ABCMdb

ABCC7 p.Trp1282*

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I-II-III-VI (protein synthesis defect, maturation defect, gating defect, reduced stability) <a href="https://www.ncbi.nlm.nih.gov/pubmed/26823392">Veit et al.</a>
admin on 2016-08-19 15:16:22

Publications

PMID: 10021451 [PubMed] Zeitlin PL et al: "Novel pharmacologic therapies for cystic fibrosis."

No. Sentence Comment

48 This has been demonstrated for W1282X and R553X in vitro. Login to comment
49 Given that W1282X mRNA is unusually stable in certain patients (10), topical and inhaled gentamicin is under study in the United States and Israel (11, 12). Login to comment
204 Similar levels of mRNA from the W1282X and the delta F508 cystic fibrosis alleles, in nasal epithelial cells. J. Clin. Invest. 93:1502-1507. 11. 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

PMID: 10069998 [PubMed] Schwiebert LM et al: "Chemokine expression in CF epithelia: implications for the role of CFTR in RANTES expression."

No. Sentence Comment

45 The following CF epithelial cells were utilized: the airway epithelial cell lines IB3-1 (bronchial; ⌬F508/W1282X compound heterozygote; a gift from Dr. Pam Zeitlin, Johns Hopkins University, Baltimore, MD; Ref. 37), CFBE41o- (bronchial; ⌬F508 homozygote; a gift from Dr. Dieter Gruenert; Ref. 5), and ⌺CFTE29o- (tracheal; ⌬F508 homozygote; a gift from Dr. Dieter Gruenert; Ref. 5) and the pancreatic adenocarcinoma cell line CFPAC-1 (⌬F508 homozygote; ATCC). Login to comment
77 IB3-1 is heterozygous for the ⌬F508 CFTR mutation (⌬F508/ W1282X), whereas CFBE41o- and ⌺CFTE29o- are homozygous for the ⌬F508 CFTR mutation. 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: 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
60 Restriction digestion and electrophoresis (Figures 2 and 3) Detection of 621ϩ1G→T, R117H, G551D, R553X, W1282X and N1303K were performed using appropriate restriction enzymes (New England Biolabs, Ozyme, Saint Quentin Yvelines, France) as described in Table IV. 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
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
47 tion panel included W1282X (2 alleles), R334W (2 alleles), S549R (1 allele), R347P (1 allele), and N1303K (1 allele). 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
70 Of the 56 subjects with idiopathic epididymal obstruction, analysis using the 31 mutation panel resulted in the identification of 5 mutant alleles: ⌬F508 (2 alleles), W1282X (2 alleles), and R117H (1 allele) (Table 2). Login to comment
83 These severe CFTR gene mutations are associated with pancreatic insufficiency and are generally class 1 through 3 mutations: ⌬F508, W1282X, N1303K, S549R, 1677delTA, R117L, 4016insT, G544S, 2423delG, V754M, and 741T→G. 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

14 Several mutations are peculiar to specific ethnic groups, i.e., W1282X is frequent among Ashkenazi (4), 1 Centro di Ingegneria Genetica scarl and Dipartimento di Biochimica e Biotecnologie Mediche, Universita` di Napoli "Federico II", 80131 Naples, Italy. 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: 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
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

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

20 While ⌬F508 and other CFTR gene alleles (e.g., W1282X, and G551D) can be categorized as severe with respect to the level of exocrine pancreatic dysfunction (20), correlations of genotype with the severity of pulmonary disease have been less clear. Login to 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
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

PMID: 10518596 [PubMed] Schneider SW et al: "Continuous detection of extracellular ATP on living cells by using atomic force microscopy."

No. Sentence Comment

73 Genotypically, the cell line is a compound heterozygote containing the ⌬F508 mutation and a nonsense mutation, W1282X, with a premature termination signal. 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: 10655317 [PubMed] Phillipson GT et al: "Congenital bilateral absence of the vas deferens, cystic fibrosis mutation analysis and intracytoplasmic sperm injection."

No. Sentence Comment

71 Clinical cycle results Male cystic Nil:nil Nil:R117H or ∆F508:nil ∆F508:R117H ∆F508: Total fibrosis genotype nil:R117C W1282X detected or ∆F508: allele1:allele2 ∆F508 Couples (n) 5 2 13 5 2 27 Mean age female 33 29 31 34 26 31 partner (years) Oocyte retrieval 7 9 22 12 3 53 cycles (n) Oocytes injected (n) 69 134 199 113 43 558 Oocytes 46 102 144 85 29 406 fertilized (n) Fertilization rate (%) (67) (76) (72) (75) (67) (73) Embryo transfers 5a 9 22 12 3 51 (ET) (n) (96%) Embryos 13 25 52 29 6 125 transferred (n) (mean per ET) (2.6) (2.8) (2.4) (2.4) (2.0) (2.5) Clinical pregnancies 3 0 9 3 2 17 (n) (33%) Embryo 23 0 21 21 33 18 implantation rate (%) Embryos frozen (n) 16 9 34 21 6 86 Cycles with 4 44 10 5 2 25 embryos frozen (57) (44) (45) (42) (67) (47) (n)(% of cycles) aOne cycle had a single oocyte which failed to fertilize, and one cycle had all embryos frozen. Login to comment
103 However, substantially larger numbers diagnosis has been successfully used for ∆F508 and W1282X of embryos will need to be transferred before analysis of but not for the less common mutations. Login to comment

PMID: 10666020 [PubMed] Rubenstein RC et al: "Sodium 4-phenylbutyrate downregulates Hsc70: implications for intracellular trafficking of DeltaF508-CFTR."

No. Sentence Comment

13 IB3-1 cells (genotype ⌬F508/W1282X) that were treated with 0.05-5 mM 4PBA for 2 days in culture demonstrated a dose-dependent reduction in Hsc70 protein immunoreactivity and mRNAlevels. Login to comment
95 IB3-1 has the CFTR genotype ⌬F508/W1282X and is a model system for study of the intracellular trafficking of ⌬F508-CFTR because the W1282X allele gives rise to an unstable and therefore untranslated mRNA. Login to comment
167 G418 promotes read through and stabilization of the otherwise unstable mRNA derived from the W1282X missense allele present in IB3-1 cells and results in the appearance of CFTR channel activity at the IB3-1 plasma membrane (2). Login to comment
185 G418, which acts on the W1282X allele and not ⌬F508-CFTR, had little effect on Hsc70 or Hsp90 but increased Hsp40 and Hsp70 immunoreactivity. Login to comment
186 Although it seems logical that increased Hsc70 might lead to reduced trafficking of CFTR derived from the W1282X allele, the W1282X-derived CFTR would have wild-type structure in the region of F508, and the F508 region may be a critical determinant of CFTR affinity for Hsc70. Login to comment
209 This is also consistent with G418 acting on the W1282X-CFTR allele present in IB3-1 and not on the ⌬F508 allele that is the target of 4PBA, glycerol, or butyrate. 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

16 In the Ashkenazi Jewish population the W1282X mutation is the most common CF-causing mutation and together with other nonsense mutations accounts for 64% of all CFTR alleles (5-7). Login to comment
21 Subsequently, Bedwell and coworkers (10) have shown in a CF bronchial epithelial cell line carrying the CFTR W1282X premature stop mutation, that gentamicin was capable of restoring CFTR expression on the apical membrane. Login to 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
87 One patient (Patient 8) who carried the W1282X/3849 ϩ 10kbC→Τ genotype showed a marked response which led to normalization of the nasal PD. Login to comment

PMID: 10720936 [PubMed] Zeitlin PL et al: "Pharmacologic restoration of delta F508 CFTR-mediated chloride current."

