D-N and 5' IVS-11; lane 6 G542X-N and 5' IVS-11; and lane 8 CF-W1468-Nand CF-508RP) or mutant primers for the same regions (lane 3 N1303K-Mand 5' IVS-21; lane 5 G551D-M and 5' IVS-11;lane 7 G542X-M and 5' IVS-11; and lane 9 AF508and CF-508RP). Login to comment
52 Multiplex amplification of four regions in normal DNA (lanes 2-5) encompassing AF508, G551D, G542X, and N1303K mutations with normal primer (N; lanes 2 and 4) or mutant (M) primer sets (lanes 3 and 5). Login to comment
53 Multiplex amplification was done using separate reactions containing a mixture of either the normal or corresponding mutant primer sets with DNA from a heterozygote for the AF508mutation (lanes 6 and 7), DNA from a heterozygote for the G542X mutation (lanes 8 and 9), and DNA from a compound heterozygote for the AF508and G542X mutations (lanes 10 and 11), respectively. Login to comment
61 We have successfully detected the G542X, G551D, and AF508 mutations using this multiplex approach. Login to comment
63 Data are shown confirming the following genotypes: a AF508 heterozygote (lanes 6 and 7), a G542X heterozygote (lanes 8 and 9), and a AF508/G542X compound heterozygote (lanes 10 and 11). Login to comment
73 For example, in one sample, the four normal primers produce normal amplification products, while the mutant primer set yields only a 174-bp fragment, consistent with heterozygosity for the G542X mu- tation. Login to comment

PMID: 1384328 [PubMed] Abeliovich D et al: "Screening for five mutations detects 97% of cystic fibrosis (CF) chromosomes and predicts a carrier frequency of 1:29 in the Jewish Ashkenazi population."

No. Sentence Comment

33 The regions encompassing the mutations of interest were simultaneously amplified by PCR using DNA primers: C16B and C16D for AF508 (Kerem et al. 1989), lli5 and 11i3 for G542X, 20i5 and 20i3 for W1282X, and 21i5 and 21i3 for N1303K (Kerem et al. 1990; Vidaud et al. 1990; Osborne et al. 1991; Zielenski et al. 1991 b). Login to comment
37 Mutation Detection Mutations AF508 and G542X were detected by using oligonucleotides oligo-N, oligo AF, 542NL, and 542X according to a method described elsewhere (Kerem et al. 1989 and 1990). Login to comment
42 The hybridization and wash conditions were as follows: W1282X-hybridization at 370C for 60 min and three washes in 2 x SSC, 0.1% SDS (twice at room temperature for 10 min and then at 590C for 10 min); AF508-hybridization 370C for 60 min and then three washes in 2 x SSC, 0.1% SDS (twice at 370C for 10 min and then at 420C for 10 min); G542X-hybridization at 420C for 2 h and then two washes in 2 x SSC, 0.1% SDS (once at 420C for 10 min and once at 450C for 10 min). Login to comment
46 The same approach was used as an alternative method to detect AF508 and G542X. Login to comment
54 Results Five mutations-W1282X, AF508, G542X, N1303K, and 3849 + lOkb C-'lT-were found in our patients. Login to comment
57 Amongthe Ashkenazi, three mutations-W1282X (48%), AF508 (30%), and G542X (12%)-accounted for 90% of the CF mutations, while mutations N1303K and 3849 + 1Okb C--T were found on an additional 7% of CF chromosomes. Login to comment
60 In the Arab patients, four mutations-AF508, N1303K, W1282X, and G542X-were found, accounting for 55% ofthe CF mutations. Login to comment
62 To evaluate the gene frequency in the Ashkenazi population, a random sample of 424 Ashkenazi individuals (848 chromosomes) was screened for the presence of the three mutations W1282X, AF508, and G542X. Thirteen individuals were identified as heterozygotes- six with the AF508 mutation and seven with the W1282X mutation. Login to comment
63 In this sample we did not identify any carrier having the G542X mutation. Login to comment
64 Discussion The predominant mutation in Caucasians, AF508, was found in all ethnic communities in Israel but at a significantly lower frequency (31%) than in northern Table 2 Distribution of CF Mutations, by Ethnic Group FREQUENCY (no.) IN Jews Ashkenazi Non-Ashkenazi Turkish Arabs MUTATION (n = 94) (n = 37) (n = 7) (n = 31) F508 ........................... .30 (28) .43 (16) .29 (2) .26 (8) G542X .................. .12 (11) .43 (3) .03 (1) W1282X ................... .48 (45) .03 (1) .14 (1) .10 (3) N1303K .................. .03 (3) .16 (5) 3849 + 10kb C-T .......... .04 (4) .14 (1) Subtotal .................. .97 .46 1.00 .55 Unidentified mutations .... .03 (3) .54 (20) 0 .45 (14) NOTE. Login to comment
82 We screened for three mutations-AF508, W1282X, and G542X-which are expected to detect 90% of the carriers. Login to comment

PMID: 1384327 [PubMed] Scriver CR et al: "Cystic fibrosis genotypes and views on screening are both heterogeneous and population related."

No. Sentence Comment

76 of CF chromosomes]) Distribution and Mutation (%) Askhenazi from Israel (Abeliovich et al. 1992 [94]; Shoshani et al. 1992 [95]): W1282X .......................................... AFS08 ............................................. G542X ............................................ 3849 + 10 kb, CT ............................ N1303K ........................................... Total ............................................ Celtic Bretons from France (Ferec et al. 1992 [365]): AF508 ............................................. 1078delT ......................................... G5S1D ............................................ 1717-1 G-A ..................................... W846X ............................................ G91R .............................................. Login to comment
78 Ten alleles at 0.27% each .................... Total ............................................ French Canadians from northeastern Quebec (Rozen et al. 1992 [181]): 48 30 12 4 3 97 60 22 4 0 4 92a 82 4 1 1 1 2 3 98a AFS08 ......... ..................... 58 621+1G-T .............................. 23 A455E .......... .................... 8 G85E ......... ..................... 1 711+1 G-T ............................... 1 G542X .......... .................... 1 Y1092X .............................. 1 N1303K ........... ................... 1 Total .......... .................... 93a a Because of rounding, individual values do not sum to the total. Login to comment

PMID: 1283149 [PubMed] Dork T et al: "A termination mutation (2143delT) in the CFTR gene of German cystic fibrosis patients."

No. Sentence Comment

86 All six identified alleles carry the typical "risk haplotype" for CF that is also associated with other common severe mutations, such as zXF508, N1303K, G542X or 621 + 1G-T (Kerem et al. 1989, 1990: Osborne et al. 1991: Zielenski et al. 1991b). Login to comment

PMID: 1283148 [PubMed] Lindner M et al: "The spectrum of CFTR mutations in south-west German cystic fibrosis patients."

No. Sentence Comment

4 Another 5 mutations accounted for a further 12.5% (4% G542X; 3% R553X; 3% N1303K; 2% 1717-1 G--~A; 0.5% G551D) whereas 6 mutations (R117H, A455E, AI507, $549I, $549N, and R1162X) were not found. Login to comment
7 Two patients, age 6 and 25 years, were compound heterozygotes for G542X and N1303K. Login to comment
25 Sequences derived from Dean et al. (1990); Kerem et al. (1990); Riordan et al. (1989); Guillermit et al. (1990); Cutting et al. (1990) Exon PCR primers Mutation Allele specific probes 4 5'-AGTCACCAAAGCAGTACAGC-3' R117H N: 5'-GCTATTCTCATCTGCATTCC-3' M: 9 5'-TAATGGATCATGGGCCATGT-3' A455 E N: 5'-ACAGTG~ITGAATGTGGTGCA-3' M: 5'-GTTTTCCTGGATTATGCCTGGCAC-3' N: 5'-GTTGGCATGCTTTGATGACGCTTC-3' M: t0 11 5'-CAACTGTGGTTAAAGCAATAGTGT-3' 5'-GCACAGATTCTGAGTAACCATAAT-3' 5'-GAGGAACGCTCTATC-3' 5'-GAGGAACACTCTATC-3' 5'-GTTGTTGGCG GTI'GCT-3' 5'-GTTGTTGGAG GTTGCT-3' zXF508 5'-CACCAAAGATGATATTTTC-3' 5'-AACACCAATGATATTTTCTT-3' AI507 1717-1G--+A N: 5'-TTGGTAATAGGACATCTCCA-3' M: 5'-TTGGTAATAAGACATCTCCA-3' G542X N: 5'-CCACCTTCTCCAAGAACTAT-3' M: 5'-CCACCTTCTCAAAGAACTAT-3 G551D N: 5'-CTCGTTGACCTCCACTCAGT-3' M: 5'-CTCGTTGATCTCCACTCAGT-3' 19 5'-GCCCGACAAATAACCAAGTGA-3' R 1162X 5'-GCTAACACATTGCTFCAGGCT-3' 21 5'-AATGTTCACAAGGGACTCCA-3' N1303K 5'-CAAAAGTACCTGTTGCTCCA-3' N: 5'-AGGGATCCAAGTTTTTTCTA-3 ' M: 5'-AGGGATCCAACTTTTTTCTA-3' Materials and methods Determination of the CFTR genotype All mutation analyses were performed on Taq-PCR (polymerase chain reaction) amplified DNA fragments (30 cycles at 92~176 72~ for 30/60/90 s) using primers as shown in Table 1 (Sambrook et al. 1989). Login to comment
26 The R117H, A455E, 1717-1G~A, AF508, G542X, G551D, and NI303K mutations were identified by allele specific oligonucleotide hybridisation (ASO, Sambrook et al. 1989) using 32p-labelled probes specific for the normal or the mutated sequence (Table 1). Login to comment
33 The other five mutations were found on a further 12% of the CF chromosomes, the most numerous of these being G542X, R553X, and N1303K (Table 2).This distribution is similar to that found in a group of patients from the north of Germany, although in contrast to our Table 2. Login to comment
34 Mutations observed in 220 defective cystic fibrosis transmembrane conductance regulator (CFTR) alleles Mutation n (%) Rll7H 0 A455E 0 AI507 0 AF508 147 (67) 1717-1G--*A 4 (2) G542X 9 (4) $549I 0 $549N 0 G551D 1 (<0.5) R553X 7 (3) R1162X 0 N1303K 6 (3) Unknown 46 (21) Total 220 (100) patients in that group R553X was considerably more common than G542X (Plieth et al. 1992). Login to comment
36 Fifty-four patients (49%) were homozygous for A508, 18 (16.5%) were compound heterozygotes for AF508 and one of the rarer mutations, and 2 were compound heterozygotes for G542X and N1303K. Login to comment
40 Genotype of 110 CF patients Genotype n (%) F508/F508a 54 (49) F508/1717-1G---~A 4 (3.5) F508/G542X 3 (3) F508/G551D 1 (1) F508/R553Xb 5 (4.5) F508/N1303K 4 (3.5) F508/unknown c 22 (20) G542X/N1303K 2 (2) G542X/unknown 4 (3.5) R553X/unknown 2 (2) Unknown/unknown d 9 (8) Total 110 (100) a Includes one Italian patient b Includes one patient with a French father and a German mother c Includes two Italian and one French patient Includes one Greek and one Turkish patient sorption is also indicated by repeated low stool chymotrypsin levels (<0.3 U/g) and a reduced excretion (< 10%) of para-amino benzoic acid (PABA) following a standardised oral challenge. Login to comment

PMID: 1279852 [PubMed] Tsui LC et al: "The spectrum of cystic fibrosis mutations."

No. Sentence Comment

61 In a study based in Milan, the data show that AF508 accounts for 55% of the CF chromosomes, whereas G542X, N1303K and 1717-1G+A are relatively more frequent than in other populations (Ref. 13 and M. Ferrari, pers. Login to comment
64 Frequent cystic fibrosis mutations Name Relative freqeenc~ Mutation Con~,~'~luence Ref. Z~508 67.2 G542X 3.4 G551D 2.4 W1282X 2.1 3905insT 2.1 N1303K 1.8 3849+10kbC-+T 1.4 1717-1G-+A 1078delT 2789+5G--+A Deletion of 3 bp between nt 1652 and t655 in exon 10 G-+T at nt 1756 in exon 11 G-+A at nt 1784 in exon 1I G-+A at nt 3978 in exon 20 Insertion of T after nt 3905 in exon 20 C-+G at nt 4041 in exon 21 C-->T in a 6.2 kb EcoRI fragment 10 kb from 5' junction of intron 19 3849+4A-+G 1.0 7tt÷IG--+T 0.9 Rl162X 0.9 1898+lG-+A 0.9 Rll7H 0.8 3659delc 0.8 G85E 0.7 2184delA 0.7 AI5W 0.5 R347P 0.5 R~ 0.4 1,3 C-+T at nt 1"789in exon 11 1.3 G-+T at nt 1 from 5' junction of intron 4 1.1 G--+A at nt 1 from 3' junction of intron 10 1.1 Deletion of T at nt 1078 in exon 7 1.1 G-cA at 5 nt from 5' end of intron 14b A-->G at 4 nt from 5' end of intron 19 G-+T at nt 1 from 5' junction of intron 5 C-+T at nt 3616 in exon 19 G-+A at nt 1 from 5' junction of intron 12 G--)A at nt 482 in exon Deletion of C at nt 3659 in exon 19 G-+A at nt 386 in exon 3 A-->G at nt 2183 and deletion of A at nt 2184 in exon 13 Deletion of 3 bp between nt 1648 and 1653 in exon 10 G-+C at nt 1172 in exon 7 G-~C at nt 1811 in exon 11 A455E 0.4 R334W 0.4 Y122X 0.3 S549R(T-+G) 0.3 Q493X 0.3 V520F 0.2 S549N 0.2 C-+A at nt 1496 in exon 9 C-+T at nt 1132 in exon 7 T-cA at nt ~i98 in exon 4 T--+G at nt 1779 in exon 11 C-+T at nt 1609 in exon 10 G-+T at nt 1690 in exon 10 G-->A at nt I778 in exon !1 Deletion of Phe at codon 508 Gly-+Stop at codon 542 12 Gly-~Asp at codon 551 10 l"rp-->Stop at codon t282 35 Frameshift -~ Asn-+Lys at codon 1303 36 Aberrant splicing -~ Arg~Stop ~ codon 553 Splice mutation 10 37 Splice mutation 12 Frameshift 38 Splice mutation _c Splice mutation? Login to comment

PMID: 1384321 [PubMed] Grebe TA et al: "Mutation analysis of the cystic fibrosis transmembrane regulator gene in Native American populations of the southwest."

No. Sentence Comment

5 Direct mutation analysis of six mutations of the CFTR gene-namely, AF508, G542X, G551D, R553X, N1303K, and W1282X-was performed on PCR-amplified genomic DNA extracted from blood samples. Login to comment
7 Of the 12 affected individuals studied, no AF508 mutation was detected; only one G542X mutation was found. Login to comment
9 All affected individuals have either an AA, AC, or CC haplotype, except for the one carrying the G542X mutation, who has the haplotype AB. Login to comment
24 These mutations are G551D (Cutting et al. 1990), G542X (Kerem et al. 1990), and R553X (Cutting et al. 1990), which are all in exon 11, and N1303K (Osborne et al. 1991), in exon 21. Login to comment
62 After hybridization, the filters were washed for 5 min at room temperature in 5 x SSC and then for 30 min in 2 x SSC at the following temperatures: 49°C for the AF508 probe and 43°C for its normal homologue, 430C for G542X and its normal sequence, and 51 'C for N1303K and its normal sequence. Login to comment
79 One patient (008-1), however, carries a single copy of G542X. Login to comment

PMID: 1281033 [PubMed] Harris A et al: "Cystic fibrosis gene."

No. Sentence Comment

98 It has been reported that the G542X mutation when present in a homozygous form may lead to a milder form of CF than AF508 homozygotes or heterozygotes AF508/G542X.57 Similarly other patients with predicted 'stop' mutations in both CF genes may be less severely affected than AF508 homozygotes.58 In other words if the 'stop' mutation actually abolishes production of CFTR this may be less deleterious than having a malfunctioning protein such as the A508 protein. Login to comment

PMID: 1281032 [PubMed] Super M et al: "Milestones in cystic fibrosis."

No. Sentence Comment

159 Homozygotes for G542X have mild disease.67 It is postulated that alternate routes of chloride transport may open up when CFTR does not function at all. Login to comment
160 Thus a protein conformational change in CFTR resulting in a signif- FIBROSIS Table 4 CF Mutations encountered in United Kingdom Mutation Delta F508 G551D R553 G542X R56OT N1303K DI507 R117H 621+1G-T G85E W1282X E60X R75Q V520F 1717-1 G-A CF chromosomes screened 1 Mutations encountered 1062 199 (non Delta F508) 199 199 199 199 199 199 199 199 199 30 15 199 199 CF chromosomes with mutation in North-West England 863 37 8 11 6 6 4 5 10 4 2 2 1 3 3 Percentage 81.2 3.48 0 75 1.03 0.58 0 58 038 0.47 0.98 0.38 0 19 ? Login to comment
171 The upper track shows 621+1 G->T, the next G551D, then G542X and the lowest track shows Delta F5O8. Login to comment
172 Two contiguous tracks belong to each specimen tested, for the absence and presence of the allele Thus the patterns shown are: negative, negative, heterozygous for Delta F508, homozygous for Delta F508, compound heterozygote for 621+1 and Delta F5O8, heterozygous for G551D, and compound heterozygote for G542X and Delta F508, then the size ladder ARMS is a registerd trademark of ICI Diagnostics Table 5 Applications of earner testing to families with a known history of CF. Login to comment
175 A positive correlation of the rare mutation G542X/Delta F508 is awaiting confirmation, but our own figure of 5 out of 7 with meconium ileus seems likely to be confirmed. Login to comment

PMID: 1284888 [PubMed] Hamosh A et al: "CFTR nonsense mutations G542X and W1282X associated with severe reduction of CFTR mRNA in nasal epithelial cells."

No. Sentence Comment

1 1, No. 7 542-544 CFTR nonsense mutations G542X and W1282X associated with severe reduction of CFTR mRNA in nasal epithelial cells Ada Hamosh12 *, Beryl J.Rosenstein2 and Garry R.Cutting1 '2 -3 1 Center for Medical Genetics, departments of Pediatrics and 3 Medicine, the Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA Received July 8, 1992; Revised and Accepted August 28, 1992 Cystic fibrosis (CF) is caused by mutations in the CF Transmembrane Conductance Regulator (CFTR) gene (1). Login to comment
4 The nonsense mutations G542X and W1282X (5) are also among the most common CFTR mutations (CF Genetic Analysis Consortium). Login to comment
6 To study the effect of these nonsense mutations upon mRNA processing, nasal epithelial cells were obtained from two carriers of the G542X mutation, three compound heterozygotes for G542X and AF5O8, two carriers of the W1282X mutation, one homozygote for the W1282X mutation and one W1282X/AF5O8 nasal polyp cell culture. Login to comment
28 For the G542X mutation, cDNA was amplified using CFTR primers Exon 7-5' and Exon 11-3' (3). Login to comment
32 Figure la shows the results of ASO hybridization to amplified genomic DNA and cDNA from one compound heterozygote for the G542X mutation. Login to comment
42 Quantitation by densitometry (The Discovery Series™ Scanner, PDI, Huntingdon Station, NY) demonstrated that the level of transcripts derived from the G542X nonsense mutation was consistently less than 10% of the normal or AF5O8 allele, while that of the W1282X mutation was consistently less than 5% of the normal or AF508 allele. In this study, we demonstrate that the CFTR nonsense mutations G542X and W1282X are associated with severely reduced levels of CFTR mRNA in nasal epithelial cells. Login to comment
43 Decreased levels of mRNA carrying the G542X mutation have been observed in both respiratory and rectal epithelia (10). Login to comment
44 These findings suggest that the G542X and W1282X mutations should result in severely decreased or undetectable CFTR protein and add to the growing evidence that nonsense mutations usually result in reduced transcript levels, as has been observed in many human disease genes (11, 12). Login to comment
47 No large scale analysis of patients carrying the G542X mutation has been reported. Login to comment
49 Approximately 3% of CF patients will be homozygous or compound heterozygous for the G542X, R553X, and W1282X mutations. Login to comment
107 Joanna Rommens for the sample of CFTR plasmid DNA, Dr Arthur Beaudet for genomic DNA from a G542X homozygote, Dr Bat-Sheva Kerem for the 542X and 542NL ASOs, and Dr Iain Mclntosh for advice. Login to comment

PMID: 1284531 [PubMed] Shackleton S et al: "G27X: a novel mutation in exon 2 of the CF gene."

No. Sentence Comment

11 To date more than 27 predicted 'stop' mutations have been defined in the CF gene (4), several of these including G542X (5), R553X (6) and W1282X (7) being sufficently common to encounter homozygotes for the mutation, thus enabling potentially more informative predictions of genotype/phenotype associations. Login to comment

PMID: 1357180 [PubMed] Cheadle J et al: "Mutation analysis of 184 cystic fibrosis families in Wales."

No. Sentence Comment

13 '`3 Marked variations in the frequency of AF508 have been reported from different populations.4 For example, in different regions of Europe, Figure 1 The ARMS multiplex analysed on a 3% NuSieve gel. Samples I to 3 are normal, 4 is a AF508 heterozygote, 5 a G542X/AF508, 6 a G551D/AF508, 7 a 621 + IG > T/AF508, and 8 a GSSID homozygote. Login to comment
25 A multiplex test based on the Amplification Refractory Mutation System (ARMS), developed by Cellmark Diagnostics,'6 allows the simultaneous detection of AF508, G551D, G542X, and 621 + 1G > T. Login to comment
27 The A reaction identifies normal 621 + 1G> T/ AF508 sequences and mutant G551D/G542X sequences, whereas the B reaction identifies mutant 621 + G> T/AF508 sequences and normal G551D/G542X sequences (fig 1). Login to comment
41 We have identified a total of 89-8% of CF mutations in the Welsh population, with AF508 accounting for 718%, 621+1G>T 6 7%, G542X 2-7%, and R1283M 2-0%. Login to comment
61 Welsh Mixed Undefined Total Mutation No % No % No % No % AF508 107/149 71-8 92/126 73 0 69/94 73 4 268/369 72-6 621 + 1G>T 10/42* 6-7 5/34* 4-0 4/25* 4-3 19/101* 51 G551D 2/42* 1-3 6/34* 4-8 3/25* 3-2 11/101* 3 0 G542X 4/42* 2-7 4/34* 3-2 1/25* 1.1 9/101* 2-4 G85E 0/41* 0-0 2/34* 1 6 3/24* 3*4 5/99* 1-4 R553X 2/42* 1-3 2/34* 16 0/25* 00 4/101* 1-1 R1283M 3/42* 2.0 0/34* 0.0 0/25* 0.0 3/101* 0-8 N1303K 1/42* 0 7 1/34* 0-8 0/24* 0.0 2/100* 0-6 AI507 2/149 1-3 0/126 0.0 0/94 0.0 2/369 0-5 R117H 1/42* 0 7 1/34* 0-8 0/25* 0.0 2/101* 0-5 1717- 1G>A 2/42* 1-3 0/34* 0 0 0/25* 0 0 2/101* 0-5 R560T 0/42* 00 0/34* 00 1/25* 1 1 1/101* 03 1154InsTC 0/40* 0 0 1/33* 0 9 0/24* 0.0 1/97* 0-3 V520F 0/42* 0 0 0/34* 0 0 0/25* 0.0 0/101* 0 0 W1282X 0/42* 0 0 0/34* 0.0 0/25* 0.0 0/101* 0 0 R347P 0/42* 0 0 0/34* 0 0 0/24* 0.0 0/100* 0 0 Q493X 0/42* 0 0 0/34* 0 0 0/24* 0 0 0/100* 00 Total (%) 89-8 90 7 86-5 891 * Non-AF508 chromosomes. Login to comment
76 In parallel to this we ran the ARMS multiplex which detects AF508, G551D, G542X, and 621 + 1G > T, thus accounting for 83-1 % of our total CF chromosomes. Login to comment
97 We wish to thank Professor P S Harper, Dr D Shaw, and Dr A Clarke for their useful comments on this manuscript, Dr L Sandkuijl for his help with the statistical analyses, Dr M 0 621 + 1G> T Total G551D Total G542X Total G85E Total R553X Total R1283M Total N1303K Total AI507 Total RI 17H Total 1717-1 Total R560T Total 1154Ins TC Total 0 1 1 o o o 0 o 0 0 2 0 o o 0 1 0 0 I 1 1 1 I I I Al-Jader, Meredith Table S Distribution of haplotypes in the uncharacterised CF chromosomes. Login to comment

PMID: 1379414 [PubMed] Ferrie RM et al: "Development, multiplexing, and application of ARMS tests for common mutations in the CFTR gene."

No. Sentence Comment

6 ARMS reactions for the most common mutations have been multiplexed to give a test which will detect the presence of the AF508, G551D, G542X, and 621 + 1G--T mutations in a DNA sample. Login to comment
57 The mutations detected, their frequencies, and the methods used to Table I CF Mutations in 1,030 Chromosomes from the Northwest of England Observed Frequency Detection Mutation (%) Methoda Reference R117H ......... .4 A Dean et al. 1990 621 + 1G>T ... 1.0 R Zielenski et al. 1991 AI507 ......... .5 S Schwartz et al. 1991 AF508 ......... 80.7 S and A Kerem et al. 1989 1717-1G>A ... .3 A Guillermit et al. 1990 G542X ......... 1.1 A Kerem et al. 1990 GSS1D ......... 3.4 R Cutting et al. 1990 RS53X ......... .8 R Cutting et al. 1990 RS60T ......... .6 R Kerem et al. 1990 W1282X ....... .2 A Vidaud et al. 1990 N1303K ........ .6 A Osborne et al. 1991 a A = ASO hybridization; R = RFLP; and S = size difference. Login to comment
65 ARMS tests were developed for the following mutations: AF508 (Riordan et al. 1989), A1507 (Schwarz et al. 1991), R117H (Dean et al. 1990), 621 + 1G-T (Zielenski et al. 1991), 1717G--oA (Guillermit et al. 1990), W1282X (Vidaud et al. 1990), GSS1D and R553X (Cutting et al. 1990), G542X and R560T (Kerem et al. 1990), and N1303K (Osborne et al. 1991). Login to comment
115 The mutations for which ARMS tests were developed were R560T, R553X, GS5iD, G542X, 1717-1G--A, 621 + 1G--T, N1303K, and W1282X. Login to comment
118 The Development of a Multiplex ARMS Test for the Four Most Common CF Mutations in the Northwest of England In order to obtain a multiplex ARMS test for these four mutations (AF508, GSSiD, G542X, and 621 + 1G-T; table 1), it was necessary to develop a method for the simultaneous detection of the two closely linked exon XI mutations, GSSiD and G542X, which are separated by only 28 bp. Login to comment
138 R553X: CACCTTGCTAAAGAAATTCTTGCTAG ................. CACCTTGCTAAAGAAATTCTTGCTAA ................. GS51D: GCTAAAGAAATTCTTGCTCGTTGCC ................. AGCTAAAGAAATTCTTGCTCGTTGCT ................. G542X: ACTCAGTGTGATTCCACCTTCTAC ...................... CACTCAGTGTGATTCCACCTTCTCA .................... 1717-1G>A: GTCTTTCTCTGCAAACTTGGAGATGTGC ............ GTCTTTCTCTGCAAACTTGGAGATGTGT ............ R117H: CACATATGGTATGACCCTCTATATAAACTC. Login to comment
152 In the multiplex, the normal ARMS reactions for AF508 and 621 + 1G--T are combined with the mutant overARMS reactions for G551D and G542X in the "A" Figure 2 Development of a single ARMS test for R117H. Login to comment
155 Shown are the results a n m n m R560T 317bp c n m n m 0551 D 286bp obtained using primers RH-d-N and RH-d-M at 0.86 pM (a), at reduced primer concentration 0.10 ItM (b), at 0.86 FM with the inclusion of AAT1 /2 control primers (c), and using primers RHh-N and RH-h-M (which are identical to RH-d-N/M, except for C/C mismatch at position - 2). Login to comment
156 b n m n m R553X 291bp * control - 220bp d n m n m G542X 256bp4- control 220bp e n m n m 621 +1G>T 380bp gn m n m f n m n m 360bp 4----- control 220bp h n m n m 1717G>A 220bp -- control - * 360bp W1282X I 178bp Figure 3 Single ARMS tests. Login to comment
161 The ARMS tests are as follows: a, R56OT; b, R553X; c, GSS1D; d, G542X; e, 621 + 1G T; f, N1303K; g, 1717G-A; and h, W1282X. Login to comment
191 In addition to the validation and application data reported here, theARMS multiplex is also being tested Table 4 Sequences and Concentration of ARMS Primers Used in the Multiplex ARMS Test Size Concentration Mutation and Sequence (5' to 3') Code (bp) Tube (x standard) AFS08: GACTTCACTTCTAATGATGATTATGGGAGA ...... DF-C A/B 1.0 GTATCTATATTCATCATAGGAAACACCACA ....... DF-j-N 160 A 1.0 GTATCTATATTCATCATAGGAAACACCATT ....... DF-w-M 157 B 2.0 Exon 11: TAAAATTTCAGCAATGTTGTTTTTGACC ......... 11-C A/B 2.0 GS51D: GCTAAAGAAATTCTTGCTCGTTACC .................. GD-j2d3-N 285 B 2.0 AGCTAAAGAAATTCTTGCTCGTTGCT ................ GD-j-M 286 A 1.0 G542X: ACTCAGTGTGATTCCACCTTCTAC..................... GX-e-N 256 B 1.0 CACTCAGTGTGATTCCACCTTCTCA ................... GX-M 257 A 1.0 621 + 1G>T: TCACATATGGTATGACCCTCTATATAAACT ....... 621-C A/B .5 TGCCATGGGGCCTGTGCAAGGAAGTATTCC ..... 621-j-N 380 A .5 TGCCATGGGGCCTGTGCAAGGAAGTATTGA .... 621-r-M 380 B .5 4 5 6 7 8 9 10 11 Figure 4 Results obtained using the standard ARMS multiplex test. Login to comment
193 The first contains the products of the normal 621 + 1G-T and AF508 primers and ofthe mutant GSS1D and G542X primers. Login to comment
194 The corresponding products for the 621 + 1G-T and AFS08 mutant primers and for the GSS1D and G542X normal primers are in the second track of the pair. Login to comment
196 The genotypes of the 11 samples are as follows: 1, normal; 2, normal; 3, normal; 4, 621 + 1G-T heterozygote; 5, G551D heterozygote; 6, G542X heterozygote; 7, AFS08 heterozygote; 8, 621 + 1G-T, AFS08; 9, GSS1D,AFS08; 10, G542X,AFS08; and 11, AFS08 homozygote. as part ofa large multicenter study. Login to comment
216 1 2 3 blank 621 +lG>T G551D - ~ G542X F508 621 + 1 G>T G551 D G542X F508 621 +lG>T G551D \_-_ G542X F508 The use of long primers (typically 30 mers) ensured that false priming events were minimized and that primer template interactions were stabilized. Login to comment
229 This approach did not work, because the yields of several of the reactions were too low (GSSlD-normal, G542X-mutant, and AFS08 mutant) or too high (621 + 1G-T-normal and mutant) when compared with the yield of the other reactions (data not shown). Login to comment
238 An additional problem in the development ofa multiplex for the four most common CF mutations is the close proximity of GSS1D and G542X; these mutations are within 28 bp of each other in exon XI of the CFTR gene. Login to comment
241 A potential problem with this method is the priming ofthe GSS1D product with the G542X primers or product. Login to comment
243 In our hands the approach worked well and allowed simultaneous detection of GS51D and G542X, although the relative yield ofthese two products was sensitive to changes in mismatch strength and primer concentration. Login to comment
58 The mutations detected, their frequencies, and the methods used to Table I CF Mutations in 1,030 Chromosomes from the Northwest of England Observed Frequency Detection Mutation (%) Methoda Reference R117H ......... .4 A Dean et al. 1990 621 + 1G>T ... 1.0 R Zielenski et al. 1991 AI507 ......... .5 S Schwartz et al. 1991 AF508 ......... 80.7 S and A Kerem et al. 1989 1717-1G>A ... .3 A Guillermit et al. 1990 G542X ......... 1.1 A Kerem et al. 1990 GSS1D ......... 3.4 R Cutting et al. 1990 RS53X ......... .8 R Cutting et al. 1990 RS60T ......... .6 R Kerem et al. 1990 W1282X ....... .2 A Vidaud et al. 1990 N1303K ........ .6 A Osborne et al. 1991 a A = ASO hybridization; R = RFLP; and S = size difference. Login to comment
66 ARMS tests were developed for the following mutations: AF508 (Riordan et al. 1989), A1507 (Schwarz et al. 1991), R117H (Dean et al. 1990), 621 + 1G-T (Zielenski et al. 1991), 1717G--oA (Guillermit et al. 1990), W1282X (Vidaud et al. 1990), GSS1D and R553X (Cutting et al. 1990), G542X and R560T (Kerem et al. 1990), and N1303K (Osborne et al. 1991). Login to comment
116 The mutations for which ARMS tests were developed were R560T, R553X, GS5iD, G542X, 1717-1G--A, 621 + 1G--T, N1303K, and W1282X. Login to comment
119 The Development of a Multiplex ARMS Test for the Four Most Common CF Mutations in the Northwest of England In order to obtain a multiplex ARMS test for these four mutations (AF508, GSSiD, G542X, and 621 + 1G-T; table 1), it was necessary to develop a method for the simultaneous detection of the two closely linked exon XI mutations, GSSiD and G542X, which are separated by only 28 bp. Login to comment
141 R553X: CACCTTGCTAAAGAAATTCTTGCTAG ................. CACCTTGCTAAAGAAATTCTTGCTAA ................. GS51D: GCTAAAGAAATTCTTGCTCGTTGCC ................. AGCTAAAGAAATTCTTGCTCGTTGCT ................. G542X: ACTCAGTGTGATTCCACCTTCTAC ...................... CACTCAGTGTGATTCCACCTTCTCA .................... 1717-1G>A: GTCTTTCTCTGCAAACTTGGAGATGTGC ............ GTCTTTCTCTGCAAACTTGGAGATGTGT ............ R117H: CACATATGGTATGACCCTCTATATAAACTC. Login to comment
159 b n m n m R553X 291bp * control - 220bp d n m n m G542X 256bp 4- control 220bp e n m n m 621 +1G>T 380bp gn m n m f n m n m 360bp 4----- control 220bp h n m n m 1717G>A 220bp -- control - * 360bp W1282X I 178bp Figure 3 Single ARMS tests. Login to comment
164 The ARMS tests are as follows: a, R56OT; b, R553X; c, GSS1D; d, G542X; e, 621 + 1G T; f, N1303K; g, 1717G-A; and h, W1282X. Login to comment
197 The corresponding products for the 621 + 1G-T and AFS08 mutant primers and for the GSS1D and G542X normal primers are in the second track of the pair. Login to comment
199 The genotypes of the 11 samples are as follows: 1, normal; 2, normal; 3, normal; 4, 621 + 1G-T heterozygote; 5, G551D heterozygote; 6, G542X heterozygote; 7, AFS08 heterozygote; 8, 621 + 1G-T, AFS08; 9, GSS1D,AFS08; 10, G542X,AFS08; and 11, AFS08 homozygote. Login to comment
220 1 2 3 blank 621 +lG>T G551D - ~ G542X F508 621 + 1 G>T G551 D G542X F508 621 +lG>T G551D \_-_ G542X F508 The use of long primers (typically 30 mers) ensured that false priming events were minimized and that primer template interactions were stabilized. Login to comment
233 This approach did not work, because the yields of several of the reactions were too low (GSSlD-normal, G542X-mutant, and AFS08 mutant) or too high (621 + 1G-T-normal and mutant) when compared with the yield of the other reactions (data not shown). Login to comment
242 An additional problem in the development ofa multiplex for the four most common CF mutations is the close proximity of GSS1D and G542X; these mutations are within 28 bp of each other in exon XI of the CFTR gene. Login to comment
245 A potential problem with this method is the priming ofthe GSS1D product with the G542X primers or product. Login to comment
247 In our hands the approach worked well and allowed simultaneous detection of GS51D and G542X, although the relative yield ofthese two products was sensitive to changes in mismatch strength and primer concentration. Login to comment

PMID: 1380943 [PubMed] Osborne L et al: "Incidence and expression of the N1303K mutation of the cystic fibrosis (CFTR) gene."

No. Sentence Comment

63 Fifteen patients were born with meconium ileus, 10 with the AF508/N1303K genotype; 4 of the remaining 5 were G542X/N1303K patients for whom data was available, and 2 patients were N1303K/unknown. Login to comment
67 All the G542X/N1303K patients were diagnosed at birth. Login to comment
75 N/A data not available Genotype Number Meana (range) age Male/ Pancreatic status Meconium Sputum female ileusb colonisation ofof patients Current At diagnosis PS PI P.aeruginosa Yes No Mean (range) of FEVj percentage of that predicted AF508 79 10 0.7 • 0.6 16 / 20 0 55 10/58 20 8 N1303K (0.5-36) (0-2.5) N1303K 10 7 1 • 1 3/3 0 6 1/6 3 1 N1303K (3-12) (0.1-1.5) G551D 6 19 9.7 • 2.2 1/ 2 0 4 0/4 3 1 N1303K (17-22) (8-12) G542X 8 7 0 • 0 2/3 0 4 4/5 0 2 N1303K (0.1-12) 621+lG---~T 1 22 18 1/0 0 1 0/1 1 0 N1303K W1282X 4 13.5 0.7 • 0.6 3 / 1 0 4 0/4 0 1 N1303K (5-23) (0.25-1.7) R560T 1 5 41 1 / 0 0 1 0/1 0 1 N1303K R553X 1 N/A N/A N/A 0 1 0/1 N/A N/A N1303K R334W 1 19 N/A 1/0 0 1 0/1 N/A N/A N1303K R1162X 1 N/A N/A N/A N/A N/A N/A N/A N/A N1303K 1717-1G---~A 2 7 N/A 0/1 N/A N/A N/A N/A N/A N1303K 3659delC 1 21 74 0/1 0 1 0/1 1 0 N1303K 1078delT 1 N/A N/A N/A N/A N/A N/A N/A N/A N1303K Other 90 12 4.3 • 5.6 9/9 5 19 2/17 4 10 N1303K (2-24) (0.1-15) 63 (32-101) 65 (46-84) 80 (66-93) N/A 55 70 N/A N/A N/A N/A N/A 26 N/A 66 a Mean +_SD b Shown as a fraction of the patients for whom data was available the percentage of FEV1 between age-matched N1303K homozygotes and AF508/N1303K heterozygotes (65% vs 75%, P> 0.1). Login to comment
94 Of the 15 patients who presented with meconium ileus, 4 were found to have the G542X/N1303K genotype. Login to comment
96 Because none of the other genotypes reported in this study showed any association with meconium ileus, it seems likely that this observation relates to the G542X, and not the N1303K, allele. Login to comment

PMID: 1379244 [PubMed] Denning GM et al: "Abnormal localization of cystic fibrosis transmembrane conductance regulator in primary cultures of cystic fibrosis airway epithelia."

No. Sentence Comment

154 The genotype of the CF cells was AF508/N1303K for CF1 and CF4, AF508/G542X for CF2, AF508/other for CF3, and other/other for CF5. Login to comment
156 The N1303K and G542X mutations are two of the more common non-AF508 mutations (see ref. Login to comment
158 As with CFTRAF508, CFTR-N1303K is not appropriately glycosylated in a recombinant system (9, 19). Login to comment
159 We expect that CFTR-G542X is a truncated protein or, if the levels of mRNA are decreased (20), that there is no G542X protein at all. Login to comment
163 Thus, we conclude that some mutant CFTR proteins, including CFTRAF508, CFTR-N1303K, CFTR-G542X, and at least one other mutant CFTR, are not present or are present at greatly reduced amounts in the apical membrane of these CF epithelia. Login to comment
211 This conclusion is valid for CFTRAF508, CFTR- Denning et al. Abnormal Localization of CFTRin CFAirway Epithelia N1303K, CFTR-G542X, and at least one other undetermined mutation. Login to comment
162 Thus, we conclude that some mutant CFTR proteins, including CFTRAF508, CFTR-N1303K, CFTR-G542X, and at least one other mutant CFTR, are not present or are present at greatly reduced amounts in the apical membrane of these CF epithelia. Login to comment
208 This conclusion is valid for CFTRAF508, CFTR- Denning et al. Abnormal Localization of CFTRin CFAirway Epithelia N1303K, CFTR-G542X, and at least one other undetermined mutation. Login to comment

PMID: 1381442 [PubMed] Gasparini P et al: "Nine cystic fibrosis patients homozygous for the CFTR nonsense mutation R1162X have mild or moderate lung disease."