No. Sentence Comment

62 (B) Class I mutations, such as W1282X, produce an early stop codon, unstable mRNA, and absence of CFTR protein. Login to comment
83 W1282X and R553X Genistein, a member of the flavonoid class of mole- can be rescued in vitro. Login to comment
84 Given that W1282X mRNA is cules, activates CFTR through a highly debated mecha- unusually stable in certain patients [42], topical, inhaled, nism [34]. 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

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

237 For example, the frequency of the W1282X mutation is 1.2% in the white population, but it is as high as 60% in Ashkenazi Jews.8 That of F508 is 70% in northern Europeans but it is less than 50% in Spanish and Hispanics.7 9 In order to provide accurate genetic counselling, it is necessary to determine the prevalent mutations in each ethnic group. Login to comment
240 The clinical diagnosis of CF has been recently reviewed.10 Although the structure and function of F508 and W1282X mutant CFTR have been studied, there is a shortage of genotype-phenotype correlation studies of rare mutations, particularly the ones that appear to be unique to Hispanic CF patients. Login to comment
294 Like those with F508/ F508, F508/W1282X, and W1282X/W1282X, patients with the 3876delA/ F508 mutation had variable pulmonary function. Login to comment
320 Since ATP hydrolysis at NBD2 terminates a burst of activities associated with opening the channel, loss of NBD2 would confer a loss of the gating control.21 A recent study shows that the Walker A motif in NBD2 is more solvent accessible than that in NBD1, suggesting a diVerence in structure and function for the two NBDs.22 In addition to 3876delA, a few other mutations in NBD2, including G1244E, S1255P, S1255X, 3905insT, W1282X, N1303K, and G1349D, all result in a PI phenotype.5 23 It should be noted that S1255P, S1255X, 3905insT, and 3876delA are all clustered around the Walker A motif. Login to comment
339 Hum Genet 1997;101:365-70. 8 Shoshani T, Augarten A, Gazit E, 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. 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

237 For example, the frequency of the W1282X mutation is 1.2% in the white population, but it is as high as 60% in Ashkenazi Jews.8 That of F508 is 70% in northern Europeans but it is less than 50% in Spanish and Hispanics.7 9 In order to provide accurate genetic counselling, it is necessary to determine the prevalent mutations in each ethnic group. Login to comment
240 The clinical diagnosis of CF has been recently reviewed.10 Although the structure and function of F508 and W1282X mutant CFTR have been studied, there is a shortage of genotype-phenotype correlation studies of rare mutations, particularly the ones that appear to be unique to Hispanic CF patients. Login to comment
294 Like those with F508/ F508, F508/W1282X, and W1282X/W1282X, patients with the 3876delA/ F508 mutation had variable pulmonary function. Login to comment
320 Since ATP hydrolysis at NBD2 terminates a burst of activities associated with opening the channel, loss of NBD2 would confer a loss of the gating control.21 A recent study shows that the Walker A motif in NBD2 is more solvent accessible than that in NBD1, suggesting a diVerence in structure and function for the two NBDs.22 In addition to 3876delA, a few other mutations in NBD2, including G1244E, S1255P, S1255X, 3905insT, W1282X, N1303K, and G1349D, all result in a PI phenotype.5 23 It should be noted that S1255P, S1255X, 3905insT, and 3876delA are all clustered around the Walker A motif. Login to comment
339 Hum Genet 1997;101:365-70. 8 Shoshani T, Augarten A, Gazit E, 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. 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

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
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
131 With respect to the W1282X mutation, conflicting data are reported in the literature. 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
172 Am J Respir Cell Mol Biol 7:485-491 Riordan JR, Rommens JM, Kerem B-S, Alon N, Rozmahel R, Grzelczak Z, Zielenski J, Lok S, Plavsic N, Chou J-L, Drumm ML, Iannuzzi MC, Collins FC, Tsui L-C (1989) Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA. Science 245:1066-1073 Shoshani T, Kerem E, Szeinberg A, Augarten A, Yahav Y, Cohen D, Rivlin J, Tal A, Kerem B (1994) Similar levels of mRNA from the W1282X and the delta F508 cystic fibrosis alleles, in nasal epithelial cells. Login to comment

PMID: 10834512 [PubMed] Kambouris M et al: "Identification of novel mutations in Arabs with cystic fibrosis and their impact on the cystic fibrosis transmembrane regulator mutation detection rate in Arab populations."

No. Sentence Comment

0 ORIGINAL PAPER M. Kambouris á H. Banjar á I. Moggari á H. Nazer á M. Al-Hamed á B. F. Meyer Identi®cation of novel mutations in Arabs with cystic ®brosis and their impact on the cystic ®brosis transmembrane regulator mutation detection rate in Arab populations Received: 18 December 1998 / Accepted: 14 May 1999 Abstract The cystic ®brosis transmembrane regulator (CFTR) gene in Arab patients with cystic ®brosis (CF) (sweat chloride >60 mmol/l) from 61 unrelated families was screened for mutations in exons 3, 4, 5, 7, 10, 11, 16 and 19 and for mutations W1282X, N1303K and 3849 + 10kbC ® T. Login to comment
43 Mutation analysis All patients were screened for known mutations 3849 + 10KbC ® T (intron 19), W1282X (exon 20) and N1303K (exon 21) by restriction enzyme digestion analysis with enzymes Mnl I, Bst OI and Hph I respectively according to standard protocols [23]. Login to comment
93 In that study, three mutations, DF508 (37.5%), W1282X (15.6%), and N1303K (9.4%) collectively accounted for 62.5% of the CF alleles. Login to comment
94 W1282X was not encountered at all in our study while the incidence of the other two mutations was signi®cantly lower among the families we examined. 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: 10922396 [PubMed] Teder M et al: "Distribution of CFTR gene mutations in cystic fibrosis patients from Estonia."

No. Sentence 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: 10933904 [PubMed] Zeitlin PL et al: "Cystic fibrosis gene therapy trials and tribulations."

No. Sentence Comment

20 Pharmacologic correction of premature-translation termination stop codon mutants in CFTR (e.g., W1282X) by topical treatment with aminoglycosides to promote readthrough to a full-length CFTR has been reported to accomplish a change of 0 to -10 mV (8). 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
27 Mutations such as R553X or W1282X contain a premature stop codon and produce an unstable mRNA transcript that is not successfully translated into protein. 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

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: 10970820 [PubMed] Rajan S et al: "Pseudomonas aeruginosa induction of apoptosis in respiratory epithelial cells: analysis of the effects of cystic fibrosis transmembrane conductance regulator dysfunction and bacterial virulence factors."

No. Sentence Comment

44 IB-3 cells (∆F508/ W1282X), a human bronchial epithelial cell line, and C-38 cells, the corrected line which expresses an episomal copy of a truncated form of CFTR and exhibits normal physiology but lacks the first extracellular domain of CFTR (17), were obtained from P. Zeitlin (Johns Hopkins University, Baltimore, MD). Login to comment
156 Thus, cells with CFTR dysfunction, whether due to the ∆F508/W1282X or homozygous ∆F508 mutations expected to accumulate in the ER, Cl-channel dysfunction due to overexpression of the R-domain with normal CFTR localization on the cell surface, or lack of CFTR expression, were all similarly susceptible to the induction of apoptosis and did not differ significantly from control strains with normal CFTR activity. Login to comment
219 Mistrafficking of ∆F508/ W1282X or ∆F508 CFTR did not prevent apoptosis after PAO1 infection, suggesting that localization of normal CFTR on the cell surface (32) is not involved in the induction of apoptosis. Login to comment

PMID: 10970832 [PubMed] Venkatakrishnan A et al: "Exaggerated activation of nuclear factor-kappaB and altered IkappaB-beta processing in cystic fibrosis bronchial epithelial cells."

No. Sentence Comment

38 IB3 cells are ⌬F508 compound heterozygotes (⌬F508/W1282X). 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

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

PMID: 11056144 [PubMed] Lewis-Jones DI et al: "Cystic fibrosis in infertility: screening before assisted reproduction: opinion."

No. Sentence Comment

67 Hum. Biol., 64, 167-174.1898ϩ1g→A R117H 2711∆T W1282X 441∆A W846X1 DeBraekeleer, M. and Ferec, C. 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

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
31 Interestingly, one patient who carried the W1282X/3849 + 10kbC→T genotype showed complete normalization of chloride transport on NPD following gentamicin administration [31••]. Login to comment

PMID: 11115444 [PubMed] Desmarquest P et al: "Genotype analysis and phenotypic manifestations of children with intermediate sweat chloride test results."

No. Sentence Comment

92 Genotype Poly T 1 -/- 7T/7T 2 R117C/- 7T/7T 3 R75X-D1270H/- 7T/7T 4 -/- 7T/7T 5 G91R/- 7T/5T 6 ⌬F508/- 7T/9T 7 -/- 7T/7T 8 -/- 7T/7T 9 S1235R/G551D 5T/7T 10 ⌬F508/- 9T/9T 11 7T/7T 12 ⌬F508/⌬F508 9T/9T 13 ⌬F508/- 7T/9T 14 -/- 7T/7T 15 ⌬F508/- 7T/9T 16 -/- 7T/5T 17 -/- 7T/7T 18 -/- 7T/7T 19 -/- 7T/9T 20 ⌬F508/- 7T/9T 21 -/- 7T/7T 22 W1282X/- 7T/5T 23 -/- 7T/7T 24 ⌬F508/3849 ϩ 10 kb C 3 T 7T/7T 1594 Clinical Investigations reported in the general population (frequency of the 5T allele in the general population, 5.2%).26 Based on the results of DNA analysis and according to the consensus statement on the diagnosis of CF, three patients (patients 9, 12, and 24) met the criteria of both respiratory manifestations and identification of two CF mutations.21 For patient 6, there was a diagnostic dilemma. 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

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

No. Sentence 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

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

No. Sentence 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

PMID: 11228252 [PubMed] Eftedal I et al: "Single intragenic microsatellite preimplantation genetic diagnosis for cystic fibrosis provides positive allele identification of all CFTR genotypes for informative couples."

No. Sentence Comment

34 In couple I, the mother was a carrier of the ∆F508 deletion, whereas the father carried the mutation W1282X. Login to comment
78 In couple I, the healthy CFTR alleles thus segregated with IVS17bTA repeat unit numbers of 29 (maternal) and 38 (paternal), whereas the maternal ∆F508 segregated with 31 and the paternal W1282X with seven repeat units respectively. 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
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

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
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

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
40 THE CONSENSUS POLICY OF SCREENING OF CF MUTATIONS IN ETHNIC GROUPS OF ISRAELI JEWSa Buchara and Iran Georgia Libya Morocco Tunis Turkey Egypt Sephardi W1089X 1 1 1 G85E 1 1 405-1 G® A 1 1 1 S549R 1 1 D1152H 1 1 1 1 T360K 1 Individuals of all ethnic groups were screened for the mutations W1282X, delF508, G5429X, N1303K, 3849110Kb C® T and 1717-1G® A. 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
69 About half of the carriers had the W1282X and only about 30% carried the delF508 mutation. 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

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

PMID: 11356077 [PubMed] Ye L et al: "Regulated expression of the human CFTR gene in epithelial cells."

No. Sentence Comment

217 As an intermediate step in the development of an inducible CFTR expression system in mice, we established a bronchial epithelial cell model with IB3 cells (⌬F508/ W1282X) (19). 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

179 Previous in vitro studies using the IB3-1 human CF bronchial airway cell line (genotype W1282X/⌬F508) demonstrated that a relatively short incubation (18-24 h) with the aminoglycoside G-418 at concentrations of 100-200 ␮g/ml restored chromosomal W1282X mRNA levels to that of the control ⌬F508 allele, induced surface-localized CFTR protein production, and conferred on cells a new, cAMP-activated [Cl- ] current (13). 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: 11404244 [PubMed] Rubenstein RC et al: "Sodium 4-phenylbutyrate downregulates HSC70 expression by facilitating mRNA degradation."

No. Sentence Comment

136 Our laboratory has previously demonstrated in the immortalized CF bronchiolar epithelial cell line IB3-1 (genotype ⌬F508/W1282X) LPHENYLBUTYRATE FACILITATES HSC70 MRNA DEGRADATION (33) that 4PBA results in an ϳ40-50% reduction in steady-state expression of HSC70 mRNA and protein (25) and improved ⌬F508 CFTR intracellular trafficking (23). Login to comment

PMID: 11404246 [PubMed] Choo-Kang LR et al: "Induction of HSP70 promotes DeltaF508 CFTR trafficking."

No. Sentence Comment

109 IB3-1 has the CFTR genotype ⌬F508/W1282X but expresses only ⌬F508 CFTR because the W1282X mutation produces an unstable, and therefore untranslated, mRNA (27, 28). Login to comment

PMID: 11404248 [PubMed] Weber AJ et al: "Activation of NF-kappaB in airway epithelial cells is dependent on CFTR trafficking and Cl- channel function."

No. Sentence Comment

41 Comparison of the endogenous activation of NF-␬B in IB3 cells (W1282X/⌬F508), a trafficking mutant similar to the homozygous ⌬F508 mutation, with that in corrected C-38 cells, which express a functional but truncated form of CFTR, was consistent with this hypothesis. Login to comment
56 IB3 cells (⌬F508/W1282X), a human bronchial epithelial cell line, and C-38 cells, "corrected" cells with normal physiology that express an episomal truncated form of CFTR (33), were obtained from P. Zeitlin (Johns Hopkins University, Baltimore, MD) and grown in LHC-8 medium (Biofluids, Rockville, MD) plus 10% FCS. Login to comment
154 In previous studies, IB3 cells, which express the W1282X/⌬F508 mutation associated with mistrafficked CFTR that accumulates in the ER, were found to have significant amounts of the p65 component of NF-␬B in nuclei under basal conditions in which there was no nuclear NF-␬B in the corrected C-38 cells (8). Login to comment
184 The homozygous ⌬F508 or the compound ⌬F508/W1282X mutation could activate NF-␬B by two independent mechanisms: cell stress associated with mistrafficking or effects directly due to lack of CFTR Cl-channel activity. Login to comment

PMID: 11438995 [PubMed] Feriotto G et al: "Biosensor technology for real-time detection of the cystic fibrosis W1282X mutation in CFTR."