No. Sentence Comment

113 We investigated both the approaches pressed so that a reduced quantity of CFTR mentioned above, but for want of genotype could be produced, as recently suggested from characterised cohorts, we think that the com- studies on nasal epithelial cells of two patients parison of the R1162X homozygotes with a homozygous for the G542X nonsense muta- 'mixed genotype' cohort (fig 1), in which chest tion. Login to comment
121 Cutting et al'6 reported two compound heterozygotes for stop mutations S1255X/G542X and W1316X/R553X (see above), respectively. Login to comment
124 Beaudet et aP7 described a patient homozygous for mutation G542X with pancreatic insufficiency and pulmonary disease milder than in the average CF patient of comparable age. Login to comment
207 Possible suppression of the termination codon in CF patients with the G542X mutation. Login to comment

PMID: 1378801 [PubMed] McIntosh I et al: "Cystic fibrosis transmembrane conductance regulator and the etiology and pathogenesis of cystic fibrosis."

No. Sentence Comment

69 Apart from the iF508 mutation, five other mutations (G542X,3 G551D, R553X, W1282X, and N1303K) occur at frequencies greater than 1% in the majority of populations (4, 16). Login to comment
109 CF mutations that occur at a frequency of 5% or greater in certain population groups Region Mutation Population group Frequency Reference Transmembrane 1-6 621 + 1GT 711+1GT French Canadian; Saguenay-Lac St. Jean French Canadian; Urban Quebec 0.23 0.09 72 72 NBF 1 A455E SF508 G542X G551D French Canadian; Saguenay-Lac St. Jean Worldwide Ashkenazi Jewish Spanish Scottish 0.08 0.30-0.88 0.12 0.05 0.05 72 14 73 74 75 Transmembrane 7-12 R1162X N.E. Italian 0.05 74 NBF 2 W1282X Ashkenazi Jewish 0.48 56, 73 press CFTR and in those used for transient expression studies (33). Login to comment

PMID: 1379210 [PubMed] Fanen P et al: "Molecular characterization of cystic fibrosis: 16 novel mutations identified by analysis of the whole cystic fibrosis conductance transmembrane regulator (CFTR) coding regions and splice site junctions."

No. Sentence Comment

55 Six of these mutations, G542X, G551D, 1717-1 G-A (Fig. l), 3659delC, R1162X, and N1303K, have been reported previously (Cutting et al., 1990; Gasparini et al., 1991b; Guillermit et al., 1990; Kerem et al., 1990; Osborne et al., 1991). Login to comment
67 T C225R R334W G542X G551D 1717-l G -+ A K710X Lys -b Stop at 710 A-+Tat2260 G628R Gly + Arg at 628 G+Aat2014 2043 delG Frameshift 1 -bp deletion W846X Trp --, Stop at 846 G-+Aat2670 2789 + 5 G - A Splice mutation G + A at 2789 + 5 Y913C Tyr --) Cys at 913 A-,Gat2870 3272-26 A -+ G Splice mutation A + G at 3272-26 W1063X Trp -+ Stop at 1063 G+Aat3321 R1066C Arg + Cys at 1066 C+Tat3328 Y1092X Tyr + Stop at 1092 C + A at 3408 3659delC Frameshift l-bp deletion 19 3732deIA Frameshift 1-bp deletion 19 K1200E Lys --, Glu at 1200 A+Gat3730 19 R1162X Arg - Stop at 1162 C + T at 3616 19 W1282X Trp + Stop at 1282 G+Aat3978 20 N1303K Asn -+ Lys at 1303 C -+ G at 4041 21 4374 + 1 G + A Splice mutation G+Aat4374+ 1 Intron 23 Asp + Gly at 44 Frameshift Frameshift Gly + Arg at 178 Splice mutation Cys + Arg at 225 Arg + Trp at 334 Gly + Stop at 542 Gly + Asp at 551 Splice mutation A+Gat263 2 2bp deletion 2 1-bp deletion 4 G --, A at 664 5 G + Tat 711 + 1 Intron 5 T+Cat805 6a C + Tat 1132 7 G + T at 1756 11 G+Aat1784 11 G + A at 1717-l Intron 10 Haplotype Restriction (XV-2c, KM-19) site change Reference A B A A or C A D A B, D B B Hinfl(-) - - - - SecI (+) MspI (6) - Mb01 (+) - 13 13 13 14a Intron 14 b 15 Intron 17a 17b 17b 17b C A B A D A A C B C XmnI (-) - - - MnlI (-) - - This study This study This study Zielenski et al. (1991) Zielenski et al. (1991) This study Gasparini et al. (1991b) Kerem et al. (1990) Cutting et al. (1990) Kerem et al. (1990); Guillermit et al. (1990) This study This study This study Vidaud et al. (1990a) Highsmith et al. (1990) Vidaud et al. (1990a) This study This study This study Bozon (personal communication) Kerem et al. (1990) This study Together with 3732delA Gasparini et al. (1991b) Vidaud et al. (1990a) Osborne et al. (1991) This study Note. Previously undescribed mutations are shown in bold type. Login to comment
108 Two mutations in exon 11-G551D and G542X-are more frequent than the other non-AF508 mutations: G542X represents 4-6% in all parts of the country except Brittany, while G551D is present at a rate of 4% in the population of Celtic origin (Ferec, personal communication). Login to comment

PMID: 1376017 [PubMed] Cutting GR et al: "Analysis of four diverse population groups indicates that a subset of cystic fibrosis mutations occur in common among Caucasians."

No. Sentence Comment

95 One mutation, G542X, was observed in all four groups. Login to comment
125 However, any explanation should take into account both the high frequency of the null allele G542X in almost all populations studied and the predominance of the nonsense mutation W1282X in Ashkenazi patients. Login to comment
212 Lerer I, Sagi M, Cutting GR, Abeliovich D (1992) Cystic fibrosis mutations delta F508 and G542X in Jewish patients. Login to comment

PMID: 1376016 [PubMed] Kristidis P et al: "Genetic determination of exocrine pancreatic function in cystic fibrosis."

No. Sentence Comment

10 This result is thus consistent with the hypothesis that PI and PS in CF are predisposed by the genotype at the CFTR locus; the PS phenotype occurs in patients who have one or two mild CFTR mutations, such as R117H, R334W, R347P, A455E, and P574H, whereas the PI phenotype occurs in patients with two severe alleles, such as AF508, A1507, Q493X, G542X, R553X, W1282X, 621 + 1G-PT, 1717-1G--'A, 556delA, 3659delC, I148T, G480C, V520F, G551D, and R560T. Login to comment
50 The next most common were GSS1D (3.1%), G542X (2.2%), and 621 + 1G--T (1.3%). Login to comment
58 Intron 10: 1717-1G-'A Exon 11: G542X .......... S549R ........... G551D .......... R553X .......... R560T .......... Exon 12: Y563N .......... P574H .......... Exon 19: 3659delC ....... Exon 20: W1282X ....... Exon 21: N1303K ..... G460-C A deletion G482-'A A deletion T575-C 621 + 1G-T C1132-T C1172- G C1496-A G1505-'T G1570-T C1609-T 3-bp deletion 3-bp deletion G1690-T G1717-1-A G1756-T T1779-G G1784- A C1789-T G1811-C T1819- A C1853- A C deletion G3978-A C4041-G Asp 110-His Frameshift Arg 117-His Frameshift Ile 148-Thr Splice mutation Arg 334-Trp Arg 347-Pro Ala 455- Glu Gly 458-'Val Gly480-Cys Gln 493- stop del of Ile 507 del of Phe 508 Val 520-Phe Splice mutation Gly 542- stop Ser 549-'Arg Gly 551-WAsp Arg 553- stop Arg 560- Thr Tyr 563- Asn Pro 574-His Frameshift Trp 1282-stop Asn 1303-Lys Dean et al. 1990 White et al. 1991 Dean et al. 1990 Zielenski et al. 1991a F. Rininsland, D. Bozon, and L.-C. Tsui, unpublished data Zielenski et al. 1991a Gasparini et al. 1991 Dean et al. 1990 Kerem et al. 1990b Cuppens et al. 1990 Strong et al. 1991 Kerem et al. 1990b Kerem et al. 1990b Kerem et al. 1989b Jones et al. 1991 Kerem et al. 1990b Kerem et al. 1990b Kerem et al. 1990b Cutting et al. 1990 Cutting et al. 1990 Kerem et al. 1990b Kerem et al. 1990b Kerem et al. 1990b Kerem et al. 1990b Vidaud et al. 1990 Osborne et al. 1990 PI or PS, but not with both. Login to comment
66 As shown in table 3, meconium ileus Table 2 1181 Table 3 Frequency of 25 CF Mutations in Chromosomes of the Toronto Study Population Mutation AF508 ...... G551D...... G542X...... 621 +1G-'T N1303K..... W1282X..... R1 17H...... 1717-1G-~A R560T...... A1507 ...... R553X...... V52OF ...... R334W ..... A455E...... I148T ...... Q493X...... P574H...... R347P ...... SS6delA ..... 3659delC .... G480C...... 444delA ..... D110H...... G458V...... S549R ...... Y563N...... Login to comment
68 Although meconium ileus was found in patients who had diverse genotypes, it appeared to be overrepresented (9/18) in patients who had the AF508/G542X genotype. Login to comment
73 Complete CF Genotypes for 394 Patients No. OF PATIENTS GENOTYPE WITH Allele 1 Allele 2 pla P AF508 ...... AF508 277 (49) 2 G551D 21 (1) 0 G542X 18 (9)c 0 621+1G-~T 11 (1) 0 AI507 7 (1) 0 N1303K 6 (1) 0 R560T 5 0 1717-lG-A 5 (1) 0 556delA 3 0 Q493X 3 0 R553X 3 (1) 0 W1282X 3 0 3659delC 2 0 1148T 1 0 R117H 0 9 A445E 0 2 P574H 0 2 R347P 0 1 G551D ..... 1717-lG-~A 2 0 621+1G-~T 1 0 G480C 1 0 G551D 1 0 V520F 1 (1) 0 G542X ..... V520F 1 0 1148T ...... W1282X 1 (1) 0 W1282X .... W1282X 1 0 N1303K .... R553X 1 (1) 0 R117H ..... R117H 0 1 G542X 0 1 R334W ..... R334W 0 1 a1 Numbers in parentheses are number of patients with neonatal meconium ileus. Login to comment
81 Table 4 Classification of CF Gene Mutations as Severe or Mild with Respect to Pancreatic Function Type of Mutation Severe (location) Mild (location) Missense (point mutation) ...... 1148T (exon 4) R117H (exon 4) G480C (exon 9) R334W (exon 7) VS2OF (exon 10) GSS1D (exon 11) R347P (exon 7) RS60T (exon 11) A455E (exon 9) N1303K (exon 21) P574H (exon 12) Single amino acid deletion ........ AFS08 (exon 10) A1507 (exon 10) Stop codon (nonsense) ..... Q493X (exon 10) G542X (exon 11) R553X (exon 11) W1282X (exon 20) Splice junction ... 621 + 1G-T (intron 4) 1717-1G-T (intron 10) Frameshift ........ 556delA (exon 4) 3659delC (exon 19) with any of the mild mutations was associated with PS. Login to comment
85 Accordingly, the mutations R117H, R334W, R347P, A455E, and P574H may be regarded as mild, whereas AF508, AI507, Q493X, G542X, R553X, W1282X, 621 + 1G-T, 1717-1G--A, 556delA, 3659delC, 1148T, G480C, V520F, GSS1D, and R560T are severe. Login to comment
99 Forexample, nine of 18 patients with the AF508/ G542X genotype have been found to have neonatal meconium ileus; this frequency is much above the overall proportion observed in our clinic (17%). Login to comment

PMID: 1373935 [PubMed] Nunes V et al: "A frameshift mutation (2869insG) in the second transmembrane domain of the CFTR gene: identification, regional distribution, and clinical presentation."

No. Sentence Comment

28 Three other mutations are relatively common in the Spanish population-G542X (Kerem et al. 1990), R1162X (Gasparini et al. 1991), and N1303K (Osborne et al. 1991), which have frequen- Letters to the Editor A C G T 4-G M N Figure I Identification of the CF mutation 2869insG by direct sequencing: comparison ofthemutated (left) and normal (right) sequences of the CFTR region containing exon 15. Login to comment
39 Of the five patients carrying this mutation, one is homozygous, andfourarecompound heterozygotes with other mutations-AF508 in two cases, G542X in one case, and an unknown mutation in the other. Login to comment
54 The four compound heterozygotes show a severe clinical course, which is probably due to the combined effect of 2869insG and either mutation AF508 or mutation G542X. Login to comment

PMID: 1375186 [PubMed] Nemeti M et al: "The occurrence of various non-delta F508 CFTR gene mutations among Hungarian cystic fibrosis patients."

No. Sentence Comment

3 To identify other common mutations in CF families from Hungary, 30 non-AF508 CF chromosomes were analyzed for selected mutations in exon 11 (G551D, R553X, G542X), intron 4 (621+1G--~T), intron 10 (1717-1G---~A), exon 20 (W1282X), and in exon 21 (N1303K) of the CFTR gene. Login to comment
4 In 6 of the 30 non-AF508 CF chromosomes the following mutations were detected: R553X, G542X, 1717-1G---~A, W1282X, and N1303K. Login to comment
16 As 13 different mutations have been reported within exon 11 alone (Cutting et al. 1990; Devoto et al. 1991; DOrk et al. 1991; Kerem et al. 1990; Sangiuolo et al. 1991; Strong et al. 1991), our first aim was to check the frequency of three of the more frequent mutations in this exon, namely G551D, R553X, and G542X. Login to comment
22 The G542X mutation was detected using the modified primer and BstNI digestion as described by Ng et al. (1991). Login to comment
25 The primer modification strategy was the same as mentioned above for detection of the G542X mutation and 1717-1G--~A splice mutation (Haliassos et al. 1989). Login to comment
32 Screening of 84 Hungarian CF chromosomes for eight CFTR gene mutations Name of mutation No. of No. of chromosomes mutant screeneda chromosomes AF508 (Exon 10) 84 54 G551D (Exon 11) 30 0 R553X (Exon 11) 30 2 G542X (Exon 11) 28 1 621+lG--*T (Intron 4) 27 0 1717-1G--~A (Intron 10) 27 1 W1282X (Exon 20) 26 1 N1303K (Exon 21) 25 1 a Chromosomes with an identified mutation were excluded for examination of other mutations Results and discussion The results of screening 84 parental CF chromosomes for these 8 mutations are summarized in Table 1. Login to comment
34 In the 6 non-AF508 chromosomes the following mutations were found: R553X (2 chromosomes), G542X, 1717-1G---,A, W1282X, and N1303K. Login to comment

PMID: 1284468 [PubMed] Cheadle JP et al: "A new missense mutation (R1283M) in exon 20 of the cystic fibrosis transmembrane conductance regulator gene."

No. Sentence Comment

5 From a sample of 373 CF chromosomes, 318 proved to have one of the following mutations: delta F508, delta 1507, G551D, R553X, G542X, R117H, 1717-1G>A, R560T and 621 + 1G>T. Login to comment

PMID: 1371263 [PubMed] Dork T et al: "Intra- and extragenic marker haplotypes of CFTR mutations in cystic fibrosis families."

No. Sentence Comment

26 A few other mutations were analysed either by allele-specific oligonucleotide hybridization (Rl17H, G542X, 1717-1 G---~A) (Dean et al. 1990b; Guillermit et al. 1990; Kerem et al. 1990), single strand conformation polymorphism (Orita et al. 1989) (R347P, 3659delC) (Dean et al. 1990b; Kerem et al. 1990), temperature gradient gel electrophoresis (Rosenbaum and Riesner 1987) (1717-1 G--~A) (Guillermitet al. 1990; Kerem et al. 1990) or by allele-specific PCR (G542X, NI303K) (Kerem et al. 1990; Osborne et al. 1991). Login to comment
92 The more frequent mutations G542X, G551D, R553X are located in sequence motifs that are evolutionarily conserved amongst the members of ABC transport proteins (Riordan et al. 1989; Hyde et al. 1990). Login to comment
98 ASO, Allele-specificoligonucleotide hybridization; TGGE, temperature gradient gel electrophoresis; SSCP, single strand conformation polymorphism Mutation Localization No. % Method of detectiona Reference R117H Exon 4 2 0.4 ASO Dean et al. (1990b) R334W Exon 7 2 0.4 RFLP MspI Gasparini et al. (1991b) R347P Exon 7 5 1.0 RFLP NcoI Dean et al. (1990b) A455E Exon 9 1 0.2 RFLP AciI Kerem et al. (1990) F508C2 Exon 10 1 0.2 Nondenaturing PAGE Kobayashi et al. (1990) AF508 Exon 10 370 74.0 Nondenaturing PAGE Kerem et al. (1989) 1717-1 G---~A Intron 10 2 0.4 TGGE Kerem et al. (1990) G542X Exon 11 5 1.0 Allele-specificPCR Kerem et al. (1990) G551D Exon 11 5 1.0 RFLP DpnII Cutting et al. (1990) R553X Exon 11 12 2.4 RFLP HincII Cutting et al. (1990) 2789 + 5 G---~A Intron 14B 3 0.6 RFLP SspI Highsmith et al. (1990) Rl162X Exon 19 1 0.2 RFLP DdeI Gasparini et al. (1991b) 3659delC Exon 19 3 0.6 SSCP Kerem et al. (1990) W1282X Exon 20 2 0.4 RFLP MnlI Vidaud et al. (1990) N1303K Exon 21 7 1.4 Allele-specificPCR Osborne et al. (1991) Unpublished 13 2.6 Unknown 66 13.2 Total 500 a All non-AF508 mutations were subsequently verified by direct genomic sequencing of the respective PCR product b F508C was first detected on an N chromosome (Kobayashi et al. 1990) and hence is suspected to represent a benign missense mutation Table 5. Login to comment
100 The four major haplotypes are indicated in bold type KM.19 D9 J44 GATT TUB9 M470V T854T TUB18 TUB20 Mutation 1 l 2 1 2 2 1 1 2 2 2 1 1 2 1 2 2 1 2 2 1 1 2 1 2 1 2 2 2 1 2 1 1 1 1 2 2 2 1 2 1 1 1 2 i 1 2 1 2 1 1 2 1 2 R347P, F508C, R1162X, 3659delC 1717-1 G--~A, G551D, R553X (n = 2), 2789 + 5 G---~A,W1282X R117H R334W, A455E, G542X, N1303K, AF508 (96%) ~F508 (4%) R553X (n = 10) a Haplotypes were assigned from the individual pedigrees mutation was located on a single KM. 19-D9-J44-GATT-TUB9-M470V-T854T haplotype. Login to comment
106 Several more frequent disease-causing sequence variations, such as R334W, A455E, G542X, and N1303K, reside on the typical AF508 haplotype. Login to comment

PMID: 1370365 [PubMed] Shoshani T et al: "Association of a nonsense mutation (W1282X), the most common mutation in the Ashkenazi Jewish cystic fibrosis patients in Israel, with presentation of severe disease."

No. Sentence Comment

10 Together with the AF508 (23% in this group), G542X, N1303K, and 1717-1G-*A mutations, the identification of 92% of cystic fibrosis chromosomes of Ashkenazi origin becomes possible. Login to comment
29 In a previous study of a small group of Israeli CF patients, four additional rare mutations (1717- 1G--A, G542X, S5491, and S549R) were found (Kerem et al. 1990b). Login to comment
56 The G542X, S5491, S549R, N1303K, and 1717- 1G--A mutations were detected by PCR and subse- quent allele specific oligo nucleotide hybridization as described elsewhere (Kerem et al. 1990b; Osborne et al. 1991). Login to comment
72 patients screened, 16 (15 Ashkenazi and 1 Arab) were homozygous for W1282X, 22 (20 Ashkenazi, 1 Sephardic, and 1 from an unclassified origin) were heterozygous for W1282X and AF508, 2 (Ashkenazi) patients were heterozygous for W1282X and G542X, and 11 patients were heterozygous for W1282X and an as yet unidentified mutation. Login to comment
77 Hence, together with AF508, G542X, N1303K, and 1717-1G--A, 92% of the CF chromosomes could be identified in Jewish patients of Ashkenazi origin. Login to comment
79 Therefore, for assessment of the severity of the W1282X mutation, it would have been appropriate to compare patients homozygous for the W1282X mutation with patients homozygous for the AF508 mutation and with patients heterozygous for Table I Analysis of Mutation Frequencies Identified in 97 Israeli CF Patients JEWISH PATIENTS ARAB Ashkenazim Sepharadim Unclassified PATIENTS No. of chromosomes sampled.... 95 51 8 40 W1282X (no. [%]) .................. 57 (60) 1 (2) 3 (38) 2 (5) AF508 (no. [%])..................... 21 (23) 18 (35) 2 (25) 10 (25) G542X (no. [%]).................... 4 (4) 2 (4)0 2 (5) N1303K (no. [%]) .................. 4 (4) 0 0 2 (5) 1717-1G-A (no. [%]) ............. 1 (1) 0 0 1 (3) S5491 (no. [%])...................... 0 0 0 2 (5) S549R (no. [%])..................... 0 1 (2) 2 (25) 2 (5) Total mutations (no. [%])...... 87 (92) 22 (43) 7 (88) 21 (53) both mutations. Login to comment
91 Two patients were heterozygous for two different termination mutations, W1282X and G542X. Login to comment

PMID: 1370807 [PubMed] Plieth J et al: "Single-strand conformation polymorphism (SSCP) analysis of exon 11 of the CFTR gene reliably detects more than one third of non-delta F508 mutations in German cystic fibrosis patients."

No. Sentence Comment

16 Indeed, two mutational "hot spots" have been identified, one of which, located within the 95-bp exon 11 (Cutting et al. 1990), contains a number of mutations including G551D, R553X, 1717-1G--~A (splice-site mutation), G542X and $549R. Login to comment
18 A combination of restriction enzyme digestion (for R553X and G551D) and/or allele-specific oligonucleotide hybridization (for G542X and 1717-1G--~A) is now routinely performed to detect known mutations in polymerase chain reaction (PCR) amplified DNA samples. Login to comment
47 Nearly half of these chromosomes contained R553X but the remainder contained G551D, G542X, 1717-1G--~A and $549R. Login to comment
54 Distribution of non-AF508mutations in 59 German patients Non-AF508mutations Chromo- % (n = 72) somes In exon 11 R553X 12 16.6 G542X 5 6.9 G551D 4 5.5 1717-1G---~A(5' splicesite) 3 4.1 $549R 2 2.8 Others 9 12.5 Undetermined 37 51.4 Fig. la-c. Login to comment
59 W Wildtype control, lane 1 $549R/ $549R, lane 2 G551D, lane 3 1717-1G---~A,lane 4 G542X, lane 5 R553X, lane 6 R553X/R553X, lane 7 G542X/1717-1 SSCP analysis was then performed upon the same set of DNA samples to test the mutation-detection efficiency of this method. Login to comment
63 Mutation-specific bands can thus be noted in patient samples bearing the heterozygous mutations G551D, 1717-1G--+A, G542X and R553X. Login to comment
64 Furthermore, individuals homozygous for the mutations $549R and R553X, and compound heterozygous for G542X/1717-1G-->A were readily distinguishable from patients heterozygous for these mutations because of the absence of wildtype bands in the former (Fig. 1). Login to comment
72 SSCP analysis performed on DNAs of six individuals with the following genotypes (nucleotide change in brackets): lanes W wildtype/wildtype, lanes 1 G551D/wildtype (G-*A), lanes 2 1717- 1G-~A/wildtype (G--~A), lanes 3 G542X/wildtype (G--~T), lanes 4 R553X/wildtype (C----~T),lanes 5 S549R/S549R(T-*G). Login to comment
75 In the case of the mutations G551D, G542X and $549, the coding strands of mutant and wild-type allele are separated, whereas the non-coding strands co-migrate. Login to comment

PMID: 1375961 [PubMed] Super M et al: "The gene defect in cystic fibrosis and clinical applications of the knowledge."

No. Sentence Comment

27 One of the stop mutations, G542X with the 49% ofpatients demonstrating homozygosity occurring in compound heterozygote form with AF5N for AF5N. Login to comment
45 83 a stop codon or G542X or W1282X), insertions at Al? Login to comment
51 Factors outside the gene seem to be associated with differing 1008 818 81.15% levels ofseverity and, ofcourse, one must remember G551D 215* 34 2.986 differing environmental influences such as time of G542X 203* 11 1.02% diagnosis, vigour oftreatment and social class which R560T 113* 6 1.00% may play a role. Login to comment

PMID: 1709778 [PubMed] Devoto M et al: "Screening for non-delta F508 mutations in five exons of the cystic fibrosis transmembrane conductance regulator (CFTR) gene in Italy."

No. Sentence Comment

27 In addition, a variable number of the same chromosomes had been previously tested, with other methods (ASO and/or digestion with restriction enzymes as described below), for the presence of other known mutations-in particular, 91 for G542X (Kerem et al. 1990), 56 for W1282X (Vidaud et al. 1990), and 96 for R553X (Cutting et al. 1990b). Login to comment
28 For DGGE screening, a first group of 61 chromosomes originated from a corresponding number of com- poundheterozygous patients who carried an identified mutation (57 deltaF508, two W1282X, one G542X, andone R553X) on one oftheirtwo CFchromosomes. Login to comment
32 Screening for CFTR gene mutations already published or known through the CF Genetic Analysis Consortium was carried out on random samples of CF chromosomes by PCR amplification ofspecific exons that was followed by digestion with restriction enzymes indicated in table 2 which recognize mutation sites inside the amplification product and, in one case (G542X), by hybridization with the allele-specific oligonucleotides (ASO). Login to comment
34 Table 2 Results of Screening for Known Mutations Total No. of No. of Chromosomes Chromosomes Overall Mutation Exon Method With the Mutationa Screenedb Frequencyc Reference R334W......... 7 MspI 2 198 1.01 X. Estivill, personal communication R347P......... 7 HhaI or NcoI 4 183 2.19 Dean et al. 1990 G542X ......... 11 ASO (DGGE) 15 (4) 176 (18) 9.79 Kerem et al. 1990 S549N......... 11 DdeI 1 159 .63 Cutting et al. 1990b G5S1D ......... 11 HincII or MboI 0 186 Cutting et al. 1990b R553X ......... 11 HincIl (DGGE) 5 (1) 186 (13) 3.02 Cutting et al. 1990b 1717-1G-A .... 11 (DGGE) (12) (109) 11.01 Guillermit et al. 1990 S1255X ......... 20 HindIII 0 130 Cutting et al. 1990a W1282X......... 20 MnlI (DGGE) 7 (3) 124 (53) 5.65 Vidaud et al. 1990 a Numbers in parentheses are number of mutations found through DGGE. Login to comment
57 In this way, a total of four G542X, one R553X, and 12 1717-1G--oA in exon 11 and of three W1282X in exon 20 could be identified (see table 2). Login to comment

PMID: 10762539 [PubMed] Mickle JE et al: "Effects of cystic fibrosis and congenital bilateral absence of the vas deferens-associated mutations on cystic fibrosis transmembrane conductance regulator-mediated regulation of separate channels."

No. Sentence Comment

47 DNA was assayed for 16 common CFTR mutations (R117H, 62111GrT, R334W, R349P, A455E, DI507, DF508, 1717-1GrA, G542X, S549N, G551D, R553X, R560T, 3849110 Kb CrT, W1282X, and N1303K), by reverse dot-blot hybridization (Mickle et al. 1998). Login to comment

PMID: 10793926 [PubMed] Vodoff MV et al: "[Acute recurrent pancreatitis and heterozygous mutation of the cystic fibrosis gene: a case report]."

No. Sentence Comment

33 La recherche des principales autres mutations (d1.507, Wl282X, G542X, 1717-lG-A. Login to comment

PMID: 10801389 [PubMed] Gomez Lira M et al: "High frequency of cystic fibrosis transmembrane regulator mutation L997F in patients with recurrent idiopathic pancreatitis and in newborns with hypertrypsinemia."

No. Sentence Comment

12 Among these rare mutations, L997F was identified in 4 (12.5%) of 32 patients with idiopathic pancreatitis (genotypes L997F/DF508, L997F/5T, and twice L997F/no mutation identified, respectively), and in 4 (8%) of 49 newborns with hypertrypsinemia (genotypes L997F/G542X, L997F/R553X, L997F/DF508, and L997F-F1052V phase unknown, respectively). Login to comment
17 This classification implies that the L997F heterozygotes compounded with common CF mutations found among the patients with idiopathic pancreatitis (DF508) and that the hypertrypsinemic newborns with negative sweat chloride (DF508, G542X, and R553X) should be diagnosed as affected by an atypical form of CF; a close follow-up is indicated for these patients. Login to comment

PMID: 10876009 [PubMed] Castaldo G et al: "Prenatal diagnosis of cystic fibrosis: a case of twin pregnancy diagnosis and a review of 5 years' experience."

No. Sentence Comment

65 Mutation and polymorphism analyses of the CFTR gene A panel of 13 CF mutations (i.e. DF508, N1303K, G542X, 1148T, R553X, W1282X, 1717-1 G . Login to comment

PMID: 10931414 [PubMed] Massie RJ et al: "Pancreatic function and extended mutation analysis in DeltaF508 heterozygous infants with an elevated immunoreactive trypsinogen but normal sweat electrolyte levels."

No. Sentence Comment

26 Measurement of Cl levels was done by colorimetry, and measurement of sodium levels was done by flame cytometry.16 Gene Mutation Analysis Blood was taken and DNA extract- ed17 for an extended cystic fibrosis transmembrane conductance regulator protein gene mutation analysis as described previously.18 The following mutations were included: ࢞F508, ࢞I507, R117H, G551D, A455E, G542X, N1303K, W1282X, 1717-1G࢐A, R560T, R347P, R334W, R553X, R1162X, S549N, 3849+10C࢐T, and 621+1G࢐T. Login to comment

PMID: 10993719 [PubMed] Wang J et al: "A novel CFTR frame-shift mutation, 935delA, in two Hispanic cystic fibrosis patients."

No. Sentence Comment

91 The two most common types of truncated CFTR proteins were present in these patients; one was missing the portion beyond the first ATP binding domain (for example, the R553X and the G542X) and the other was truncated beyond the second ATP binding domain (for example the W1282X). Login to comment

PMID: 11104661 [PubMed] Mateu E et al: "Worldwide genetic analysis of the CFTR region."

No. Sentence Comment

23 Only four other mutations (G542X, N1303K, G551D, and W1282X) have overall allele frequencies among CF chromosomes 11% (Estivill et al. 1997). Login to comment
122 Haplotype backgrounds for the major CF mutations are: 1-2, for DF508, G542X, and N1303K mutations, and 2-1, for G551D and W1282X mutations (Morral et al. 1996). Login to comment

PMID: 11113843 [PubMed] Callen A et al: "A simplified cyclic adenosine monophosphate-mediated sweat rate test for quantitative measure of cystic fibrosis transmembrane regulator (CFTR) function."

No. Sentence Comment

60 Among the females with CF, 7 had homozygous ࢞F508 genotypes; 2 had ࢞F508/unknown genotypes; and one each had a genotype of ࢞F508/G551D, ࢞F508/R117H, ࢞F508/3489 + 10 kb C to T, ࢞F508/G542X, ࢞F508/R347P, and R117H/unknown. Login to comment
61 Of the males with CF, 11 had homozygous ࢞F508 genotypes, one had a ࢞F508/G542X genotype, and 2 had unknown genotypes. Login to comment

PMID: 11232455 [PubMed] Federici S et al: "[CFTR gene analyis in 207 patients with cystic fibrosis in southwest France: high frequency of N1303K and 1811+1.6bA>G mutations]."

No. Sentence Comment

47 Le criblage des mutations a &#e9;t&#e9; effectu&#e9; par &#e9;tapes avec des m&#e9;thodes incluant toutes une amplification pr&#e9;alable par PCR (polymerase chain reaction) suivie d`une d&#e9;tection des h&#e9;t&#e9;roduplexes pour la mutation ࢞F508 ou d`une analyse par hybridation en dot blot inverse avec la trousse INNO-Lipa CF8 (Innogenetics, Zwiljnaarde, Belgique) pour les mutations ࢞F508, G542X, N1303K, G551D, R553X, W1282X, 1717G>A et ࢞I507. Login to comment
58 Cinq autres mutations ont une fr&#e9;quence sup&#e9;rieure &#e0; 1 % : G542X (5,3 %), N1303K (3,9 %), 1811+1,6kbA>G (3,4 %), 1717-1G>A (1,4 %) et R334W (1,2 %). Login to comment
61 Origine g&#e9;ographique (% all&#e8;les) Sud-Ouest (nos donn&#e9;es) France [6] Italie/Espagne [12, 16] a b c d/e (n = 414) (n = 114) (n = 7 190) (n = 3 492/1 944) ࢞F508 64,2 57 67,21 51/50,6 G542X 5,3 5,3 2,89 5/8 N1303K 3,9 7,9 2,05 5/ ? Login to comment
76 La mutation G542X, d&#e9;j&#e0; connue pour avoir une fr&#e9;quence &#e9;lev&#e9;e dans le sud de l`Europe et les pays m&#e9;diterran&#e9;ens [2], repr&#e9;sente 5,3 % des chromosomes CF de notre s&#e9;rie alors que la fr&#e9;quence nationale est de 2,9 %. Login to comment
77 L`analyse des chromosomes CF originaires du seul Sud-Ouest depuis au moins deux g&#e9;n&#e9;rations montre une fr&#e9;quence identique de 5,3 %, sugg&#e9;rant que l`augmentation de fr&#e9;quence de G542X par rapport &#e0; la moyenne nationale n`est pas li&#e9;e &#e0; un effet fondateur. Login to comment
78 Pour ces quatre mutations, ࢞F508, N1303K, 1811+1,6kbA>G et G542X, les deux distributions (population fran&#e7;aise et population du Sud-Ouest) sont significativement diff&#e9;rentes au seuil de 5 % (p < 0,05). Login to comment
133 Ces r&#e9;sultats sont en accord avec d`autres donn&#e9;es sugg&#e9;rant que la mutation N1303K fait partie avec ࢞F508 et G542X des trois mutations apparues il y a plus de 30 000 ans [9, 10]. Login to comment
143 Enfin, si les quatre mutations les plus fr&#e9;quentes du Sud-Ouest (࢞F508, G542X, N1303K et 1811+1,6kbA>G) ne sont pas retrouv&#e9;es, le risque r&#e9;siduel n`est que de 1/130, montrant l`int&#e9;r&#ea;t d`un d&#e9;pistage cibl&#e9; des mutations, avec en particulier la recherche de la mutation 1811+1,6kbA>G chez les patients originaires de cette r&#e9;gion. Login to comment

PMID: 11530206 [PubMed] Glick MC et al: "Activity of fucosyltransferases and altered glycosylation in cystic fibrosis airway epithelial cells."

No. Sentence Comment

103 Some mutations (e.g., G542X) produce a truncated transcript and no protein, while other mutations (e.g., R117H) produce a protein that has impaired conduction properties. Login to comment

PMID: 11755047 [PubMed] Gomez-Llorente MA et al: "Analysis of 31 CFTR mutations in 55 families from the South of Spain."

No. Sentence Comment

5 Seven more mutations (G542X, R334W, R1162X, 2789 + 5G ! Login to comment
29 A I.10 R117H E.4 G542X E.11 Y122X E.4 G551D E.11 711 + 1G ! Login to comment
48 Interestingly, this frequency is Table 2 CFTR mutations identified in 55 families (350 chromosomes) from the south of Spain Mutations Frequency (%) Location Exon/Intron DF508 43.5 E.10 G542X 11.4 E.11 R334W 5.0 E.7 R1162X 3.0 E.19 2789 + 5G ! Login to comment
53 They were G542X, R334W, R1162X, 2789 + 5G ! Login to comment
55 G542X was the second most common mutation found in the present study, at a similar frequency to that reported for the rest of the Spanish population [2]. Login to comment
56 G542X and DF508 together represented 80% of all mutations detected in the present study. Login to comment

PMID: 11755605 [PubMed] Hamilton JW et al: "Gentamicin in pharmacogenetic approach to treatment of cystic fibrosis."

No. Sentence Comment

75 THE LANCET ߦ Vol 358 ߦ December 15, 2001 2015 COMMENTARY Effect of CFTR mutations in epithelial cells Lumen Cytoplasm Nucleus Class 4 (eg, R117H) Class 3 (eg, G551D) Class 2 (eg, èc;F508) Class 1 (eg, G542X) Class 5 (eg, A455E) Apical surface Basolateral surface ATP CFTR MSD NBD NBD RD Golgi ER CFTR gene Collectively, the five mutant classes result in little or no functional CFTR expression at the apical surface of epithelial cells, but through different mechanisms. Login to comment
76 Class 1 mutations are nonsense, frameshift, and splice-junction mutations (such as the nonsense mutation G542X) that cause little or no translation of CFTR mRNA to protein. Login to comment

PMID: 12531063 [PubMed] Lim M et al: "Therapeutic strategies to correct malfunction of CFTR."

No. Sentence Comment

60 Type Genotype Phenotypea Defect Potential therapeutics Class I G542X PI No CFTR synthesis, aminoglycosides 621 + 1 G ࢐T No cell surface Cl- 3905insT transport W1282X R553X 1717-1 G ࢐ A Class II F508b PI Defective CFTR 4-PBA, flavonoids, N1303K trafficking and chemical chaperones, P574Hb processing xanthines A455Eb Class III G551D PI Defective channel flavonoids, milrinone G551S regulation, reduced or absent Cl-transport Class IV R117H PS Reduced Cl-transport 4-PBA, xanthines, R334W flavonoids G314E R347P F508b P574Hb ClassV 3849 + 10 kb C࢐T PS Reduced number of flavonoids, milrinone, 2789 + 5 G ࢐A normal CFTR proteins 4-PBA 3272 - 26 A ࢐ G Reduced Cl-transport A455Eb 3120+1 G࢐A 1811 + 1.6 kb A ࢐ G a PI indicates pancreatic insufficiency; PS indicates pancreatic sufficiency. Login to comment

PMID: 12531100 [PubMed] McAuley DF et al: "Cystic fibrosis: basic science."

No. Sentence Comment

23 After the ࢞F508 mutation, substitution mutations such as G542X (2.4%) and G551D (1.8%) are the next most common mutations.2 Patients who are homozygous for the ࢞F508 gene generally have lung disease, pancreatic insufficiency, obstructive azoospermia, and universally have elevated sweat chlorides. Login to comment

PMID: 12706377 [PubMed] Streit C et al: "CFTR gene: molecular analysis in patients from South Brazil."

No. Sentence Comment

2 The present work aimed (1) to detect sequence alterations in the nucleotide binding regions and at the membrane spanning domain of the CFTR gene and (2) to detect the following frequent mutations R347P, R347H, R334W, and Q359K (located in exon 7), DF508 (located in exon 10), G542X, G551D, R553X, and S549N (located in exon 11), W1282X (located in exon 20), and N1303K (located in exon 21). Login to comment
7 Frequencies of G542X, R334W, R553X, and W1282X mutations in our population were 3.25, 1.3, 0.65, and 0.65%, respectively. Login to comment
34 The main aims of the present work were (1) to establish the frequency of the DF508 mutation this studied population, (2) to identify alterations in the nucleotide sequence of the exons 3, 5, and 7 which are located in the first membrane spanning domain (MSD1); of exons 9, 10, 11, and 12 which are located in the first nucleotide binding domain (NBD1); of exons 19, 20, 21, and 22 which are located in the second nucleotide binding domain (NBD2) of the CFTR gene, and finally (3) to identify some specific frequent mutations (R347P, R347H, R334W, Q359K, G542X, G551D, R553X, S54 9N, W1282X, and N1303K) in these patients. Login to comment
59 Restriction fragment length polymorphism Mutations R347P, R347H, R334W, Q359K (located in exon 7), G542X, S549N, G551D, R553X mutations (exon 11), W1282X (exon 20), and N1303K (exon 21) were identified by restriction fragment length polymorphism (RFLP) protocol, using specific restriction endonucleases. Login to comment
61 RFLP using BstNI was used to detect the G542X mutation, because this alteration destroys the recognition site for this enzyme. Login to comment
66 Positive controls were used along with samples to be tested for G542X, G551D, and R553X mutations during the experiments. Login to comment
76 Screening of four additional mutations (G542X, R553X, R334W, and W1282X) together with DF508 Table 2 Mutations detected in 77 CF patients from south region of Brazil Mutation Location Number of alleles Frequency (%) R334W Exon 7 2 1.3 R347P Exon 7 0 0 R347H Exon 7 0 0 Q359K Exon 7 0 0 DF508 Exon 10 75 48.7 S549N Exon 11 0 0 G542X Exon 11 5 3.2 G551D Exon 11 0 0 R553X Exon 11 1 0.7 W1282X Exon 20 1 0.7 N1303K Exon 21 0 0 ? Login to comment
83 Three patients (3.9%) carry the G542X mutation in only one allele and an unknown mutation in the other (G542X/?). Login to comment
84 Two patients (2.6%) were a compound heterozygote for the DF508 and the G542X mutation (DF508/G542X). Login to comment
101 On the other hand, estimated frequencies of G542X, N1303K, and W1282X mutations among alleles of affected patients in our population were 8.35, 1.6, and 0.8%, respectively [26]. Login to comment
102 Frequencies of DF508, G542X, G551D, and R553X mutations in our study were similar to that established for South Europe [27]. Login to comment
111 The G542X and R553X mutations showed frequencies similar to those observed in south European countries (http://www.genet.sickids.on.ca) [25]. Login to comment
113 DNA screening for four common CF mutations (G542X, R553X, R334W, and W1282X), together with DF508, enabled the detection of 84 out of the 154 CF alleles in our sample, that represents 54.5% of studied alleles. Login to comment

PMID: 12767731 [PubMed] McKone EF et al: "Effect of genotype on phenotype and mortality in cystic fibrosis: a retrospective cohort study."