No. Sentence Comment

0 HUMAN MUTATION 18:7081 (2001) (c) 2001 WILEY-LISS, INC. METHODS Biosensor Technology for Real-Time Detection of the Cystic Fibrosis W1282X Mutation in CFTR Giordana Feriotto,1 Alessandra Ferlini,2 Anna Ravani,2 Elisa Calzolari,2 Carlo Mischiati,3 Nicoletta Bianchi,3 and Roberto Gambari1,3* 1 Biotechnology Center, Ferrara University, Ferrara, Italy 2 Department of Experimental and Diagnostic Medicine, Ferrara University, Ferrara, Italy 3 Department of Biochemistry and Molecular Biology, Ferrara University, Ferrara, Italy Communicated by Richard G.H. Cotton In the present paper, biospecific interaction analysis (BIA) was performed using surface plasmon resonance (SPR) and biosensor technologies to detect the Trp1282Ter mutation (W1282X) of the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) gene. Login to comment
2 Second, we immobilized on different SA5 sensor chips biotinylated polymerase-chain reaction (PCR) products from a normal subject as well as from heterozygous and homozygous W1282X samples. Login to comment
3 The results obtained show that both allele-specific 10-and 12-mer oligonucleotides are suitable probes to detect W1282X mutations of the cystic fibrosis gene under standard BIA experimental conditions. Login to comment
4 During the association phase performed at 25°C, discrimination between mismatched and full matched hybrids was readily and reproducibly observed by using the 10-mer W1282X probes. Login to comment
7 By this procedure, it is possible to perform real-time monitoring of hybridization between target single stranded PCR products obtained by using as substrates DNA isolated from normal or heterozygous subjects, and homozygous W1282X CF samples and oligonucleotide probes, therefore enabling a one-step, non-radioactive protocol to perform diagnosis. Login to comment
11 The W1282X mutation (MIM# 602421.0022), located in exon 20, was first observed in a French patient with cystic fibrosis by Vidaud et al. [1990]. Login to comment
16 Shoshani et al. [1992] cited evidence that the W1282X mutation is the most common CF mutation in the Ashkenazi Jewish population, where it ispresenton50-60%ofCFchromosomes.Patients homozygous for the W1282X mutation and patients heterozygous for the F508del and W1282X mutations had similarly severe disease reflected by pancreatic insufficiency, high incidence of meconium ileum, poor nutritional status, and variable pulmonary function and complications [Shoshani et al., 1992]. Login to comment
23 In the present paper, we first immobilized on a SA5 sensor chip a single stranded biotinylated oligonucleotide containing the sequence involved in the tryptophan 1282 -> TER mutation (W1282X) of the cystic fibrosis transmembrane conductance regulator (CFTR) gene (Online Mendelian Inheritance in Man, OMIM# 602421, according to Antonarakis and Nomenclature Working Group [1998]). Login to comment
25 Second, we employed the most efficient oligonucletide probes to determine the presence of the W1282X mutations within PCR products from normal subjects, as well as from heterozygous and homozygous samples. Login to comment
26 MATERIALS AND METHODS Synthetic Oligonucleotides The CFTR W1282X region was amplified with the primers CF1, 5'-TGA GAC TAC TGA ACA CTGAA-3', CF2, 5'-GCT CAC CTG TGG TAT CAC T-3', and 5'-end biotinylated CF3 oligonucleotide, 5'- AAG GAG AAA TCC AGA TCG A-3'. Login to comment
27 The target oligonucleotide (M- CFt-21) and the normal (N-CFp) and the mutated (M-CFp) W1282X oligonucleotide probes (see Fig. 1 for nucleotide sequences) were purchased from Pharmacia (Uppsala, Sweden) and purified by HPLC. Login to comment
28 Polymerase-Chain Reaction In each PCR reaction, 100 ng of human genomic DNA was amplified by Taq DNA polymerase using the CF1 and CF2 primers, amplifying the W1282X region of the CFTR gene. Login to comment
32 Map of the CFTR gene region involved in the W1282X mutation causing CF and location of the CF1, CF3 (forward), and CF2 (reverse) PCR primers. Login to comment
34 The DNA probes (N-CFp and M-CFp) recognizing normal and mutated W1282X sequences are also shown. Login to comment
52 Computer-Assisted Prediction of Secondary Structure of Single Stranded PCR Products Secondary structures of single stranded CFTR PCR products carrying both normal and mutated W1282X sequences were determined using the MFOLD software (version 3.0) developed by Zuker et al. [1999] and Mathews et al. [1999]. Login to comment
69 Taken together, these results conclusively demonstrate that, with our BIA experimental conditions, the 17-mer DNA probes are not suitable for identification of the W1282X mutation. Login to comment
71 However, the use of 9-10 mers DNA probes allows identification of the W1282X mutation during the association phase; whereas contrary, longer DNA probes (12-13 mers) allow identification of the mutation during the dissociation phase. Login to comment
72 Immobilization on a SA5 Sensor Chip of Target CF PCR Products From a Normal Subject or Heterozygous and Homozygous W1282X CF Samples Figure 1 shows the location of the CF1, CF2, and CF3 PCR primers within the exon 20 portion of the CFTR gene carrying the W1282X mutation [Riordan et al., 1989]. Login to comment
89 Increase of Resonance Units (RU) Following Injections of CFp Probes to SA5-Sensor Chips Carrying Target M-CFt-21 Mer Target: M-CFt-21 mer N-W1282X M-W1282X CFp probe RUfin-RUi RUres-RUi RUfin-RUi RUres-RUi 9-mer 2 5 145 13 10B-mer 7 12 179 10 10A-mer 9 13 218 32 11-mer 92 21 261 144 12-mer 197 14 299 242 13-mer 246 42 342 322 17-mer 556 509 566 550 (Dynabeads, DYNAL, Oslo, Norway). Login to comment
91 In both cases, injections of appropriate single-stranded PCR products to sensor chips carrying immobilized N-CFp and M-CFp probes caused very low increase of RU; in addition non-satisfactory discrimination between normal and homozygous W1282X samples was observed (data not shown). Login to comment
93 This is expected to be the case in the CF W1282X PCR system, as suggested by the analysis shown in Figure 4, showing the theorical secondary structures of the single-stranded CFTR PCR products carrying normal (Fig. 4A) or mutated (Fig. 4B) W1282X sequences. Login to comment
96 The ∆G° was found to be -7.9 kcal/mole and -8.6 kcal/mole for normal and W1282X mutant CF PCR products, respectively. Login to comment
97 Tm was 43.6 and 44.3 for normal and W1282X mutant CF PCR products, respectively. Login to comment
98 Accordingly to these preliminary experiments, we decided 1) to immobilize on the sensor chips the W1282X PCR products from normal subjects, as well as from heterozygous and homozygous samples and 2) to inject the N-CFp and M-CFp DNA probes. Login to comment
101 The final W1282X PCR products were in any case further purified with Microcon-30. Login to comment
102 Direct sequencing of the PCR products confirmed the presence of 1) normal CF sequence (Fig. 5A), 2) mixed normal and mutated W1282X sequences (Fig. 5C), and 3) mutated W1282X sequences (Fig. 5B) in PCR products obtained by using as target DNA isolated from normal subject or heterozygous and homozygous W1282X CF samples. Login to comment
106 Hybridization of DNA Probes to Target CF PCR Products A representative example of the binding of N-CFp and M-CFp 12-mer DNA probes to CF PCR products from normal, heterozygous, and homozygous CF W1282X samples is shown in Figure 5D-G. Login to comment
110 By contrast, the complexes generated after the binding of the same probe to PCR products from a homozygous W1282X sample were found to be unstable (Fig. 5G, dotted line). Login to comment
111 Intermediate stability (50% decrease of RUres-RUi) was found for complexes generated after binding of the N- CFp12-mer DNA probes to PCR products from heterozygous W1282X samples (Fig. 5F, dotted line). Login to comment
114 By contrast, the complexes generated after the binding of the same probe to PCR products from homozygous W1282X sample were found to be stable (Fig. 5G). Login to comment
115 Intermediate stability (50% decrease of RUres-RUi) was found for complexes generated after binding of the M-CFp12-mer DNA probes to PCR products from heterozygous W1282X samples (Fig. 5F). Login to comment
117 Secondary structures of single stranded CFTR PCR products carrying both normal (A) and mutated (B) W1282X sequences. Login to comment
121 The nucleotide W1282X mutation is arrowed. Login to comment
123 A-C: Characterization of biotinylated PCR products from normal subjects(A), homozygous W1282X samples (B) or heterozygous subjects (C). Login to comment
125 D: Experimental strategy for detecting the W1282X mutation. Login to comment
127 In this experiment 25 µl of normal (dotted lines) and mutated (solid line) 6 µM CFp-12 mers solutions were injected to flow cells carrying PCR products from normal subjects (E), heterozygous subjects (F) or homozygous W1282X samples (G). Login to comment
129 The sensorgrams shown in this figure have been obtained by subtracting to the experimental sensorgrams, sensorgrams obtained by injecting HBS-EP. A comparison of the binding efficiencies of the CFp-9 mer, 10A mer, and 12 mer DNA probes to CF PCR products from a normal subject or heterozygous and homozygous CF W1282X samples are shown in Table 2. Login to comment
132 On the contrary, binding of the N-CFp-10A probe was detectable to flow cells carrying PCR products from normal and heterozygous W1282X samples. No hybridization of N-CFp-10A probe was found to the flow cells carrying CF PCR products from homozygous W1282X sample. Login to comment
133 Conversely, binding of the M-CFp-10A mer probe was detectable to flow cells carrying PCR products from heterozygous and homozygous W1282X samples. No hybridization of M-CFp-10A probe was found to the flow cells carrying CF PCR products from a normal subject. Login to comment
134 It should be noted that the values of RUfin obtained by injecting the same CF probe on flow cells carrying different W1282X PCR products could be different, depending on the amounts of immobilized PCR products and to the secondary structures of the single-stranded PCR product itself. Login to comment
142 Taken together, the obtained results suggest that the CF index could be introduced to discriminate between CF PCR products from normal subject and heterozygous or homozygous W1282X samples. Login to comment
143 DISCUSSION In the present paper, we demonstrate that allele-specific 10 and 12 mer oligonucleotides are suitable probes to detect the W1282X point mutation of the cystic fibrosis gene by performing biospecific interaction analysis (BIA) and employing surface plasmon resonance (SPR) [Malmqvist, 1993] and biosensor technologies. Login to comment
145 This procedure makes it possible to monitor the real-time hybridization between target single stranded PCR products obtained by using as substrates DNA isolated from normal subject or heterozygous and homozygous W1282X CF samples and oligonucleotide probes, therefore enabling a one-step, non-radioactive protocol to perform diagnosis. Login to comment
147 Increase of Resonance Units (RU) Following Injections of W1282X Probes to SA5-Sensor Chips Carrying Single Stranded Target PCR Products Target: PCR products Normal Heterozygous Homozygous (-/-) (-/M-W1282X) (M-W1282X/M-W1282X) W1282X probe RUfin-RUi RUres-RUi RUfin-RUi RUres-RUi RUfin-RUi RUres-RUi N-CFp-9 mer 17 9 12 10 11 10 M-CFp-9 mer 10 11 10 9 9 11 N-CFp-10A mer 38 26 29 20 7 10 M-CFp-10A mer 10 12 36 15 29 13 N-CFp-12 mer 52 51 78 36 37 10 M-CFp-12 mer 59 16 70 32 39 41 is readily and reproducibly observed by using the CFp-10 mer probes. Login to comment
152 Increased hybridization efficiency could be obtained either by using PCR primers amplifying CF sequences lacking secondary structures at the level of W1282X mutation, or by using as molecular probes molecules able to hybridize with target DNA independently of secondary structures, such as the recently described peptide nucleic acids (PNAs) [Egholm et al., 1993; Sawata et al., 1999]. Login to comment
162 CF W1282X index in six different experiments. 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: 11472971 [PubMed] Bals R et al: "Salt-independent abnormality of antimicrobial activity in cystic fibrosis airway surface fluid."