No. Sentence Comment

47 ARTICLES 1672 THE LANCET ߦ Vol 361 ߦ May 17, 2003 ߦ www.thelancet.com Panel 1: Frequencies of CFTR mutations* CFTR Allele CFTR Allele mutation frequency (%) mutation frequency èc;F508 69&#b7;4% 2789+5G࢐A 0&#b7;3% Unknown 15&#b7;7% R1162X 0&#b7;3% G542X 2&#b7;3% G85E 0&#b7;3% G551D 2&#b7;2% R560T 0&#b7;2% èc;I507 1&#b7;6% R334W 0&#b7;2% W1282X 1&#b7;4% 3659èc;C 0&#b7;2% N1303K 1&#b7;2% A455E 0&#b7;1% R553X 0&#b7;9% 711+1G࢐T 0&#b7;1% 621+1G࢐T 0&#b7;8% 1898+1G࢐A 0&#b7;1% R117H 0&#b7;7% 2184èc;A 0&#b7;1% 3849+10 kbC࢐T 0&#b7;7% S549N 0&#b7;1% 1717-IG࢐A 0&#b7;5% 1078èc;T 0&#b7;03% R347P 0&#b7;3% *n=17 853. Login to comment
48 Panel 2: Functional classification of CFTR alleles Class Functional effect of Allele mutation I Defective protein G542X, R553X, W1282X, production R1162X, 621-1G࢐T, 1717-1G࢐A, 1078èc;T, 3659èc;C II Defective protein èc;F508, èc;I507, N1303K, processing S549N III Defective protein G551D, R560T regulation IV Defective protein R117H, R334W, G85E, conductance R347P V Reduced amounts of 3849+10KbC࢐T, functioning CFTR protein 2789+5G࢐A, A455E Unknown 711+1G࢐T, 2184DA, 1898+1G࢐A Total cohort Genotyped cohort (n=28 455) (n=17 853) Person-years at risk 152 011 96 870 Sex (% male) 53% 52% Race (% white) 96% 96% Age (years) 11&#b7;9 (11&#b7;1) 10&#b7;9 (11&#b7;2) Age at diagnosis (years) 3&#b7;5 (7&#b7;1) 3&#b7;6 (7&#b7;5) Sweat test (mmol/L) 101 (19) 100 (20) FEV1 (L) 1&#b7;72 (0&#b7;91) 1&#b7;80 (0&#b7;92) FEV1 (% predicted) 69 (29) 72 (28) FVC (L) 2&#b7;41 (1&#b7;18) 2&#b7;50 (1&#b7;21) FVC (% predicted) 81% (28) 84% (24) Height (cm) 121% (41) 117% (41) Weight (kg) 30&#b7;0 (21&#b7;3) 28&#b7;6 (21&#b7;8) Pancreatic insufficiency (%) 90% 87% P aeruginosa colonisation (%) 49% 46% Number of deaths (%) 3548 (12%) 1547 (9%) Data are mean (SD) unless otherwise stated. Login to comment
61 Standardised mortality rates did not differ between patients homozygous for èc;F508 and the èc;F508 heterozygotes with the G551D, G542X, N1303K, W1282X, R553X, 621+1G࢐T, and 1717-1G࢐A alleles. Login to comment
64 ARTICLES THE LANCET ߦ Vol 361 ߦ May 17, 2003 ߦ www.thelancet.com 1673 Patients Person-years Deaths Crude Standardised p valueߤ (n) mortality mortality rate* rate* (95% CI) Genotype èc;F508/èc;F508 9144 51 164 1019 19&#b7;9 21&#b7;8 (20&#b7;5-23&#b7;1) &#b7;&#b7; èc;F508/G551D 593 3247 60 18&#b7;5 16&#b7;6 (12&#b7;4-20&#b7;8) 0&#b7;019 èc;F508/G542X 574 3239 57 17&#b7;6 18&#b7;9 (14&#b7;1-23&#b7;7) 0&#b7;257 èc;F508/N1303K 303 1778 30 16&#b7;9 16&#b7;2 (10&#b7;3-22&#b7;0) 0&#b7;063 èc;F508/W1282X 278 1618 36 22&#b7;3 21&#b7;6 (14&#b7;5-28&#b7;6) 0&#b7;950 èc;F508/R553X 230 1335 21 15&#b7;7 25&#b7;0 (11&#b7;8-38&#b7;1) 0&#b7;641 èc;F508/621-1G࢐T 213 1268 27 21&#b7;0 19&#b7;2 (11&#b7;6-26&#b7;7) 0&#b7;503 èc;F508/1717-1G࢐A 120 619 13 21&#b7;0 20&#b7;6 (9&#b7;9-31&#b7;4) 0&#b7;833 èc;F508/èc;I507 318 897 8 8&#b7;9 8&#b7;0 (2&#b7;7-13&#b7;3) <0&#b7;0001 èc;F508/R117H 177 844 8 9&#b7;5 4&#b7;7 (0&#b7;8-8&#b7;5) <0&#b7;0001 èc;F508/3849+10 kbC࢐T 151 700 13 18&#b7;6 11&#b7;9 (5&#b7;0-18&#b7;9) 0&#b7;006 èc;F508/2789+5G࢐A 86 444 4 9&#b7;0 4&#b7;4 (0&#b7;0-8&#b7;9) <0&#b7;0001 èc;F508/other 3434 19 170 372 19&#b7;4 17&#b7;6 (15&#b7;8-19&#b7;4) 0&#b7;0002 Other/other 2232 10 494 233 22&#b7;2 20&#b7;5 (17&#b7;9-23&#b7;1) 0&#b7;380 *Per 1000 person-years. Login to comment
67 Table 2: Standardised and crude mortality rates (including organ transplantation) by genotype Genotype No of Age at Sweat FEV1 FVC Height Weight Pancreatic P&#b7; aeruginosa Subjects Diagnosis Chloride (% predicted)* (% predicted)* (cms)* (kg)* Insufficiency Colonization (yrs) (mmol) (%)ߤ (%)ߤ èc;F508/èc;F508 6 213 2&#b7;5 &#b1; 0&#b7;1 104 &#b1; 0&#b7;2 77 &#b1; 0&#b7;3 89 &#b1; 0&#b7;3 141 &#b1; 0&#b7;2 37&#b7;0 &#b1; 0&#b7;1 92 (91-92) 60 (59-61) èc;F508/G551D 411 3&#b7;7 &#b1; 0&#b7;3ߥ 108 &#b1; 0&#b7;9ߥ 76 &#b1; 1&#b7;2 89 &#b1; 1&#b7;2 142 &#b1; 0&#b7;7&#a7; 38&#b7;2 &#b1; 0&#b7;6&#a7; 92 (89-94) 59 (54-64) èc;F508/G542X 389 1&#b7;9 &#b1; 0&#b7;2 104 &#b1; 0&#b7;8 79 &#b1; 1&#b7;2 91 &#b1; 1&#b7;2 141 &#b1; 0&#b7;7 37&#b7;3 &#b1; 0&#b7;5 93 (89-95) 57 (52-62) èc;F508/N1303K 213 2&#b7;1 &#b1; 0&#b7;3 106 &#b1; 1&#b7;2 80 &#b1; 1&#b7;8 91 &#b1; 1&#b7;7 141 &#b1; 1&#b7;0 37&#b7;1 &#b1; 0&#b7;6 92 (87-95) 61 (55--68) èc;F508/W1282X 205 1&#b7;6 &#b1; 0&#b7;2 103 &#b1; 1&#b7;2 80 &#b1; 1&#b7;7 92 &#b1; 1&#b7;6 141 &#b1; 0&#b7;9 37&#b7;4 &#b1; 0&#b7;7 94 (90-97) 59 (52-65) èc;F508/R553X 164 2&#b7;5 &#b1; 0&#b7;4 106 &#b1; 1&#b7;4 76 &#b1; 1&#b7;8 89 &#b1; 1&#b7;6 139 &#b1; 0&#b7;9 35&#b7;4 &#b1; 0&#b7;7&#a7; 90 (85-94) 60 (53-67) èc;F508/621-1G 162 2&#b7;5 &#b1; 0&#b7;4 107 &#b1; 1&#b7;3 78 &#b1; 1&#b7;8 89 &#b1; 1&#b7;5 143 &#b1; 1&#b7;0&#a7; 38&#b7;8 &#b1; 0&#b7;8&#a7; 87 (80-91)&#a7; 57 (49-64) èc;F508/èc;I507 149 8&#b7;5 &#b1; 1&#b7;1ߥ 95 &#b1; 1&#b7;9ߥ 86 &#b1; 2&#b7;1ߥ 93 &#b1; 1&#b7;8&#a7; 137 &#b1; 1&#b7;4&#a7; 37&#b7;4 &#b1; 1&#b7;25 84 (78-89)ߥ 39 (31-48)ߥ èc;F508/R117H 123 13&#b7;7 &#b1; 1&#b7;2ߥ 80 &#b1; 1&#b7;9ߥ 91 &#b1; 2&#b7;1ߥ 97 &#b1; 1&#b7;7ߥ 143 &#b1; 1&#b7;8 42&#b7;9 &#b1; 1&#b7;7ߥ 65 (55-73)ߥ 22 (16-29)ߥ èc;F508/3849+10 kB 114 11&#b7;3 &#b1; 0&#b7;9ߥ 72 &#b1; 2&#b7;5ߥ 77 &#b1; 2&#b7;1 87 &#b1; 1&#b7;9 144 &#b1; 1&#b7;4&#a7; 41&#b7;2 &#b1; 1&#b7;2ߥ 66 (57-74)ߥ 69 (59-77) èc;F508/2789+5G 63 13&#b7;4 &#b1; 1&#b7;6ߥ 102 &#b1; 2&#b7;1 88 &#b1; 2&#b7;8ߥ 97 &#b1; 2&#b7;3ߥ 140 &#b1; 2&#b7;5 41&#b7;8 &#b1; 2&#b7;2&#a7; 71 (59-81)ߥ 32 (22-44)ߥ èc;F508/1717-1G 74 1&#b7;3 &#b1; 0&#b7;3 103 &#b1; 2&#b7;0 75 &#b1; 2&#b7;7 86 &#b1; 2&#b7;4 139 &#b1; 1&#b7;5 35&#b7;7 &#b1; 0&#b7;9 96 (88-99) 59 (48-69) èc;F508/R560T 46 1&#b7;7 &#b1; 0&#b7;5 104 &#b1; 2&#b7;0 84 &#b1; 3&#b7;3ߥ 96&#b1; 2&#b7;8&#a7; 142 &#b1; 1&#b7;9 38&#b7;4 &#b1; 1&#b7;4 91 (79-97) 63 (48-75) èc;F508/R347P 44 5&#b7;9 &#b1; 1&#b7;1&#a7; 105 &#b1; 2&#b7;6 76 &#b1; 3&#b7;0 90 &#b1; 2&#b7;9 142 &#b1; 2&#b7;4 38&#b7;7 &#b1; 1&#b7;8 67 (52-79)ߥ 53 (38-68) èc;F508/G85E 43 9&#b7;2 &#b1; 1&#b7;8ߥ 99 &#b1; 2&#b7;3&#a7; 76 &#b1; 2&#b7;5 90 &#b1; 2&#b7;5 142 &#b1; 2&#b7;9 38&#b7;3 &#b1; 2&#b7;2 88 (75-95) 52 (35-68) èc;F508/3659DC 40 1&#b7;1 &#b1; 0&#b7;4 105 &#b1; 2&#b7;1 76 &#b1; 3&#b7;9 88 &#b1; 4&#b7;1 139 &#b1; 1&#b7;9 36&#b7;6 &#b1; 1&#b7;2 92 (77-97) 55 (39-69) èc;F508/A455E 29 14&#b7;3 &#b1; 2&#b7;0ߥ 89 &#b1; 3&#b7;1ߥ 98 &#b1; 4&#b7;0ߥ 104 &#b1; 3&#b7;4ߥ 138 &#b1; 3&#b7;4 42&#b7;1 &#b1; 2&#b7;5&#a7; 60 (41--76)ߥ 17 (8-32)ߥ èc;F508/R334W 28 13&#b7;2 &#b1; 3&#b7;0ߥ 104 &#b1; 3&#b7;2 86 &#b1; 3&#b7;4&#a7; 94 &#b1; 3&#b7;3 138 &#b1; 3&#b7;2 42&#b7;3 &#b1; 3&#b7;5 67 (46-82)ߥ 51 (32--70) èc;F508/R1162X 26 1&#b7;9 &#b1; 1&#b7;1 101 &#b1; 2&#b7;3 77 &#b1; 4&#b7;2 92 &#b1; 4&#b7;6 138 &#b1; 1&#b7;8 36&#b7;5 &#b1; 1&#b7;4 92 (75-98) 65 (47-80) èc;F508/1898+1G 20 1&#b7;2 &#b1; 0&#b7;3 99 &#b1; 2&#b7;8 83 &#b1; 4&#b7;1 94 &#b1; 4&#b7;4 138 &#b1; 3&#b7;3 35&#b7;1 &#b1; 2&#b7;1 85 (61--95) 63 (39-82) èc;F508/2184DA 20 2&#b7;3 &#b1; 0&#b7;9 106 &#b1; 5&#b7;3 82 &#b1; 4&#b7;3 92 &#b1; 4&#b7;4 141 &#b1; 3&#b7;0 36&#b7;5 &#b1; 1&#b7;5 94 (69-99) 60 (38-79) èc;F508/711+1G 17 1&#b7;3 &#b1; 0&#b7;5 108 &#b1; 4&#b7;6 83 &#b1; 4&#b7;2 94 &#b1; 4&#b7;4 137 &#b1; 3&#b7;4 36&#b7;7 &#b1; 2&#b7;9 100 73 (50-88) èc;F508/S549N 11 6&#b7;4 &#b1; 1&#b7;9&#a7; 109 &#b1; 5&#b7;7 67 &#b1; 6&#b7;1 77 &#b1; 7&#b7;2 140 &#b1; 3&#b7;2 36&#b7;7 &#b1; 2&#b7;6 92 (62-99) 71 (40--90) èc;F508/Other 2 262 5&#b7;8 &#b1; 0&#b7;2ߥ 99 &#b1; 0&#b7;4ߥ 80 &#b1; 0&#b7;5ߥ 91 &#b1; 0&#b7;5ߥ 141 &#b1; 0&#b7;3 38&#b7;1 &#b1; 0&#b7;3ߥ 86 (84-87)ߥ 50 (48-52)ߥ Other/Other 1 551 7&#b7;5 &#b1; 0&#b7;3ߥ 93 &#b1; 0&#b7;6ߥ 82 &#b1; 0&#b7;6ߥ 90 &#b1; 0&#b7;6&#a7; 141 &#b1; 0&#b7;4 38&#b7;3 &#b1; 0&#b7;3ߥ 81 (80-84)ߥ 40 (38-43)ߥ Data are mean (SE) unless otherwise indicated. Login to comment

PMID: 1372093 [PubMed] Cuppens H et al: "Simultaneous screening for 11 mutations in the cystic fibrosis transmembrane conductance regulator gene by multiplex amplification and reverse dot-blot."

No. Sentence Comment

35 Mutation Number of CF chromosomes with the mutation Reference AF508 138(71-1%) 3 G542X 11 (5 .7%) 9 N1303K 6(3-1%) 15 1717-1G--*A 5 (2.6%) 8, 9 A455E 2 (1 .0%) 9 W1282X 2 (1 .0%) 10 G458V 1 (0.5%) 4 A1507 1 (0.5%) 9 Unidentified 28 (14.4%) cation was carried out on a DNA Thermal Cycler (Perkin Elmer-Cetus Instruments) . Login to comment
63 Cystic fibrosis patients homozygous for the AF508, G542X and N1303K mutations were available in our Belgian population. Login to comment
75 PCR fragments obtained by multiplex amplification of normal genomic DNA, genomic DNA of a carrier for the A1507 mutation, and genomic DNA of patients homozygous for the AF508, G542X or N1303K mutations were hybridized . Login to comment
82 The G542X, N1303K and 1717-1G->A mutations turned out to be the most frequent in non-AF508 CF chromosomes in our population . Login to comment
97 621 + IG-T A455E G458V A1507 AF508 1717-IG - A G542X G551D R553X WI282X N 1303 K 621+IG- .T A455E G458V A1507 AF508 1717-I G-> A G542X G551D R553X W1282X N1303K Fig. 2. Login to comment
101 A E M W Non-radioactive CF reverse dot-blot 37 B F M W C M W D M W G H 621 + IGT A455E G458V A1507 A F508 1717-IGA G542X G551D R553 X W1282X N1303K 621+IG-ߦT A455E G458V L 1507 AF508 1717-IG- A G542 X G551D R553X W1282X N 1303 K A F M W G B M W C H M W D M W E J M W Fig. 3. Login to comment
103 Hybridization of PCR fragments obtained by multiplex amplification of G458V/G542X (A), AF508/AF508 (B), AF508/? Login to comment
105 denotes a yet unidentified CF mutation) (C), AF508/N1303K (D), AF508/G542X (E), C458V/normal (F), AF508/1717-1G-+A (G), G542X/? Login to comment

PMID: 1377276 [PubMed] Lerer I et al: "Cystic fibrosis mutations delta F508 and G542X in Jewish patients."

No. Sentence Comment

0 I Med Genet 1992 29: 131-133 Cystic fibrosis mutations AF508 and G542X in Jewish patients I Lerer, M Sagi, G R Cutting, D Abeliovich Abstract We have screened our CF patients for mutations in exons 10 and 11 of the CFTR gene. Login to comment
1 Two mutations, AF508 and G542X, have been found in 66 Jewish CF patients. Login to comment
3 The G542X mutation accounts for 13% of the Ashkenazi CF mutations and has been found in three out of seven chromosomes of Jewish patients from Turkey (probably descended from Ashkenazi immigrants). Login to comment
4 The G542X mutation was not found in any of the other non-Ashkenazi patients. Login to comment
5 All the G542X bearing chromosomes have the same haplotype. Login to comment
6 Based on these observations it is concluded that the G542X mutation was introduced into the Jewish people after the split into Ashkenazi and non-Ashkenazi. Login to comment
8 The majority of these are rare mutations observed in single families but some mutations are relatively frequent.3 We have screened CF patients for the AF508 mutation and for G542X, G551D, R553X, and S549N or I, all within exon 11, and for the splice mutation 1717-1G-.A. Login to comment
9 Two mutations have been found among the Jewish patients, AF508 and G542X. Login to comment
18 Exon 11 was amplified by PCR using 1 li-5 and 1 i-3 as primers.3 The mutations G542X and 1717-1G--A were analysed by ASO hybridisation. Login to comment
32 The G542X mutation was found in 14 CF chromosomes, in 11 (13%) chromosomes of Ashkenazi origin and in three out of a total of seven (43%) chromosomes of Turkish origin. Login to comment
33 None ofthe other Sephardic CF chromosomes had the G542X mutation. Login to comment
34 We did not find any patients homozygous for the G542X mutation. Login to comment
35 The haplotype of the G542X bearing chromosomes was allele 1 of T6/20-MspI, haplotype B at the D7S23 locus, allele 1 of J3.11/ MspI, allele 2 of both MetH/TaqI and MetD/ BanI, and allele 1 of MetD/TaqI. Login to comment
38 Locus Met D7S23 CFTR D7S8 DNA probe MetH MetD MetD KM19 - XV2c T6/20 J3.11 Enzyme TaqI TaqI BanI PstI TaqI MspI MspI Allele haplotype 1 2 1 2 1 2 1-1 2-1 1-2 2-2 1 2 1 2 A B C D Normal chromosomes Ashkenazi (n=52) 25 24 34 4 17 33 15 8 27 2 19 3 26 25 Non-Ashkenazi (n=30) 14 9 15 7 12 17 6 4 16 4 12 3 14 16 AF508 chromosomes (n = 43) Ashkenazi (n=25) 13 4 13 0 13 5 0 22 0 3 18 0 2 21 Non-Ashkenazi (n= 18) 8 3 8 3 7 7 1 17 0 0 12 0 2 13 G542X chromosomes (n = 14) Auhrkiesho (gi (=3) 1 6 7 0 0 9 0 14 0 0 12 0 11 0 CF chromosomes, unknown mutations (n = 70) Ashkenazi (n=48) 28 2 22 1 24 6 0 43 4 1 617 3 40 Non-Ashkenazi (n=22) 11 7 15 1 12 8 1 8 9 1 7 2 7 11 Table 2 Allelic association coefficient (A)* of closely linked RFLPs and the AF508 mutation. Login to comment
47 G542X is a termination mutation in codon 542 of the putative CFTR protein gene. Login to comment
51 This argument is strengthened by the fact that one of the families from Turkey with G542X has the surname Ashkenazi, which was given to the Ashkenazi immigrants. Login to comment
52 The high proportion of G542X in the patients from Turkey indicates a possible founder effect. Login to comment
53 The haplotype ofthe G542X chromosome is unique, even when one examines the distant RFLPs at the Met and J3.11 loci. Login to comment
55 It would be interesting to compare the haplotypes of those G542X chromosomes to those from other sources in Europe. Login to comment
56 The mutations AF508 and G542X together account for less than 50% of the CF mutations in the Jewish patients. Login to comment
70 132 Cystic fibrosis mutations AF508 and G542X in 3rewish patients 4 Cutting GR, Kasch LM, Rosenstein BJ, et al. A cluster of cystic fibrosis mutations in the first nucleotide-binding fold of the CFTR protein. Login to comment
106 U U KJ _// 1 6 133 #P's -d- ,Ilk, -44 I 44 .4w 0 Aw. of -40 VI* A&- Case 2 .3 16M... ........A 4 to 11%, "W... ow A Case 3 S. group.bmj.com on December 5, 2015 - Published by http://jmg.bmj.com/ Downloaded from G542X in Jewish patients. Login to comment

PMID: 14613688 [PubMed] Flodrops H et al: "[Clinical aspects and genetic specificities of cystic fibrosis in Reunion Island]."

No. Sentence Comment

82 = mutation non identifi&#e9;e. Tableau 3 Distribution des mutations &#e0; la R&#e9;union Mutation Nombre de chromosomes Total % Total cumul&#e9; nord (1) sud (2) D F508 53 34 87 51,8 87 Y122X 17 24 41 24,4 128 3120+1G࢐A 6 2 8 4,8 136 A455E 2 1 3 1,8 139 G551D - 1 1 0,6 140 2789+5G࢐A 1 - 1 0,6 141 1161 del C - 1 1 0,6 142 1078 del T - 1 1 0,6 143 1717-1G࢐A 1 - 1 0,6 144 G542X - 1 1 0,6 145 ??? Login to comment

PMID: 14623323 [PubMed] Mendes F et al: "Unusually common cystic fibrosis mutation in Portugal encodes a misprocessed protein."

No. Sentence Comment

147 To date, 14 patients carrying A561E were identified in Portugal; nine are compound heterozygotes with F508del, one with G542X and four are homozygous for A561E mutation (Pacheco et al., personal communication and manuscript in preparation). Login to comment

PMID: 14685937 [PubMed] Groman JD et al: "Variation in a repeat sequence determines whether a common variant of the cystic fibrosis transmembrane conductance regulator gene is pathogenic or benign."

No. Sentence Comment

32 Each of the 27 fathers with 5T had one of the following mutations: DF508 (18), G542X (2), 1812-1GrA (2), DI507 (1), 936delTA (1), N1303K (1), 3600af9;2insT (1), or 1717-1 GrA (1). Login to comment
37 Each of the 98 patients with CBAVD had 5T with one of the following mutations: DF508 (78), G542X (6), N1303K (3), 711af9;1GrT (2), R1066C (2), R1162X (2), R764X (1), Y563X (1), H609R (1), L206W (1), or R334W (1). Login to comment

PMID: 15298139 [PubMed] Lewis MJ et al: "Cystic fibrosis."

No. Sentence Comment

9 G542X is the most frequent mutation in Caucasians after ࢞F508, occurring at a frequency of 2%. Login to comment
95 ēa; ēa;Table 3ēa; ēa; Recommended Mutation Panel for Cystic Fibrosis Carrier Screening ࢞F508 ࢞I507 G542X G551D W1282X N1303K R553X 621+1G>T R117H 1717-1G>A A455E R560T R1162X G85E R334W R347P 711+1G>T 1898+1G>A 2184delA 1078delT 3849+10kbC>T 2789+5G>A 3659delC I148T 3120+1G>A I506V* I507V* F508C* 5T/7T/9T* * Reflex tests. Login to comment

PMID: 15463882 [PubMed] Hubert D et al: "Diagnosis of cystic fibrosis in adults with diffuse bronchiectasis."

No. Sentence Comment

47 We used an oligonucleotide ligation assay using a commercially available kit (Cystic Fibrosis Assay, Applied Biosystems, Foster City, CA, USA) to seek 31 mutations in the CFTR gene (F508del, I507del, Q943X, V520F, 1717y1GࡊA, G542X, G551D, R553X, R560T, S549R, S549 N, 3849q10kbCࡊT, 3849q4AࡊG, R1162X, 3659delC, W1282X, 3905insT, 621q1GࡊT, R117H, Y122X, 711q1GࡊT, 1078delT, R347P, R347H, R334 W, A455E, N1303K, G85E, 1898q1GࡊA, 2183AAࡊG, 2789q5GࡊA) which allowed to detect 82% of the CF alleles in France. Login to comment
128 The consensus opinion is Table 3 Sensitivity of the sweat test and genotyping for the diagnosis of cystic fibrosis Positive diagnosis of CF Number of patients (percentage) Sweat test (sweat chloride)60 mmol l ) y1 37 (80%) Molecular analysis: -screening for 31 mutations 18 (39%) -complete screening 36 (78%) Combination of sweat test and molecular analysis: -sweat testqscreening for 31 mutations 42 (91%) -sweat testqcomplete screening 45 (98%) Table 4 Efficacy of the CFTR genetic analysis according to the screening method used Identified mutations Two mutations At least one mutation No mutations Screening for F508del Number of patients (%) 3 (7%) 31 (67%) 15 (33%) Screening for nine mutations* Number of patients (%) 6 (13%) 36 (78%) 10 (22%) Screening for 31 mutations** Number of patients (%) 18 (39%) 43 (93%) 3 (7%) Complete screening Number of patients (%) 36 (78%) 46 (100%) 0 Nine mutations: F508del, I507del, G542X, G551D, R553X, 621q1GࡊT, G85E, R117H, N1303K. Login to comment
129 * 31 mutations: F508del, I507del, Q493X, V520F, 1717y1GࡊA, G542X, G551D, R553X, R560T, S549R, S549 N, 3849q10kbCࡊT, 3849q ** 4AࡊG, R1162X, 3659delC, W1282X, 3905insT, 621q1GࡊT, R117H, Y122X, 711q1GࡊT, 1078delT, R347P, R347H, R334 W, A455E, N1303K, G85E, 1898q1GࡊA, 2183AAࡊG, 2789q5GࡊA. that the laboratory criteria for the diagnosis of CF should be expanded to include identification of CFTR mutations and abnormal bioelectrical properties of the nasal epithelium, in addition to the sweat test w7x. Login to comment
148 The F508del mutation was found in 31 patients and the G542X mutation was found in five patients. Login to comment

PMID: 15665983 [PubMed] Araujo FG et al: "Prevalence of deltaF508, G551D, G542X, and R553X mutations among cystic fibrosis patients in the North of Brazil."

No. Sentence Comment

14 ࢞F508 is the most common CF mutation (66%) in the worldwide populations studied to date, although other mutations such as G542X (2.4%), G551D (1.6%), N1303K Brazilian Journal of Medical and Biological Research (2005) 38: 11-15 ISSN 0100-879X Short Communication (1.3%), and W1282X (1.2%) (5-13) may be relatively frequent depending on the ethnic origin of the population. Login to comment
24 (8)about CF in S&#e3;o Paulo State demonstrated the presence of the G542X, N1303K and W1282X mutations, with frequencies of 8.35, 1.6 and 0.8%, respectively. Login to comment
26 (7) first reported two patients from the city of Rio de Janeiro carrying the G542X mutation and five other patients carrying splicing mutations 3120+1G࢐A. ThewidespectrumofCFmutations(more than 900 already described) and the heterogeneous ethnic origin of the Brazilian population are important factors that must be considered to draw a broader map of this disease in the Brazilian territory. Login to comment
27 Thus, the main objective of the present study was to investigate the four most frequent CF mutations (࢞F508, G542X, G551D, and R553X) in a sample of patients with an established clinical diagnosis of CF in the North region of Brazil. Login to comment
33 Region Number of alleles Mutations (%) Reference ࢞F508 G542X G551D R553X South Rio Grande do Sul 106 49.1 2.8 0 0 5 Rio Grande do Sul 154 48.7 3.2 0 0.7 12 Santa Catarina 58 55.2 3.5 0 0 5 Santa Catarina 48 27 0 0 0 9 Paran&#e1; 100 39 9 0 2 5 Southeast S&#e3;o Paulo 110 52.7 10 0.9 2.7 5 Rio de Janeiro 88 30.7 2.3 1.1 0 6 Rio de Janeiro 148 25.7 0 0 0 7 Rio de Janeiro 34 35.3 - - - 9 Minas Gerais 62 32.6 4.2 0 0 5 North Bel&#e9;m 66 22.7 0 3 0 Present study approved this research. Login to comment
36 The four mutations (࢞F508, G542X, G551D, and R553X) were amplified using primers and conditions described below. Login to comment
38 The volume 50 &#b5;l was used to observe the G542X, G551D and R553X mutations (exon 11). Login to comment
40 A region of 114 bp was amplified and then three mutations were investigated: G542X, G551D and R553X. Login to comment
44 The mutation G542X made use of the endonuclease BstN I. Login to comment
45 For the individuals who presented the pattern (+/+), which indicates absence of the mutation G542X, the investigation of a second restriction site was made for the endonuclease HincII (G551D). Login to comment
50 The analysis of the G542X, G551D and R553X mutations were observed by 9% polyacrylamide gel electrophoresis. Login to comment

PMID: 16635477 [PubMed] Lucarelli M et al: "A 96-well formatted method for exon and exon/intron boundary full sequencing of the CFTR gene."

No. Sentence Comment

26 None of these subjects showed any clinical manifestations of CF, nor were any positive for CFTR mutations when analyzed by means of the PCR/OLA/SCS method (Celera Diagnostics) [21], which searches for the most common worldwide 31 CFTR mutations (G85E, R117H, Y122X, 621+1G->T, 711+1G->T, 1078delT, R347P, R347H, R334W, A455E, DF508, DI507, Q493X, V520F, 1717-1G->A, G542X, G551D, R553X, R560T, S549R(T->G), S549N, 1898+1G->A, 2183AA->G, 2789+5G->A, R1162X, 3659delC, 3849+10kbC->T, 3849+4A->G, W1282X, 3905insT, N1303K), including the 12 most common in Italy [1,22]. Login to comment

PMID: 16678503 [PubMed] Ngiam NS et al: "Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations in Asians with chronic pulmonary disease: a pilot study."

No. Sentence Comment

102 These are R117H (exon 4), 621UVG>T (intron 4), F508del (exon 10), 1717-1 G>A (intron 10), G542X (exon 11), G551D (exon 11), R553X (exon 11), R1162X (exon 19), W1282X (exon 20) and N1303K (exon 21). Login to comment

PMID: 16713399 [PubMed] Castellani C et al: "The genetic background of osteoporosis in cystic fibrosis: association analysis with polymorphic markers in four candidate genes."

No. Sentence Comment

74 CFTR analysis Patients selected for the study had been characterized previously for CFTR mutations with a reverse dot blot (RDB) Table 1 Anthropometric and CF-associated variables in normal, osteopenic and osteoporotic patients Group 1 normal bone density Group 2 osteopenia Group 3 osteoporosis Statistical evaluation Numerosity 15/82 46/82 21/82 - Mean age (years) 27.73T4.19 26.71T5.93 28.1T9.51 NS Males/females 9/6 19/27 11/10 NS CFTR genotype F508del/UK: 3 UK/ UK: 3 F508del/ F508del: 2 F508del/ G542X: 2 F508del/ R553X: 2 1717-1G> AvW1282X: 1 F508del/ N1303K: 1 G542X/UK: 1 F508del/F508del: 6 UK/UK: 5 F508del/ UK: 3 2183AA>G/UK: 3 2789+5G> A /UK: 3 F508del/N1303K: 3 F508del / R1162X: 3 F508del/2183AA>G: 2 N1303K/ N1303K: 2 R1162X/R1162X: 2 R1162X/ 2183AA>G: 2 2183AA>G/G542X: 1 F508del/ 1898+3A>G: 1 F508del/2789+5G> A: 1 F508del/711+5G>A: 1 F508del/ Q353X: 1 I507del/R1162X: 1 Q552X/ UK: 1 N1303K/G542X: 1 R1162X/3849+ 10KbC>T: 1 R1162X/711+5G>A: 1 T338I/ UK: 1 R553X/UK: 1 F508del/F508del: 4 F508del/ UK: 3 F508del/N1303K: 2 UK/ UK: 2 2789+5G>A/2789+5G> A: 1 F508del/1898+3A>G: 1 F508del/ 2183AA>G: 1 F508del/3849+10KbC> T: 1 F508del/G542X: 1 F508del/ R1066H: 1 F508del/R1162X: 1 Q552X/: 1 R352Q/: 1 R553X/UK: 1 Weight (kg) 61.7T5.89 56.5T8.25 48.9T9.40 p <0.0001 BMI 22.6T1.3 20.3T2.7 18T2.9 p <0.0001 PS/PI 3/12 10/36 7/14 NS FEV1% predicted 52.33T16.73 49.82T21.44 37.1T21.07 p =0.0205 NS = not significant. Login to comment
80 assay which allows the simultaneous analysis of the commonest CFTR mutations in North-eastern Italy (F508del, I507del, R117H, R1162X, 2183AA>G, N1303K, 3849+10KbC>T, G542X, 1717-1G>A, R553X, Q552X, G85E, 711+5G>A, W1282X, 3132delTG and 2789+5G>A) [25]. Login to comment

PMID: 16963320 [PubMed] Perez MM et al: "CFTR gene analysis in Latin American CF patients: heterogeneous origin and distribution of mutations across the continent."

No. Sentence Comment

42 Some have concentrated in the search of specific mutations that are Table 1 Mutations found in the Latin American CF patients Exon 1 p.L6VÌe; Exon 3 p.W57X, p.R75X, p.G85E Exon 4 p.R117H Exon 6a p.H199Y, p.V201M, p.L206W, p.Q220X, p.V232D, c.846delTÌe; Exon 6b p.Y275XÌe;, c.935delA Exon 7 p.R334W, p.R347P, p.Y362XÌe;, c.1078delT, c.1215delG Exon 8 c.1323_1324insAÌe; Exon 9 c.1460_1461delATÌe;, c.1353_1354insTÌe;,# Exon 10 p.I506T, p.I507del, p.F508del Exon 11 p.G542X, p.S549N, p.S549R, p.G551D, p.G551S, p.R553X, p.L558S, p.A559T, c.1782delA Exon 12 p.S589I Exon 13 p.H609RÌe;, p.P750L, p.V754M, c.1924_1930del, c.2055_2063del, c.2183AA NG;c.2184delA, c.2184delA, c.2185_2186insC, c.2347delG, c.2566_2567insTÌe;, c.2594_2595delGTÌe; Exon 14a p.R851L, c.2686_2687insTÌe; Exon 15 c.2869_2870insG Exon 16 c.3120+1GNA Exon 17a p.I1027T, c.3171delC, c.3199_3204del Exon 17b p.G1061R, p.R1066C, p.W1069X#, p.W1089X, p.Y1092X, p.W1098CÌe; Exon 19 p.R1162X, p.W1204X, p.Q1238X, c.3617_3618delGAÌe;#, c.3659delC Exon 20 p.W1282X, p.R1283M Exon 21 p.N1303K, c.4016_4017insT Exon 22 c.4160_4161insGGGGÌe; 5' flanking c.-834GNT Intron 2 c.297-1GNAÌe;, c.297-2ANG Intron 3 c.406-1GNA Intron 4 c.621+1GNT Intron 5 c.711+1GNT Intron 8 c.IVS8-5T Intron 10 c.1716GNA, c.1717-1GNA Intron 11 c.1811+1.6KbANG, c.1812-1GNA Intron 12 c.1898+1GNA, c.1898+3ANG Intron 14 c.2789+2_2789+3insA, c.2789+5GNA Intron 17a c.3272-26ANG Intron 17b c.3500-2ANGÌe; Intron 19 c.3849+1GNA, c.3849+10KbCNT Intron 20 c.4005+1GNA, c.4005-1GNA# Mutations are listed according to their position in the gene. Login to comment
46 of chromosomes analysed p.F508del p.G542X p.W1282X p.N1303K p.R1162X p.L6VÌe; p.W57X p.R75X p.G85E p.R117H p.H199Y p.V201M p.L206W p.Q220X p.V232D p.Y275XÌe; p.R334W p.R347P p.Y362XÌe; p.I506T Argentina 98 61 440 258 18 12 12 2 1 1 3 1 5 1 310 181 20 7 5 5 7 0 5 0 222 135 15 7 5 1 26 14 2 1 1 150 88 6 6 1 2 3 Subtotal and frequency (%) 1246 100 737 59.15 61 4.90 27 2.17 28 2.25 9 0.72 1 0.08 1 0.08 13 1.04 1 0.08 13 1.04 1 0.08 Brazil 468 221 26 11 74 38 2 1 320 155 28 3 8 8 4 1 2 1 1 8 122 62 120 38 10 3 148 38 4 0 0 48 15 154 75 5 1 0 2 0 386 154 24 6 10 17 9 0 10 1 18 4 0 0 2 0 0 0 0 Subtotal and frequency (%) 1858 100 800 43.06 99 5.33 11 0.59 34 1.83 25 1.35 13 0.70 1 0.05 2 0.11 1 0.05 1 0.05 20 1.07 1 0.05 Chile 72 21 36 11 3 0 44 22 4 3 1 1 100 45 7 5 0 2 0 2 0 Subtotal and frequency (%) 252 100 99 41.28 14 5.55 8 3.17 3 1.19 3 1.19 Colombia 184 77 7 2 1 2 1 34 13 2 1 1 Subtotal and frequency (%) 218 100 90 41.28 9 4.13 3 1.38 2 0.92 2 0.92 1 0.46 Costa Rica Frequency (%) 48 100 11 22.91 12 25.00 0 0 0 0 0 Cuba Frequency (%) 144 100 49 34.03 Ecuador 32 11 1 50 16 2 2 20 5 0 0 0 Subtotal and frequency (%) 102 100 32 31.37 2 1.96 1 0.98 2 1.96 Mexico 194 79 12 4 3 1 1 1 2 80 36 4 1 Subtotal and frequency (%) 274 100 115 41.97 16 5.84 5 1.82 3 1.09 1 0.36 1 0.36 1 0.36 2 0.73 Uruguay Frequency (%) 76 100 43 56.58 6 7.89 2 2.63 3 3.95 3 3.95 2 2.63 Venezuela 54 16 2 82 41 Subtotal and frequency (%) 136 100 57 41.91 2 1.47 Total 4354 2033 221 49 72 42 1 1 3 32 1 1 1 2 1 1 1 39 1 1 2 Frequency (%) 100 46.69 5.08 1.13 1.65 0.96 0.02 0.02 0.07 0.73 0.02 0.02 0.02 0.05 0.02 0.02 0.02 0.90 0.02 0.02 0.05 The five most frequent mutations are shown on the left-hand side, followed by the rest of the mutations in 5'-3' and exon-intron order. Login to comment
62 The p.G542X mutation, with a total frequency of 5.07% (25% in Costa Rica to 1.47% in Venezuela), is the second most frequent mutation in Latin America, with the exception of Colombia and Costa Rica. Login to comment
64 Costa Rica is a unique case, where p.G542X (12/48 chromosomes) and p.F508del (11/48 chromosomes) have almost the same frequencies. Login to comment
85 Costa Rica sits on an isolated branch, apparently due to the weight given by the exceptionally high frequency of the p.G542X mutation in these patients (25%). Login to comment
89 Table 3 Most frequent mutations (N1%) in Latin American patients Country Chromosomes analysed p.F508del p.G542X p.N1303K p.W1282X p.R1162X Unknown n % n % n % n % n % n % Argentina 1246 737 59.15 61 4.90 28 2.25 27 2.17 9 0.72 271 21.75 Brazil 1858 800 43.06 99 5.33 34 1.83 11 0.59 25 1.35 789 42.46 Chile 252 99 39.28 14 5.55 0 0.00 8 3.17 3 1.19 115 45.63 Colombia 218 90 41.28 9 4.13 2 0.92 3 1.38 2 0.92 84 38.53 Costa Rica 48 11 22.92 12 25.00 - - - - - - 25 52.08 Cuba 144 49 34.03 - - - - - - - - 95 65.97 Ecuador 102 32 31.37 2 1.96 1 0.98 - - - - 65 63.72 Mexico 274 115 41.97 16 5.84 5 1.82 - - - - 88 32.11 Uruguay 76 43 56.58 6 7.89 2 2.63 - - 3 3.95 11 14.47 Venezuela 136 57 41.91 2 1.47 - - - - - - 77 56.62 Total 4354 2033 46.69 221 5.08 72 1.65 49 1.13 42 0.96 1620 37.21 A - sign indicates that these mutations were not tested in the sample of patients, therefore their real frequency remains unknown. Login to comment
101 Furthermore, if we take three of the most frequent mutations in Europeans (p.F508del, p.G542X and p. N1303K), along with a very frequent mutation in Italians, p.R1162X [9], the percentage of these in Argentinean and Uruguayan CF patients adds up 67% and 71%, respectively, of the mutations (Table 3). Login to comment
111 As discussed, another way to disclose similarities or differences in the distribution of mutations in the CF patients from Latin Table 6 Screening panel of CFTR mutations Country Total number of mutations Minimum panel Detection power Uruguay 12 6 mutations: p.F508del, p.G542X, p.R1162X, p.N1303K (p.R334W, p.G85E) 78% Argentina 52 7 mutations: p.F508del, p.G542X, p.R1162X, p.W1282X, p.N1303K (p.R334W, p.G85E) 71% M&#e9;xico 35 8 mutations: p.F508del, p.G542X, p.N1303K (p.R75X, p.I507del, p.S549N,c.406-1GNA, c.3849+10kbGNA) 58% Colombia 19 7 mutations: p.F508del, p.G542X, p.R1162X, p.W1282X, p.N1303K (p.S549R, c.1811+1.6kbANG) 56% Brazil 41 6 mutations: p.F508del, p.G542X, p.R1162X, p.W1282X, p.N1303K (p.R334W) 53% The total number of mutations found in each country is indicated in the second column from left. Login to comment
126 In this country, p. G542X (25%) is the first mutation, followed by p.F508del (22.92%) (Table 3). Login to comment
127 As argued by the authors, this unusual high frequency of p.G542X, which is almost four times that observed overall in Spain (7.66%) and Andalusia (8.6%) [9], could be a consequence of a strong founding effect due to the small number of settling families from this region established in Costa Rica in the XVIth-XVIIth century. Login to comment

PMID: 17573123 [PubMed] Amaral MD et al: "Molecular targeting of CFTR as a therapeutic approach to cystic fibrosis."