No. Sentence Comment

33 The CF patients (average age 8.8 yr, range 1 to 24 yr) were characterized regarding their genotype (eight ⌬F508 homozygous, one ⌬F508/2789 ϩ 5G-A, one ⌬F508/2184delA, one ⌬F508/W1282X, one ⌬F508/ (Received in original form November 13, 2000 and in revised form February 7, 2001) Address correspondence to: James M. Wilson, M.D., Ph.D., 3601 Spruce St., 204 Wistar Institute, Philadelphia, PA 19104-4268. Login to 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

54 This ®gure is much lower than in European populations (48.8%) where several mutations such as G551D, N1303K, and W1282X are relatively frequent and associated with haplotype B (EWGCFG, 1990; Castaldo et al., 1996]. 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

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

PMID: 11491166 [PubMed] Wilschanski M et al: "Nasal potential difference measurements in patients with atypical cystic fibrosis."

No. Sentence Comment

57 112 PI 35 38 F 3849z10kbCRT/W1282X 100 PS 44 23 F DF508/? Login to comment
58 80 PS 83 28 F 3849z10kbCRT/DF508 80 PS 88 16 M 3849z10kbCRT/W1282X 67 PS 95 FEV1: forced expiratory volume in one second; M: male; F: female; PS: pancreatic sufficiency; PI: pancreatic insufficiency; ? Login to comment
164 - Clinical parameters of patients referred with questionable cystic Fibrosis (CF) QCF-CF QCF-non-CF p-value Subjects n 24 46 Age yrs 12.17¡10.49 19.13¡11.9 0.013 Sweat chloride mmol?L-1 56¡17 39¡18 v0.001 FEV1 % pred 83.6¡19.7 83.7¡32.9 NS Positive sputum clutures# 4 9 NS CFTR mutations W1282X/5T(2) 5T/5T(1) v0.001} W1282X/3849z10kbC-wT(1) DF508(3) 0.04z DF508/5T(1) 5T(3) D1152H/5T(1) DF508(1) Male infertility 1 3 NS Pancreatic insufficiency 1 1 NS Data are preserted as mean¡SD. Login to comment

PMID: 11491179 [PubMed] Rodgers HC et al: "Pharmacological treatment of the biochemical defect in cystic fibrosis airways."

No. Sentence Comment

48 Forskolin-induced chloride secretion in IB3-1 cells expressing DF508/W1282X, and in primary human nasal epithelium, was increased by 4-PBA [13]. Login to comment
60 Similar results were seen in the human airway cell line IB3 derived from a DF508/W1282X CF patient [20]. Login to comment
105 IB3 cells, heterozygous for W1282X treated with G418 or gentamicin, showed increased cAMP mediated current, although possibly via the ORCC rather than CFTR [42]. 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

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: 11600715 [PubMed] Solinas A et al: "Duplex Scorpion primers in SNP analysis and FRET applications."