No. Sentence Comment

46 Class I mutations, which abrogate protein production, often include mutations that generate premature stop codons (e.g. G542X) that lead to mRNA degradation by nonsense-mediated decay. Login to comment

PMID: 18788470 [PubMed] Flores-Martinez SE et al: "XV-2c/KM19 haplotypes analysis of cystic fibrosis patients from western Mexico."

No. Sentence Comment

3 The F508del and G542X mutations were strongly associated with haplotype B (96.7% and 100% of chromosomes, respectively). Login to comment
71 Of the 64 CF chromosomes, 30 carried the F508del mutation, 7 the G542X mutation, and the remaining 27 chromosomes carried the 3849+10 Kb C>T, 621+1 G>T, G551D, R553X, F311de1, R352Q, R74W mutations, as well as the new mutation 2053-2060del (unpublished data) or unidentified mutations; all of these were grouped as "other" (Table II). Login to comment
72 The majority of the chromosomes with the F508del mutation (29/30) were found on chromosomes with haplotype B (96.7%), whereas all 7 chromosomes carrying the G542X mutation were on chromosomes with haplotype B (100%). Login to comment
78 (%) of XV-2c/KM19 haplotypes Chromosomes A B C D CF (n=64) 10 (15.6%) 46 (71.9%) 5 (7.8%) 3 (4.7%) F508del (n=30) - 29 (96.7%) - 1 (3.3%) G542X (n=7) - 7 (100%) - - Other* (n=27) 10 (37.0%) 10 (37.0%) 5 (18.5%) 2 (7.4%) Non-CF (n=30) 18 (60%) 0 (0%) 9 (30%) 3 (10%) *Chromosomes bearing detected mutations (3849+10 Kb C>T, 621+1 G>T, G551D, R553X, F311del, R352Q, R74W, 2053-2060del), or unidentified mutations. Login to comment
99 The difference between the studies is more evident when the frequencies of haplotype B and the G542X mutation are compared. Login to comment
101 (20) reported that 56.7% of CF chromosomes were mainly associated with haplotype B, and that the G542X mutation was associated with haplotype B in 72.7% of the chromosomes. Login to comment
102 In our CF chromosomes, haplotype B was present in 71.9% of CF chromosomes and in 100% of G542X chromosomes (Table III). Login to comment
124 Herein, we have identified a very high association of the F508del mutation and an even higher association of G542X mutation with haplotype B. Login to comment
128 Therefore, a haplotype analysis using markers KM19 and XV-2c might be useful as a first screening strategy to offer a molecular diagnosis for the western Mexican families, emphasizing the fact that, in our study, haplotype B was absent in all chromosomes of individuals free of the clinical features of CF, and because the association of the F508del and G542X mutations with haplotype B in CF patients from western Mexico was higher than reported in Latin American and some Caucasian populations. Login to comment
129 The use of XV-2c/KM19 haplotype analysis as a first screening strategy could offers several advantages, such as: the assessment of the carrier risk of patients, particularly with F508del and G542X mutations; the screening of individuals bearing mutations in the CFTR gene (heterozygotes detection); and allowing the implementation of detection programs for carrier detection of known and unknown mutations in first-degree relatives of CF patients who wish to know their carrier status. Login to comment

PMID: 18797695 [PubMed] Vidigal PV et al: "p.F508del in a heterogeneous cystic fibrosis population from Minas Gerais, Brazil."

No. Sentence Comment

19 Among the various CF mutations, a deletion of 3 bp at codon 508 (p.F508del) is the most frequent accounting for two-thirds of the global CFchromosomes.Only4othermutations(G542X,N1303K, G551D, and W1282X) have overall frequencies above 1% among CF chromosomes. Login to comment

PMID: 18801689 [PubMed] Robin G et al: "[Why and how to assess hypospermia?]."

No. Sentence Comment

153 C`est pourquoi, le recours aux kits de recherche de mutations du g&#e8;ne CFTR qui ne permettent de d&#e9;pister qu`une trentaine de mutations impliqu&#e9;es dans les formes s&#e9;v&#e8;res compl&#e8;tes de la mucoviscidose (comme les mutations DF508 (70 %), G542X (3 %), N1303K (2 %). Login to comment

PMID: 18822253 [PubMed] Munck A et al: "[The French nationwide cystic fibrosis newborn screening program: strategy and results]."

No. Sentence Comment

50 L`organigramme du DNN (fig. 1) pr&#e9;voit une valeur seuil de TIR &#e0; J3 d&#e9;termin&#e9;e sur les donn&#e9;es des r&#e9;gions fran&#e7;aises ayant d&#e9;but&#e9; ce d&#e9;pistage il y a plus de 10 ans afin de s&#e9;lec- Mutations recherch&#e9;es par le Kit Elucigen dans le cadre du d&#e9;pistage n&#e9;onatal de la mucoviscidose (Kit CF30) : F508del ; I 507del ; 1078delT, 1717-1 G>A ; 2183AA>G ; 3659delC ; 3849+10kbC>T ; 621+1G>T ; A455E ; E60X ; G542X ; G551D ; N1303K ; R1162X ; R117H ; R334W ; R347P ; R553X ; S1251N ;W1282X ; 1811+1.6kbA>G ; 2789+5G>A ; 3120+1G>A ; 3272-26A>G ; 394delT ; 711+1G>T ; G85E ; Y1092X ; Y122X ;W846X. Login to comment

PMID: 19014055 [PubMed] Yalcin E et al: "Cystic fibrosis in a boy with meconium ileus and mild clinical phenotype associated with 2183AA-G/D1152H genotype."

No. Sentence Comment

31 These nine patients carried delF508, G542X, G1244E and 2789+5G-A on the other CF allele. Login to comment

PMID: 19627168 [PubMed] Rowe SM et al: "Pharmaceuticals targeting nonsense mutations in genetic diseases: progress in development."

No. Sentence Comment

484 [26] They extended this work to the four most common disease-causing mutations in CFTR (G542X, R553X, R1162X, and W1282X), including studies in an immortalized lower airway cell line (IB3-1) isolated from a CF patient heterozygous for the W1282X CFTR mutation. Login to comment
518 Suppression of PTCs in Animal Models Two mouse models have been developed that possess PTCs in disease-causing genes, including the mdx mouse (a model of muscular dystrophy) and the transgenic G542X-hCFTR mouse (a model of CF). Login to comment
522 Complementary studies in the G542X-hCFTR mouse (expressing the human G542X CFTR cDNA under regulatory control of the FABP promoter on a Cftr knockout background) confirmed that gentamicin treatment increased the detection of full-length CFTR protein in the gut (the site of CF-related mortality in this genetic model) and was associated with the appearance of cAMP-stimulated Cl-conductance in isolated gut tissue studied ex vivo. Login to comment
524 Follow-up studies confirmed these effects and extended the findings to clinically relevant doses of both gentamicin and amikacin; amikacin suppressed the G542X-hCFTR premature stop mutation more effectively than gentamicin at clinically relevant doses. Login to comment
530 [24] In the G542X-hCFTR mouse, oral and intraperitonealadministration led to detectable full-length CFTR localization at the apical cell membrane of gut glandular cells by immunofluorescent staining, and improved Cl-conductance as assayed by transepithelial ion transport. Login to comment
571 A rank order of Y122X, W1282X, G542X, and R1162X was seen among the most frequent stop mutations after gentamicin treatment, with relative suppression varying by as much as 7.2-fold, post-therapy. Login to comment
585 [60] The detection of rescued CFTR activity in several patients with the G542X CFTR mutation (and others) in the studies conducted in Israel[55] and France/ Belgium,[64] suggests that the treatment effect is not limited to individuals with the W1282X mutation and that the agent can potentially exhibit a broad spectrum of activity across multiple PTCs in vivo. Login to comment

PMID: 20098842 [PubMed] Perone C et al: "Frequency of 8 CFTR gene mutations in cystic fibrosis patients in Minas Gerais, Brazil, diagnosed by neonatal screening."

No. Sentence Comment

2 Other common mutations in Brazil are G542X, R1162X, and N1303K. Login to comment
3 The aim of this study was to analyze the frequency of 8 mutations (F508del, G542X, R1162X, N1303K, W1282X, G85E, 3120+1G>A, and 711+1G>T) in a sample of 111 newborn patients with cystic fibrosis diagnosed by the Cystic Fibrosis Neonatal Screening Program of Minas Gerais State. Login to comment
5 An allele frequency of 48.2% was observed for the F508del mutation, and allele frequencies of 5.41, 4.50, 4.05, and 3.60% were found for the R1162X, G542X, 3120+1G>A, and G85E mutations, respectively. Login to comment
16 Other mutations such as G542X, G551D and N1303K are commonly found throughout the world, depending on geographical and ethnic features (5). Login to comment
18 Other common mutations in this region are G542X, N1303K, W1282X, and R1162X (6). Login to comment
26 Despite the large variations in ethnicbackgroundamongdifferentregions,G542X,N1303K and R1162X have been considered to be the most frequent non-F508del mutations in Brazil (6,11,13). Login to comment
29 The objective of the present investigation was to determine the frequency of 8 CFTR mutations (G85E, 711+1G>T, F508del, G542X, 3120+1G>A, R1162X, W1282X, and N1303K) in 111 sweat test-positive newborns screened by the CFNS program in the State of Minas Gerais, Brazil. Login to comment
43 The mutations are: G85E, 711+1G>T, F508del, G542X, 3120+1G>A, R1162X, W1282X, and N1303K. Login to comment
47 Mutation Primer sequence (5` ࢐ 3`) Amplicon size (bp) Annealing temperature (&#b0;C) G85E-S GGA GAT TTA TGT TCT ATG G 245 52 G85E-M GGA GAT TTA TGT TCT ATG A G85E-R GTA AAT TGC CAC CCG TGT TCC AGG 711+1G>T-S CCA ACA ACC TGA ACA AAT TTG ATG AAG 340 64 711+1G>T-M CCA ACA ACC TGA ACA AAT TTG ATG AAT 711+1G>T-R TTG CTC AGG TAT CAT ATC TGG CC F508del-S ACC ATT AAA GAA AAT ATC ATC TT 262 54 F508del-M ACC ATT AAA GAA AAT ATC ATT GG F508del-R TGC AAG CTT CTT AAA GCA TA G542X-S GCA GAG AAA GAC AAT ATA GTT CTT G 213/217 58 G542X-M GTT TGC AGA GAA AGA CAA TAT AGT TCT TTT G542X-R CCA CTA GCC ATA AAA CCC CAG G 3120+1G>A-S CTT ACC ATA TTT GAC TTC ATC CAG G 191 62 3120+1G>A-M CTT ACC ATA TTT GAC TTC ATC CAG A 3120+1G>A-R TTA CTA AAC TTA TGT CTA TTT TGA AGG C R1162X-S TTA TTT CAG ATG CGA TCT GTG AGC C 117 63 R1162X-M TTA TTT CAG ATG CGA TCT GTG AGC TT R1162X-R AAT CAT AAC TTT CGA GAG TTG GCC W1282X-S GGG ATT CAA TAA CTT TGC AAC AGT GG 203 67 W1282X-M GGG ATT CAA TAA CTT TGC AAC AGT GA W1282X-R TCT GCC TAT GAG AAA ACT GCA CTG GAG N1303K-S TTT TTT CTG GAA CAT TTA GAA AAA AC 137 58 N1303K-M TTT TTT CTG GAA CAT TTA GAA AAA AG N1303K-R GCC ATT TGT GTT GGT ATG AGT TAC CCC The -S suffix indicates a wild allele specific primer, the -M suffix a mutant allele primer, and the -R suffix the primer used in both wild and mutant allele amplification. Login to comment
63 R1162X, G542X, 3120+1G>A, and G85E were the most frequent non-F508del mutations observed, comprising 12 (5.4%), 10 (4.5%), 9 (4.1%), and 8 (3.6%) of the chromosomes studied. Login to comment
69 28 (25.23%) 34.38 (30.97%) F508del / G542X 5 (4.50%) 4.84 (4.36%) F508del / 3120+1G>A 4 (3.60%) 4.36 (3.93%) F508del / R1162X 4 (3.60%) 5.81 (5.23%) F508del / G85E 4 (3.60%) 3.87 (3.49%) F508del / 711+1G>T 2 (1.80%) 0.97 (0.87%) F508del / W1282X 1 (0.90%) 0.48 (0.43%) F508del / N1303K 1 (0.90%) 0.97 (0.87%) G542X / ? Login to comment
84 Mutation N Frequency (%) Cumulative frequency (%) G85E 8 3.60 3.60 711+1G>T 2 0.90 4.50 F508del 107 48.20 52.70 G542X 10 4.50 57.20 3120+1G>A 9 4.05 61.25 R1162X 12 5.41 66.66 W1282X 1 0.45 67.11 N1303K 2 0.90 68.01 Unknown alleles 71 31.99 Total 222 100.00 100.00 N = number of observed alleles. Login to comment

PMID: 20166764 [PubMed] Becq F et al: "Cystic fibrosis transmembrane conductance regulator modulators for personalized drug treatment of cystic fibrosis: progress to date."

No. Sentence Comment

67 [25,26] Besides F508del, other frequent mutations are found in North African CF patients, in particular W1282X, G542X, R1162X and N1303K. Login to comment
97 Class I includes nonsense, frame shift and splice site mutations (e.g. stop mutations: G542X, R553X, W1282X) leading to unstable transcripts and failure of CFTR translation. Login to comment
133 [47] In a prospective phase II clinical trial on CF patients selected for expressing CFTR variants with a class I mutation (G542X, W1282X), oral administration of ataluren reduced the epithelial electrophysiological abnormalities caused by CFTR channel dysfunction. Login to comment

PMID: 20619026 [PubMed] Ras JE et al: "[Cystic fibrosis in a woman aged seventy]."

No. Sentence Comment

63 TABEL 1 Classificatie van mutaties in het 'cystic fibrosis transmembrane conductance regulator`(CFTR)-gen op chromosoom 7 klasse mechanisme enkele bekende mutaties I geen synthese van het CFTR-eiwit G542X R553X W1282X R1162X 621-1G࢐T 1717-1G࢐A 1078࢞T 3659࢞C II defect in eiwitrijping met voortijdig afbraak ࢞F508 ࢞I507 N1303K S549N III verstoorde regulatie van de CFTR-functie G551D R56OT IV verstoorde conductie van chloride of verstoorde kanaalopening R117H R334W G85E R347P V minder synthese van het CFTR-eiwit 3849+10KbC࢐T 2789+5G࢐A A455E TABEL 2 Diagnostiek van cystische fibrose test testuitslag klassieke CF* niet-klassieke CFߤ zweettest chlorideconcentratie > 60 mmol/l chlorideconcentratie ࣘ 60 mmol/l neuspotentiaalmeting afwijkend niet-afwijkend CFTR-mutatie-analyse 2 mutaties 2 mutaties CF = cystische fibrose; CFTR = 'cystic fibrosis transporter regulator`-gen. Login to comment

PMID: 22043142 [PubMed] Lilley M et al: "Newborn screening for cystic fibrosis in Alberta: Two years of experience."

No. Sentence Comment

46 These include the following mutations: delF508, I507del, G542X, G85E, R117H, 621+1G࢐T, 711+1G࢐T, G551D, R334W, R347P, A455E, 1717-1G࢐A, R560T, R553X, N1303K, 1898+1G࢐A, 2184delA, 2789+5G࢐A, 3120+1G࢐A, R1162X, 3659delC, 3849+10kbC࢐T, W1282X, 1078delT, 394delTT, Y122X, R347H, V520F, A559T, S549N, S549R, 1898+5G࢐T, 2183AA࢐G, 2307insA, Y1092X, M1101K, S1255X, 3876delA and 3905insT. Login to comment

PMID: 22527665 [PubMed] Smaczny C et al: "[Emergencies in adult mucoviscidosis patients]."

No. Sentence Comment

19 Bei Neugeborenen kommt es typischerweise zu einem Tab. 1ߓ Typische Mutationen bei der Mukoviszidose Mutationsklasse Defektbeschreibung Beispiele (alte Nomenklatur) I Vollst&#e4;ndigerVerlust der CFTR-Protein- synthese R553X, G542X, N1303K, Êf; 1717-1 G &#e1;ߙ A II St&#f6;rung der Reifung und des intrazellul&#e4;- renTransports des CFTR-Proteins DF508 III Regulationsst&#f6;rung des Ionenkanals G551D IV St&#f6;rung der Ionenleitf&#e4;higkeit des CFTR-Kanals R347H, R117H V Verminderte CFTR-Konzentration in der Zelle 3849+10kBÊf;C &#e1;ߙ T VI Beschleunigter CFTR-Abbau ߕ CFTRÉe;Cystic fibrosis transmembrane conductance regulator". Login to comment

PMID: 22672057 [PubMed] Keeling KM et al: "Suppression of premature termination codons as a therapeutic approach."

No. Sentence Comment

218 The G542X mutation, found in 2% of Caucasian CF patients, is the most common CFTR nonsense mutation. Login to comment
234 Studies to examine suppression of a CFTR nonsense mutation utilized a transgenic mouse that carried a human CFTR cDNA containing the G542X nonsense mutation. Login to comment
236 The CFTR-G542X transgene was then crossed into a Cftrtm1Cam knockout mouse, resulting in a mouse that was suitable to evaluate the ability of suppression therapy to restore CFTR protein function (Du et al., 2002). Login to comment
244 In summary, a number of different drugs were found to suppress the common G542X mutation in a transgenic CF mouse model. Login to comment
518 Aminoglycoside suppression of a premature stop mutation in a Cftr-/- mouse carrying a human CFTR-G542X transgene. Login to comment
521 Clinical doses of amikacin provide more effective suppression of the human CFTR-G542X stop mutation than gentamicin in a transgenic CF mouse model. Login to comment
524 PTC124 is an orally bioavailable compound that promotes suppression of the human CFTR-G542X nonsense allele in a CF mouse model. Login to comment
531 Poly-l-aspartic acid enhances and prolongs gentamicin-mediated suppression of the CFTR-G542X mutation in a cystic fibrosis mouse model. Login to comment

PMID: 22682487 [PubMed] Ferec C et al: "[Genetics and modifier genes, atypical and rare forms]."

No. Sentence Comment

39 La mutation G542X est fr&#e9;quente dans les populations du pourtour m&#e9;diterran&#e9;en. Login to comment

PMID: 23142604 [PubMed] Gelfond D et al: "Gastrointestinal complications of cystic fibrosis."

No. Sentence Comment

20 The most common genotypes in infants with MI are severe mutations (F508del, G542X, W1282X, R553X, G551D), although most patients with these mutations do not present with MI.9 Recent genome-wide association studies have been able to account for approximately 17% of the phenotypic variability,14 implying that other non-CFTR genetic factors also contribute to this clinical presentation. Login to comment

PMID: 23199563 [PubMed] Leonard A et al: "[Mucoviscidosis: CFTR mutation-specific therapy: a ray of sunshine in a cloudy sky]."

No. Sentence Comment

125 Gentamicine par voir intraveineuse Une premie `re e &#b4;tude a e &#b4;value &#b4; les taux de chlorure dans la sueur et le PN - a ` 6 reprises - chez 5 patients porteurs d`une seule mutation de classe I (dont 3 G542X) et 5 patients homozygotes F508del [37]. Login to comment
130 Dans une partie distincte du travail, les auteurs de &#b4;montraient in vitro une translecture en pre &#b4;sence de gentamicine 4 a ` 7 fois plus efficace pour la mutation Y122X que pour les mutations W1282X, G542X et R1162X. Login to comment
317 [21] Du M, Liu X, Welch EM, et al. PTC124 is an orally bioavailable compound that promotes suppression of the human CFTR-G542X nonsense allele in a CF mouse model. Login to comment

PMID: 23207607 [PubMed] Larusch J et al: "Genetics of pancreatitis with a focus on the pancreatic ducts."

No. Sentence Comment

119 These drugs have been reported and reviewed in a number of articles in detail, both in ongoing clinical trials and approved by FDA F508del and G551D (65), G542X, W1282X and all other premature termination mutations (66, 67), leading us to speculate on the impact or utility of these drugs on pancreatitis. Login to comment

PMID: 23209179 [PubMed] Ferec C et al: "Assessing the Disease-Liability of Mutations in CFTR."

No. Sentence Comment

37 Worldwide, only a limited number of mutant alleles display a frequency higher than 1%, as for example the G542X (p.Gly542X), which is common in the Mediterranean area of Europe and Africa, which may be associated with the Phoenician migration around the Mediterranean Sea (Loirat et al. 1997). Login to comment
41 In North America, the distribution of CFTR mutations reflects European descent (the five more common mutations in the U.S. with afrequencyover 1% are F508del, G542X, G551D, W1282X, and N1303K) (Bobadilla et al. 2002). Login to comment
55 Mutations in CFTR including G542X, R553X (p.Arg553X), and W1282X have been shown to lead to NMRD in primary airway cells (Hamosh et al. 1991, 1992b; Will et al. 1995). Login to comment
93 On identification of the CFTR gene, it was shown that F508del and several other loss-of-function mutations including G551D and G542X are highly associated with pancreatic insufficiency. Login to comment
114 PI-CF patients bearing nonsense mutation G542X have shown the highest rate of MI, whereasthosewith F508del have an intermediate rate, and patients with the G551D mutation have a relatively low rate of MI (Hamosh et al. 1992a; Kristidis et al. 1992; Feingold and Guilloud-Bataille 1999). Login to comment

PMID: 23276700 [PubMed] Krenkova P et al: "Distribution of CFTR mutations in the Czech population: positive impact of integrated clinical and laboratory expertise, detection of novel/de novo alleles and relevance for related/derived populations."

No. Sentence Comment

49 Results Altogether we found 91 different CFTR mutations (Table 1), with only seven being present at a frequency N1%: F508del (67.42%), CFTRdele2,3(21kb) (5.75%), G551D (2.92%), N1303K (2.42%), G542X (2.0%), 3849+10kbCNT (1.67%) and 1898+1GNA (1.42%) (using the legacy/traditional nomenclature). Login to comment
73 Similarly, we presume that the "Mediterranean" mutation G542X [8] is, according to historical patterns of CE colonization [17], the most prevalent in the Danube basin, i.e. in SK, HU, AT and DE. Login to comment
89 Mutations/HGVS nomenclature/ Mutations/traditional nomenclature, legacy name/ Czech Republic 2012 (this study) (N=1200) Slovakia 2010 (N=856) Eastern Hungary 2011 (N=80) Germany Bavaria 2002 (N=250) Austria Tyrol 1997 (N=126) Austria NorthEast, North- North 2002 (N=118) Poland (N=1726) c.1521_1523delCTT F508del 67.42 66.80 70.00 74.00 74,60 70.30 57.0 c.54-5940_273+10250del21 kb CFTRdele2,3/21kb 5.75 2.26 5.00 1.2* 2.6# NA 1.80 c.1652GNA G551D 2.91 b0.50 0.00 6.40 1.60 2.50 0.50 c.3909CNG N1303K 2.42 2.03 5.00 2.40 0.00 NA 1.80 c.1624GNT G542X 2.00 4.06 3.75 3.20 2.40 5.10 2.60 c.3718-2477CNT 3849+10kbCNT 1.67 4.28 0.00 NA 0.00 3.40 2.70 c.1766+1GNA 1898+1GNA 1.42 b0.50 0.00 NA 0.00 NA NA c.1040GNC R347P 0.92 1.10 1.25 0.80 1.60 2.50 NA c.2012delT 2143delT 0.92 1.10 0.00 NA 0.00 NA NA c.3140-26ANG 3272-26ANG 0.67 b0.50 0.00 NA 0.00 NA NA c.3846GNA W1282X 0.58 b0.50 0.00 NA 0.00 NA 0.70 c.1007TNA I336K 0.58 0.00 0.00 NA 0.00 NA NA c.1657CNT R553X 0.50 0.90 0.00 1.20 0.00 NA 1.90 c.2657+5GNA 2789+5GNA 0.50 0.00 0.00 NA 2.40 NA NA c.2834CNT S945L 0.50 0.00 0.00 NA 0.00 NA NA c.2052_2053insA 2184insA 0.42 1.58 5.00 NA 0.00 NA NA Legend: data for Slovakia [12], Eastern Hungary [14], Germany-Bavaria [13], Austria-Tyrol [18], Austria North East and North West [13], Poland and *[8], and # [16]. Login to comment

PMID: 23317763 [PubMed] van Meegen MA et al: "CFTR-mutation specific applications of CFTR-directed monoclonal antibodies."

No. Sentence Comment

3 Mutant CFTR was detected in HEK293 cells transiently expressing the mutations; G542X, R1162X, F508del, N1303K, G551D, R117H, A455E. Login to comment
14 Class I mutations such as G542X and R1162X encode for premature stop codons and affect CFTR protein translation [6]. Login to comment
76 We selected wt-CFTR, F508del (class II), G542X (I), R1162X (I), G551D (III), R117H (IV), A455E (V), and N1303K (II) that were ectopically expressed in HEK293 cells. Login to comment
79 G542X could only be detected by L12B4 (50 kDa) and R1162X was detected around 110 kDa but not using NBD2 and C-terminal-specific mAbs. Login to comment
111 G551D was expressed at levels comparable to wt-CFTR, expression of R117H, N1303K, A455E and R1162X was intermediate, and low levels were observed for F508del and G542X. Login to comment
114 As expected, expression levels for R1162X were similar to empty vector, however, some expression was consistently observed for G542X, possibly due to production of an alternative transcript from this cDNA construct downstream of position 542. Login to comment
145 Western blots containing 25 bc;g of total protein of HEK293 cells transiently transfected with pcDNA3 containing; CFTR-wt, F508del, G542X, R1162X, G551D, R117H, A455E, N1303K or empty vector. Login to comment
153 Mutant CFTR G542X and F508del could not be detected by mAb 450. Login to comment
155 Detection of CFTR was limited for F508del and A455E and CFTR mutants G542X and R1162X were not detectable. Login to comment

PMID: 23361109 [PubMed] Sorio C et al: "Impaired CFTR function in mild cystic fibrosis associated with the S977F/T5TG12complex allele in trans with F508del mutation."

No. Sentence Comment

39 This prediction is consistent with the case reported in the literature, where a subject carrying the S977F mutation, in addition to a "severe" classic CF-causing mutation on the other allele (CFTR genotype G542X/S977F), presented with clinical evidence of CF [9]. Login to comment

PMID: 23378603 [PubMed] Thauvin-Robinet C et al: "CFTR p.Arg117His associated with CBAVD and other CFTR-related disorders."

No. Sentence Comment

44 The other mutations consisted of c.3846G>A (p.Trp1282*, W1282X) (2%), c.1624G>T (p.Gly542*, G542X) (2%), c.262_263del (394delTT) (2%), c.1585-1G>A (1717-1G>A) (2%) and other mutations (25%). Login to comment

PMID: 23454013 [PubMed] Denny RA et al: "Recent developments in targeting protein misfolding diseases."

No. Sentence Comment

55 Class I mutations contribute to the formation of proteins with incomplete length and provide protein with complete loss of activity (i.e., mutation: G542X). Login to comment

PMID: 23457166 [PubMed] Derichs N et al: "Targeting a genetic defect: cystic fibrosis transmembrane conductance regulator modulators in cystic fibrosis."

No. Sentence Comment

24 In fact, notwithstanding the common F508del variant, only four CFTR mutations have a frequency .0.1%: G551D, W1282X, G542X and N1303K, having a worldwide prevalence of around 1-3% each [9, 11]. Login to comment
28 For example, G542X is a nonsense or stop mutation, where introduction of a premature termination codon (or stop codon) results in premature cessation of translation and production of truncated CFTR protein. Login to comment

PMID: 23457168 [PubMed] Elborn JS et al: "The impact of personalised therapies on respiratory medicine."

No. Sentence Comment

52 This optimism must TABLE 1 Mechanism of action and targets of emerging cystic fibrosis transmembrane conductance regulator (CFTR) modulators Mutation class Nature of defect Example mutations Pancreatic function# Modulator strategy Agents in development I Biosynthesis G542X Insufficient Suppressor Suppressor and potentiator" Ataluren II Trafficking F508del Insufficient Corrector Corrector plus potentiator VX-809 plus ivacaftor+ VX-661 plus ivacaftor+ III Channel gating G551D Insufficient Potentiator Ivacaftor (FDA approved, G551D) Other gating mutations?" Login to comment

PMID: 23470247 [PubMed] Giordano S et al: "Molecular and functional analysis of the large 5' promoter region of CFTR gene revealed pathogenic mutations in CF and CFTR-related disorders."

No. Sentence Comment

115 Case 7 had c.-1308A>G in trans with G542X; he has PI and mild pulmonary expression. Login to comment
151 Diagnosis Clinical expression Sweat chloride (mEq/L) CFTR genotype FEV 1% Current age (years) 1 CBAVD CBAVD alone 38 [N1303K;c.-674T>C]/c.-674T>C 90 32 2 CBAVD CBAVD alone 36 F508del/c.-674T>C 106 28 3 CBAVD CBAVD alone 36 F508del/c.-674T>C 104 30 4 CF PI, mild P, no L 70 F508del/c.-869T[8_9] 78 41 5 CF PI, mild P, nasal polyposis, chronic sinusitis, no L 76 F508del/[TG12-T5-470V; c.-1308A>G] 80 30 6 CF PI, mild P, colonization by P. aeruginosa, no L 68 N1303K/c.-1308A>G 84 32 7 CF PI, mild P, no L 71 G542X/c.-1308A>G 80 17 8 CF PI, severe P, severe L 115 [2789&#fe;5G>A;c.-1773_ -1772delAT]Y849X* 44 20 9 CF PI, mild P, no L 90 F508del/c.-1773_-1772delAT 76 28 10 CBAVD CBAVD alone 40 F508del/c.-812T>G 96 31 11 CBAVD CBAVD alone 23 F508del/c.-812T>G 102 41 12 CF PS, mild P, no L 20 F508del/[1525-1delG;TG12-T5-470V;c.-2200G>A]y 84 20 13 CF PS, mild P, no L 70 F508del/c.-3632G>T 88 26 14 CBAVD CBAVD alone 22 c.-5914A>G/U 98 *The patient originally had the genotype 2789&#fe;5G>A/unknown; during the present study, we revealed the second mutation (ie, Y849X). Login to comment

PMID: 23523379 [PubMed] Rechitsky S et al: "PGD for cystic fibrosis patients and couples at risk of an additional genetic disorder combined with 24-chromosome aneuploidy testing."

No. Sentence Comment

42 [1075C>A; 1079C>A] p.[Gln359Lys; Thr360Lys] Exon 8 1 1 1 4 1 1 R297Q c.890G>A p.Arg297Gln Exon 8 1 1 1 2 0 0 R347P c.1040G>C p.Arg347Pro Exon 8 3 5 2 4 1 1 T338I c.1013C>T p.Thr338Ile Exon 8 1 1 1 2 1 1 DF508 c.1521_1523delCTT p.Phe508del Exon 11 130 195 172 345 88 (4) 92 DI507 c.1519_1521delATC p.Ile507del Exon 11 1 5 5 11 2 1 Q493R c.1478A>G p.Gln493Arg Exon 11 5 5 2 2 2 2 1717-1G-A c.1585-1G>A - Intron 11 6 10 9 18 6 8 G542X c.1624G>T p.Gly542X Exon 12 14 17 15 34 10 10 G551S c.1651G>A p.Gly551Ser Exon 12 1 1 1 2 1 1 G551D c.1652G>A p.Gly551Asp Exon 12 12 22 19 33 7 8 I556V c.1666A>G p.Ile556Val Exon 12 1 2 2 4 1 1 R553X c.1657C>T p.Arg553X Exon 12 3 4 2 4 0 0 R560T c.1679G>C p.Arg560Thr Exon 12 1 1 1 2 1 2 1898+1G-A c.1766 &#b1; 1G>A - Intron 13 1 1 1 2 1 1 2184delA c.2052delA p.Lys684AsnfsX38 Exon 14 1 1 0 0 0 0 G622D c.1865G>A p.Gly622Asp Exon 14 1 1 1 3 0 0 N703S c.2108A>G p.Asn703Ser Exon 14 1 2 2 3 2 2 S737F c.2210C>T p.Ser737Phe Exon 14 1 1 0 0 0 0 2622+1G-A c.2490 &#b1; 1G>A - Intron 14 1 5 5 13 1 1 2752-26A-G c.2620-26A>G - Intron 15 1 2 2 4 0 0 2789+5G-A c.2657 &#b1; 5G>A - Intron 16 3 5 4 8 0 0 3120G-A c.2988G>A - Exon 18 2 2 1 2 1 0 3067-72del c.3067_3072del p.Ile1023_Val1024del Exon 19 1 1 1 1 0 0 I1027T c.3080T>C p.Ile1027Thr Exon 19 1 1 1 1 0 0 L997F c.2991G>C p.Leu997Phe Exon 19 1 2 2 4 1 (1) 0 M1028R c.3083T>G p.Met1028Arg Exon 19 1 1 1 2 1 2 F1052V c.3154T>G p.Phe1052Val Exon 20 1 1 0 0 0 0 Y1092X c.3276C>A p.Tyr1092X Exon 20 1 2 1 2 1 1 A1136T c.3406G>A p.Ala1136Thr Exon 21 1 2 1 2 1 0 D1152H c.3454G>C p.Asp1152His Exon 21 3 7 7 15 1 1 3659 del C c.3528delC p.Lys1177SerfsX15 Exon 22 2 4 3 7 3 3 R1162X c.3484C>T p.Arg1162X Exon 22 1 3 2 5 2 2 S1235R c.3705T>G p.Ser1235Arg Exon 22 2 3 3 5 2 1 3849+10kbC>T c.3717 &#b1; 12191C>T - Intron 22 2 4 4 5 0 0 W1282X c.3846G>A p.Trp1282X Exon 23 15 20 20 42 11 11 N1303K c.3909C>G p.Asn1303Lys Exon 24 9 12 11 24 4 5 Q1352H c.4056G>C p.Gln1352His Exon 25 1 1 1 1 1 1 Total 265 404 345 685 172 (6a ) 175 Values are n unless otherwise stated. Login to comment
53 Almost half of these (195/404 cycles) were performed for DF508 mutation, one-quarter (103/404 cycles)forsixotherfrequentmutations(W1282X,R117H,G551D, G542X, N1303K, 1717-1G>A), and only a few for each of the remaining 45 CFTR mutations (Table 2). Login to comment
56 (CA)n EXON 4 (GATT)n Intron 4 Poly T tract Intron 10 R117H G--A R75XH C--T A120T G--A I148T T--C A349V C--T 1259 Ins A 621+1 G--T EXON 3 EXON 7 EXON 8 Delta I 507 EXON 10 Delta F 508 EXON 11 1717-1 G--A G542X G--T G550X G--T G551D G--A R553X C--T R560T G--C EXON 19 EXON 20 EXON 21 R1162X C--T W1282X G--A N1303K C--G IVS 1 Mutations in CFTR gene (PGD PERFORMED FOR 52 MUTATIONS) IVS 6 a IVS 8 (CA)n (CA)n IVS 17b (TA)n (CA)n D7S486 D7S522 D7S633 D7S677 D7S2847 D7S655 115,89 116.07 117.01 117.13 117.19 117.20 118.6 118.81 Mb IVS8-1 IVS8-2 Figure 1 Mutations (above) and linked markers (below) in CFTR that were used in multiplex PCR. Login to comment
81 Because the female partner was double heterozygous, involving two different mutations (R117H and G542X), and the male partner was a carrier of R117H mutation, PGD was based on blastomere biopsy. Login to comment
88 Two unaffected embryos (nos. 6 and 7) were transferred, resulting in an unaffected pregnancy and birth of a healthy baby girl, confirmed to be a carrier of the maternal G542X mutation. Login to comment
109 (Upper panel) Pedigree, showing that the maternal partner is a double-heterozygous CF-affected patient, with two different CFTR mutations, R117H and G542X, while the paternal partner is a carrier of the 1717 mutation. Login to comment

PMID: 23540394 [PubMed] Altamura N et al: "Tobramycin is a suppressor of premature termination codons."

No. Sentence Comment

73 Discussion In CF at least 5-10% of the CF alleles carry a nonsense mutation (e.g. G542X, R553X, R1162X, W1282X; CF Mutation Analysis Consortium, http://www.genet.sickkids.on.ca/cftr/) that causes a premature arrest of translational termination thus preventing the synthesis of a full-length, often non-functional or partially functional, CFTR [4]. Login to comment

PMID: 23613805 [PubMed] Schippa S et al: "Cystic fibrosis transmembrane conductance regulator (CFTR) allelic variants relate to shifts in faecal microbiota of cystic fibrosis patients."

No. Sentence Comment

37 Patient Sex Age (years) CFTR allele, = CFTR allele, R Criterion I(a) Criterion II (1 = severe, 0 = mild)(b) Pancreatic status(d) FEV1% BMI 1 M 17 F508del M1V 2 (1) 1 65 17.91 2 F 23 F508del Y569D 2 (1) 0 97 18.66 3 (s1)(c) F 20 P1013L F508del 2 (0) 0 87 18.67 4 M 11 F508del L997F (without R117L) 2 0 0 110 21.33 5 (s1)(c) M 11 P1013L F508del 2 (0) 0 100 23.14 6 M 8 R553X F508del 2 1 0 80 15.87 7 M 3 F508del unknown 2 (0) 0 nd nd 8 F 33 F508del F508del 1 1 1 73 18.61 9 M 10 F508del L1077P 2 1 0 94 19.79 10 M 9 F508del G542X 2 1 1 100 16.00 11 F 9 4167delCTAAGCC L1065P 3 nd 1 76 14.57 12 F 14 R117C (without (TG)12T5) F508del 2 0 0 94 18.44 13 F 11 F508del 991del5 2 1 1 109 17.80 14 M 42 (TG)12T5 F508del 2 0 0 106 23.78 15 (s2)(c) M 9 F508del F508del 1 1 1 82 15.45 16 M 10 F508del R347P 2 (0) 0 89 15.91 17 (s2)(c) F 6 F508del F508del 1 1 1 110 15.20 18 (s3)(c) M 39 2789+5G.A N1303K 3 nd 0 105 19.33 19 (s3)(c) F 41 2789+5G.A N1303K 3 nd 0 80 19.47 20 F 26 N1303K W1282X 3 nd 1 90 19.57 21 M 7 CFTRdele2,3 (21 kb) N1303K 3 nd 1 107 12.85 22 F 9 F508del L997F (without R117L) 2 0 0 113 25.21 23 M 7 P5L W1282X 3 nd 0 89 22.31 24 M 9 2789+5G.A F508del 2 (1) 1 97 15.60 25 F 2 F508del F508del 1 1 1 nd nd 26 F 32 N1303K N1303K 3 nd 1 107 21.22 27 M 14 L1065R T338I 3 nd 0 116 21.50 28 M 12 711+3A.G S549R(A.C) 3 nd 0 97 20.00 29 M 13 unknown R117H (without (TG)12T5) 3 nd 0 104 19.36 30 M 14 F508del G542X 2 1 1 84 21.87 31 F 13 F508del F508del 1 1 1 85 18.00 32 F 41 2789+5G.A N1303K 3 nd 1 84 21.08 33 F 21 L1065P F508del 2 (0) 0 62 18.29 34 F 50 D1152H F508del 2 (0) 0 63 23.74 35 M 29 F508del 2790-2A.G 2 (1) 0 92 24.46 36 F 45 unknown W1282X 3 nd 0 69 23.42 a (Hm = 1; Ht = 2; N = 3). Login to comment
62 Class I, II or III: G542X, W1282X, F508del, N1303K, L1065P, L1077P, Y569D, S549R(A.C). Login to comment

PMID: 23617438 [PubMed] Van de Weert-van Leeuwen PB et al: "Optimal complement-mediated phagocytosis of Pseudomonas aeruginosa by monocytes is cystic fibrosis transmembrane conductance regulator-dependent."

No. Sentence Comment

54 Immune cells were isolated from healthy control subjects and patients with CF who carried a G542X/G54X, G542X/F508 del mutation or F508 del/F508 del mutation. Login to comment
64 To confirm CFTR antibody specificity, whole-cell CFTR expression levels were compared with those of isotype control antibodies, and CF cells were derived from a subject with two CFTR nonsense mutations (G542X/G542X), a mutation of which it is known that these cells have no expression of CFTR. Login to comment
86 To confirm CFTR specificity further, whole-blood immune cells were isolated from a healthy control subject and a CF patient with two nonsense mutations (G542X/ G542X), with an expectation of absent expression of CFTR. Login to comment
88 CFTR expression in nasal epithelial cells from a healthy control subject, but not in a patient with CF (G542X/G542X), further supported the contention that our staining procedure could detect CFTR (Figure 1C). Login to comment
93 We confirmed staining specificity in CD141 monocytes from a healthy control subject and a patient with CF and a homozygous G542X/G542X mutation (Figure 2B). Login to comment
118 (B) Whole-cell CFTR (red) expression in peripheral blood immune cells of a healthy control subject, compared with a patient with a G542X/G542X mutation, using L12B4 and 570. Login to comment
119 (C) Whole-cell CFTR (green) expression in nasal epithelial cells of a healthy control subject and a patient with a G542X/G542X mutation, using L12B4. Login to comment
128 (B) Flow cytometric analysis of whole-cell CFTR expression in monocytes of a healthy control subject compared with a patient with CF and carrying a homozygous G542X mutation, using the CFTR mAbs 570 and L12B4. Login to comment

PMID: 23712087 [PubMed] Torresani T et al: "Newborn screening for cystic fibrosis in Switzerland--consequences after analysis of a 4 months pilot study."

No. Sentence Comment

48 CFTR mutation screening (2nd tier) The SNSL determined the seven most common CFTR mutations in Switzerland with an in-house developed kit (SWISS PANEL: F508del, 3905insT, G542X, R553X, W1282X, 1717-1GNA, N1303K) [10,1]. Login to comment

PMID: 23724185 [PubMed] Farjadian S et al: "Clinical and genetic features in patients with cystic fibrosis in southwestern iran."

No. Sentence Comment

10 The G542X, R334W and N1303K mutations were detected each in one patient, the first of whom was also a ࢞F508 carrier. Login to comment
26 Genomic DNA was extracted from 200 &#b5;L of whole blood with the QiaAmp DNA Mini Kit (Qiagen, Valencia, CA, USA) and 29 common CFTR gene mutations (D1152H, 1717-1G>A, G542X, W1282X, N1303K, ࢞F508, 3849+10kbC>T, 394delTT, 621+1G>T, S1251N, G551D, R117H, R1162X, R334W, A455E, 2183AA>G, 3659delC, 1078delT, ࢞I507, R347P, R553X, E60X, 3120+1G>A, 2789+5G>A, 1898+1G>A, 711+1G>T, G85E, 2184delA and R560T) were analyzed with the ELUCIGENE CF29 v. 2 kit using four multiplex PCR. Login to comment
33 Table 1: Early clinical symptoms in patients from southwestern Iran with cystic fibrosis (n=45) Frequency Clinical symptoms 38 (84%) Chronic cough Respiratory symptoms 37 (82%) Bronchiolitis 35 (78%) Recurrent pneumonia 34 (76%) Purulent sputum 31(69%) Recurrent wheeze 18 (40%) Atelectasias 6 (13%) Bronchiectasis 4 (9%) Recurrent sinusitis 2 (4%) Hemoptysis 1(2%) Cor pulmonale 37 (82%) Steatorrhea Gasterointestinal symptoms 24 (53%) Growth failure 9 (20%) Liver disease 6 (13%) Distal intestinal obstruction 3 (7%) Diarrhea 2 (4%) Constipation 2 (4%) Meconium ileus 2 (4%) Dehydration Other symptoms 2 (4%) Heat exhaustion --- Vasculitis --- Diabetes 214 CFTR Gene Mutations in CF Patients Iran J Pediatr; Vol 23 (No 2), Apr 2013 Published by: Tehran University of Medical Sciences (http://ijp.tums.ac.ir) Table 2: Frequencies of CFTR gene mutations in a sample of patients in southwestern Iran with cystic fibrosis n=45 CFTR gene mutations 8 (18%) ࢞F508 (M)/ ࢞F508 (M) 3 (7%) ࢞F508 (N)/ 2183AA>G 2 (4%) ࢞F508 (N)/ R1162X 1 (2%) ࢞F508 (N)/ R334W 1 (2%) ࢞F508 (N)/ N1303K 1 (2%) ࢞F508 (M)/ G542X 1 (2%) ࢞F508 (M)/ 2183AA>G 1 (2%) ࢞F508 (M)/ ࢞F508 (N) 27 (60%) Undefined Parental consanguinity was found in 40 patients (89%) and a family history of CF was reported by 15 patients (37%) in this group. Login to comment
82 Jalalirad M, Houshmand M, Mirfakhraie R, et al. First study of CF mutations in the CFTR gene of Iranian patients: detection of DeltaF508, G542X, W1282X, A120T, R117H, and R347H mutations. Login to comment

PMID: 23727931 [PubMed] Dekkers JF et al: "A functional CFTR assay using primary cystic fibrosis intestinal organoids."

No. Sentence Comment

127 (d) Forskolin-induced swelling of rectal organoids derived from three individual healthy controls, two individuals with a mild cystic fibrosis genotype (F508del A455E) and nine individuals with a severe cystic fibrosis genotype (one individual with E60X 4015ATTTdel, one with F508del G542X, one with F508del L927P and six with F508del F508del). Login to comment
134 (Healthy controls, n = 3; mild cystic fibrosis, n = 2; severe cystic fibrosis (F508del F508del), n = 5; severe cystic fibrosis (other; E60X 4015ATTTdel and F508del G542X), n = 2; mean &#b1; s.d.). Login to comment
150 0 500 1,000 1,500 2,000 2,500 0 500 1,000 1,500 2,000 2,500 3,000 0 400 800 1,200 1,600 C8 Corr-4a C8 + Corr-4a VX-809 VX-770 VX-809 + VX-770 VRT-325 Corr-4a VRT-325 + Corr-4a CF1 CF6 CF5 CF4 CF3 CF2 F508del L927P F508del G542X E60X 4015delATTT F508del F508del b d a c 0 20 40 60 80 100 120 V R T - 3 2 5 C o r r - 4 a C 8 V X - 8 0 9 V X - 7 7 0 V R T - 3 2 5 + C o r r - 4 a C 8 + C o r r - 4 a V X - 8 0 9 + V X - 7 7 0 C o n t r o l C o n t r o l F508del F508del HC F508del A455E Organoid swelling (absolute AUC t = 60) Organoid swelling (absolute AUC t = 60) Organoid swelling (absolute AUC t = 60) Organoid swelling (normalized AUC t = 60) Figure 5ߒ Differential FIS between organoids from subjects with cystic fibrosis after chemical CFTR restoration. Login to comment
390 Rectal organoids from healthy controls and subjects with cystic fibrosis were generated from four rectal suction biopsies after ICMs obtained (i) during standard cystic fibrosis care (one individual each harboring E60X 4015ATTTdel, F508del G542X or F508del L927P and five individuals harboring F508del F508del), (ii) for diagnostic purposes (one healthy control) or (iii) during voluntary participation in studies approved by the University Medical Center Utrecht and Erasmus MC ethics committees (two healthy controls and one individual harboring F508del F508del). Login to comment

PMID: 23758905 [PubMed] de Lima Marson FA et al: "Genetic interaction of GSH metabolic pathway genes in cystic fibrosis."

No. Sentence Comment

54 Data was recorded by the PF BREEZE software version 3.8B for Windows 95/98/NT [32] and the following markers were included: forced Table 2 Genotypic characteristic of gene polymorphisms at GCLC, GSTM1, GSTT1, and GSTP1 genes and CFTR gene mutation among cystic fibrosis patients Gene Chromosome position Location Variation Genotype MAF p* C/C C/T T/T GCLC, rs17883901 6p12 Promoter region C/T 144 (80%) 29 (16.11%) 7 (3.89%) 0.12 <0.005 1 A/A A/G G/G GCLC, rs137852340 6p12 Promoter region A/G 118 (65.56%) 56 (31.11%) 6 (3.33%) 0.19 >0.05 GSTP1, rs1695 11q13 Exon 5 A/G 97 (53.89%) 74 (41.11%) 9 (5%) 0.26 >0.05 Wt/Wt + Wt/del del/del GSTM1 1p13.3 Deletion 108 (60%) 72 (40%) GSTT1 22q11.23 Deletion 117 (65%) 63(35%) CFTR mutation genoytpe N Frequency F508del/F508del 57 31.67% F508del/G542X 12 6.67% F508del/R1162X 5 2.78% F508del/N1303K 4 2.22% F508del/R553X 1 0.56% F508del/S4X 1 0.56% F508del/1717-1G>A 1 0.56% G542X/R1162X 1 0.56% G542X/I618T 1 0.56% G542X/2183A>G 1 0.56% R1162X/R1162X 1 0.56% F508del/- 45 25.00% G542X/- 5 2.78% R1162X/- 1 0.56% -/- 44 24.45% GCLC glutamate-cysteine ligase catalytic subunit, GSTM1 Glutathione S-transferase Mu 1, GSTT1 Glutathione S-transferase theta 1, GSTP1 Glutathione S-transferase P1, CFTR Cystic fibrosis transmembrane conductance regulator, C Cytosine, T Thymine, A Adenine, G Guanine, < minor than, > bigger than, MAF minor allele frequency, % percentage, *p value for Hardy-Weinberg Equilibrium, N number of patients, Wt Wild allele, del deleted allele, (-) CFTR mutation no identified. Login to comment
59 The CFTR gene mutations were investigated by PCR technique (F508del) and the restriction fragment length polymorphism (RFLP) method (G542X, R1162X, R553X, G551D and N1303K). Login to comment

PMID: 23791427 [PubMed] Jabr S et al: "Quantification of major urinary metabolites of PGE2 and PGD2 in cystic fibrosis: correlation with disease severity."

No. Sentence Comment

113 Mutations Mutation class Severity Number Pancreatic sufficiency (n) W128X/W128X I/I Severe 1 0 I507/Q890X I/I Severe 1 0 F508del/G542X II/I Severe 2 0 F508del/2188AA4G II/I Severe 1 0 F508del/N1303K II/I Severe 3 0 F508del/1677delTA II/I Severe 1 0 F508del/2188AA4G II/I Severe 1 0 F508del/F508del II/II Severe 10 0 F508del/Q890X II/II Severe 1 0 F508del/E1308X II/II Severe 1 0 F508del/5T-12TG II/III Moderate 2 0 G542X/G85V I/III Moderate 1 0 F508del/124del23kbp II/III Moderate 1 0 G542X/M1137V I/III Moderate 1 1 I507/L206W I/IV Mild 1 0 F508del/L206W I/IV Mild 4 2 711+1G4L206W I/IV Mild 1 1 N1303K/3272-26A4G I/IV Mild 1 1 F508del/F587I II/V Mild 1 1 n&#bc;Number. Login to comment

PMID: 23810505 [PubMed] Prach L et al: "Novel CFTR variants identified during the first 3 years of cystic fibrosis newborn screening in California."

No. Sentence Comment

26 Newborns were screened using the California method, which includes i) analysis of serum immunoreactive trypsinogen (IRT) levels using the AutoDELFIA neonatal IRT L kit (PerkinElmer, Waltham, MA) in all newborn blood spot specimens, ii) CFTR mutation panel [29-40 mutations (the mutations on the California panel were selected for the most part according to allelic frequencies found in a comprehensively genotyped group of California CF cases to achieve a 95% race/ethnicity-specific rate of CF case detection in black, white, and Hispanic individuals in California and include c.1585-1G>A, c.1680-1G>A, c.1973-1985del13insAGAAA, c.2175_2176insA, c.164 &#fe; 2T>A (removed on August 12, 2008), c.2988 &#fe; 1G>A, c.3717 &#fe; 12191C>T, c.3744delA, c.274-1G>A, c.489 &#fe; 1G>T, c.579 &#fe; 1G>T, p.A559T, p.F311del, p.F508del, p.I507del, p.G542X, p.G551D, p.G85E, p.H199Y, p.N1303K, p.R1066C, p.R1162X, p.R334W, p.R553X, p.S549N, p.W1089X, p.W1204X (c.3611G>A), p.W1282X, c.1153_1154insAT [added October 4, 2007], c.1923_1931del9insA, c.3140-26A>G, c.531delT, c.803delA, c.54-5940_273 &#fe; 10250del21kb, p.P205S, p.Q98R, p.R75X, p.S492F [added December 12, 2007], c.3659delC, p.G330X, p.W1204X [c.3612G>A] [added August 12, 2008] [Signature CF 2.0 ASR; Asuragen Inc., Austin, TX])] testing of specimens with IRT 62 ng/mL (highest 1.5%), iii) CFTR gene scanning and sequence analysis (Ambry Test: CF; Ambry Genetics, Aliso Viejo, CA) for specimens found to have only one mutation after CFTR mutation panel testing, and iv) referral to 1 of 15 pediatric CF care centers (CFCs) for sweat chloride (SC) testing and follow-up of all newborns with either two CFTR mutations detected during panel testing or one CFTR mutation detected during panel testing and one (or more) additional CFTR mutation and/or variant detected during sequencing. Login to comment
59 of parents receiving CFTR mutation testing Diagnosis/ status Study participants with positive NBS results 1 W, H 83.5 p.F508del* c.2554_2555insTy 7T/9T 2 CF 2 H 527.0 p.F508del c.-877C>T p.F1107L 7T/9T 0 CF 3 W 86.5 p.F508del p.V562Iy c.-837T>Cy 5Tyz /9T 1 CF 4 H 222.3 p.F508del p.I556V c.1278delC NA 0 CF 5 H, O 93.5 p.F508del* c.-152G>Cy 7T/9T 2 CF 6 W, H, B, O 95.4 p.F508del* p.L323Py 5Tyz /9T 2 CF 7 H 70.5 p.F508del p.L32M 7T/9T 0 CF 8 W 209.5 p.F508del c.2883_2886dupGTCA 9T/9T 0 CF 9 H 155.7 p.F508del* c.2349_2350insT 7T/9T 1 CF 10 O 146.8 p.F508del* c.3718-24G>Ay 5Tyx /9T 2 CF 11 B 99.4 p.A559T* p.L206Wy c.-448A>G* 7T/9T 2 CF 12 W, H 90.3 p.P205S p.K114del 7T/7T 0 CF 13 H 69.7 p.P205S p.K114del 7T/7T 0 CF 14 H 82.9 c.274-1G>A* c.-602A>Ty 7T/7T 2 CF 15 W 106.6 p.F508del* c.-461A>Gy c.-983A>T* 7T/9T 2 CRMS 16 W, B 83.9 p.F508del c.4243-5C>T 5T*x /9T 1 CRMS 17 W 81.5 p.F508del* p.I1027T* p.Y325C 7T/9T 2 CRMS 18 H 70.7 p.F508del c.-967T>C 9T/9T 0 CRMS 19 W, H 62.4 p.F508del* c.-635A>G 7T/9T 1 CRMS 20 H 65.4 p.F508dely c.2490 &#fe; 14G>T* 7T/9T 2 CRMS 21 W 69.3 p.F508del* c.744-15T>Cy 7T/9T 2 CRMS 22 W, H, O 66.2 p.F508del p.D249Y 7T/9T 0 CRMS 23 H 94.8 p.F508del p.R811S 7T/9T 0 CRMS 24 W 75.8 p.F508del* p.H1375Ny 7T/9T 2 CRMS 25 H 63.0 p.F508del p.L136P 7T/9T 0 CRMS 26 W, O 63.0 p.F508del* p.M1140L 7T/9T 1 CRMS 27 W, O 91.7 p.F508del p.V1198M 9T/9T 0 CRMS 28 H 69.3 p.F508dely c.1767-13T>G* 7T/9T 2 CRMS 29 H 108.8 p.F508del p.V1322L 7T/9T 0 CRMS 30 H 96.4 p.F508dely p.C76R* 7T/9T 2 CRMS 31 H 69.0 c.3140-26A>G c.-510G>A* 7T/7T 1 CRMS 32 H 100.2 p.G542X c.-684G>A* 7T/9T 1 CRMS 33 H 84.1 c.1153_1154insAT* c.-730A>Gy 7T/7T 2 CRMS 34 H 62.9 c.1973_ 1985del13insAGAAA* p.D112Gy 7T/7T 2 CRMS 35 H 116.7 c.3744delA* p.T887P 7T/7T 1 CRMS 36 B 73.3 c.2988 &#fe; 1G>A c.-288G>C 7T/9T 0 CRMS 37 H 93.5 p.R75X c.3367 &#fe; 3A>C 7T/7T 0 CRMS 38 W, H 81.4 c.3717 &#fe; 12191C>T* c.-769A>Gy 7T/7T 2 CRMS 39 W 79.0 c.3717 &#fe; 12191C>Ty p.R668Cy p.T1396P* 7T/9T 2 CRMS 40 H 87.3 c.274-1G>A p.F315S 7T/7T 0 CRMS 41 H 79.7 p.G542X c.869 &#fe; 8G>T 7T/9T 0 CRMS 42 O 79.8 p.R553X p.T1478R 7T/7T 0 CRMS 43 H 70.5 p.A559T* c.-448A>G* 7T/7T 2 Carrier 44 B 76.2 p.A559T* c.-448A>G* 7T/7T 1 Carrier 45 W, H 69.2 p.G85E* c.744-15T>C* 5Tyz /7T 2 Carrier 46 W 69.1 p.N1303K* c.2490 &#fe; 14G>A* 7T/9T 1 Carrier 47 W, O 111.7 p.F508del c.3963 &#fe; 6G>T 7T/9T 0 ND{ 48 W 80.1 p.F508del p.R1128G 7T/9T 0 ND{ (table continues) sequencing. Login to comment

PMID: 23818513 [PubMed] Rowe SM et al: "Cystic fibrosis transmembrane regulator correctors and potentiators."

No. Sentence Comment

9 The F508del mutation, which is present in at least one allele in 90% ofCFpatients,impairsCFTRfolding,stabilityat the endoplasmic reticulum and plasma membrane, and chloride channel gating (Dalemans etal.1991;Denningetal.1992;Lukacsetal.1993; Duetal.2005a).Othermutationsprimarilyalter channelgating(e.g.,G551D),conductance(e.g., R117H),ortranslation(e.g.,G542X)(Welshand Smith1993).ThefundamentalpremiseofCFTR corrector and potentiator therapy for CF is that Editors: John R. Riordan, Richard C. Boucher, and Paul M. Quinton Additional Perspectives on Cystic Fibrosis available at www.perspectivesinmedicine.org Copyright # 2013 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/cshperspect.a009761 Cite this article as Cold Spring Harb Perspect Med 2013;3:a009761 1 correction of the underlying defects in the cellular processing and chloride channel function of CF-causing mutant CFTR alleles will be of clinical benefit. Login to comment

PMID: 23866907 [PubMed] Landaburu I et al: "Genetic testing of sperm donors for cystic fibrosis and spinal muscular atrophy: evaluation of clinical utility."

No. Sentence Comment

51 The panel of mutations studied was: S549N, S549R, R553X, G551D, V520F, I507del, F508del, 3876delA, 1717-1G->A, G542X, R560T, 3120+1G->A, A455E, R117H, 394delTT, 2183AA- >G, 2184delA, 2789+5G->A, 1898+1G->A, 621+1G->T, 711+1G- >T, G85E, R347P, R347H, W1282X, R334W, 1078delT, 3849+10kbC->T, R1162X, N1303K, 3659delC, 3905insT. Login to comment
68 With respect to the relative distribution of the mutations observed, 3 of the 5 cases (60%) were F508del, and the remaining two (40%) were G542X. Login to comment
105 With regard to the relative frequency of mutations detected in our donor candidate population, two different mutations, F508del and G542X, were detected. Login to comment

PMID: 23922647 [PubMed] Rowe SM et al: "Optimizing nasal potential difference analysis for CFTR modulator development: assessment of ivacaftor in CF subjects with the G551D-CFTR mutation."

No. Sentence Comment

66 Characteristic Part 1 Part 2 Placebo (n = 4) Ivacaftor TOTAL (n = 20) Placebo (n = 4) Ivacaftor TOTAL (n = 19) 25 mg/75 mg (n = 4) 75 mg/25 mg (n = 4) 75 mg/150 mg (n = 4) 150 mg/75 mg (n = 4) 150 mg (n = 8) 250 mg (n = 7) Sex, n (%) Male 2 (50) 1 (25) 4 (100) 1 (25) 1 (25) 9 (45) 3 (75) 3 (38) 4 (57) 10 (53) Female 2 (50) 3 (75) 0 3 (75) 3 (75) 11 (55) 1 (25) 5 (63) 3 (43) 9 (47) Race, n (%) White 4 (100) 4 (100) 4 (100) 4 (100) 4 (100) 20 (100) 4 (100) 8 (100) 7 (100) 19 (100) Age, yr, median (range) 36 (19-48) 31 (22-51) 41 (22-50) 26 (19-34) 21 (19-33) 30 (19-51) 24 (18-42) 23 (18-40) 21 (20-38) 21 (18-42) BMI, kg/m 2 , median (range) 23 (22-29) 23 (20-24) 24 (19-27) 20 (19-24) 21 (17-26) 23 (17-29) 22 (21-23) 22 (20-23) 23 (20-25) 22 (20-25) CFTR genotype G551D/F508del 3 (75) 4 (100) 4 (100) 2 (50) 3 (75) 16 (80) 4 (100) 7 (88) 5 (71) 16 (84) G551D/1078delT 1 (25) - - - - 1 (5) - - - - G551D/G551D - - - - 1 (25) 1 (5) - - - - G551D/N1303K - - - 1 (25) - 1 (5) - - - - G551D/R553X - - - 1 (25) - 1 (5) - - - - G551D/3849+10 kbC - - - - - - - - 1 (14) 1 (5) G551D/6214R1G+7T - - - - - - - 1 (13) - 1 (5) G551D/G542X - - - - - - - - 1 (14) 1 (5) % Predicted FEV 1 , median (range) 40% to ,70%, n (%) 3 (75) 3 (75) 4 (100) 2 (50) 4 (100) 16 (80) 2 (50) 5 (63) 3 (43) 10 (53) 70% to ,90%, n (%) - - - 1 (25) - 1 (5) .90%, n (%) - 1 (25) - 1 (25) - 3 (15) 2 (50) 1 (13) 1 (14) 4 (21) Sweat chloride, mmol/L, median (range) 105.25 (97.00- 112.00) 107.50 (60.00-117.00) 104.50 (102.00-117.00) 97.50 (92.00-102.50) 99.00 (83.00-104.00) 102.00 (60.00-117.00) 93.75 (88.00- 109.50) 100.13 (86.75- 112.50) 97.25 (84.75- 115.75) 95.50 (84.75- 115.75) BMI, body-mass index; CFTR, cystic fibrosis transmembrane conductance regulator; FEV 1 , forced expiratory volume in one second. Login to comment

PMID: 23934280 [PubMed] Lee RJ et al: "Vasoactive intestinal peptide regulates sinonasal mucociliary clearance and synergizes with histamine in stimulating sinonasal fluid secretion."

No. Sentence Comment

182 To further test the role of CFTR in this synergistic fluid secretion, we measured basal and stimulated ASL heights in ALI cultures derived from CF patient cells (nafd;3 patients; genotypes were èc;F508/èc;F508, W1282X/N1303K, and èc;F508/G542X). Login to comment

PMID: 23934925 [PubMed] Rab A et al: "Cigarette smoke and CFTR: implications in the pathogenesis of COPD."

No. Sentence Comment

69 Only six other mutations have a frequency of greater than 1% in the CF population (G542X, W1282X, G551D, 621 af9; G&#a1;T, N1303K, and R553X) (157). Login to comment
123 Alternative approaches have included high-throughput screens to identify small molecules that promote either 1) F508del CFTR rescue and delivery to the cell surface (108), 2) read-through of premature stop mutations to override nonsense mutations and help translation to produce full-length proteins (e.g., G542X, W1282X, etc.) (160), or 3) potentiation of channel-gating mutations such as G551D (151). Login to comment

PMID: 23953609 [PubMed] Lu S et al: "Different cystic fibrosis transmembrane conductance regulator mutations in Chinese men with congenital bilateral absence of vas deferens and other acquired obstructive azoospermia."

No. Sentence Comment

70 In this study, we analyzed exons 10 and 11 CFTR gene in CBAVD and other acquired obstructive azoospermia because common mutations such as F508del, D507, G551D, G542X, R560T, and R553X associated with CF in Caucasians were frequently identified in these exons. Login to comment

PMID: 23977124 [PubMed] Cifani N et al: "Reactive-oxygen-species-mediated P. aeruginosa killing is functional in human cystic fibrosis macrophages."

No. Sentence Comment

61 Patient Age Gender Genotype CF13 23 F F508del/F508del CF14 30 F F508del/W1282X CF15 16 F F508del/574delA CF16 34 M F508del/unknown CF17 15 M F508del/F508del CF18 24 F F508del/2,3del21Kb CF19 30 M F508del/F508del CF20 35 F N1303K/H119R CF21 52 M F508del/F508del CF22 30 M F508del/F508del CF23 41 M F508del/F508del CF24 33 M F508del/S549R(A_.C) CF25 39 M F508del/G542X CF26 31 F W1282X/W1282X CF27 30 M F508del/N1303K CF28 28 F F508del/F508del CF29 31 F F508del/G542X doi:10.1371/journal.pone.0071717.t001 CFTR expression was analysed on RNA samples isolated from non-CF macrophages using real-time PCR, as previously reported [21]. Login to comment

PMID: 23983009 [PubMed] Devesa I et al: "Targeting protein-protein interactions to rescue Deltaf508-cftr: a novel corrector approach to treat cystic fibrosis."

No. Sentence Comment

6 The CF phenotype is caused by more than 1000 mutations of the CFTR gene including missense, such as R117H or G551D that significantly reduce channel activity, and nonsense like G542X, R553X or W1282X, which abrogate protein expression (Kreindler, 2010). Login to comment

PMID: 24014130 [PubMed] Langfelder-Schwind E et al: "Molecular testing for cystic fibrosis carrier status practice guidelines: recommendations of the National Society of Genetic Counselors."

No. Sentence Comment

172 G542X, W1282X II Cause structural alterations to the CFTR protein and prevent it from moving to the cell surface. Login to comment

PMID: 24030637 [PubMed] Deeks ED et al: "Ivacaftor: a review of its use in patients with cystic fibrosis."

No. Sentence Comment

37 The in vitro effect of ivacaftor on CFTR mutant proteins with minimal chloride transport, such as those with mutations affecting CFTR synthesis (e.g. G542X) [5] or severely affecting CFTR conductance (e.g. R334W) or processing (e.g. F508del [13]) [5, 16], was minimal [5, 13] or less than its effect on CFTR proteins with mild conductance or processing defects [16]. Login to comment

PMID: 24040112 [PubMed] Clancy JP et al: "Multicenter intestinal current measurements in rectal biopsies from CF and non-CF subjects to monitor CFTR function."

No. Sentence Comment

223 In addition, Bedwell and colleagues have shown that transgenic mice carrying the human G542X mutation in CFTR that are treated with suppressors of premature termination codons (aminoglycosides, ataluren) have detectable CFTR function in intestinal tissue studied by ICM [46-49]. Login to comment

PMID: 24106596 [PubMed] Mehdizadeh Hakkak A et al: "Analysis of CFTR Gene Mutations in Children with Cystic Fibrosis, First Report from North-East of Iran."

No. Sentence Comment

7 Results: Among 112 alleles, 24 mutated alleles (21.42%) were detected: ƊF508 (10.71%), 1677delTA (3.57%), S466X (3.57%), N1303K (0.89%), G542X (0.89%), R344W (0.89%), L467F (0.89%). Login to comment
20 Although, the prevalence and types of mutations vary in different populations based on their geographic and ethnic origins (9, 10), a few mutations (p.F508del, p.G542X, p.N1303K, p.G551D, p.W1282X) have higher frequencies than others. Login to comment
53 Demographic, clinical, and family characterizations of patients with specific CFTR mutation No of patients Sex Sweat chloride (meq/lit) Pancreatic insufficiency Age of clinical presentation onset (month) First clinical symptom/sign Consanguinity of parents Mutation status 1 M 110 + 6 Steatorrhea/Hepatomegaly First cousin ƊF508/ ƊF508 2 M 115 + 5 Steatorrhea/Cough/ Hepatomegaly First cousin ƊF508/ ƊF508 3 F 130 + 2 Steatorrhea/Cough Wheezing/Skin rash First cousin ƊF508/ ƊF508 4 F 180 + 1 Steatorrhea/Cough/Vomiting/E dema/Hepatomegaly First cousin ƊF508/ ƊF508 5 M 93 + 3.5 FTT/Steatorrhea First cousin once removed ƊF508/ ƊF508 6 M 100 + At birth Wheezing/Meconium ileus - ƊF508/U* 7 M 115 + 2 Steatorrhea/Cough/Fever First cousin once removed ƊF508/U 8 M 90 + 6 Cough/Wheezing - N1303K/U 9 F 70 + At birth Meconium ileus/Crackle First cousin G542X/U 10 F 80 - 5 Cough/Wheezing/Fever - R334W/U 11 M 109 + 1 Fever/Wheezing/Cough Second cousin S466X/ S466X 12 M 120 + 10 Cough/Wheezing/Steatorrhea - S466X/U 13 M 100 + At birth Wheezing/Meconium ileus First cousin S466X/U 14 M 100 + 5.5 Rectal prolapse/Cough/ Wheezing/Steatorrhea First cousin 1677delTA/ 1677delTA 15 M 85 + 3 FTT/Sreatorrhea/Wheezing/ Cough First cousin 1677delTA/ 1677delTA 16 F 93 + 4 Steatorrhea - 1531C/T (L467F)/U * Unknown mutation PCR-RFLP was operated for identification of p.Arg334Trp and p.Arg347Pro mutations and revealed only one heterozygote status for p.Arg334Trp mutation. Login to comment
65 Total chromosomes: 100%, known mutations: 21.42%, unknown mutations: 78.58% cDNA name Protein name Legacy name Number of chromosomes detected Exon/Intron Description Detection method c.1000C>T p.Arg334Trp R334W 1 (0.89* -4.16 &#f0ff; ) Exon 8 C to T at 1132 PCR-RFLP c.1397C>G p.Ser466X S466X 4 (3.57 - 16.66) Exon 11 C to G at 1529 Sequencing c.1399C>T p.Leu467Phe 1531C/T (L467F) 1 (0.89 - 4.16) Exon 11 C or T at 1531 Sequencing c.1521-1523delCTT p.Phe508del ƊF508 12 (10/71 - 50) Exon 11 deletion of 3 bp between 1652 and 1655 ARMS and Sequencing c.1545-1546delTA p.Tyr515X 1677delTA 4 (3.57 - 16.66) Exon 11 deletion of TA from 1677 Sequencing c.1624G>T p.Gly542X G542X 1 (0.89 - 4.16) Exon 12 G to T at 1756 ARMS c.3909C>G p.Asn1303Lys N1303K 1 (0.89 - 4.16) Exon 24 C to G at 4041 ARMS * % of all analyzed chromosomes &#f0ff; % of all mutated chromosomes Alibakhshi et al (2008) (13) explored 69 Iranian CF patients sampled from different geographic areas and ethnic groups around Iran. Login to comment

PMID: 24183914 [PubMed] Guo JJ et al: "Genotype-specific alterations in vascular smooth muscle cell function in cystic fibrosis piglets."

No. Sentence Comment

12 The second most common CF-causing mutation (G542X) prematurely terminates CFTR transcription [1]. Login to comment

PMID: 24210900 [PubMed] Berkhout MC et al: "Sinonasal manifestations of cystic fibrosis: a correlation between genotype and phenotype?"

No. Sentence Comment

163 Genotype Frequency; N (%) Class of mutation F508del/F508del 61 (58.7) I-III F508del/3849 + 10kbC 2 (1.9) IV-V F508del/N1303K 2 (1.9) I-III F508del/R1162X 2 (1.9) I-III F508del/A455E 12 (11.5) IV-V F508del/3272-26A N G 5 (4.8) IV-V F508del/E528X 1 (1.0) I-III F508del/S1251N 3 (2.9) IV-V F508del/R75Q 1 (1.0) IV-V F508del/G542X 2 (1.9) I-III F508del/1717-1G N A 1 (1.0) I-III F508del/Ser489X 1 (1.0) I-III F508del/4382delA 1 (1.0) -a F508del/L1077 1 (1.0) I-III F508del/1813insC 1 (1.0) -b A455E/S1251N 1 (1.0) IV-V A455E/E60X 1 (1.0) IV-V 3272-26A N G/G970R 1 (1.0) IV-V 3272-26A N G/R1162X 1 (1.0) IV-V F508del/UNK 2 (1.9) -c R117H-7T/UNK 1 (1.0) -d UNK/UNK 1 (1.0) -e Total 104 (100.4) One patient with pancreatic sufficiency and diagnosed at 46 years of age (class IV-V). Login to comment

PMID: 24251786 [PubMed] Xue X et al: "Synthetic aminoglycosides efficiently suppress cystic fibrosis transmembrane conductance regulator nonsense mutations and are enhanced by ivacaftor."

No. Sentence Comment

1 Using a dual-luciferase reporter system containing the four most prevalent CF transmembrane conductance regulator (CFTR) nonsense mutations (G542X, R553X, R1162X, and W1282X) within their local sequence contexts (the three codons on either side of the PTC), we found that NB124 promoted the most readthrough of G542X, R1162X, and W1282X PTCs. Login to comment
3 NB124 restored CFTR function to roughly 7% of wild-type activity in primary human bronchial epithelial (HBE) CF cells (G542X/ delF508), a highly relevant preclinical model with endogenous CFTR expression. Login to comment
5 NB124 treatment rescued CFTR function in a CF mouse model expressing a human CFTR-G542X transgene; efficacy was superior to gentamicin and exhibited favorable pharmacokinetic properties, suggesting that in vitro results translated to clinical benefit in vivo. Login to comment
28 For example, poly-L-aspartic acid, a compound previously shown to significantly reduce aminoglycoside toxicity, was found to increase both the level and duration of readthrough in a CFTR-G542X transgenic mouse (13). Login to comment
34 One of the early compounds produced, NB54, suppressed PTCs to a level comparable to gentamicin in immortalized and primary human CF cells, as well as in the CFTR-G542X transgenic mouse model, while exhibiting low toxicity, suggesting a potential advantage of this approach (21). Login to comment
43 Dual Luciferase Assay Readthrough cassettes contained the G542X, R553X, R1162X, or W1282X CFTR PTCs (or the corresponding wild-type codon) together with three codons of upstream and downstream human CFTR sequence (Figure 2A; see also Table E1 in the online supplement). Login to comment
62 Cftr knockout mice expressing a human CFTR-G542X transgene under intestine-specific rat fatty acid binding protein were treated by subcutaneous injection once daily for 14 days (6, 13, 15). Login to comment
76 To test suppression of the four most common CFTR PTCs (G542X, R553X, R1162X, and W1282X), we constructed dual-luciferase reporters that each contained a Renilla gene, a firefly gene, and a CFTR readthrough cassette with each PTC, and the context of three additional codons on either side of the PTC (Figure 2A). Login to comment
95 Initially, we treated the CFTR-corrected CFBE41o2 cells expressing the G542X dual-luciferase reporter with NB124. Login to comment
108 To assess the efficacy of synthetic aminoglycosides, FRT-G542X cells were treated for 48 hours, then CFTR activity determined by the change in Gt after forskolin (10 mM) activation. Login to comment
115 When taken together, these results indicated that NB124 suppresses the relatively common CFTR-G542X mutation more efficiently than other tested aminoglycosides. Login to comment
119 We therefore next used CFTR functional assays on primary HBE cells (CFTR genotype G542X/ delF508) to evaluate the PTC suppression efficacy of synthetic aminoglycosides. Login to comment
124 Partial Restoration of CFTR Function in Cftr2/2 Mice Expressing a Human CFTR-G542X Transgene The in vitro results described previously here demonstrate that several synthetic aminoglycosides suppress CFTR PTCs more effectively than gentamicin, with NB124 most effectively restoring CFTR function across several clinically relevant alleles, including CFTR-G542X, the most common disease-causing nonsense allele. Login to comment
125 Based on those results, we next tested the ability of NB124 to suppress CFTR in a Cftr knockout mouse line expressing a human CFTR-G542X transgene under control of the intestine-specific rat fatty acid-binding protein promoter (referred to hereafter as Cftr2/2 hCFTR-G542X). Login to comment
128 Figures 5A and 5B show representative Isc tracings from Cftr1/1 hCFTR-G542X and Cftr2/2 hCFTR-G542X mice (positive and Figure 3. Login to comment
129 Improved CFTR function and expression in CFTR-G542X-expressing Fischer rat thyroid (FRT) monolayers. Login to comment
133 *P , 0.05, ***P , 0.001, ****P , 0.0001 versus vehicle or gentamicin negative controls, respectively), and Figures 5C and 5D show Isc tracings from Cftr2/2 hCFTR-G542X mice treated with 60 mg/kg gentamicin and 30 mg/kg NB124, respectively. Login to comment
134 These data are summarized in Figure 5E, which shows a scatter plot of forskolin-stimulated Isc from ileum samples obtained from untreated and treated Cftr2/2 hCFTR-G542X mice. Login to comment
135 The mean forskolin-stimulated Isc was 5.7 (6 3.7) mA/cm2 in ileum samples from untreated Cftr2/2 hCFTR-G542X mice (negative controls), and 255.7 (6 36.1) mA/cm2 in samples from wild-type mice (positive controls). Login to comment
136 In Cftr2/2 hCFTR-G542X mice treated with 30 mg/kg gentamicin, we did not observe a significant increase in Isc relative to the untreated controls (5.3 6 4.1 mA/cm2 ). Login to comment
138 In contrast, significant increases in forskolin-stimulated Isc were observed in Cftr2/2 hCFTR-G542X mice treated with 30 and 60 mg/kg NB124 (14.7 6 7.8 and 12.4 6 9.2, respectively). Login to comment
141 When taken together, these results indicate that NB124 restores greater CFTR function (and at a 2-fold lower dose) than gentamicin in Cftr2/2 hCFTR-G542X transgenic mice, and has a slightly more favorable dose-response relationship. Login to comment
152 Because reliable readthrough assays in primary HBE cell monolayers and in vivo found that NB124 suppresses the G542X-CFTR nonsense mutation roughly 2.5-fold more effectively than gentamicin in vivo, these results indicate that the efficacy:toxicity ratio of NB124 is approximately 10-fold better than gentamicin. Login to comment
156 Restoration of CFTR function in CF primary human bronchial epithelial (HBE) cells derived from a G542X/F508del donor. Login to comment
170 Representative tracings of (A) untreated Cftr1/1 hCFTR-G542X mice (WT control), (B) untreated Cftr2/2 hCFTR-G542X (negative control), (C) gentamicin-treated Cftr2/2 hCFTR-G542X (60 mg/ kg), and (D) NB124-treated Cftr2/2 hCFTR-G542X (30 mg/kg). Login to comment
171 (E) Scatter plot of all data from Cftr2/2 hCFTR-G542X mice (untreated, gentamicin treated, and NB124 treated). Login to comment
177 Representative images are shown from (F) untreated Cftr2/2 hCFTR-G542X (negative control), (G) gentamicin-treated Cftr2/2 hCFTR-G542X (60 mg/kg), and (H) NB124-treated Cftr2/2 hCFTR-G542X (30 mg/kg). Login to comment
193 We found that three CFTR UGA mutations (G542X, R1162X, and W1282X) exhibited qualitatively similar responses to the compounds and showed maximal suppression with NB124. Login to comment
216 Finally, we used a mouse model that expressed a human CFTR-G542X transgene in a Cftr knockout background to compare the functional results obtained with NB124 and gentamicin (Figure 5). Login to comment

PMID: 24309546 [PubMed] Durupt S et al: "[Therapeutic update in cystic fibrosis]."