No. Sentence Comment

8 We have demonstrated their use in allelic discrimination at the W1282X locus of the ABCC7 gene and shown that they can be used in assays where fluorescence resonance energy transfer is required. Login to comment
28 We report the use of duplex Scorpions in allelic discrimination at the W1282X locus of the ABCC7 gene (8,9), we compare them to stem-loop Scorpions and demonstrate the use of FRET duplex Scorpions. Login to comment
35 Real-time PCR Human genomic DNA samples, NA 11472 (wild-type) and NA 1723 (W1282X heterozygote), were purchased from Coriell. Login to comment
37 Sequence data for the ABCC7 locus W1282X were obtained from GenBank (11) (see Table 1 for accession numbers and mismatches). Login to comment
41 The design of duplex Scorpions was adapted from the stem-loop version previously evaluated on the W1282X locus (2). Login to comment
56 GenBank accession numbers for locus W1282X Locus GenBank accession no. Login to comment
57 Mutation site Base change Probe-target mismatch W1282X M55127 395 G→A C-A Figure 1. Login to comment
71 Oligonucleotide name Code Oligonucleotide sequence W1282X reverse primer GGCTAAGTCCTTTTGCTCAC Stem-loop FAM Scorpion W-001 2CCCGCGCCTTTCCTCCACTGTTGCGCGCGGG43ATGGTGTGTCTTGGGATTCA Duplex FAM Scorpion 1 W-002 2CTTTCCTCCACTGTTGC3ATGGTGTGTCTTGGGATTCA Quencher oligonucleotide standard W-003 GCAACAGTGGAGGAAAG4 Quencher oligonucleotide short W-004 CAGTGGAGGAAAG4 W1282X FRET stem-loop Scorpion W-005 5CCCGCG8CCTTTCCTCCACTGTTGCGACGCGGG76ATGGTGTGTCTTGGGATTCA W1282X FRET duplex Scorpion 6 base separation W-006 5CTTTCC6CCACTGTTGC3ATGGTGTGTCTTGGGATTCA Double quencher oligo 6 base separation W-007 GCAACAGTGG7GGAAAG4 Internal quencher oligonucleotide W-008 GCAACAGTGG7GGAAAG8 W1282X FRET duplex Scorpion 11 base separation W-009 5CTTTCCTCCAC6GTTGC3ATGGTGTGTCTTGGGATTCA Double quencher oligo 11 base separation W-010 GCAAC7GTGGAGGAAAG4 W1282X FRET duplex Scorpion 3 base separation W-011 5CTT6CCTCCACTGTTGC3ATGGTGTGTCTTGGGATTCA Double quencher oligo 3 base separation W-012 GCAACAGTGGAGG7AAG4 transition rate and cooling at 40°C for 30 s. Login to comment
124 The Scorpions were again evaluated on the W1282X locus and FRET duplex Scorpions were derived from the normal W1282X duplex Scorpion W-002 (Table 2). Login to comment

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

No. Sentence Comment

23 For example, the frequency of the W1282X mutation is about 1 to 2% in Caucasians but is as high as 60% in Ashkenazi Jews [Cystic Fibrosis Genetic Analysis Consortium, 1994; Shoshani et al., 1992]. 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
210 It also differs from that reported for Argentine patients [Chertkoff et al., 1997], where W1282X accounts for 3.1% of mutant alleles, compared to 0.8% in this study, while S549N mutation was not found in a total of 228 Argentine CF chromosomes, compared to 2.4% in our study. 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
921 Association of a nonsense mutation (W1282X), the most common mutation in the Ashkenazi Jewish cystic fibrosis patients in Israel, with presentation of severe disease. Login to comment

PMID: 11717455 [PubMed] Poschet JF et al: "Molecular basis for defective glycosylation and Pseudomonas pathogenesis in cystic fibrosis lung."

No. Sentence Comment

107 Hyperacidification of TGN in CF Cell line TGN pH IB3-1 (mutant) 6.0 Ϯ 0.1 (n ϭ 17)* C38 (corrected) 6.6 Ϯ 0.1 (n ϭ 18) S9 (corrected) 6.7 Ϯ 0.1 (n ϭ 24) CFT1 (mutant) 6.2 Ϯ 0.1 (n ϭ 10)* CFT1-LCFSN (corrected) 6.7 Ϯ 0.1 (n ϭ 9) CFT1-LC3 (mutant) 6.3 Ϯ 0.1 (n ϭ 10) CFT1-⌬F508 (mutant) 6.2 Ϯ 0.1 (n ϭ 19) IB3-1 is a human bronchial cell line derived from a patient with a ⌬F508/ W1282X CFTR (25). Login to comment

PMID: 11739639 [PubMed] Dormer RL et al: "Correction of delF508-CFTR activity with benzo(c)quinolizinium compounds through facilitation of its processing in cystic fibrosis airway cells."

No. Sentence Comment

22 IB3-1 cells (delF508/W1282X) (a generous gift of P. Zeitlin) (Zeitlin et al., 1991) were routinely cultured in 5% CO2 incubators in LHC-8 medium (Biofluids Inc., Rockville, MO) supplemented with 10% fetal bovine serum and 100 U/ml penicillin/streptomycin. 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: 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: 11809765 [PubMed] Poschet JF et al: "Hyperacidification of cellubrevin endocytic compartments and defective endosomal recycling in cystic fibrosis respiratory epithelial cells."

No. Sentence Comment

20 IB3-1 is a human bronchial epithelial cell line derived from a CF patient with a ⌬F508/W1282X CFTR mutant genotype (21). Login to comment
96 The endosomal (cellubrevin) and plasma membrane (GPI)-targeted pHluorin GFP probes were transfected into well characterized human bronchial epithelial cells (21, 22): IB3-1 (from a compound heterozygote CFTR ⌬F508/W1282X CF patient), C38 (IB3-1 cells corrected with a functional CFTR lacking the first ecto-loop), and S9 (IB3-1 cells corrected with a full size functional CFTR cDNA). Login to comment
194 TABLE I Hyperacidification of TGN38 and cellubrevin-labeled compartments in CF respiratory epithelial cells Cell linea Apparent pHb mean Ϯ S.E. IB3-1 (mutant) pH 6.2 Ϯ 0.1 (n ϭ 19) C38 (corrected) pH 6.7 Ϯ 0.1 (n ϭ 15) S9 (corrected) pH 6.7 Ϯ 0.1 (n ϭ 32) CFT1 (mutant) pH 6.1 Ϯ 0.1 (n ϭ 15) CFT1-LCFSN (corrected) pH 6.6 Ϯ 0.03 (n ϭ 14) CFT1-LC3 (mutant) pH 6.0 Ϯ 0.1 (n ϭ 15) CFT1-⌬F508 (mutant) pH 6.2 Ϯ 0.1 (n ϭ 19) a IB3-1 is a human bronchial cell line derived from a CF patient with a ⌬F508/W1282X CFTR mutant genotype (21). Login to comment

PMID: 11810271 [PubMed] Tzetis M et al: "Qualitative and quantitative analysis of mRNA associated with four putative splicing mutations (621+3A-->G, 2751+2T-->A, 296+1G-->C, 1717-9T-->C-D565G) and one nonsense mutation (E822X) in the CFTR gene."