No. Sentence Comment

110 Classe I II III D&#e9;faut Synth&#e8;se Maturation R&#e9;gulation Exemple G542X F508del G551D Fr&#e9;quence globale 4 % 73 % 3 % Fr&#e9;quence en France 3,5 % 63 % 1 % Correction Lecture forc&#e9;e Prot&#e9;ger la d&#e9;gradation Restaurer la fonction Mol&#e9;cule test&#e9;e PTC 124 Ataluren VX-809 Lumacaftor Lumacaftor + Ivacaftor Ivacaftor r&#e9;alis&#e9;e chez 140 patients &#e2;g&#e9;s de 12 ans et plus, l`ivacaftor n`a pas permis d`am&#e9;lioration significative sur l`ensemble des crit&#e8;res de jugements d&#e9;finis (VEMS, poids, qualit&#e9; de vie) &#e0; l`exception de la concentration en ions chlorures dans la sueur (crit&#e8;re secondaire) [28]. Login to comment
236 [34] Du M, Liu X, Welch EM, Hirawat S, Peltz SW, Bedwell DM. PTC124 is an orally bioavailable compound that promotes suppression of the human CFTR-G542X nonsense allele in a CF mouse model. Login to comment

PMID: 24357848 [PubMed] Zvereff VV et al: "Cystic fibrosis carrier screening in a North American population."

No. Sentence Comment

63 This threshold could not be reached Table 1ߒ CFTR allele frequency identified by the CF32 mutation panel Varianta Number of detected alleles Mutation (%) Legacy nomenclature HGVS nomenclature F508delb p.F508del 31,142 68.69 R117Hb p.R117H 5,198 11.46 G542Xb p.G542X 1,162 2.56 G551Db p.G551D 989 2.18 W1282Xb p.W1282X 824 1.82 3120ߙ+ߙ1G>Ab c.2988ߙ+ߙ1G>A 706 1.56 N1303Kb p.N1303K 648 1.43 R553Xb p.R553X 487 1.07 3849ߙ+ߙ10kbC>Tb c.3717ߙ+ߙ12191C>T 436 0.96 621ߙ+ߙ1G>Tb c.489ߙ+ߙ1G>T 410 0.90 1717-1G>Ab c.1585-1G>A 388 0.86 2789ߙ+ߙ5G>Ab c.2657ߙ+ߙ5G>A 382 0.84 I507delb p.I507del 258 0.57 R334Wb p.R334W 257 0.57 R1162Xb p.R1162X 211 0.47 G85Eb p.G85E 199 0.44 1898ߙ+ߙ1G>Ab c.1766ߙ+ߙ1G>A 170 0.37 R347Hc p.R347H 160 0.35 3659delCb c.3528delC 155 0.34 3876delAc c.3744delA 153 0.34 R560Tb p.R560T 132 0.29 S549Nc p.S549N 125 0.28 3905insTc c.3773dupT 121 0.27 R347Pb p.R347P 117 0.26 2184delAb c.2052delA 107 0.24 A455Eb p.A455E 106 0.23 711ߙ+ߙ1G>Tb c.579ߙ+ߙ1G>T 65 0.14 394delTTc c.262_263delTT 56 0.12 V520Fc p.V520F 54 0.12 1078delTc c.948delT 52 0.11 2183AA>Ga,c c.2051_2052delAAinsG 37 0.08 S549Rc p.S549R 31 0.07 Total 45,338 100 a 2183AA>G variant was added to the panel in 2010. b Variants from ACMG/ACOG CF screening panel. c Classified as a CF-causing mutation by the CFTR2 Database. ACMG, American College of Medical Genetics and Genomics; ACOG, American College of Obstetricians and Gynecologists; CF, cystic fibrosis; HGVS, Human Genome Variation Society. Table 2ߒ Continued on next page Table 2ߒ CFTR allele frequency identified by the CF69 mutation panel Varianta Allele frequency Mutation (%) Legacy nomenclature HGVS nomenclature F508delb p.F508del 1,868 60.49 R117Hb p.R117H 274 8.87 D1152Hc p.D1152H 125 4.05 G542Xb p.G542X 98 3.17 L206Wd p.L206W 73 2.36 3120ߙ+ߙ1G>Ab c.2988ߙ+ߙ1G>A 65 2.10 G551Db p.G551D 47 1.52 N1303Kb p.N1303K 42 1.36 W1282Xb p.W1282X 38 1.23 3849ߙ+ߙ10kbC>Tb c.3717ߙ+ߙ12191C>T 28 0.91 3876delAd c.3744delA 28 0.91 F311dele p.F312del 24 0.78 I507delb p.I507del 24 0.78 R553Xb p.R553X 24 0.78 R117Cd p.R117C 22 0.71 621ߙ+ߙ1G>Tb c.489ߙ+ߙ1G>T 21 0.68 1717-1G>Ab c.1585-1G>A 18 0.58 S549Nd p.S549N 18 0.58 R334Wb p.R334W 17 0.55 2789ߙ+ߙ5G>Ab c.2657ߙ+ߙ5G>A 16 0.52 G85Eb p.G85E 14 0.45 3199del6e c.3067_3072delATAGTG 12 0.39 R1066Cd p.R1066C 11 0.36 1898ߙ+ߙ1G>Ab c.1766ߙ+ߙ1G>A 10 0.32 R347Hd p.R347H 10 0.32 R1162 Xb p.R1162X 9 0.29 W1089Xd p.W1089X 9 0.29 2184delAb c.2052delA 8 0.26 2307insAd c.2175dupA 8 0.26 1078delTd c.948delT 7 0.23 R75Xd p.R75X 7 0.23 3120G>Ad c.2988 G>A 6 0.19 3659delCb c.3528delC 6 0.19 Q493Xd p.Q493X 6 0.19 R1158Xd p.R1158X 6 0.19 R560Tb p.R560T 6 0.19 1812-1G>Ad c.1680-1G>A 5 0.16 2055del9>Ad c.1923_1931del9insA 5 0.16 406-1G>Ad c.274-1G>A 5 0.16 A559Td p.A559T 5 0.16 R347Pb p.R347P 5 0.16 S1255Xd p.S1255X 5 0.16 1677delTAd c.1545_1546delTA 4 0.13 711ߙ+ߙ1G>Tb c.579ߙ+ߙ1G>T 4 0.13 E60Xd p.E60X 4 0.13 R352Qd p.R352Q 4 0.13 Y1092Xd p.Y1092X 4 0.13 2183AA>Gd c.2051_2052delAAinsG 3 0.10 3791delCd c.3659delC 3 0.10 3905insTd c.3773dupT 3 0.10 by 10 variants: the 2143delT, A455E, S549R, Y122X, and M1101K mutations, typically observed in Caucasians; 935delA, 2869insG, and Q890X in Hispanics; and 405+3A>C and G480C in the African-American population. Login to comment

PMID: 24440239 [PubMed] Muthuswamy S et al: "Spectrum and distribution of CFTR gene mutations in asthma and chronic pancreatitis cases of North Indian population."

No. Sentence Comment

3 Methods: A total of 800 subjects including 400 controls, 250 asthma cases and150 chronic pancreatitis cases were analyzed for 6 mutations (F508del, G542X, G551D, R117H, W1282X, and S549N) and IVS8 Tn polymorphism. Login to comment
6 The carrier frequency of F508del, G542X, G551D, R117H, S549N and T5 was 0.015, 0.025, 0.02, 0.005, 0.005, and 0.022 respectively. Login to comment
44 ARMS PCR Identification of F508del, G551D, G542X, R117H and W1282X mutations were carried out by ARMS PCR (Ferrie et al., 1992). Login to comment
63 Mutation Primer Method Amplicon (size in bp) Reference DF508 C GACTTCACTTCTAATGATGATTATGGGAG ARMS Ferrie et al. (1992) N GTATCTATATTCATCATAGGAAACACCAC 160 M GTATCTATATTCATCATAGGAAACACCAT 157 G551D C TAAAATTTCAGCAATGTTGTTTTTGACC N GCTAAAGAAATTCTTGCTCGTTGCC 285 M AGCTAAAGAAATTCTTGCTCGTTGCT 286 G542X C TAAAATTTCAGCAATGTTGTTTTTGACC N ACTCAGTGTGATTCCACCTTCTAC 256 M CACTCAGTGTGATTCCACCTTCTCA 257 R117H C CACATATGGTATGACCCTCTATATAAACT N CCTATGCCTAGATAAATCGCGATAGAAC 237 M CCTATGCCTAGATAAATCGCGATAGAAT 237 S549N For TTCAGCAATGTTGTTTTGACCAAC RFLP (DdeI) N: 13 + 238 + 174 H: 13 + 238 + 174 + 412 M: 13 + 412 Kerem et al. (1990) Rev CACAGATTCTGAGTAACCATAATC IVS8 Tn For1 TAATGGATCATGGGCCATGT Nested PCR (Xmn1) 5T - 84 7T - 86 9T - 88 Chillon et al. (1995) Rev1 ACAGTGTTGAATGTGGTGCA For2 CCGCCGCTGTGTGTGTGTGTGTGTTTTT Rev2 GGATCCAGCAACCGCCAACA 3. Login to comment
71 Controls (n = 400) Minor allele frequency of F508del, G542X, G551D, R117H and S549N observed to be 0.0075, 0.0125, 0.01, 0.0025 and 0.0025 respectively (Table 2). Login to comment
73 We further stratified data as per their prevalence and found G542X to be the most common mutation with the frequency of 2.49%, followed by G551D, F508del, R117H and S549N with 2.00%, 1.50%, 0.50% and 0.50% respectively and 2.24% for 5T allele (Fig. 1A). Login to comment
76 The frequency of individuals falling in different mutations were 10%, 5.6%, 4.4%, 2.0%, 1.6% and 0.4% with respect to IVS8 T5, G551D, G542X, S549N, F508del and R117H (Fig. 1B). Login to comment
87 G542X mutation The conversion of glycine residue at 542 position to termination codon (G542X) interrupts mRNA processing. Login to comment
89 Among CP patients, G542X mutation prevalence was 6.7% (10/150), followed by asthma patients and controls with 4.4% (11/250) and 2.5% (10/400) respectively. Login to comment
91 However, in asthma patients G542X heterozygosity was slightly higher in relative to controls but statistically insignificant. Login to comment
112 Serial no. Mutation General population (400) Asthma (250) Chronic pancreatitis (150) 1 DF508 0.0075 0.0080 0.0433 2 G542X 0.0125 0.0220 0.0333 3 G551D 0.01 0.0280 0.03 4 R117H 0.0025 0.0020 0.0066 5 S549N 0.0025 0.0100 0.0133 6 IVS8-5T 0.01125 0.0580 0.02 thrive, pancreatic insufficiency, elevated sweat electrolytes, late-stage diabetes and cardiac failure, besides male infertility due to congenital bilateral absence of the vas deferens (CBAVD) (Schrijver et al., 2005). Login to comment
118 A) Among the studied 5 mutation and 1 polymorphism, G542X mutation accounts for 27% (10 out of 37) in controls and the least one is S549N of 5% (2 out of 37). Login to comment
134 Serial No. Mutation General population (n = 400)% Asthma (n = 250)% Chronic pancreatitis (n = 150)% Chi square-testÌe; P value Asth vs ctrl Cp vs ctrl Asth vs CP 1 DF508 1.5 1.6 8.7 NS 0.0002 0.0013 2 G542X 2.5 4.4 6.7 NS 0.03 NS 3 G551D 2.0 5.6 6.0 0.02 0.02 NS 4 R117H 0.5 0.4 1.3 NS NS NS 5 S549N 0.5 2 2.7 NS NS NS 6 IVS8-5T 2.2 10 4.0 b0.0001 NS 0.03 7 Total 9.3 24 29.3 b0.0001 b0.0001 NS Ìe; P b 0.05 is considered significant (Bold values). Login to comment
142 Recently, Shastri and Kabra reported 1161delC, 3849 + 10kbC-T and S549N as other most common mutations in India (Shastri and Kabra 2008), which is in agreement with other reports (Sharma et al., 2009b); however in the control group of the present study 1161delC and 3849+ 10kbC-T mutations were not found (unpublished data) whereas G542X, W1282X, 621 + 1G N T that occur in lesser percentage among Hispanic and non-Hispanic Caucasians (Watson et al., 2004) were not found in earlier studies from India while the present study recorded that G542X mutation is quite common among our controls (2.5%), asthmatic (4.4%) and CP (6.7%) cases in heterozygous nature. Login to comment
145 Based on our data G551D, G542X, F508del, T5, R117H and S549N mutations may be considered for Indian subjects. Login to comment
146 In conclusion, our study indicates that CFTR mutations had been overlooked in our population while the carrier frequency of mutations F508del, G542X, and G551D are 3/200, 1/50 and 1/40, respectively, that is more common with reference to 1/238 of F508del in an earlier report by Kapoor et al. (2006). Login to comment

PMID: 24483936 [PubMed] Lentini L et al: "Toward a rationale for the PTC124 (Ataluren) promoted readthrough of premature stop codons: a computational approach and GFP-reporter cell-based assay."

No. Sentence Comment

12 The most commonly observed mutations include deletion of a codon at position 508 (delta-F508), a missense mutation at position 551, and a nonsense mutation at position 542 (G542X).34 Cystic fibrosis patients with nonsense-mutation essentially produce no CFTR protein, thus suffering a more severe form of the disease. Login to comment
16 Therefore, we performed the first computational study to investigate putative codon-specific supramolecular interactions between the PTC124 and an 11 codon long sequence corresponding to the CFTR fragment coding mRNA bearing a G542X nonsense mutation (i.e., UGA at position 542). Login to comment
158 Five MD simulations of 100 ns were conducted on the complex between the 1,2,4-oxadiazole ligand (PTC124), and four models of mRNA constituted by a sequence of 33 ribonucleotides of the CFTR gene, that differ in the identity of the central codon normally expressing aminoacid 542: (i) GGA, as found in the wild type mRNA; (ii) UGA, mimicking the G542X nonsense mutation; (iii) UAG, and (iv) UAA, representing the other two types of premature stop codons. Login to comment

PMID: 24517344 [PubMed] Raju SV et al: "Impact of heterozygote CFTR mutations in COPD patients with chronic bronchitis."

No. Sentence Comment

81 As expected based on genotype-phenotype correlations in the disease [33], HBE cells derived from a F508del CFTR heterozygote had slightly lower CFTR activity at baseline than wild type monolayers as measured by Table 1 List of CFTR mutations analyzed F508del R117H 1717-1G > A R117C G85E R334W 1898 + 1G > A Y122X A455E R347P 2184delA G178R I507del R553X 2789 + 5G > A G314E G542X R560T 3120 + 1G > A G330X G551D W1282X 3659delC R347H N1303K 621 + 1G > T K710X 406-1G > A R1162X 711 + 1G > T E60X G480C R1066C W1089X V520F A559T S1196X Q1238X S1251N S1255X 663delT 935delA 1161delC 1288insTA 2184insA 2307insA 2711delT 2869insG R709X R764X R1158X 574delA Q493X 1898 + 5G > T 3905insT I506T 3849 + 10kbC > T 712-1G > T Q98R Q552X S549N 1078delT H199Y 444delA S549R (T > G) 2143delT P205S 2043delG 1811 + 1.6kbA > G 3272-26A > G L206W 3791delC Y1092X (C > G) 3199del6 F508C 2108delA Y1092X (C > A) D1152H V520I 3667del4 394delTT 3876delA M1101K 1677delTA W1098X (TGA) 1812-1G > A 4016insT 1609delCA 3171delC response to forskolin stimulation (49.3 &#b1; 11.5 bc;A/cm2 in CFTR (+/+) vs. 40.5 &#b1; 5.3 bc;A/cm2 in CFTR (+/-), although this was not statistically significant (Figure 1A,B). Login to comment

PMID: 24529904 [PubMed] Le Henaff C et al: "Enhanced F508del-CFTR channel activity ameliorates bone pathology in murine cystic fibrosis."

No. Sentence Comment

13 (Am J Pathol 2014, 184: 1132e1141; http://dx.doi.org/10.1016/j.ajpath.2013.12.027) Cystic fibrosis (CF), which is caused by mutations of the CF transmembrane conductance regulator (CFTR), is characterized by multiorgan pathology that begins early in life.1e4 Brittle bones have been reported in children, adolescents, and adults with CF, independently of sex and age; this has been termed CF-related bone disease.5e8 Bone fragility may exclude patients from candidacy for lung transplantation, which imposes limitations on the best therapeutic option for these patients at the advanced stages of the disease.9 Clinical data have suggested a multifactorial etiology of CF-related skeletal deficits, including vitamin K and D insufficiency, calcium malabsorption, malnutrition and pancreatic insufficiency, delayed puberty, sex steroid deficiency, pulmonary infection/systemic inflammation, and frequent glucocorticoid therapy.10e13 Whether Cftr gene dysfunction plays a direct role in bone metabolism remains to be elucidated; however, this has been hypothesized on the basis of animal studies with the Cftr-null14,15 and F508del-Cftr mouse models.16,17 We previously reported that CF mice homozygous for the F508del-CFTR mutation develop a severe osteopenic phenotype in both sexes.16 In humans, the expression of CFTR protein has been identified in bone cells.18 We recently discovered defective CFTR-mediated Cl channel activity and a severe deficit of the release of osteoprotegerin (a key regulator in bone turnover) in primary osteoblasts (cells that form bone) obtained from a 25-year-old man with CF with the F508del/G542X mutation in CFTR.19 These data raise the hypothesis that the mutation in the Cftr gene may play a role in CF-related skeletal disease. Login to comment

PMID: 24532752 [PubMed] Lane MA et al: "A new era in the treatment of cystic fibrosis."

No. Sentence Comment

8 Mutations in the gene encoding the protein CFTR can be divided into five categories on the basis of the effect they have on protein synthesis:6 > Class I defects (eg G542X) disrupt synthesis of CFTR and include nonsense and frameshift mutations that lead to premature termination codons (PTCs) and a lack of protein production. Login to comment

PMID: 24561283 [PubMed] Ikpa PT et al: "Cystic fibrosis: toward personalized therapies."

No. Sentence Comment

1592 Just four other mutations, notably G551D (class III), W1282X, G542X (class I), and N1303K (class II) have a worldwide prevalence of 1-3% each, whereas only 20 mutations have a frequency above 0.1%. Login to comment

PMID: 24583165 [PubMed] Bonadia LC et al: "CFTR genotype and clinical outcomes of adult patients carried as cystic fibrosis disease."

No. Sentence Comment

53 2 8 I I s s a l C / I I s s a l C l e d 8 0 5 F / E 5 8 G 1 1 G542X/I618T Class I/Class IV 74.6 72.8 91 97 82.8 84.9 1 G542X/2183AA>G Class I/Class I 111 181 114 105 112.5 143 5 . Login to comment
82 2 7 V I s s a l C / I I s s a l C H 2 5 1 1 D / l e d 8 0 5 F 2 2 F508del/1584-18672pb A>G Class II/Class V 63.7 90.7 61.5 93.1 62.6 91.9 2 P205S/G542X Class IV/Class I 102 136.2 93.1 112.3 97.55 124.25 6 . Login to comment

PMID: 24586523 [PubMed] Zietkiewicz E et al: "CFTR mutations spectrum and the efficiency of molecular diagnostics in Polish cystic fibrosis patients."

No. Sentence Comment

71 Exon / intron (legacy) Exon / intron (Ensembl) Protein change SVM value cDNA (HGVS nomenclature) gDNA (cDNA +132 bp) Number of PL CF chromosomes Reference a Mutations in trans Pathogenic mutations 1 1 L15Ffs10X c.43delC 175delC 1 CFMDB 1717-1G.A 2 2 G27V 21.92 c.80G.T 212G.T 1 Novel F508del 2 2 S18RfsX16 c.54-5940_273 +10250del21kb exon2,3del21kb 66 IL19 various CF mutations i2 i2 IVS2_Donor c.164+1G.A 296+1G.A 3 CFMDB various CF mutations 3 3 G85E 22.61 c.254G.A 386G.A 1 IL17 unknown 3 3 E60X c.178G.T 310G.T 0 IL17 x 3 3 L88IfsX22 c.262_263delTT 394delTT 0 IL17 x 4 4 E92K 21.92 c.274G.A 406G.A 2 CFMDB c.164+1G.A; c.2051- 2AA.G 4 4 L101X c.302T.G 434T.G 1 CFMDB c.3717+12191C.T 4 4 K114IfsX5 c.341_353del13bp 473del13bp 1 Novel F508del 4 4 R117H 20.35 c.350G.A 482G.A 5 IL17 F508del; 2x unknown 4 4 R117C 22.07 c.349C.T 481C.T 2 CFMDB S1206X;1x unknown 4 4 L137_L138insT c.412_413insACT L138ins 1 CFMDB F508del 4 4 R153I 22.61 c.458G.T 590G.T 2 Novel F508del; c.3527delC i4 i4 IVS4_Donor c.489+1G.T 621+1G.T 5 IL17 F508del; c.489+1G.T 5 5 L165X c.494T.A 626T.A 1 Novel F508del i5 i5 IVS5_Donor c.579+1G.T 711+1G.T 0 IL19 x i5 i5 IVS5_Donor c.579+3A.G 711+3A.G 2 CFMDB 2,3del21kb; c.2052-3insA i5 i5 IVS5_Donor c.579+5G.A 711+5G.A 0 IL17 x 7 8 F311L 20.90 c.933C.G 965C.G 2 CFMDB 2x F508 7 8 G314R 20.58 c.940G.A 1072G.A 4 CFMDB various CF mutations 7 8 F316LfsX12 c.948delT 1078delT 1 IL17 unkown 7 8 R334W 22.41 c.1000C.T 1132C.T 6 IL17 various CF mutations 7 8 I336K 22.07 c.1007T.A 1139T.A 2 CFMDB 2,3de21kb; F508del 7 8 R347P 22.27 c.1040G.C 1172G.C 11 IL17 various CF mutations i7 i8 IVS8_Donor c.1116+2T.A 1248+2T.A 1 Novel Q1412X 9 10 A455E 22.61 c.1364C.A 1496C.A 0 IL17 x i9 i10 IVS10_Donor c.1392+1G.A 1524+1G.A 1 CFMDB c.3816-7delGT 10 11 S466X c.1397C.G 1529C.G 1 CFMDB G542X 10 11 I507del c.1519_1521delATC 1651delATC 2 IL19 F508del 10 11 F508del c.1521_1523delCTT 1654delCTT 805 IL19 various CF mutations i10 i11 IVS11_Acceptor c.1585-1G.A 1717-1G.A 27 IL19 various CF mutations 11 12 G542X c.1624G.T 1756G.T 25 IL19 various CF mutations 11 12 G551D 21.24 c.1624G.T 1756G.T 5 IL19 various CF mutations 11 12 Q552X c.1654C.T 1786C.T 0 IL19 x 11 12 R553X c.1657C.T 1789C.T 14 IL19 various CF mutations 11 12 R560T 21.92 c.1679G.C 1811G.C 0 IL19 x i12 i13 IVS13_Donor c.1766+1G.A 1898+1G.A 6 IL19 various CF mutations i12 i13 IVS13_Donor c.1766+1G.C 1898+1G.C 1 CFMDB F508del 13 14 H620P 21.73 c.1859A.C 1991A.C 1 CFMDB F508del 13 14 R668C//G576A 21.61//1.73 c.2002C.T//c.1727G.C 2134C.T// 1859G.C 5 b CFMDB// rs1800098 c.1585-1G.A; 4 unknown 13 14 L671X c.2012delT 2143delT 27 IL17 various CF mutations 13 14 K684SfsX38 c.2051_2052delAAinsG 2183AA.G 10 IL17 various CF mutations 13 14 K684NfsX38 c.2052delA 2184delA 0 IL17 x 13 14 Q685TfsX4 c.2052_2053insA 2184insA 15 CFMDB various CF mutationsc , 1 unknown Table 2. Cont. Exon / intron (legacy) Exon / intron (Ensembl) Protein change SVM value cDNA (HGVS nomenclature) gDNA (cDNA +132 bp) Number of PL CF chromosomes Reference a Mutations in trans 13 14 L732X c.2195T.G 2327T.G 1 CFMDB F508del 14A 15 R851X c.2551C.T 2683C.T 3 CFMDB various CF mutations 14A 15 I864SfsX28 c.2589_2599del11bp 2721del11bp 2 CFMDB F508del; 2,3del21kb i14B i16 IVS16_Donor c.2657+2_2657+3insA 2789+2insA 1 CFMDB F508del i14B i16 IVS16_Donor c.2657+5G.A 2789+5G.A 0 IL17 unkown 15 17 Y919C 21.02 c.2756A.G 2888A.G 1 CFMDB unknown 15 17 H939HfsX27 c.2817_2820delTACTC 2949delTACTC 1 Novel unkown i15 i17 IVS17_Donor c.2908+3A.C 3040+3A.C 1 Novel F508del i16 i18 IVS18_Donor c.2988+1G.A 3120+1G.A 0 IL19 x 17A 19 I1023_V1024del c.3067_3072delATAGTG 3199del6 0 IL19 x i17A i19 IVS19 c.3140-26A.G 3272-26A.G 9 IL19 various CF mutations 17B 20 L1065R 21.90 c.3194T.G 3326T.G 1 CFMDB F508del 17B 20 Y1092X c.3276C.A 3408C.A 1 CFMDB R334W i18 i21 IVS21_Donor c.3468+2_3468+3insT 3600+2insT 11 CFMDB various CF mutationsd , 1 unknown 18 21 E1126EfsX7 c.3376_3379delGAAG 3508delGAAG 1 Novel F508del 19 22 R1158X c.3472C.T 3604C.T 2 CFMDB F508del; R553X 19 22 R1162X c.3484C.T 3616C.T 1 IL17 F508del 19 22 L1177SfsX15 c.3528delC 3659delC 4 IL17 various CF mutations 19 22 S1206X c.3617C.A 3749C.A 1 CFMDB R117C i19 i22 IVS22 c.3717+12191C.T 3849+10kbC.T 58 IL17 various CF mutations 20 23 G1244R 22.62 c.3730G.C 3862G.C 1 CFMDB F508del 20 23 S1251N 22.28 c.3752G.A 3884G.A 0 IL19 x 20 23 L1258FfsX7 c.3773_3774insT 3905insT 0 IL19 x 20 23 V1272VfsX28 c.3816_3817delGT 3944delGT 1 CFMDB c.1392+1G.A 20 23 W1282X c.3846G.A 3978G.A 9 IL19 various CF mutations 21 24 N1303K 22.62 c.3909C.G 4041C.G 18 IL19 various CF mutations 22 25 V1327X c.3979delG 4111delG 1 Novel F508del 22 25 S1347PfsX13 c.4035_4038dupCCTA c.4167dupCCTA 1 CFMDB 2,3del21kb 23 26 Q1382X c.4144C.T 4276C.T 1 CFMDB F508del 23 26 Q1412X c.4234C.T 4366C.T 2 CFMDB F508del; c.1116+2T.A i23 i26 IVS26_Donor c.4242+1G.T 4374+1G.T 1 CFMDB F508del Sequence changes of uncertain pathogenic effect, tentatively counted as mutations 6A 6 E217G 0.30 c.650A.G 782A.G 1 CFMDB; rs1219109046 unknown 7 8 R352Q 20.01 c.1055G.A 1187G.A 1 CFMDB; rs121908753 F508del 7 8 Q359R 0.33 c.1076A.G 1208A.G 1 CFMDB F508del i8 i9 IVS9 c.1210-12T5_1210- 34_35 (TG)12 1332-12Tn_- 34TGm 6 CFMDB F508del; 3x unknown i8 i9 IVS9 c.1210-12T5_1210- 34_35 (TG)13 1332-12Tn_- 34TGm 2 CFMDB 2143delT; 1x unknown i8 i9 IVS9 c.1210-12T8 1332-12Tn 1 Novel unknown 10 11 I506V 20.21 c.1516A.G 1648A.G 1 CFMDB; rs1800091 unknown 12 13 V562L 0.79 c.1684G.C 1816G.C 1 CFMDB; rs1800097 unknown 13 14 G723V 0.44 c.2168G.T 2300G.T 1 CFMDB; rs200531709 unknown 15 17 D924N 0.03 c.2770G.A 2902G.A 1 CFMDB; rs201759207 unknown patient with F508del on another allele) was not supported by the SVM value (+0.35); the patient was PS and had ambiguous chloride values (45, 64 and 83 mmol/L). 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101 The more recent estimates provide much lower values, ranging from 1:5000 [14], 1:6000 cited in WHO 2002 report [15] to 1:7500 for Southeastern Poland estimated for a 1-year period of Table 2. Cont. Exon / intron (legacy) Exon / intron (Ensembl) Protein change SVM value cDNA (HGVS nomenclature) gDNA (cDNA +132 bp) Number of PL CF chromosomes Reference a Mutations in trans 15 17 L967S 0.27 c.2900T.C 3032T.C 1 CFMDB; rs1800110 unknown 18 21 D1152H 0.50 c.3454G.C 3586G.C 1 CFMDB; rs75541969 F508del Sequence changes considered as lacking pathogenic effect 4 4 I148T 2.04 c.443T.U 575T.U 4 IL19e unknown 13 14 I752V 0.35 c.2254A.G 2386A.G 1 Novelf F508 15 17 S912L 2.12 c.2735C.T 2867C.T 1 CFMDBg ; rs121909034 F508 Legend: a IL19 i 17 - mutations included in the INNOLiPA tests (see below); CFMDB - non-INNOLiPA mutations present in the CTFR mutation database; novel - mutations first reported in this study; b in three chromosomes R668C with G576A in trans; c F508del, c.1585-1G.A, G542X, N1303K or c.579+3A.G; d F508del, G542X, R553X or N1303K; e not pathogenic if not in cis with c.3067-72del6 (l.n.3199del6); f not pathogenic - see explanation the text; g not pathogenic if not in cis with G1244V. Login to comment
102 a Mutations detected by two INNOLiPA_CFTR tests (legacy names): IL19 (INNOLiPA_CFTR19): F508del; G542X; N1303K; W1282X; G551D; 1717-1G.A; R553X; CFTRdele2,3(21kb); I507del; 711+1G.T; 3272-26A.G; 3905insT; R560T; 1898+1G.A; S1251N; I148T; 3199del6; 3120+1G.A; Q552X. Login to comment
121 Three mutations in our reduced data set were significantly (p,0.03) less frequent than in Warsaw (F508del: 67.2% vs 71.8%; G542X: 1.98% vs 2.92%; N1303K: 1.47% vs 2.92%), while two mutations were significantly more frequent (c.3468+2_3468+3insT: 0.86% vs 0.10%; c.489+1G.T: 0.43% vs 0%; G314R: 0.34% vs 0%). Login to comment
137 Mutations a Poland Czechs Slovakia c Germany Lithuania W. Ukraine E. Hungary Romania c Bulgaria Serbia Greece Number of chromosomes 1476 1200 856 700 98 264 80 256 208 352 874 F508del 54.54 b 67.42 d 66.80 d 72.00 d 52.0 54.17 70.00 56.3 65.38 d 72.28 d 53.40 exon2,3del21kb (l.n.CFTRdele2,3_21kb) 4.47 5.75 2.26 1.2 f 2.0 4.17 5.00 1.6 NA 0 e 0.34 e c.3717+12191C.T (l.n.3849+10kbC.T) 3.93 1.67 e 4.28 1.00 e NA 0.76 0 0.4 e 1.44 0 e 0.11 e c.2012delT (l.n.2143delT) 1.83 0.92 1.10 0.71 0 1.14 0 0 e 0 0 e 0 e c.1585-1G.A (l.n.1717-1G.A) 1.83 0.33 e NA 0.86 0 0.38 1.25 0.4 0 0 e 0 e G542X 1.69 2.00 4.06 d 1.43 0 2.65 3.75 3.9 3.37 2.57 3.90 d R347P 1.57 0.92 1.10 1.57 0 0 1.25 NA 1.44 0 e 0.11 e N1303K 1.22 2.42 2.03 2.29 2.0 4.92 d 5.00 0.8 6.73 d 0 2.63 c.2052-2053insA (l.n.2184insA) 1.02 0.42 1.58 0.57 0 7.20 d 5.00 d 0 0.48 0.28 0 e R553X 0.95 0.50 0.90 2.29 4.2 d 0.38 0 NA 0 0 0 c.3468+223insT (l.n.3600+2insT) 0.75 0.25 NA 0 e 0 NA 0 NA 0 0 0 e c.2051-2052AA.G (l.n.2183AA.G) 0.68 0.08 NA 0.57 0 0.38 0 0.8 0 0 1.38 W1282X 0.61 0.58 0.50 0.71 1.0 2.27 0 2.3 d 0.96 0 0.67 c.3140-26A.G (l.n.3272-26A.G) 0.61 0.67 0.50 0.86 0 0.76 0 0.4 0 0 0.81 l.n.IVS8 T 5 _TG 12-13 0.54 NA NA NA 0 NA NA NA NA 0 NA R334W 0.41 0.25 NA 0.29 0 0.76 0 0.4 0 0.28 0.81 c.1766+1G.A (l.n.1898+1G.A) 0.41 1.42 d 0.50 0 0 1.14 0 NA 0 0 0.11 c.489+1G.T (l.n.621+1G.T) 0.34 0.42 NA 0.14 0 0.76 0 0.8 0 2.86 d 5.72 d R117H 0.34 NA NA 0.29 0 0 0 0.4 0 0 0.23 G551D 0.34 2.91 d 0.50 1.00 0 0 0 0 0 0 0.34 G314R 0.37 0 NA 0 0 0 0 NA 0 0 0 R668C 0.34 0 NA 0 0 0 0 NA 0 0 0 c.3528delC (l.n.3659delC) 0.27 0.17 NA 0.57 0 0 0 NA 0 0 0 c.164+1G.A (l.n.296+1G.A) 0.20 0.08 NA 0 0 0 0 NA 0 0 0 R851X 0.20 0.08 NA 0 0 0 0 NA 0 0 0 I336K 0.14 0.58 NA 0.45 0 0 0 NA 0 0 0 R1158X 0.14 0.08 NA 0 0 0 0 NA 0 0 1.03 E92K 0.14 0.08 NA 0 0 0.38 0 NA 0 0 0 R153I 0.14 0 NA 0 0 0 0 NA 0 0 0 c.579+3A.G (l.n.711+3A.G) 0.14 0.17 NA 0 0 0 0 NA 0 0 0.69 c.2589-2599del11bp (l.n.2721- 31del11bp) 0.14 0.08 NA 0 0 0.38 0 NA 0 0 0 I507del 0.14 0.08 NA 0.15 0 0 0 0 0 0.28 0.69 R117C 0.14 0.08 NA 0.15 0 0 0 NA 0 0 0.23 of mutation panels [20]), listed in Table 4, were compared to those reported for several Central and Southeastern European countries [21-29]. Login to comment

PMID: 24593045 [PubMed] Marson FA et al: "Polymorphisms in the glutathione pathway modulate cystic fibrosis severity: a cross-sectional study."

No. Sentence Comment

47 CFTR mutation identification CFTR mutation identification was performed by polymerase chain reaction (PCR) for F508del and the fragment-length polymorphism method for G542X, R1162X, R553X, G551D, and N1303K mutations. Login to comment
121 An analysis of genotypic combinations for GSTM1 and GSTP1 polymorphic loci showed that changes in GSTP1 activities Table 3 Genotyping of GCLC, GSTM1, GSTT1, and GSTP1 polymorphisms and CFTR mutations Gene Chromosomal position Location Polymorphism MAF HWE p-valuea GCLC, rs17883901 6p12 Promoter region C > T 0.12 9.97 <0.005 GCLC, rs137852340 6p12 Promoter region A > G 0.19 0.04 >0.05 GSTP1, rs1695 11q13 Exon A > G 0.25 1.11 >0.05 GSTM1 1p13.3 Deletion GSTT1 22q11.23 Deletion CFTR mutation N Frequency F508del/F508del 57 31.67% F508del/G542X 12 6.67% F508del/R1162X 5 2.78% F508del/N1303K 4 2.22% F508del/R553X 1 0.56% F508del/S4X 1 0.56% F508del/1717-1G > A 1 0.56% G542X/R1162X 1 0.56% G542X/I618T 1 0.56% G542X/2183A > G 1 0.56% R1162X/R1162X 1 0.56% F508del/- 45 25.00% G542X/- 5 2.78% R1162X/- 1 0.56% -/- 44 24.45% MAF, Minor allele frequency; HWE, Hardy Weinberg Equilibrium; a P-value for Hardy-Weinberg Equilibrium; N, Number of patients; -, No identified CFTR mutation. Login to comment

PMID: 24631642 [PubMed] Fanen P et al: "Genetics of cystic fibrosis: CFTR mutation classifications toward genotype-based CF therapies."

No. Sentence Comment

74 23 ACMG recommended panel of classic CF-causing mutations G85E R117H R334W R347P A455E I507del F508del G542X G551D R553X R560T R1162X W1282X N1303K 621 + 1G > T 711 + 1G > T 1717 - 1G > A 1898 + 1G > A 2184delA 2789 + 5G > A 3120 + 1G > A 3659delC 3849 + 10kbC > T Additional or alternative mutations present at significant frequencies in an ethnic population served by a newborn screening program may be assessed. Login to comment

PMID: 24685677 [PubMed] Pranke IM et al: "Biosynthesis of cystic fibrosis transmembrane conductance regulator."

No. Sentence Comment

1372 The nonsense and frameshift mutations, belonging to the Class I, lead to creation of premature termination codons (PTCs) such as W1282X, G542X, Y122X, and result either in the synthesis of truncated and unstable protein or in the decrease of the half-lives of mutant mRNAs. Login to comment

PMID: 24696795 [PubMed] Sahami A et al: "Mutation Analysis of Exons 10 and 17a of CFTR Gene in Patients with Cystic Fibrosis in Kermanshah Province, Western Iran."

No. Sentence Comment

30 In addition to ࢞F508 mutation, these mutations vary greatly in their frequency and distribution, but most of them are very rare. Only four mutations (p.G542X, p.N1303K, p.G551D, and p.W1282X) have overall frequencies greater than 1% (5). Login to comment

PMID: 24727426 [PubMed] Wang Y et al: "Understanding how cystic fibrosis mutations disrupt CFTR function: from single molecules to animal models."

No. Sentence Comment

1947 Common examples include G542X, the second most common CF mutation, prevalent in Mediterranean countries and W1282X, the most common CF mutation in Ashkenazi Jews. Login to comment

PMID: 24917112 [PubMed] Bar-On O et al: "Increasing nontuberculous mycobacteria infection in cystic fibrosis."

No. Sentence Comment

118 The most frequent CFTR mutations in our cohort were W1282X, ƊF508, G542X, D1152H, 3849 + 10kbC࢐T. Login to comment

PMID: 24932877 [PubMed] Bell SC et al: "New pharmacological approaches for cystic fibrosis: promises, progress, pitfalls."

No. Sentence Comment

492 Common mutations in class I include G542X (common in Brittany and Southern France), R1162X (common in Austria and Northern Italy), or W1282X (reaching 48% amongst Ashkenazi Jews) (Bobadilla et al., 2002). Login to comment
544 Mutation Alternative name Allele frequency (% of total known) in ECFSPR 2010 Allele frequency (% of total known mutations) in 2010 ECFSPR F508del 64.5 Most frequent mutation worldwide Southeast to Northwest increasing prevalence in Europe IL 25.5 to DK 82.6 Mutations with an overall EU prevalence above 1% G542X Mediterranean mutation 2.5 GR 6.7, ES 6.0 N1303K Ancient Phoenician mutation 1.9 IT 4.2 W1282X Jewish Ashkenazi mutation 1.2 IL 22.4 G551D Celtic mutation 1.1 IE 7.3 1717-1GNA Italian mutation 1.0 IT 3.7 Mutations with an overall EU prevalence below 0.5% G85E PT 3.5 A455E Dutch mutation NL 3.5 CFTR dele 2,3 Slavic mutation CZ 5.2, BY 6.7 394delTT Nordic mutation SE 7.9, DK 2.0 3905insT Swiss mutation CH 2.4 R1162X Italian mutation IT 7.8 A561E Portuguese mutation PT 3.2 Abbreviations ECFSPR - European Cystic Fibrosis Society Patient Registry. Login to comment
547 Class Type of defect List of mutations attributed to this class Class I Defective protein production Nonsense mutations: G542X, R1162X, RW1282X Deletions and insertions: CFTRdele2,3; 1078delT; 1717-1G ࢐ A; 3659delC; 621+1G N T Class II Defective protein processing G85E, F508del, I507del, R560T, A561E, R1066C, N1303K Class III Defective protein regulation (gating) G178R, S549N, S549R, G551D, G551S, G970R, G1244E, S1251N, S1255P, G1349D Class IV Defective protein conductance R334W, R347P, R117H Class V Reduced amount of functioning protein 2789+5G ࢐ A, 3272-26ANG, 3849+10KbC ࢐ T, A455E Class VI Reduced cell surface stability Rescued F508del, c.120del23 Unclassified All other mutations, including those unknown a F508del-CFTR pocket (at NBD1:ICL4 interface) (Farinha et al., 2013). Login to comment
577 Class I mutations, which abrogate protein production, often include mutations that generate premature stop codons, class Ia (e.g. G542X) that lead to mRNA degradation by nonsense-mediated decay or those affecting canonical splice sites class Ib (e.g. 1717 - 1GNA). Login to comment

PMID: 24959313 [PubMed] Coutinho CA et al: "TNF-alpha polymorphisms as a potential modifier gene in the cystic fibrosis."