No. Sentence Comment

59 593 594 Table1Genotype/phenotypeoftheCFTRpatientsa DevelopmentPulmonaryfunctionCFTRgenotypeAge (yrs) SexAgeat diagnosis Sweattest (mEq/l) Meconium ileusHeight (%-ile) Weight (%-ile) Pancreatic status FEV1 (%) FVC (%) Other Bacterial pathogens Other clinical features F508del/621+3AÆÆÆÆG6FBirth108.5Yes<50%>50%PI10398-Sa,Klebsiella- F508del/621+3AÆÆÆÆG7M2mos93.6No>10%~25%PI131132-Sa,Hi,Sa- 1898+1GÆÆÆÆT/621+3AÆÆÆÆG18F3mos82.1No>97%<90%PI7370Bronchi- ectasis Sa,PaDiabetes W1282X/621+3AÆÆÆÆG2F8mos100.9No<75%>75%PI---Hi,Psputida- F508del/2751+2TÆÆÆÆA5MBirth85.7Yes75%75%PI---Sa,Pa- 3120+1GÆA/296+1GÆÆÆÆC33M27yrs93.1No>75%~50%PI133128-Pa- 1717-9TÆÆÆÆC-D565G/Nb 7F5yrs41.4No??PS? 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

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

PMID: 11893723 [PubMed] Flotte TR et al: "Recombinant adeno-associated virus gene therapy for cystic fibrosis and alpha(1)-antitrypsin deficiency."

No. Sentence Comment

24 In Vitro Studies For in vitro studies of CFTR complementation, the immortalized CF bronchial epithelial cell line IB3-1 (genotype deltaF508/W1282X) was cultured in LHC-8E medium with 10% fetal bovine serum (37°C; 5% CO2).25 The constructs to be tested either were transfected using a reagent (Lipofectin; Invitrogen; Carlsbad, CA) or were infected at a multiplicity of infection ranging from 100 to 10,000 physical particles per cell. 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
81 I G542 (6), R553X (3), W1282X (3), 3659delC (1), 3905insT (2). Login to comment
82 II ⌬F508 (36), W1282X (1) III G551D (10), N1303K (4), R560T (2), A559T (1) IV R117H (14), R347H (3) V 3849 ϩ 10KbC→T (7), 3120G→A (3) AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 165 2002 All patients were recruited from a single center, and the sample size of this study was large compared with previously published studies of exercise capacity in children with CF (21). 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
104 In this study, the 5T allele was found in a patient having the W1282X mutation (Table 1). 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: 11984593 [PubMed] Egan ME et al: "Calcium-pump inhibitors induce functional surface expression of Delta F508-CFTR protein in cystic fibrosis epithelial cells."

No. Sentence Comment

192 Genotypically, IB3-1 is a compound heterozygote containing the ∆F508 mutation and W1282X. 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
90 For instance, W1282X and 3849π10KbC»T mutations, which are highly prevalent in the Ashkenazi Jewish population (20, 21), were found within the seven most common mutations in the present population with significantly higher frequencies than those observed in Southern European countries. 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

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
180 W1282X is a mutation of single origin that has historically been associated with the Ashkenazi Jews. Login to comment
182 As with all other population specific mutations, the W1282X mutation is seen within the mutational arrays of the multitude of countries that have had a significant Ashkenazi Jewish influence. 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

190 Nine of them were homozygotes and five were compound heterozygotes, carrying on the other chromosome a severe mutation which is usually rare in our population: there were two nonsense mutations (Q220X, W1282X), two splice mutations (4005+1 G→A, 1717-1 G→A), and one frameshift mutation (3129del4). 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

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

47 A, N1303K, W1282X), oligonucleotide ligation assay with the CF-OLA kit (PE-Biosystems, Foster City, CA) (31 mutations detected: DF508, DI507, Q493X, V520F, 1717-1G ! Login to comment
50 G, R1162X, 3659delC, W1282X, 3905insT, N1303K, G85E, 621 þ 1G ! 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

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

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

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

No. Sentence Comment

18 Several mutations are frequent in specific populations: W1282X among Ashkenazi [Shoshani et al., 1992], 2143delT in Germany [Dork et al., 1994], Y122X in Iceland [Chevalier-Porst et al., 1994], T338I in Sardinia, and 2183AA > G and R1162X in Northeast Italy [Rendine et al., 1997]. Login to 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
66 On the contrary, a severe pulmonary phenotype was reported in 16 CF patient homozygotes for W1282X [Shoshani et al., 1992], and more recently in the first CF patient homozygote for the R1158X nonsense mutation [Castaldo et al., 1999], while a double heterozygote for R1158X showed a mild phenotype [Frossard et al., 2000]. 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
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
295 Table 2 Genotype and clinical features in pancreatic sufficient boys Pt no. Age (y) Sweat chloride CFTR mutations FEV1 Wt Ht Sh. score 10 5 45 ∆F508/3849+10kb C→T 106% 50 28 95 11 7 107 ∆F508/unknown 85% 10 20 84 12 12 44 W1282X/5T 115% 75 65 100 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
76 After the 5T allele, the relative frequent mutations with two to four alleles were: R117H (four alleles), W1282X (four alleles), G551D (three alleles), L206W (three alleles) and D1270 (two alleles). 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
100 Two relatively frequent compound heterozygotes were F508/ R117H (3/33) and W1282X/5T (4/33). 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

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

No. Sentence 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
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

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: 12386452 [PubMed] Rhim AD et al: "Terminal glycosylation in cystic fibrosis (CF): a review emphasizing the airway epithelial cell."

No. Sentence Comment

97 Modulation of CF terminal glycosylation phenotype by CFTR expression Cell type1 Transfection2 Compared with non-transfected cells3 Reference CF/T1 wtCFTR ↓ Fucα1,3/4GlcNAc; ↑ SA [62] wtCFTR ↓ Fucα1,3/4GlcNAc; ↑ SA [4] wtCFTR ↓ Fucα1,3/4GlcNAc; ↑ Fucα1,2Gal [17] wtCFTR ↓ PNA4 [29] IB3 wtCFTR ↓ PNA [28] wtCFTR ↓ PNA [29] wtCFTR ↓ asialo GM1 [27] CFPAC wtCFTR ↓ asialo GM1 [27] 9/HTEo- CFTR R-domain ↑ asialo GM1 [63] F508 ↓ SNA5 [26] CFTR R-domain ↓ SNA [26] C127 F508 ↓ WGA6 [25] 1 Cell line in which the experiments were conducted: CF/T1, immortalized CF tracheal epithelial cells ( F508/ F508); IB3, CF bronchial cells ( F508/ W1282X); CFPAC, immortalized CF pancreatic epithelial cells; 9/HTEo-, immortalized non-CF human tracheal epithelial cells with constitutive expression of wtCFTR; C127, mouse mammary epithelial cells. 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: 12403695 [PubMed] Aldallal N et al: "Inflammatory response in airway epithelial cells isolated from patients with cystic fibrosis."

No. Sentence Comment

37 CF Cell Line without and with Integrated Complementation by Wild-Type CFTR METHODS Previous reports indicate that the IB3-1 CF airway epithelial cell line releases more IL-8 under basal conditions and in response toHuman Airway Epithelial Cells TNF-␣ and P. aeruginosa compared with matched wild-typeThe CF airway epithelial cell line IB3-1 (genotype ⌬F508/W1282X) CFTR-complemented cell lines (23, 47, 48). Login to comment
110 However, a significant decrease in IL-8 IB3-1 cells (that contain heterozygous ⌬F508 and W1282X secretion induced by IL-1beta treatment was observed in this cell CFTR mutant genes) and primary CF airway epithelial cells line after infection with adenovirus expressing either transgene. 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: 12421695 [PubMed] Tucker TA et al: "Transient transfection of polarized epithelial monolayers with CFTR and reporter genes using efficacious lipids."