No. Sentence Comment

45 Population characterization for the TNF-b1; and CFTR genotypes, Shwachman-Kulczycki and Kanga scores, transcutaneous oxygen saturation of hemoglobin and forced expiratory volume in the first second (%) (FEV1 ) of forced vital capacity Patient TNF-b1; genotype CFTR genotype Shwachman-Kulczycki Kanga Oxygen saturation FEV1 % -238G>A -308G>A MVG G/G G/A F508del/F508del Moderate Normal Normal Normal JPD G/G G/A F508del/F508del **** Normal Normal Mild RSR G/A A/A F508del/F508del Excellent Normal Mild Normal EVM G/G A/A F508del/R1162X Excellent Normal Mild Severe IFM G/G A/A F508del/F508del **** **** **** **** MLA G/G A/A F508del/F508del **** Exacerbate Normal Moderate VLPC G/G A/A F508del/F508del Moderate Normal Normal Normal MAB G/G A/A F508del/F508del Severe Exacerbate Mild Severe EVSMS G/G A/A F508del/F508del **** Normal Normal Mild YBK G/G A/A F508del/F508del Moderate Normal Normal Normal HB G/A A/A F508del/G542X **** Normal Severe Severe WSP G/G A/A F508del/G542X Moderate Normal Mild Severe DRG G/G A/A F508del/F508del **** **** **** **** BBK G/G G/A F508del/N1303K **** **** **** **** AO G/G A/A F508del/F508del **** Exacerbate Mild Mild LSM G/A A/A F508del/F508del Excellent Normal Normal Moderate VAL G/G A/A F508del/F508del Good Normal Mild Mild LFSA G/G A/A F508del/F508del **** Normal Mild Mild IBN G/G A/A F508del/R553X Excellent Normal Normal Normal CAQ G/G G/G F508del/G542X **** Normal Normal Mild MEMZ G/A A/A F508del/F508del **** Normal Normal Normal TMG G/G G/G F508del/F508del Moderate Normal Normal Normal JMGR G/G G/A F508del/N1303K **** Normal Normal **** MAP G/A G/G F508del/F508del **** **** **** **** AX G/G A/A F508del/F508del Good Normal Normal Normal LPOL G/G G/A F508del/N1303K Good Normal Normal **** EG G/G A/A F508del/R1162X Good Normal Normal Normal NCB G/G G/A F508del/R553X **** Normal Mild Severe FVV G/G A/A F508del/G542X Excellent Normal Normal Normal LSS G/G A/A F508del/F508del **** Exacerbate Moderate **** RNC G/G A/A F508del/F508del **** Normal Normal **** FEL G/G A/A F508del/G542X Moderate Normal Normal Moderate GOV G/G G/A F508del/F508del **** Normal Normal **** CVAR G/G A/A F508del/G542X **** Normal Normal **** EAG G/G A/A F508del/F508del **** Normal Mild **** AVM G/G G/G DF508/G542X Excellent Normal Normal Normal BSG G/G A/A G542X/R1162X Good Exacerbate Mild Mild GPNS G/A A/A F508del/F508del **** Normal Normal **** CAL G/G A/A DF508/G542X Good Normal Normal Normal MOS G/G G/G F508del/F508del Moderate Normal Normal **** FSC G/G A/A F508del/F508del Good Normal Normal Normal ITVS G/G G/A F508del/F508del **** Normal Normal Normal JRL G/G G/G F508del/F508del Mild Normal Normal **** GPT G/A A/A F508del/F508del Excellent Normal Normal Normal some patients were decolonized until the beginning of the study period, being not included in the statistical analysis. Login to comment
69 The F508del allele had the highest prevalence (79.59%), followed by G542X (9.18%), R1162X (6.12%), N1303K (3.06%) and R553X (2.04%). Login to comment

PMID: 25010724 [PubMed] Sharma H et al: "Increased frequency of CFTR gene mutations identified in Indian infertile men with non-CBAVD obstructive azoospermia and spermatogenic failure."

No. Sentence Comment

53 Other common mutations viz., 621+1GNT, G542X, G551D and W1282X were screened by multiplex ARMS PCR (Ferrie et al., 1992). Login to comment

PMID: 25033378 [PubMed] LaRusch J et al: "Mechanisms of CFTR functional variants that impair regulated bicarbonate permeation and increase risk for pancreatitis but not for cystic fibrosis."

No. Sentence Comment

95 CFTR variant %Cases %Uctrls OR p-value %Cases w/N34S OR w/N34S p-value w/N34S CF/BD or BD/BD 2.5 0.1 31.9 ,0.0001 5.5 7.46 0.12 All CF 8.7 3.3 2.76 ,0.0001 16.4 5.65 ,0.0001 F508del CF 6.9 3.1 2.32 ,0.0001 14.5 5.13 ,0.0001 IVS8T5** CF 9.9 8.2 1.24 0.079 10.9 1.37 0.47 2789+5G.A CF 0.3 0.0 0.028 0.0 3849+10kbC.T CF 0.3 0.0 0.028 0.0 N1303K CF 0.3 0.0 0.027 0.0 621+1G.T CF 0.1 0.0 0.13 1.8 ,0.0001 2184delA CF 0.1 0.0 0.13 0.0 3120+1G.A CF 0.1 0.0 0.13 0.0 G551D CF 0.2 0.1 2.50 0.20 0.0 0.00 0.83 W1282X CF 0.2 0.1 2.50 0.20 0.0 0.00 0.83 G542X CF 0.2 0.0 0.059 0.0 R1162X CF 0.1 0.0 0.13 0.0 2183AA.G CF 0.0 0.1 0.17 0.0 0.00 0.83 All BD 14.2 9.8 1.50 0.002 25.5 4.63 ,0.0001 R75Q BD 6.3 6.2 1.02 0.30 16.4 2.97 0.003 S1235R BD 2.4 1.4 1.69 0.052 1.8 1.30 0.80 R117H CF/BD 2.3 0.7 3.49 0.0007 5.5 8.74 0.0002 L967S BD 1.1 0.2 6.87 0.002 1.8 11.17 0.014 L997F BD 0.8 1.0 0.82 0.26 1.8 1.84 0.55 D1152H BD 0.4 0.0 0.014 0.0 D1270N BD 0.3 0.2 1.25 0.29 0.0 0.00 0.71 R170H BD 0.3 0.0 0.028 0.0 R74Q BD 0.3 0.1 3.02 0.17 1.8 21.15 0.002 Other M470V 76.1 74.2 1.11 0.14 70.9 0.85 0.59 T854T 57.3 57.8 0.98 0.29 45.5 0.61 0.071 Q1463Q 39.6 39.5 1.01 0.30 40.0 1.02 0.94 1001+11C.T* 13.4 10.9 1.27 0.016 14.5 1.40 0.42 125G.C 10.3 9.7 1.07 0.26 12.7 1.36 0.45 P1290P 7.6 7.9 0.95 0.28 7.3 0.91 0.86 1716G.A 4.5 4.1 1.10 0.26 1.8 0.43 0.39 R668C 1.0 1.4 0.72 0.19 0.0 0.00 0.38 G576A 0.7 1.2 0.58 0.11 0.0 0.00 0.41 computationally modeled the molecular structure, and studied the dynamics, of wild type (WT) and mutated CFTR channels. Login to comment
124 We identified the R75Q, R117H, L967S, L997F, D1152H, and S1235R CFTRBD variants as well as CFTRCF -associated variants (e.g., F508del, G542X) in cases with rhinosinusitis. Login to comment
129 We identified R75Q, R117H, and S1235R as well as the CFTRCF variants F508del, G542X and 2789+5G,A in male cases with infertility. Login to comment
269 67 SNPs (125GtoC, 1716G.A, 1717-1G.A, 1898+1G.A, 2183AA.G, 2184delA, 2789+5G.A, 3120+1G.A, 3659delC, 3849+10kbC.T, 621+ 1G.T, 711+5G.A, A455E, D110H, D1152H, D1270N, D443Y, D579G, F1052V, F1074L, F508C, F508del, G1069R, G1244E, G1349D, G178R, G542X, G551D, G551S, I1131L/V, I148T, I336K/T, I507del, I807M, IVS8T5, K1180T, L1065P, L967S, L997F, M1V, M470V, M952I, M952T, N1303K, P67L, Q1463Q, R1070Q, R1162X, R117C, R117H, R170H, R258G, R297Q, R31C, R352Q, R553X, R668C, R74W, R75Q, S1235R, S1255P, S485R, S977F, T338I, T854T, V201M, W1282X) were multiplexed into 6 wells; 14 SNPs (S492F, S945L, R74Q, R560T, R1162L, G85E, I1027T, R334W, R347P, G576A, 711+1G.T, 1001+11C.T, P1290P, 3199del6) were ascertained separately via TaqMan Gene Expression Assays, with repeat confirmation of all positive results. Login to comment

PMID: 25077647 [PubMed] Lyon E et al: "Molecular genetic testing for cystic fibrosis: laboratory performance on the College of American Pathologists external proficiency surveys."

No. Sentence Comment

87 These included 621+1, F508del, A455A, 1717-1, R117H, I507del, 3659delC, G85E, G542X, G551D, R553X, R347P, W1282X, N1303K, and R560T. Login to comment
108 Two other genotypes were also associated with relatively low analytical sensitivities (Figure 2): a heterozygous I507del challenge (2004) and a homozygous G542X sample (2009). Login to comment
110 The most common incorrect responses for the homozygous G542X challenge included reporting heterozygosity for G542X and incomplete entries (not reporting the second allele, rather than entering G542X in both allele fields). Login to comment
118 90 95 A (621 + 1G>T/A455E) (G542X/G542X) (I507 wild type or negative?) Login to comment
139 The homozygous G542X challenge in the 2009 survey was closely examined to determine whether the interpretation matched the given result. Login to comment
140 In all cases for which G542X was not entered in both allele fields, the interpretation was consistent with a result of one mutation or no mutations detected. Login to comment
182 For example, the G542X homozygous genotype and the I507del heterozygous genotype were difficult challenges (Figure 2), but both of these genotypes are rare, especially in the context of population-based screening. Login to comment

PMID: 25083129 [PubMed] Pettit RS et al: "CFTR Modulators for the Treatment of Cystic Fibrosis."

No. Sentence Comment

11 Table 1 Classification of Gene Mutations That Cause Cystic Fibrosis1,12,14 Class Exemplar Mutation Description I G542X Presence of premature termination codons (PTCs) causes CFTR protein synthesis to be defective or absent. Login to comment

PMID: 25097766 [PubMed] Fass UW et al: "Defining a mutational panel and predicting the prevalence of cystic fibrosis in oman."

No. Sentence Comment

23 Other mutations are less frequent and only four, G542X, N1303K, G551D and W1282X, haveallelefrequenciesabove1%inCaucasianpatients.15 Nonetheless, regional and geographical differences of common Caucasian mutations exist in various ethnic subpopulations.15 Similarly comprehensive molecular epidemiological data about CF in Arab populations are missing. Login to comment

PMID: 25122143 [PubMed] Audrezet MP et al: "Comprehensive CFTR gene analysis of the French cystic fibrosis screened newborn cohort: implications for diagnosis, genetic counseling, and mutation-specific therapy."

No. Sentence Comment

53 Because only a limited number of functional studies have assessed the pathogenicity of variants, mutations have been classified in previous studies according to their disease-causing potential.16,22,23 Based on the recommendations and data from these studies (UMD-CFTR-France),24 variants were classified into four groups: A, CF-causing; B, associated with CFTR-RDs; C, no clinical consequences; and D, unknown or Table 1ߒ Allelic frequencies of CF30-kit mutations, identified in neonates with CF, and correspondence between traditional mutation nomenclature and that on the Human Genome Variation Society website Frequency (F) % Mutation Legacy mutation nomenclature Number of alleles/2,320 % of alleles/2,320 Cumulative % ࣙ5 p.Phe508del F508del 1,560 67.24 67.24 p.Gly542* G542X 113 3.19 10.51 p.Asn1303Lys N1303K 81 1.98 c.1585-1G>A 1717-1G>A 48 1.47 1.00ࣙFࣙ4.99 c.2657ߙ+ߙ5G>A 2789ߙ+ߙ5G>A 37 1.42 p.Arg553* R553X 36 1.29 p.Gly551Asp G551D 31 1.16 p.Tyr122* Y122X 26 0.97 6.86 c.2988ߙ+ߙ1G>A 3120ߙ+ߙ1G>A 22 0.82 c.579ߙ+ߙ1G>T 711ߙ+ߙ1G>T 18 0.67 p.Ile507del I507del 17 0.63 c.3140-26A>G 3272-26A>G 16 0.59 0.40ࣙFࣙ0.99 p.Arg347Pro R347P 15 0.56 p.Arg1162* R1162X 15 0.56 p.Trp1282* W1282X 14 0.52 p.Tyr1092* Y1092X 13 0.48 c.2051_2052delinsG 2183AA>G 12 0.45 c.3528delC 3659delC 11 0.41 c.1680-886A>G 1811ߙ+ߙ1.6kbA>G 9 0.39 p.Gly85Glu G85E 8 0.34 3.06 p.Ser1251Asn S1251N 7 0.30 p.Arg334Trp R334W 7 0.30 p.Arg117His R117H 7 0.30 0.1ࣙFࣙ0.39 p.Trp846* W846X 6 0.26 c.489ߙ+ߙ1G>T 621ߙ+ߙ1G>T 6 0.26 c.948delT 1078delT 5 0.22 p.Ala455Glu A455E 5 0.22 p.Glu60* E60X 4 0.17 c.262_263delTT 394delTT 4 0.17 c.3718-2477C>T 3849ߙ+ߙ10kbC>T 3 0.13 Total 2,034 87.67 87.67 Mutations are clustered into four groups of frequency intervals (>5%, 1-4.99%, 0.99-0.4%, and <0.4%). Login to comment

PMID: 25178872 [PubMed] Gravina LP et al: "Mannose-binding lectin gene as a modifier of the cystic fibrosis phenotype in Argentinean pediatric patients."

No. Sentence Comment

116 c Other severe mutations: 1717-1G-NA, G542X, N1303K, W1282X, G551D, DI507, 3659delC. Login to comment

PMID: 25280757 [PubMed] Bagheri-Hanson A et al: "Intestinal current measurement versus nasal potential difference measurements for diagnosis of cystic fibrosis: a case-control study."

No. Sentence Comment

39 For sweat stimulation and collection, the Macroduct&#ae; system (Wescor, Table 1 Characteristics and CFTR response of pancreatic insufficient (CF-PI) and pancreatic sufficient (CF-PS) patients with CF and controls CF-PI (n = 12) CF-PS (n = 6) CF-all (n = 18) Controls (n = 13) Age, years 24.0 &#b1; 6.1 23.3 &#b1; 11.8 22.8 &#b1; 8.0 30.6 &#b1; 10.4 22.0 (19.0 - 26.0) 16.0 (14.5 - 30.5) 20.5 (18.3 - 25.3) 25.0 (23.5 - 35.5) Gender, females:males 3:9 5:1 8:10 7:6 Body mass index Z-score -1.18 &#b1; 0.80 -0.62 &#b1; 1,41 -0.99 &#b1; 1.03* 0.00 &#b1; 0.65* -1.05 (-2.40 - 0.00) 1.41 (-0.20 - 0.70) -0.90 (-2.60 - 0.70) 0.00 (-1.10 - 1.30) Sweat chloride (mmol/l) 110 &#b1; 13** 86 &#b1; 14** 102 &#b1; 17* 19 &#b1; 8* 106 (92 - 140) 90 (70 - 99) 104 (70 - 140) 19 (10 - 36) NPD CFTR response average Ɗ0Cl- + Iso (mV) 4.6 &#b1; 3.9 1.5 &#b1; 4.1 3.6 &#b1; 4.1* -13.6 &#b1; 8.5* 5.1 (-3.0 -11.9) 1.5 (-3.2 - 6.23) 4.5 (-3.2 - 11.9) -12.7 (-26.4 - -1.92) ICM CFTR response average ƊIsc (bc;A/cm2) ) (forskolin/IBMX + carbachol + histamine) -0.3 &#b1; 8.1 5.3 &#b1; 10.9 1.6 &#b1; 9.2* 77.8 &#b1; 34.8* -0.6 (-12.6 - 17.9) 5.0 (-9.7 - 19.0) 0.1 (-12.6 - 19.0) 65.3 (39.6 -140.9) Genotyping F508/F508 (6&#d7;) F508/R347P (2&#d7;) 148 T/R117H-7 T F508/G551D (2&#d7;) F508/3849 + 10 kb C- > T (2&#d7;) F508/- F508/G542X F508/R334W --/-- F508/N1303K F508/? Login to comment

PMID: 25304080 [PubMed] Dell'Edera D et al: "Analysis of cystic fibrosis gene mutations in children with cystic fibrosis and in 964 infertile couples within the region of Basilicata, Italy: a research study."

No. Sentence Comment

47 The molecular analysis of the CFTR gene revealed that the two Table 1 Number of subjects tested who were carriers of the cystic fibrosis transmembrane regulator gene Mutation Men Women Total G551D 1 2 3 R553X 0 1 1 F508del 35 32 67 N1303K 7 8 15 I148T 4 9 13 G542X 3 6 9 DI507 2 0 2 L1077P 0 2 2 D1152H 1 6 7 W1282X 2 0 2 2183 AA>G 3 0 3 1259insA 0 1 1 4016insT 1 0 1 I507del 1 0 1 2789+5G>A 1 0 1 4382delA 0 2 2 G1244E 1 0 1 621+3A>G 1 0 1 Total 63 69 132 Figure 1 76 patients with cystic fibrosis and positive sweat test, all have two genes mutated. Login to comment
49 brothers, aged 26 and 29 years old respectively, were both 'compound heterozygotes G542X/D1152H`, while the third one, aged 37 years old, was 'compound heterozygotes G542X/E831X`. Login to comment
59 As mentioned before, molecular screening Table 2 Comparison between the results obtained in this study and those obtained in a previous study Castaldo et al. [14] Mutations observed in the present study F508del 55.8% (29) 48.62% (141) N1303K 3.8% (2) 9.31% (27) G542X 3.8% (2) 8.96% (26) W1282X 3.8% (2) 1.03% (3) 2183AA>G 5.8% (3) 2.76% (8) R1162X 0 0 1717-1G>A 1.9% (1) 0 T338I 0 0 R347P 0 0.69% (2) 711+5G>A 0 0 852del22 5.8% (3) 1.03% (3) 4382delA 0 0.69% (2) 1259insA 0 0.34% (1) 4016insT 0 0.34% (1) R553X 0 0.34% (1) R1158X 0 0 L1077P 0 1.03% (3) I502T 0 0 3849+10kbC>T 1.9% (1) 0.34% (1) D579G 0 0.69% (2) G1244E 3.8% (2) 0 G1349D 0 0.34% (1) 2789+5G>A 0 1.03% (3) 711+1G>T 0 0 L1065P 0 0 2522insC 0 0 E585X 0 0 G85E 0 0 G178R 0 0 D1152H 0 3.10% (9) I148T-3195del6 0 0 I148T (alone) 0 4.48% (13) R334W 0 0 DI507 0 0.69% (2) I1005R 0 0 3272-26A>G 0 0 2711delT 0 0 L558S 1.9% (1) 0.34% (1) W1063X 0 0 D110H 0 0 S549R (A>C) 1.9% (1) 0.69% (2) 2184insA 0 0 3131del22 0 0 Table 2 Comparison between the results obtained in this study and those obtained in a previous study (Continued) R709N 0 0 A349V 0 0 4015insA 0 0 Y849X 1.9% (1) 0.34% (1) G551D 0 1.03% (3) 621+3A>G 0 0.34% (1) E831X 0 0 I507del 0 0.69% (2) IVS8 TG12/t5 0 1.03% (3) H139R (A->G) 0 0.34% (1) 1248+1G>A 0 0.34% (1) R74W;V201M;D1270N 0 0.69% (2) S1455X 0 0.34% (1) dele 2,3 (21kb) 0 0.34% (1) 991del5 0 0.34% (1) UNKNOWN 7 %(4) 4.83% (14) F508C 0 0.69% (2) TOTAL 52 290 of CF is highly recommended in the USA by the National Institutes of Health Consensus Development Conference Statement on genetic testing for cystic fibrosis [17]. Login to comment
79 The test has a sensitivity and a specificity of more than Table 3 List of 60 mutations in the cystic fibrosis transmembrane regulator gene (specificity 100%) F508del I507del F508C 621+1G>T D110H E585X G1349D I502T 1706del17 1677delTA R117H H139R 1898+1G>A 4015delA G542X 1717-1G>A Q552X 852del22 G178R 1898+3A>G G551D S549R(A>C) 2183AA>G T338I 991del5 1898+5G>T N1303K 4016insT 3849+10kb C>T R347P R334W 2184insA G85E 711+5G>A 711+1G>T 1259insA R347H 2522insC 2789+5G>A W1282X G1244E R1066H R352Q 3120+1G>A I148T 3199del6 S912X R1158X 1717-8G>A R1066C R1162X 4382delA D1152H L1077P D579G 3272-26A>G L1065P R553X PoliT: 5T, 7T, 9T 1874insT 3659delC 99%. Login to comment

PMID: 25336504 [PubMed] Barrio R et al: "Management of endocrine disease: Cystic fibrosis-related diabetes: novel pathogenic insights opening new therapeutic avenues."

No. Sentence Comment

29 The F508del mutation is present in 90% of CF patients worldwide (7) and only four other mutations (G551D, W1282X, G542X, and N1303K) have a minor but substantial prevalence (1-3% each) worldwide (8). Login to comment

PMID: 25386751 [PubMed] Noveski P et al: "SNaPshot assay for the detection of the most common CFTR mutations in infertile men."

No. Sentence Comment

2 Here, we describe single base extension (SNaPshot) assay for detection of 11 common CFTR mutations: F508del, G542X, N1303K, 621+1G-.T, G551D, R553X, R1162X, W1282X, R117H, 2184insA and 1717-1G-.A and IVS8polyT variants. Login to comment
37 Here, we present a rapid, reliable, cost-effective and simple assay for testing of 11 CFTR (NM_000492.3) mutations: F508del (c.1521_1523delCTT), G542X (c.1624G.T), N1303K (c.3909C.G), 621+1G-.T (c.489+1G.T), G551D (c.1652G. Login to comment
69 Mutation analyzeda Name Sequence 59-.39 Exon/intron amplified (bp)b Length of PCR fragment amplified in bp 621+1G-.T, R117H CFTR ex4/F TCTTGTGTTGAAATTCTCAGGGTA exon4 (216) 374 CFTR ex4/R CCAGCTCACTACCTAATTTATGACA delF508 CFTR ex10/F TGAATCCTGAGCGTGATTTG exon10 (192) 302 CFTR ex10/R TGGGTAGTGTGAAGGGTTCAT G542X, G551D, R553X CFTR ex11/F GCCTTTCAAATTCAGATTGAGC exon11 (95) 288 CFTR ex11/R CTAGCCATAAAACCCCAGGA 2184insA CFTR ex13/F TGCAATAAAACATTAACAAAATGC exon13 (724) 480 CFTR ex13/R GGGAGTCTTTTGCACAATGG R1162X CFTR ex19/F TGTGAAATTGTCTGCCATTCTT exon19 (249) 369 CFTR ex19/R TGCTTCAGGCTACTGGGATT W1282X CFTR ex20/F CTGAATTATGTTTATGGCATGG exon20 (156) 249 CFTR ex20/R TTTTTCTGGCTAAGTCCTTTTG N1303K CFTR ex21/F TGATGGTAAGTACATGGGTGTTTC exon21 (90) 257 CFTR ex21/R CCCCTTTCA AAATCATTTCAG IVS8-5T/7T/9T CFTR intron 8/F GGCCATGTGCTTTTCAAACT intron8 (194) 194 CFTR intron 8/R AAGAAGAGGCTGTCATCACCA a Legacy name. Login to comment
73 CFTR mutation cDNA name according to HGVS (ref. seq. NM_000492.3) Sequence (59-.39) Orientation SNaPshot Result (normal/mutant allele) Size of extended fragment in base pairs (normal allele/mutant allele)a Concentration in mix (mM)b G542X c.1624G.T CAGTGTGATTCCACCTTCTC Reverse C/A (24.9/25.9) 3 N1303K c.3909C.G CCCACTGTTCATAGGGATCCAA Reverse G/C (26.3/26.9) 5 F508del c.1521_1523delCTT CCCCTGGCACCATTAAAG- AAAATATCAT Forward C/T (29.6/31.0) 1 R117H c.350G.A 15(C)GGATAACAAGGAGGAAC Forward G/A (33.6/35.3) 7 IVS8-5T/7T/9T c.1210-12T[5_9] TGTGTGTGTGTGTGTGTGTTTTT Forward A/T 5T - 32.3 7T,9T - 33.4 1 621+1G-.T c.489+1G.T CCCTAGCTATGTTTAGTTTG- ATTTATAAGAAG Forward G/T (37.2/38.2) 5 IVS8-7T/9T c.1210-12T[7_9] 14(C)GTGTGTGTGTGTGT- GTGTTTTTTT Forward A/T 7T - 44.0 9T - 44.9 2 2184insA c.2052_2053insA 13(C)GTCTCCTGGACAGAAAC- AAAAAAA Forward C/A (38.7/39.7) 8 1717-1 G-.A c.1585-1G.A 9(C)GACTCTCTAATTTTC- TATTTTTGGTAATA Forward G/A (41.3/41.7) 2 G551D c.1652G.A 21(C)TGGAATCACACTGAG- TGGAG Forward G/A (43.4/43.9) 4 R553X c.1657C.T 24(C)AATCACACTGAGT- GGAGGTCAA Forward C/T (46.2/47.2) 2 W1282X c.3846G.A 28(C)GGATTCAATA- ACTTTGCAACAGTG Forward G/A (51.6/52.6) 1 R1162X c.3484C.T 29(C)ATTTCAGATG- CGATCTGTGAGC Forward C/T (51.0/52.0) 4 a Data generated on ABI PRISM 3130 Genetic Analyzer with POP-4 polymer, 36-cm capillary array and sized against GeneScan-120 LIZ size standard. Login to comment
98 [1521_1523delCTT];[ = ] 3 100% G542X/[2] c. Login to comment
100 [489+1G.T];[ = ] 2 100% G542X/F508del c. Login to comment
115 Among the oligozoospermic men five patients carried CF mutation (3 with F508del and 2 with G542X) but one of them also carried the CFTR-RD mutation, i.e. 5T allele. Login to comment
120 Compound heterozygosity for CF mutation (F508del or G542X) and CFTR-RD mutation (IVS8-5T) was present in higher frequency among patients with obstructive azoospermia (22.7%), when compared to the fertile controls (0%) p = 3.4261025 and all other groups of infertile men: non-obstructive azoospermia/severe oligozoospermia (1.14%, p = 1.1661023 ), azoospermia (0%, p = 3.3261024 ), oligozoospermia (0.92%, p = 4.8961024 ) and normoasthenoteratozoospermia (0%, p = 4.5461024 ). Login to comment
139 Patients CFTR genotype Intron8 polyT genotype N % Azoospermia [2]/[2] 5T/7T 8 10.1% [2]/[2] 5T/9T 1 1.3% [2]/[2] 7T/7T 56 70.9% [2]/[2] 7T/9T 14 17.7% Total 79 100.0% Oligozoospermia delF508/[2] 7T/9T 2 1.9% delF508/[2] 9T/9T 1 0.9% G542X/[2] 5T/9T 1 0.9% G542X/[2] 7T/9T 1 0.9% [2]/[2] 5T/7T 4 3.7% [2]/[2] 7T/7T 79 73.1% [2]/[2] 7T/9T 20 18.5% Total 108 100.0% Normoasthenoteratozoospermia delF508/[2] 7T/9T 1 1.4% delF508/[2] 9T/9T 2 2.7% [2]/[2] 5T/7T 6 8.2% [2]/[2] 7T/7T 49 67.1% [2]/[2] 7T/9T 14 19.2% [2]/[2] 9T/9T 1 1.4% Total 73 100.0% Fertile Controls delF508/[2] 7T/9T 2 1.5% [2]/[2] 5T/7T 8 5.9% [2]/[2] 5T/9T 1 0.7% [2]/[2] 7T/7T 96 70.6% [2]/[2] 7T/9T 27 19.9% [2]/[2] 9T/9T 2 1.5% Total 136 100.0% Note: [2] means no CF mutation detected on single chromosome. Login to comment
160 We have genotyped one patient to have F508del/ IVS8-5T genotype, with histopathological diagnosis of testicular atrophy and one oligozoospermic patient with G542X/IVS8-5T genotype. Login to comment
162 These results imply that F508del/IVS8-11TG-5T genotype might not be a cause of the infertility in the first patient, while G542X/IVS8-12TG-5T genotype is most probably a cause of infertility in the second patient. Login to comment
163 Similar to F508del, G542X has never been found in linkage disequilibrium with IVS8-5T [39]. Login to comment

PMID: 25404111 [PubMed] Cutting GR et al: "Cystic fibrosis genetics: from molecular understanding to clinical application."

No. Sentence Comment

73 The level and/or content of CFTR transcripts can be affected by disease-causing variants in the promoter (for example, c.-234T࢐A (also known as -102T࢐A in legacy nomenclature))140 and splice sites (for example, c.3717ߙ+ߙ12191ߙC࢐T (legacy 3849ߙ+ߙ10ߙkb C࢐T))141 , or by variants that introduce a premature termination codon (PTC) and that lead to RNA decay (for example, p.Gly542X; (legacy G542X)142 . Login to comment
305 Nature Reviews | Genetics * * * G542X G551D 3849+10kbC࢐T Clinical response Clinical response Clinical response Clinical response Function Quantity Function Quantity Function Quantity Function Quantity F508del F508del a b c d Function Quantity Therapy Ivacaftor P5 Potentiators PTC suppressor Splicing corrector Lumacaftor C4 Expression Correctors Figure 3 | Molecular treatments for cystic fibrosis. Login to comment
323 Suppression of the cryptic splice sitecanincreaseCFTRproteinlevelsabove10%ofnormal145 .Thenonsense variant G542X (also known as p.Gly542X) introduces a premature termination codon (PTC) that causes severe reduction in mRNA levels and anabsenceoftheCFTRprotein.UseofPTCsuppressorsincreasestranscript andproteinlevels,leadingtoamodestrecoveryofCFTRfunctionthatfalls short of a clinical response. Login to comment

PMID: 25481366 [PubMed] Oueslati S et al: "Preliminary study of haplotypes linked to the rare cystic fibrosis E1104X mutation."

No. Sentence Comment

62 The most common CF mutations (F508del, G542X and N1303K), provide an exceptional opportunity for the analysis of association between microsatellite allelic systems and SNP`s. Login to comment

PMID: 25583415 [PubMed] Terlizzi V et al: "Clinical expression of patients with the D1152H CFTR mutation."

No. Sentence Comment

85 Legacy name Protein name CDNA name Patients Homozygous for the D1152Ha D1152H p.Asp1152His c.3454GNC 7 Compound heterozygous for class I-II-III mutationsa : 74 F508del p.Phe508del c.1521_1523delCTT 43 G542X p.Gly542X c.1624GNT 7 N1303K p.Asn1303Lys c.3909CNG 4 1717-1GNA No protein name c.1585-1GNA 4 R1158X p.Arg1158X c.3472CNT 4 2183AANG p.Lys684SerfsX38 c.2051_2052delAAinsG 2 W1282X p.Trp1282X c.3846GNA 2 711 + 1GNT No protein name c.579 + 1GNT 1 Y849X p.Tyr849X c.2547CNA 1 L1065P p.Leu1065Pro c.3194 TNC 1 4016insT p.Ser1297PhefsX5 c.3884_3885insT 1 R1066H p.Arg1066His c.3197GNA 2 R1066C p.Arg1066Cys c.3196CNT 1 4382delA p.Glu1418ArgfsX14 c.4251delA 1 Compound heterozygous for class IV-V mutationsa : 8 (TG)12T5 No protein name Not available 2 2789 + 5GNA No protein name c.2657 + 5GNA 1 D579G p.Asp579Gly c.1736ANG 1 [R74W;V201M; D1270N] No protein name Not available 1 3849 + 10KbCNT No protein name c.3717 + 12191CNT 1 R347H p.Arg347His c.1040GNA 1 R347P p.Arg347Pro c.1040GNC 1 a Protein name and cDNA name from the CFTR2 database (http://www.http. com//www.cftr2) and http://www.genet.sickkids.on.ca/Home.html. Login to comment

PMID: 25592785 [PubMed] Marson FA et al: "Demographic, clinical, and laboratory parameters of cystic fibrosis during the last two decades: a comparative analysis."

No. Sentence Comment

27 Demographic, clinical, and laboratory markers The demographic, clinical, and laboratory variables analyzed in this study were sex (male/female), ethnicity (Caucasian or non-Caucasian), age, age range, number of deaths, clinical manifestations (respiratory and digestive), age at diagnosis, comorbidities [pancreatic insufficiency (PI), meconium ileus (MI), and diabetes mellitus (DM)], nutritional status as determined by weight and height on a growth curve (weight and height below the 10th percentile), oxygen saturation (SpO2) (>95%, 91%-95%, or <91%), sweat chloride level, microorganisms in the sputum (Staphylococcus aureus, mucoid and nonmucoid Pseudomonas aeruginosa, and Burkholderia cepacia), spirometry findings (normal, restrictive lung disease, obstructive lung disease, or mixed respiratory disorder) [14], genetic screening for the CFTR mutations [F508del (rs113993960, c.1521_ 1523delCTT), G542X (rs113993959, c.1624G > T), N1303K (rs80034486, c.3909C > G), G551D, R553X (rs74597325, c.1657C > T), and W1282X (rs77010898, c.3846G > A)], Shwachman-Kulczycki score (SKS) (excellent or good, mild, or moderate or severe) [15], and fecal fat. Login to comment
82 Older patients constitute a major proportion of the Table 1 Comparison of data (demographic, clinical, and laboratory markers) of patients with cystic fibrosis from a Brazilian referral center during the decades of 1990 to 2000 and 2000 to 2010 Demographic and clinical markers Category DI (1990-2000) DII (2000-2010) p Number of patients 104 181 Age Mean: 10 years 9 months &#b1; 6.33 months Mean :16 years 7 months &#b1; 13.16 months <0.001 Median: 9 years Median: 12 years 10 months Range: 11 months to 31 years 2 months Range: 6 months to 73 years 10 months Sex Male 53.8% 49.7% 0.539 Female 46.2% 50.3% Ethnicity Caucasian 93.3% 92.0% 0.818 NonCaucasian 6.7% 8.0% Consanguineous parents 6.2% 1.1% 0.054 Manifestation Respiratory 89.4% 91.7% 0.528 Digestive 59.6% 83.3% <0.001 Onset of symptoms Mean: 16 months Mean: 91.75 months <0.001 Median: 3 months Median: 3 months Range: 0-20 years Range: 0-60 years Age at diagnosis Mean: 4 years 2 months Mean: 2 years 10 months <0.001 Median: 2 years 4 months Median: 2 years Range: 0 to 29 years 11 months Range: 0-60 years Meconium ileus 5.8% 15.0% 0.021 Diabetes mellitus 4.8% 18.5% 0.001 Nutritional status Weight below 10th percentile 69.9% 35.71% <0.001 Height below 10th percentile 56.6% 40.82% 0.025 SpO2 >95% 59.5% 55.5% 0.713 91%-95% 32.9% 34.7% <91% 7.6% 9.8% Sweat test <60 mEq/L* 10.6% - 60-100 mEq/L 28.8% 40.51% >100 mEq/L 60.6% 59.49% Bacteria Staphylococcus aureus 80.2% 78.5% 0.880 Pseudomonas aeruginosa 76.0% 55.8% 0.001 Mucoid P. aeruginosa 53.1% 42.0% 0.085 Burkholderia cepacia 5.2% 14.4% 0.016 Mucoid and nonmucoid P. aeruginosa 51.0% 21.85% <0.001 Spirometry Normal 27.3% 34.4% <0.001 Restrictive ventilatory disorder 18.2% 48.9% Obstructive lung disorder 25.4% 14.5% Mixed respiratory disorder 29.1% 2.3% CFTR mutation F508del homozygotes 18.75% 26.5% <0.001 F508del heterozygotes 62.5% 22.7% G542X 4.17% 6.45% N1303K 2.08% 1.1% G551D 1.04% - patients seen at CF centers, and older age can be associated with variations in CF diagnosis and treatment [22]. Login to comment

PMID: 25674778 [PubMed] Baker MW et al: "Improving newborn screening for cystic fibrosis using next-generation sequencing technology: a technical feasibility study."

No. Sentence Comment

15 Correspondence: Mei W. Baker (mwbaker@wisc.edu) Improving newborn screening for cystic fibrosis using next-generation sequencing technology: a technical feasibility study Mei W. Baker, MD1,2 , Anne E. Atkins, MPH2 , Suzanne K. Cordovado, PhD3 , Miyono Hendrix, MS3 , Marie C. Earley, PhD3 and Philip M. Farrell, MD, PhD1,4 Table 1ߒ CF-causing or varying consequences mutations in the MiSeqDx IUO Cystic Fibrosis System c.1521_1523delCTT (F508del) c.2875delG (3007delG) c.54-5940_273ߙ+ߙ10250del21kb (CFTRdele2,3) c.3909C>G (N1303K) c.3752G>A (S1251N) Mutations that cause CF when combined with another CF-causing mutation c.1624G>T (G542X) c.2988ߙ+ߙ1G>A (3120ߙ+ߙ1G->A) c.3964-78_4242ߙ+ߙ577del (CFTRdele22,23) c.613C>T (P205S) c.1021T>C (S341P) c.948delT (1078delT) c.2988G>A (3120G->A) c.328G>C (D110H) c.200C>T (P67L) c.1397C>A (S466X(C>A)) c.1022_1023insTC (1154insTC) c.2989-1G>A (3121-1G->A) c.3310G>T (E1104X) c.3937C>T (Q1313X) c.1397C>G (S466X(C>G)) c.1081delT (1213delT) c.3140-26A>G (3272-26A->G) c.1753G>T (E585X) c.658C>T (Q220X) c.1466C>A (S489X) c.1116ߙ+ߙ1G>A (1248ߙ+ߙ1G->A) c.3528delC (3659delC) c.178G>T (E60X) c.115C>T (Q39X) c.1475C>T (S492F) c.1127_1128insA (1259insA) c.3659delC (3791delC) c.2464G>T (E822X) c.1477C>T (Q493X) c.1646G>A (S549N) c.1209ߙ+ߙ1G>A (1341ߙ+ߙ1G->A) c.3717ߙ+ߙ12191C>T (3849ߙ+ߙ10kbC->T) c.2491G>T (E831X) c.1573C>T (Q525X) c.1645A>C (S549R) c.1329_1330insAGAT (1461ins4) c.3744delA (3876delA) c.274G>A (E92K) c.1654C>T (Q552X) c.1647T>G (S549R) c.1393-1G>A (1525-1G->A) c.3773_3774insT (3905insT) c.274G>T (E92X) c.2668C>T (Q890X) c.2834C>T (S945L) c.1418delG (1548delG) c.262_263delTT (394delTT) c.3731G>A (G1244E) c.292C>T (Q98X) c.1013C>T (T338I) c.1545_1546delTA (1677delTA) c.3873ߙ+ߙ1G>A (4005ߙ+ߙ1G->A) c.532G>A (G178R) c.3196C>T (R1066C) c.1558G>T (V520F) c.1585-1G>A (1717-1G->A) c.3884_3885insT (4016insT) c.988G>T (G330X) c.3197G>A (R1066H) c.3266G>A (W1089X) c.1585-8G>A (1717-8G->A) c.273ߙ+ߙ1G>A (405ߙ+ߙ1G->A) c.1652G>A (G551D) c.3472C>T (R1158X) c.3611G>A (W1204X) c.1679ߙ+ߙ1.6kbA>G (1811ߙ+ߙ1.6kbA->G) c.274-1G>A (406-1G->A) c.254G>A (G85E) c.3484C>T (R1162X) c.3612G>A (W1204X) c.1680-1G>A (1812-1G->A) c.4077_4080delTGTTinsAA (4209TGTT->AA) c.2908G>C (G970R) c.349C>T (R117C) c.3846G>A (W1282X) c.1766ߙ+ߙ1G>A (1898ߙ+ߙ1G->A) c.4251delA (4382delA) c.595C>T (H199Y) c.1000C>T (R334W) c.1202G>A (W401X) c.1766ߙ+ߙ3A>G (1898ߙ+ߙ 3A->G) c.325_327delTATinsG (457TAT->G) c.1007T>A (I336K) c.1040G>A (R347H) c.1203G>A (W401X) c.2012delT (2143delT) c.442delA (574delA) c.1519_1521delATC (I507del) c.1040G>C (R347P) c.2537G>A (W846X) c.2051_2052delAAinsG (2183AA->G) c.489ߙ+ߙ1G>T (621ߙ+ߙ 1G->T) c.2128A>T (K710X) c.1055G>A (R352Q) c.3276C>A (Y1092X (C>A)) c.2052delA (2184delA) c.531delT (663delT) c.3194T>C (L1065P) c.1657C>T (R553X) c.3276C>G (Y1092X (C>G)) c.2052_2053insA (2184insA) c.579ߙ+ߙ1G>T (711ߙ+ߙ 1G->T) c.3230T>C (L1077P) c.1679G>A (R560K) c.366T>A (Y122X) c.2175_2176insA (2307insA) c.579ߙ+ߙ3A>G (711ߙ+ߙ 3A->G) c.617T>G (L206W) c.1679G>C (R560T) - c.2215delG (2347delG) c.579ߙ+ߙ5G>A (711ߙ+ߙ 5G->A) c.1400T>C (L467P) c.2125C>T (R709X) - c.2453delT (2585delT) c.580-1G>T (712-1G->T) c.2195T>G (L732X) c.223C>T (R75X) - c.2490ߙ+ߙ1G>A (2622ߙ+ߙ1G->A) c.720_741delAGGGAG AATGATGATGAAGTAC (852del22) c.2780T>C (L927P) c.2290C>T (R764X) - c.2583delT (2711delT) c.1364C>A (A455E) c.3302T>A (M1101K) c.2551C>T (R851X) - c.2657ߙ+ߙ5G>A (2789ߙ+ߙ5G->A) c.1675G>A (A559T) c.1A>G (M1V) c.3587C>G (S1196X) - Mutations/variants that were validated in this study are in bold. CF, cystic fibrosis. Table 1ߒ Continued on next page reduce carrier detection and potentially improve the positive predictive value (PPV), the NBS goals of equity and the highest possible sensitivity become more difficult to achieve. Login to comment

PMID: 25697318 [PubMed] Lay-Son R G et al: "[CFTR gene sequencing in a group of Chilean patients with cystic fibrosis]."

No. Sentence Comment

24 Otras mutaciones llamadas "comunes" a nivel mundial, es decir con frecuencias > 1%, incluyen p.G542X, p.G551D, p.N1303K y p.W1282X. Login to comment

PMID: 25824995 [PubMed] Salinas DB et al: "Benign outcome among positive cystic fibrosis newborn screen children with non-CF-causing variants."

No. Sentence Comment

55 There were no sweat chloride results meeting CF diagnostic criteria of ࣙ60 mmol/L in the N-CF group, and only one subject with three variants (G542X, G576A, R668C) had values in the "possible CF" category (ࣙ40 mmol/L) beyond 6 months. Login to comment

PMID: 25835118 [PubMed] Sisman G et al: "Mutation analysis of PRSS1, SPINK1 and CFTR gene in patients with alcoholic and idiopathic chronic pancreatitis: A single center study."

No. Sentence Comment

45 DNA samples were multiplied by multiplex PCR with a CF 22Mut and CF 14Mut+Tn strip assay kit which has 36 common mutations of the CFTR gene (DF508, DI507, F508C, I502T, 1706del17, 1677del TA, G542X, 1717-1G>A, R553X, Q552X, G551D, S549R(A>C), N1303K, 4016insT, R1162X, R1158X, W1282X, G1244E, 2789+5G>A, 2183AA>G, 711+5G>A, 711+1G>T, G85E, 3849+10kbC>T, 621+1G>T, R117H, D1152H, L1065P, R1066H, L1077P, 4382delA, 1259insA, 852del22, R347P, T338I, S912X and Allele5T-7T-9T). Login to comment

PMID: 25874479 [PubMed] Loukas YL et al: "Clinical diagnostic Next-Generation sequencing: the case of CFTR carrier screening."

No. Sentence Comment

36 Sample code Source Genotype NA18668*2 Coriell Cell Repositories* CFTR, CFdelex2,3/p.F508del NA07830 Coriell Cell Repositories* CFTR, F508del/556delA NA11275 Coriell Cell Repositories* CFTR, 3659delC/F508del NA11277 Coriell Cell Repositories* CFTR, I507del/wt NA11860 Coriell Cell Repositories* CFTR, 3849af9;10kb,Cb0e;T/3849af9;10kb,Cb0e;T 40C2 CDC** CFTR, F508del/R334W 10C4 CDC** CFTR, 2184delA/394delTT CDC2 CDC** CFTR, F508del/Exon 17&#aa;-17b-18del 212C4 CDC** CFTR, F508del/3659delC 412C2 CDC** CFTR, F508del/R334W 213C4 CDC** CFTR, W1282X/W1282X 21C2 CDC** CFTR, 1717-1Gb0e;A/1154insTC 412C5 CDC** CFTR, F508del/2183AAb0e;G 412C1 CDC** CFTR, 2184delA/394delTT 212C5 CDC** CFTR, F508del/3849af9;10KbCb0e;T 38C4 CDC** CFTR, R553X/wt 48C1 CDC** CFTR, F508del/G542X 48C3 CDC** CFTR, F508del/G551D 19C4 CDC** CFTR, F508del/R560T 19C5 CDC** CFTR, G551D/G551D 29C3 CDC** CFTR, 621af9;1Gb0e;T/N1303K 29C5 CDC** CFTR, F508del/2789af9;5Gb0e;A 49C1 CDC** CFTR, 3120af9;1Gb0e;A/L467P# 49C3 CDC** CFTR, 621af9;1Gb0e;T/R1162X 40C5 CDC** CFTR, 711af9;1Gb0e;T/wt 21C1 CDC** CFTR, A455E/F508del 112C2 CDC** CFTR, 1898af9;1Gb0e;A/F508del 214C5 CDC** CFTR, F508del/3140-26Ab0e;G *http://ccr.coriell.org/; **CDC, Center for Disease Control & Prevention, http://www.cdc.gov/; #According to CDC report, its clinical significance is unknown. Login to comment
94 Mutation cDNA Coverage Score Reference allele (F/R strand) Mutant allele (F/R strand) Genotype F508del* c.1521_1523delCTT 2080 26.5 491/557 523/504 HET 556delA c.424delA 2168 26.7 524/557 547/536 HET 3659delC* c.3528delC 2359 27.0 573/605 566/609 HET I507del c.1519_1521delATC 2246 26.8 508/612 619/501 HET 3849af9;10kb,Cb0e;T c.3717af9;12191Cb0e;T 3596 28.4 - 1834/1756 HOM 3849af9;10kb,Cb0e;T c.3717af9;12191Cb0e;T 4169 29.0 1023/1059 1116/967 HET R334W* c.1000Cb0e;T 2473 27.1 636/599 626/609 HET 2184delA* c.2052delA 3069 27.9 734/801 792/738 HET 394delTT* c.262_263delTT 3176 28.0 775/811 819/766 HET W1282X c.3846Gb0e;A 4268 29.0 - 2168/2096 HOM 1717-1Gb0e;A c.1585-1Gb0e;A 3863 28.7 922/1007 985/944 HET 1154insTC c.1022_1023insTC 4021 28.8 1058/1039 979/941 HET 2183AAb0e;G c.2051_2052delAAinsG 3927 28.8 1023/996 974/926 HET R553X c.1657Cb0e;T 6027 30.2 1532/1480 1476/1534 HET G542X c.1624Gb0e;T 3862 28.7 933/996 925/1002 HET G551D c.1652Gb0e;A 5225 29.7 1257/1351 1341/1268 HET G551D c.1652Gb0e;A 4862 29.5 - 2487/2369 HOM R560T c.1679Gb0e;C 3542 28.4 861/908 915/853 HET 621af9;1Gb0e;T* c.489af9;1Gb0e;T 2256 26.8 534/592 606/519 HET N1303K c.3909Cb0e;G 2126 26.6 534/528 492/568 HET 2789af9;5Gb0e;A c.2657af9;5Gb0e;A 3453 28.3 824/901 895/828 HET 3120af9;1Gb0e;A c.2988af9;1Gb0e;A 3021 27.8 721/787 802/707 HET L467P c.1400Cb0e;T 3848 28.7 928/993 1003/920 HET R1162X c.3484Cb0e;T 4180 29.0 1021/1065 1112/976 HET 711af9;1Gb0e;T c.579af9;1Gb0e;T 4222 29.0 1036/1072 1001/1108 HET A455E c.1364Cb0e;A 5621 30.0 1365/1443 1438/1370 HET 1898af9;1Gb0e;A c.1766af9;1Gb0e;A 2934 27.7 683/782 702/762 HET 3272-26Ab0e;G 3140-26Ab0e;G 3755 28.6 902/973 1008/867 HET of the majority of CFTR mutations carriers in our region. Login to comment

PMID: 25910067 [PubMed] Lucarelli M et al: "A Genotypic-Oriented View of CFTR Genetics Highlights Specific Mutational Patterns Underlying Clinical Macrocategories of Cystic Fibrosis."

No. Sentence Comment

167 The W19X(TAG) (p.Trp19*) mutation was found in a CF-PI male patient with a G542X/W19X(TAG) (p. Login to comment
191 [Trp1282*];[Thr465Asn] 5 G542X/W19X(TAG) c. Login to comment
276 These patients had the following mutations on the other allele: F508del (p.Phe508del) (1 CF-PI), G542X (p.Gly542*) (1 CF-PI), 2789+5G>A (c.2657+5G>A) (1 CF-PS). Login to comment
318 These patients had the following mutations on the other allele: F508del (p.Phe508del) (3 CF-PS, 5 CFTR-RD and 10 CBAVD), N1303K (p.Asn1303Lys) (1 CF-PS, 3 CFTR-RD and 1 CBAVD), 1717-1G>A (c.1585-1G>A) (3 CF-PS and 1 CFTR-RD), W1282X (p.Trp1282*) (3 CFTR-RD), G542X (p.Gly542*) (1 CF-PS, 1 CFTR-RD and 1 CBAVD), Y849X (p.Tyr849*) (1 CFTR-RD), 3849+10kbC>T (c.3717+12191C>T) (1 CFTR-RD), R1162X (p.Arg1162*) (1 CBAVD), S549R(A>C) (p.Ser549Arg) (1 CFTR-RD) and unknown (1 CF-PS and 3 CBAVD). Login to comment
381 [Glu479*;Val754Met] F508del c.1521_1523delCTT CF-PI CF-causing p.Phe508del 1717-8G>A c.1585-8G>A CF-PI CF-causing 1717-1G>A c.1585-1G>A CF-PI CF-causing D529N c.1585G>A CF-PI nd p.Asp529Asn G542X c.1624G>T CF-PI CF-causing p.Gly542* S549R(A>C) c.1645A>C CF-PI CF-causing p.Ser549Arg S549N c.1646G>A CF-PI CF-causing p.Ser549Asn S549R(T>G) c.1647T>G CF-PI CF-causing p.Ser549Arg G551D c.1652G>A CF-PI CF-causing p.Gly551Asp Q552X c.1654C>T CF-PI CF-causing p.Gln552* R553X c.1657C>T CF-PI CF-causing p.Arg553* L558S c.1673T>C CF-PI unknown significance p.Leu558Ser Y569D c.1705T>G CFTR-RD,CBAVD unknown significance p.Tyr569Asp Continued on next page 2 0 | L U C A R E L L I E T A L . Login to comment

PMID: 25940043 [PubMed] Corvol H et al: "Translating the genetics of cystic fibrosis to personalized medicine."

No. Sentence Comment

48 T p.Gly542X (G542X) 2.6% c.1521_1523del p.Phe508del (F508del) 70% c.1652G . Login to comment

PMID: 25963003 [PubMed] Ooi CY et al: "Inconclusive diagnosis of cystic fibrosis after newborn screening."

No. Sentence Comment

108 TABLE 3 Characteristics of Subjects With CFSPID Who Later Met Diagnostic Criteria of CF Subject Number Allele 1 Allele 2 Ethnicity NBS IRT, mg/L Initial Sweat Chloride, mmol/L Highest Sweat Chloride, mmol/L Country 1 F508del R117C White 105.8 36 61 Canada 2 F508del S1455X White 66.6 46 74 Canada 3 F508del P67L White 151.2 38 38 Canada 4 F508del L206W White 83.8 58 64 Canada 5 G542X L206W White 67 49 66 Canada 6 F508del L206W White 59.9 45 45 Canada 7 R1162X R117H-7T White 126 36 70 Italy 8 2183AA.G R117C White 129 32 32 Italy 9 F508del R117C White 80.4 48 56 Canada e OOI et al including in newborn-screened infants with equivocal CF diagnosis and in older individuals with single-organ manifestations of CF.17,18,20-22 As in the case of the 7 subjects who were initially classified as CFSPID but who were subsequently recognized to carry 2 disease-causing mutations on the basis of the CFTR2 project, the diagnostic consequences (benign versus disease-causing) of the CFTR mutations identified in all of the other subjects with CFSPID may not be apparent until later on, when new genetic information becomes available and classification of CFTR mutations currently considered to be of "unknown" consequences is updated. Login to comment

PMID: 26002249 [PubMed] Hadj Fredj S et al: "Prenatal diagnosis of cystic fibrosis: 10-years experience."

No. Sentence Comment

77 Ten different CFTR mutations were identified, including F508del (51.28%), E1104X (12.82%), N1303K (8.97%), G542X (8.97%), 711 + 1 G!T (6.41%), W1282X (5.12 %), R785X (1.28 %) and V754M (1.28%). Login to comment
91 Fetus genotype Number Percentage (%) F508del/- 14 28.57 F508del/F508del 6 12.24 E1104X/- 3 6.12 N1303K/- 3 6.12 E1104X/N1303K 2 4.08 F508del/711 + 1 G!T 1 2.04 E1104X/E1104X 1 2.04 W1282X/W1282X 1 2.04 711 + 1 G!T/711 + 1 G!T 1 2.04 4268 + 2T!G/4268 + 2T!G 1 2.04 G542X/- 1 2.04 -/- 15 30.61 ''-``: absence of mutation. Login to comment

PMID: 26014425 [PubMed] Girardet A et al: "The improvement of the best practice guidelines for preimplantation genetic diagnosis of cystic fibrosis: toward an international consensus."

No. Sentence Comment

78 Table 1 Examples of common CF-causing, indetermined, and non CF-causing variants (modified from5,8,17) HGVS nomenclature Legacy name cDNA nucleotide name Protein name CF-causing variantsa F508del c.1521_1523delCTT p.Phe508del G542X c.1624G4T p.Gly542* G551D c.1652G4A p.Gly551Asp N1303K c.3909C4G p.Asn1303Lys W1282X c.3846G4A p.Trp1282* 621+1G4T c.489+1G4T CFTRdele2,3 c.54-5940_273 +10250del21080 p.Ser18Argfs*16 E60X c.178G4T p.Glu60* G85E c.254G4A p.Gly85Glu 394delTT c.262_263delTT p.Leu88Ilefs*22 711+1G4T c.579+1G4T R347P c.1040G4C p.Arg347Pro A455E c.1364C4A p.Ala455Glu Q493X c.1477C4T p.Gln493* I507del c.1519_1521delATC p.Ile507del R553X c.1657C4T p.Arg553* R560T c.1679G4C p.Arg560Thr 1898+1G4A c.1766+1G4A 2183AA4G c.2051_2052delAAinsG p.Lys684Serfs*38 2789+5G4A c.2657+5G4A 3120+1G4A c.2988+1G4A M1101K c.3302 T4A p.Met1101Lys R1162X c.3484C4T p.Arg1162* 3659delC c.3528delC p.Lys1177Serfs*15 M1V c.1 A4G p.? Login to comment

PMID: 26021452 [PubMed] Corvol H et al: "[Challenges of personalized medicine for cystic fibrosis]."

No. Sentence Comment

36 Cette classe inclut les mutations non-sens et celles qui produisent un codon stop pre &#b4;mature &#b4;, comme la mutation G542X ; classe II : mutations perturbant le processus de &#ab; maturation &#bb; cellulaire de la prote &#b4;ine et son ciblage vers la membrane plasmique. La prote &#b4;ine mutante n`est pas adresse &#b4;e au bon endroit et reste en ge &#b4;ne &#b4;ral localise &#b4;e dans le cytoplasme ou ` elle est de &#b4;grade &#b4;e. Login to comment
273 Aminoglycoside suppression of a premature stop mutation in a Cftr/ mouse carrying a human CFTR-G542X transgene. Login to comment
283 [28] Du M, Liu X, Welch EM, et al. PTC124 is an orally bioavailable compound that promotes suppression of the human CFTR-G542X nonsense allele in a CF mouse model. Login to comment

PMID: 26087176 [PubMed] Dupuis A et al: "Prevalence of meconium ileus marks the severity of mutations of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene."

No. Sentence Comment

11 In this severe spectrum MIP scores further distinguished between mutation types, for example, G542X (0.31) with a high, F508del (0.22) with a moderate, and G551D (0.08) with a low MIP score. Login to comment
63 Canadian studies for CF modfier genes 2,492 3,153 43,432 3,596 1,788 2,230 23,397 16,023 3 716 3,438 860 15% (19%) 1,902 2,576 PIP and MIP derivation FEV1 and zBMI modeling MIP calculation following correction of MI variable 23,301 2,413 510 21% (25%) 20% (23%) 13% (15%) Total F508del/others MI prevalence uncorrected (estimated) Missing or incomplete genotype Available for analysis Canadian CF patient registry, born after 1980 US CF patient registry German CF patient registry CF patient registry, North Italy Table 1ߒ Meconium ileus prevalence scores for the most common cystic fibrosis-causing variants p. F508del/other variants Class PIP Canada, (n) MIP, (n) Canada United States Germany Italy HGVS Legacy name c.262_263delTT 394delTT I 0.38 (50) c.3472C>T R1158X I 0.37 (35) c.1558G>T V520F 0.35 (43) c.3484C>T R1162X I 0.34 (135) 0.17 (14) 0.22 (45) c.2012delT 2143delT I 0.33 (13) c.3276C>A or G Y1092X I 0.92 (13) 0.09 (12) 0.33 (55) c.3846G>A W1282X I 1.00 (13) 0.29 (13) 0.32 (442) 0.17 (20) c.1477C>T Q493X I 1.00 (11) 0.19 (11) 0.32 (102) c.3528delC 3659delC I 0.31 (139) c.579ߙ+ߙ1G>T 711ߙ+ߙ1G>T 0.97 (39) 0.30 (38) 0.31 (54) c.178G>T E60X I 0.30 (66) c.1657C>T R553X I 1.00 (16) 0.28 (16) 0.30 (415) 0.24 (107) c.1585-1G>A 1717-1G>A I 1.00 (12) 0.23 (12) 0.29 (367) 0.22 (38) 0.16 (22) c.1766ߙ+ߙ1G>A 1898ߙ+ߙ1G>A 0.29 (139) c.1624G>T G542X I 0.99 (73) 0.31 (72) 0.29 (976) 0.21 (79) 0.22 (33) c.1521_1523delCTT F508del II 0.99 (1292) 0.22 (1260) 0.27 (15391) 0.21 (1910) 0.20 (230) c.1679G>C R560T II 0.27 (123) c.3744delA 3876delA 0.27 (22) c.2128A>T K710X I 0.26 (12) c.1519_1521delATC I507del II 1.00 (20) 0.21 (19) 0.25 (162) c.3909C>G N1303K II 0.98 (40) 0.13 (39) 0.25 (534) 0.23 (80) 0.14 (62) c.489ߙ+ߙ1G>T 621ߙ+ߙ1G>T I 1.00 (90) 0.24 (88) 0.25 (369) 0.21 (11) c.3266G>A W1089X I 0.25 (17) c.1675G>A A559T 0.24 (21) c.988G>T G330X 0.24 (10) c.3773_3774insT 3905insT 0.23 (78) c.2988ߙ+ߙ1G>A 3120ߙ+ߙ1G>A 0.22 (121) c.443T>C I148T;3199del6 1.00 (15) 0.22 (15) c.2052delA 2184delA I 0.21 (89) 0.22 (10) c.2051_2052delAAinsG 2183AA>G 0.20 (73) 0.20 (42) c.948delT 1078delT 0.19 (20) c.1652G>A G551D III 0.96 (54) 0.08 (53) 0.15 (979) 0.09 (84) c.254G>A G85E 0.50 (24) 0.06 (24) 0.14 (137) 0.00 (10) c.3196C>T R1066C 0.14 (42) c.1466C>A S489X 1.00 (14) 0.14 (14) c.3808G>A D1270N 0.13 (19) c.1055G>A R352Q 0.12 (18) c.579ߙ+ߙ5G>A 711ߙ+ߙ5G>A 0.12 (30) c.2175_2176insA 2307insA 0.11 (24) c.349C>T R117C 0.10 (37) c.1040G>C R347P IV 0.18 (11) 0.19 (11) 0.10 (130) 0.02 (56) c.350G>A R117H IV 0.05 (21) 0.00 (21) 0.07 (666) 0.02 (19) c.2657ߙ+ߙ5G>A 2789ߙ+ߙ5G>A V 0.25 (20) 0.00 (20) 0.06 (271) 0.01 (21) c.1040G>A R347H 0.06 (55) c.2988G>A 3120G->A 0.06 (36) c.328G>C D1152H IV 0.06 (124) c.3717ߙ+ߙ12191C>T 3849ߙ+ߙ10kbC>T V 0.07 (14) 0.00 (14) 0.05 (299) 0.01 (42) 0.00 (15) c.1364C>A A455E V 0.16 (45) 0.01 (41) 0.05 (109) c.1000C>T R334W IV 0.18 (11) 0.00 (10) 0.05 (92) c.617T>G L206W 0.06 (18) 0.05 (17) 0.04 (52) c.3302T>A M1101K 0.04 (17) c.200C>T P67L V 0.07 (14) 0.00 (14) Meconium ileus prevalence (MIP) and pancreas insufficiency prevalence (PIP) scores are presented. Login to comment
74 The highest MIP scores were calculated for mutations with premature termination, such as G542X (class I mutation, MIP 0.31), followed by F508del (class II mutation, MIP 0.22); the lowest MIP score was for G551D (class III mutation, MIP 0.08) (P = 0.0009). Login to comment

PMID: 26115565 [PubMed] Mall MA et al: "Targeting ion channels in cystic fibrosis."

No. Sentence Comment

607 Class I mutations such as G542X can be targeted with so called read-through agents. Login to comment

PMID: 26137539 [PubMed] Awatade NT et al: "Measurements of Functional Responses in Human Primary Lung Cells as a Basis for Personalized Therapy for Cystic Fibrosis."

No. Sentence Comment

3 Methods: The effect of lumacaftor was investigated in primary HBE cells from non-CF and CF patients with F508del/F508del, A561E/A561E, N1303K/G542X, F508del/G542X and F508del/Y1092X genotypes by measurements of Forskolin plus Genistein-inducible equivalent short-circuit current (Ieq-SC-Fsk + Gen) in perfused open-circuit Ussing chambers. Login to comment
35 In addition we tested VX-809 in HBE cells bearing 2 nonsense mutations: G542X and Y1092X, both in heterozygosity with F508del. Login to comment
42 Culture Conditions of Primary Human Bronchial Epithelial Cells Human lung tissues from CF donors with the F508del/F508del (2 donors), A561E/A561E, N1303K/G542X, F508del/G542X and F508del/ Y1092X genotypes, were obtained from the Cardio-Thoracic Surgery Department (University Hospital la Fe, Valencia, Spain) after receiving patient's written consent and approval by the hospital Ethics Committee. Login to comment
58 Response to lumacaftor for Class II Mutants Assessed by CFTR-Mediated Chloride Secretion The effects of 24 h-treatment with lumacaftor were assessed here by determining CFTR-mediated Cl-secretion in HBE cells from CF donors with the following genotypes (Fig. 1): wt/wt control (a, b); F508del/F508del-Donor 1 (c, d); F508del/F508del-Donor 2 (e, f); A561E/A561E (Fig. 1g, h) and also on the additional genotypes (Fig. 2): N1303K/G542X (a, b), F508del/G542X (c, d); F508del/ Y1092X (e, f). Login to comment
59 Since G542X is a "null" variant (i.e., generating no protein) results on the latter are representative of the N1303K variant, albeit in a single dose. Login to comment
61 These results show that Fsk + Gen responses of F508del/F508del (2 donors), A561E/A561E F508del/G542X and F508del/Y1092X cells after VX-809/lumacaftor treatment were significantly different from those under DMSO, while that of N1303K/G542X cells was not significantly different (Fig. 3b). Login to comment
69 These data again clearly show a positive effect of VX-809 on HBE cells with genotypes F508del/ F508del (both donors), A561E/A561E, F508del/G542X and F508del/ Y1092X but not on N1303K/G542X cells. Login to comment
71 It is also interesting to note the difference in responses by the F508del/G542X and F508del/Y1092X cells. Login to comment
72 Since F508del/ Y1092X cells (but not F508del/G542X cells) already exhibit levels of Ieq-sc-Fsk or Ieq-sc-Fsk + Gen before VX-809, we assessed Fig. 2. Login to comment
73 Effect of lumacaftor (VX-809) on cAMP-induced Isc-eq in primary cultures of HBE cells from CF patients with different CFTR mutations. Original Ussing chamber (open-circuit) recordings showing transepithelial voltage measurements (Vte) obtained for CF primary airway HBE monolayers with different genotypes: N1303K/G542X (a, b); F508del/G542X (c, d); and F508del/Y1092X (e, f). Login to comment
77 Data, show that the levels of Y1092X-transcripts are higher than those from G542X (Table S3), indicating that Y1092X transcripts are less prone to degradation through nonsense-mediated decay. Login to comment
110 Data presented here also show a positive effect of VX-809 on HBE cells with genotypes F508del/G542X (~4% vs non-CF) and F508del/Y1092X (~7% vs non-CF) but not on N1303K/G542X cells. Login to comment
117 In contrast to the effect on A561E/A561E HBE cells, the magnitude of the response of lumacaftor-treated N1303K/G542X cells was just slightly higher by ~2-fold (both under Fsk and Gen) and not statistically different from that in DMSO-treated cells. Login to comment
123 Secondly, it is possible that the response of a single copy of N1303K (the other CFTR allele is G542X, a "null" variant) may be insufficient to observe an effect similar in magnitude to that of A561E/A561E or F508del/F508del cells. Login to comment
124 Contradicting the latter hypothesis are the positive responses of the F508del/G542X and F508del/Y1092X cells, showing that VX-809 can elicit a detectable effect on a single dose of F508del, in contrast to N1303K. Login to comment
125 Interestingly, the response of F508del/Y1092X cells is almost double to that of F508del/G542X. Login to comment
126 While difference could be due to intrinsic responses of the F508del alleles from each of these donors, it is also plausible that the Y1092X mutation, given its localization towards the C-terminus of the protein, does not totally abolish the production of functional CFTR protein, in contrast to G542X. Login to comment
128 Moreover, the levels of Y1092X-transcripts (Table S3) are higher than those from G542X, again indicating that Y1092X transcripts are less prone to degradation through nonsense-mediated decay. Login to comment

PMID: 26137547 [PubMed] Becq F et al: "Predicting CFTR activity with front-runner cystic fibrosis drugs."

No. Sentence Comment

20 The authors evaluated and compared the efficacy of correctors lumacaftor (VX-809) and its analogue C18 on epithelial cell preparations obtained from donors with different CF genotypes - homozygous for F508del, A561E or heterozygous N1303K/ G542X, F508del/G542X, F508del/Y1092X. Login to comment

PMID: 26142488 [PubMed] Pibiri I et al: "Enhancement of premature stop codon readthrough in the CFTR gene by Ataluren (PTC124) derivatives."

No. Sentence Comment

17 The most commonly observed mutations include three base pair deletion causing the loss of phenylalanine at position 508 (delta-F508), a missense mutation at position 551 and a nonsense mutation at position 542 (G542X) known as a class I mutation type. Login to comment

PMID: 26160248 [PubMed] Krzyzanowska P et al: "Exogenous and endogenous determinants of vitamin K status in cystic fibrosis."

No. Sentence Comment

122 The genotypes of the studied patients were as follows: F508del/F508del (nߙ=Èa;ߙ74); F508del/- (nߙ=Èa;ߙ23); F508del/3849ߙ+Èa;ߙ10ߙkbCߙ>Èa;ߙT (nߙ=Èa;ߙ6); F508del/2143delT (nߙ =Èa;ߙ 6); F508del/R553X (nߙ =Èa;ߙ4); F508del/2183AAߙ>Èa;ߙG (nߙ=Èa;ߙ3); F508del/1717-1G>Èa;A (nߙ=Èa;ߙ3); F508del/CFTRdele2,3(21ߙkb) (nߙ=Èa;ߙ3); F508del/3272-26Aߙ>Èa;ߙG (nߙ=Èa;ߙ 2); F508del/N1303K (nߙ =Èa;ߙ2); F508del/4374ߙ+Èa;ߙ1Gߙ>Èa;ߙT (nߙ=Èa;ߙ1); F508del/621ߙ+Èa;ߙ1Gߙ>Èa;ߙT (nߙ=Èa;ߙ 1); F508del/3659delC (nߙ =Èa;ߙ1); F508del/ G1244R (nߙ =Èa;ߙ 1); F508del/G542X (nߙ =Èa;ߙ 1); F508del/R117H (nߙ =Èa;ߙ 1); F508del/R334W (nߙ =Èa;ߙ1); G542X/- (nߙ=Èa;ߙ2); CFTRdele2,3(21ߙkb)/- (nߙ=Èa;ߙ2); CFTRdele2,3(21ߙkb)/CFTRdele2,3(21ߙkb) (nߙ=Èa;ߙ1); 1717-1-Gߙ>Èa;ߙA/ CFTRdele2,3(21ߙkb) (nߙ=Èa;ߙ1); 3849ߙ+Èa;ߙ10ߙkbCߙ>Èa;ߙT/- (nߙ=Èa;ߙ1); 3849ߙ+Èa;ߙ10ߙkbCߙ>Èa;ߙT/1717ߙ-Èa;ߙ1Aߙ>Èa;ߙG (nߙ=Èa;ߙ1); N1303K/- (nߙ=Èa;ߙ1); N1303K/3272-26Aߙ>Èa;ߙG (nߙ=Èa;ߙ1); G542X/R553X (nߙ=Èa;ߙ1); 1524ߙ+Èa;ߙ1Gߙ>Èa;ߙA/E585X (nߙ=Èa;ߙ1); 2183AAߙ>Èa;ߙG/- (nߙ=Èa;ߙ1); 2184insA/622-1Gߙ>Èa;ߙA (nߙ=Èa;ߙ1); 2143delT/R1102X (nߙ=Èa;ߙ1); 3272-26Aߙ>Èa;ߙG/- (nߙ=Èa;ߙ1); 3659delC/- (nߙ=Èa;ߙ1); R347P/R347P (nߙ=Èa;ߙ1); S1196X/Q1382X (nߙ=Èa;ߙ1). Login to comment

PMID: 26255232 [PubMed] Zomer-van Ommen DD et al: "Limited premature termination codon suppression by read-through agents in cystic fibrosis intestinal organoids."

No. Sentence Comment

31 Human organoid culture and functional CFTR measurements Crypts were isolated from rectal biopsies of six subjects with cystic fibrosis (E60X/4015delATTT, E60X/F508del, G542X/ F508del, R1162X/F508del, W1282X/F508del and F508del/ F508del) as previously described (20). Login to comment
46 We next assessed read-through by G418 and PTC124 in organoids compound heterozygous for F508del and a nonsense mutation (E60X, G542X, R1162X and W1282X) (Fig. 2A). Login to comment
70 3 of PTC124, and included CFTR mutations that were previously associated with PTC124 read-through, such as G542X (c.1624G- N T) and W1282X (c.3846G- N A) (cftr2.org). Login to comment

PMID: 26358851 [PubMed] Nefzi M et al: "Contribution of M470V variant to cystic fibrosis: First study in CF and normal Tunisian population."

No. Sentence Comment

106 Genotype analysis We identified five CF mutations in our cohort: F508del mutation (63.20%), which is the most frequent mutation N1303K (4.4%), G542X (2.94%), E1104X (2.94%) and 1524 + 5insC (1.47%) utilizing the obtained data from previously carried out molecular study using different techniques (DGGE, DHPLC and sequencing) [7]. Login to comment

PMID: 26386752 [PubMed] Stafler P et al: "The impact of a national population carrier screening program on cystic fibrosis birth rate and age at diagnosis: Implications for newborn screening."

No. Sentence Comment

55 Mutation DF508 G542X W1282X N1303K 3849 + 10kbC- N T D1152H 405 + 1G࢐A G85E S549R W1089X 1717 + 1G࢐A I1234Va Y1092Xb 3121-1G N Ab 3120 + 1kbdel8.6 kbc 2183AA N Gc 4010delTATTc The first 14 mutations served as the panel used for Jewish population carrier screening program during the study period. Login to comment

PMID: 26431978 [PubMed] Jacquot J et al: "Bone disease in cystic fibrosis: new pathogenic insights opening novel therapies."

No. Sentence Comment

79 In human osteoblasts obtained from a 25-year-old CF male with the F508del/ G542X mutation in CFTR, we discovered a defective CFTR-mediated Cl-channel activity and a severe deficit of the production of OPG [59] which is a key regulator in bone density [60]. Login to comment

PMID: 26500004 [PubMed] Pepermans X et al: "Identification and frequencies of cystic fibrosis mutations in central Argentina."

No. Sentence Comment

99 rs name HGVS p. name HGVS c. name Legacy name n (%) Screening panel CFTR1 database CFTR2 database rs199826652 p.Phe508del c.1521_1523delCTT F508del 94 (56.6) Yes Yes CF-causing rs113993959 p.Gly542* c.1624G N T G542X 7 (4.2) Yes Yes CF-causing No p.Asn1303Lys c.3909C N G N1303K 5 (3) Yes Yes CF-causing rs74767530 p.Arg1162* c.3484C N T R1162X 4 (2.4) Yes Yes CF-causing rs75961395 p.Gly85Glu c.254G N A G85E 3 (1.8) Yes Yes CF-causing rs78756941 NA c.489 + 1G N T 621 + 1G N T 3 (1.8) Yes Yes CF-causing rs76713772 NA c.1585-1G N A 1717-1G N A 3 (1.8) Yes Yes CF-causing No p.Lys684Serfs*38 c.2051_2052delAAinsG 2183AA N G 3 (1.8) Yes Yes CF-causing rs397508173 p.Ser4* c.11C N A S4X 2 (1.2) No Yes No rs121909011 p.Arg334Trp c.1000C N T R334W 2 (1.2) Yes Yes CF-causing rs77010898 p.Trp1282* c.3846G N A W1282X 2 (1.2) Yes Yes CF-causing rs397508141 p.Leu34_Gln39del c.100_117delTTGTCAGACATATACCAA 232del18 1 (0.6) No Yes No No p.Leu49Pro c.146 T N C L49P &#a7; 1 (0.6) No No No rs77834169 p.Arg117Cys c.349C N T R117C 1 (0.6) Yes Yes CF-causing No p.Arg117Pro c.350G N C R117P 1 (0.6) No Yes No rs80282562 p.Gly178Arg c.532G N A G178R 1 (0.6) Yes Yes CF-causing rs121908803 p.Pro205Ser c.613C N T P205S 1 (0.6) No Yes CF-causing rs121908752 p.Leu206Trp c.617 T N G L206W 1 (0.6) Yes Yes CF-causing No p.Arg347Pro c.1040G N C R347P 1 (0.6) Yes Yes CF-causing rs397508155 p.Tyr362* c.1086 T N A Y362X 1 (0.6) No Yes No rs74597325 p.Arg553* c.1657C N T R553X 1 (0.6) Yes Yes CF-causing rs1800098 + rs1800100 p.[Gly576Ala(;)Arg668Cys] c. Login to comment

PMID: 7505422 [PubMed] Lester LA et al: "Delta F508 genotype does not predict disease severity in an ethnically diverse cystic fibrosis population."

No. Sentence Comment

41 CFTR Mutation Analysis All persons were tested for the following mutations: SF508, G542X, G551D, G553X, W1282X, N1303K, 621 +IG-*T, R117H, S549N, 3849+lOkbC-T, l6O9delCA, and R1162X. Login to comment
59 Frequencies of 12 CF With Cystic Fibrosis TR Mutations in 119 Patients Mutation Frequency SF508 0.559 G542X 0.092 G5SID 0.029 R553X 0.004 W1282X 0.012 N1303K 0.021 621 + IG -p 0.012 RII7H 0.004 R1162.X 0.008 3849 + lOkbC T 0.008 S549N 0 l6O9delCA 0 Unidentified 0.248 groups were not significantly different with respect to current age, presence of pancreatic insufficiency, clinical presentation, or associated complications common in CF patients. Login to comment

PMID: 7533609 [PubMed] Korst RJ et al: "Gene therapy for the respiratory manifestations of cystic fibrosis."

No. Sentence Comment

99 Alleles G551D, S5491, A455E, and G542X account for 10-20% of the non-L\F508 mutations. Login to comment

PMID: 8697849 [PubMed] Colin AA et al: "Pulmonary function and clinical observations in men with congenital bilateral absence of the vas deferens."

No. Sentence Comment

38 His stool description Table 1.Age, Sweat Sodium and Chloride Concentration and Ratio, and Genotype Subject/Age, yr Symptoms Sweat Na+: mEq/L Sweat Cl mEq/L Na:Cl Ratio CFTR Genotype Polythymidine Splice Variant l*/32 2*/27 3f/30 4/23 5*/22 6*/31 7*/37 8/30 9/41 10/31 11/31 12/38 13/40 14/32 15/31 16/43 17/40 18/27 Asthma Malabsorption Bronchitis Asthma 100 39 53 37 36 36 26 46 42 35 83 74 44 44 44 28 21 106 80 37 51 35 34 34 24 45 43 32 79 75 46 44 40 32 22 0.94 1.05 1.03 1.06 1.05 1.05 1.08 1.00 0.98 1.09 1.05 0.99 0.96 1.00 1.10 0.90 0.95 AF508/R117H AF508/R117H AF508/- AF508/- AF508/- AF508/- AF508/- R117H/- Q493X/- AF508/- AF508/- AF508/R117H G551D/R117H G551D/D1152H AF508/- G542X/- R117H/- -/- 7/9 7/9 5/9 5/9 7/7 7/9 7/9 NT$ 7/7 NT NT 7/9 7/7 7/7 5/9 5/9 7/7 5/9 * Subject 1 and 2 are brothers. Login to comment

PMID: 9056882 [PubMed] Righetti PG et al: "Recent advances in capillary electrophoresis of DNA fragments and PCR products."

No. Sentence Comment

58 Thus the experimental parameters Biochemical Society Transactions M/M I 270 ' G542X Figure 2 CZE analysis of three mutants [I7 17- IG+A (a), G542X (c) and I784delG (d)] in exon I I of the CFTR gene All conditions were as in Figure I , except that the buffer was 8.9 mM Trisborate. Login to comment
68 Figure 2 shows the analysis of a set of intermediate-low-melting fragments, amplified from patients with cystic fibrosis heterozygous for different mutations in exon 11 of the CFTR gene [1717-1G+A (Figure 2a), G542X (G-T at 1756; Figure 2c) and 1784delG (Figure 2 4 1 with their respective normal control (Figure 2e). Login to comment

PMID: 9092029 [PubMed] Durieu I et al: "[Male infertility caused by bilateral agenesis of the vas deferens: a new clinical form of cystic fibrosis?]."

No. Sentence Comment

46 Vingt-deux mutations du gene CFTR ont Cte recher- chtes : les cinq plus frequentes (AF508, G542X, N1303K, 1717-G--A, G85E) et les 17 suivantes : R117H, 556delA, R334W, R347H, R347P, S549N, S5491, S549R, G551D, R553X,R560T,G1244E3,S1255X,W1282X,R1283K,3898 ins C, D1270N. Login to comment
55 Quatorze sujetsCtaienth&&o- zygotespourlesmutationsAF508 (12), G542X (un) et D1270N (un). Login to comment
76 Le testdela sueurest positif chez dix sujets.Six sujetssont heterozygotes pour la mutationAF508 ou G542X et ont un testdela sueurntgatif. Login to comment
120 DF508, G542X and Nl303K are the most common of the 36 mutations screened in the CFTR gene of 427 french CF chromosomes. Login to comment