No. Sentence Comment

50 CFT-1 and CFBE41o-cells are homozygous for the ⌬F508-CFTR mutation, whereas IB3-1 bears the ⌬F508-CFTR and W1282X-CFTR mutations. Login to comment

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

No. Sentence 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

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

PMID: 12452372 [PubMed] Gaia E et al: "Germline mutations in CFTR and PSTI genes in chronic pancreatitis patients."

No. Sentence Comment

56 All mutations (W1282X, N187K, R352Q, ⌬F508, R75Q, R31C, 621ϩ2T-ϾG, I197V, K68N, R1162X) were found in heterozygotes, indicating that these patients are carriers of a single mutation. Login to comment
78 PATIENTS CARRYING THE CFTR MUTATION* Pt Sex Age (yr) Age at onset (yr) Alcohol (g/day)† Familial CFTR mutations Exocrine insufficiency Diabetes mellitus(Յ10) (10-40) (40-80) T.B. M 59 23 (Յ10) No W1282X Yes No B.G. M 40 29 (Յ10) Yes N187K No No E.P. M 40 34 (Յ10) No R352Q No Yes D.N. M 53 47 (10-40) No R75Q Yes No R.L. F 57 44 (Յ10) No R31C No No T.F. M 56 *‡ (Յ10) No 621 ϩ 2T 3 G Yes No F.G. M 54 46 (10-40) No I197V Yes No V.M. M 65 *† (10-40) No K68N Yes No B.L. F 57 56 (10-40) Yes ⌬F508 No Yes T.G. M 25 24 (Յ10) No R1162X No No *This table shows the characteristics of chronic pancreatitis patients, carriers of CFTR mutations. Login to comment
86 Of the 10 CFTR gene mutations found, three belong to class I (W1282X, 621ϩ2T-ϾG, R1162X) and are associated to absence of or reduced proteic synthesis. 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

44 The CFTR genotypes 3849 þ 10Kb C-T/DF508 and 3849 þ C-T/W1282X have been observed in a few fertile men with CF. Login to comment
45 In contrast to 3849 þ 10Kb C-T genotypes where mild degrees of infertility have been described, the DF508 and W1282X mutations are associated with ''severe`` degrees of infertility. Login to comment

PMID: 12506110 [PubMed] Huang S et al: "Defective activation of c-Src in cystic fibrosis airway epithelial cells results in loss of tumor necrosis factor-alpha-induced gap junction regulation."

No. Sentence Comment

49 IB3-1 cells, a human bronchial epithelial cell line derived from a patient with CF (⌬Phe-508/W1282X) and C38 cells, the rescued cell line, which expresses a plasmid encoded copy of a functional CFTR (40, 41), were kindly provided by Dr. P. L. Zeitlin (The Johns Hopkins University School of Medicine, Baltimore, MD). Login to comment

PMID: 12509457 [PubMed] Estell K et al: "Plasma membrane CFTR regulates RANTES expression via its C-terminal PDZ-interacting motif."

No. Sentence Comment

48 Experiments employed IB3-1 cells (bronchial; ⌬F508/W1282X compound heterozygote; a gift from Pam Zeitlin, Johns Hopkins University, Baltimore, Md.) (44). Login to comment
110 For these experiments, cells of IB3-1, a CF airway epithelial cell line that is heterozygous for the CFTR mutation (W1282X/ ⌬F508 [44]), were utilized. 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: 12630958 [PubMed] Devaney J et al: "Cystic fibrosis mutation frequencies in an Irish population."

No. Sentence Comment

18 In a selected cohort of 40 patients, six other common ABCC7 mutations were screened for, using PCR-REA: R347P, A455E, R1162X, 384910kbC> T, W1282X and N1303K. Login to comment
27 Samples (n 40) were screened using an in-house optimized protocol to screen for six additional mutations (R347P, A455E, R1162X, 3849 10kbC > T, W1282X and N1303K). Login to comment

PMID: 12634855 [PubMed] Perri F et al: "On the role of CFTR, PSSR1 and PST1/SPINK1 in idiopathic chronic pancreatitis."

No. Sentence Comment

24 Table 1 Sequence variation identified in the PRSS1, PSTI, and CFTR genes in 37 Italian patients with ICP CFTR Patient PRSS1 PSTI Mutant PolyT 1 - a - W1282X/N 7T/9T 2 - - N187K/N 7T/7T 3 - - 711+1G/1T 7T/7T 4 - - R75Q/N 7T/9T 5 - - NDb ND 6 - - - 5T/9T 7 - - - 5T/7T 8 - - - 5T/7T 9 - - - 5T/7T 10 - - - 5T/7T 11 - P55S - 5T/7T 12 to 37 - - - 7T/7T or 7T/9T a Indicates two wild alleles. Login to comment

PMID: 12651880 [PubMed] Witt H et al: "Chronic pancreatitis and cystic fibrosis."

No. Sentence Comment

430 Nucleus Class I defective protein synthesis (R553X, W1282X, 3950delT) Class II abnormal processing/trafficking (del508, N1303K) Class VI defective regulation of other ion channels (del508, G551D) Class V reduced synthesis (3849+10kbC>T) Class IV decreased conductance (R117H, R347P, D1152H) Class III defective activation (G551D) I II VI V III IV RD ATP Endoplasmic reticulum NBD NBD Golgi mutations result in a decreased amount of functional protein by abnormal splicing or reduced trafficking. 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
104 Thus, a correlation between distances based on CF mutation frequencies and distances based on other polymorphisms, once the shared effects of geographic distance are Figure 5 Geographical distribution (a) and spatial autocorrelogram (b) of the W1282X 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 6 Spatial autocorrelogram of genetic diversity calculated as expected heterozygosity of CF mutations (a) and of genetic diversity calculated as Y of CF mutations (b). 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

8 One was heterozygous for the W1282X mutation and the other was heterozygous for the DF508 mutation. Login to comment
39 Genomic DNA was used as a template in several polymerase TABLE I. Summary of Patients With CAUV Analyzed for CFTR Mutations Patient Renal system Skeleton Hearing Karyotype Affected relatives CFTR mutations 479 Normal Normal Normal 46,XX autosomal translocation None N/N 484 Normal Normal Normal 46,XX Sister N/N 485 Normal Normal Normal 46,XX Sister N/N 489 Normal Absent 12th ribs, L5 sacralization Normal 46,XX None N/N 504 Unknown Unknown Unknown Unknown Unknown N/Na 524 Renal agenesis Normal Normal 46,XX None N/N 575 Normal Normal Normal Unknown None N/Na 593 Unknown Normal Normal Unknown None N/Na 594 Normal Normal Normal Unknown None N/Na 595 Normal Normal Normal 46,XX None N/N 686 Unknown Normal Normal Unknown None N/N 687 Renal agenesis Thoracolumbar dextroscoliosis Normal 46,XX None N/N 688 Normal Normal Normal Unknown None N/W1282X 704 Normal Normal Normal 46,XX None N/N 705 Normal Normal Normal Unknown None N/DF508 706 Normal Normal Normal Unknown None N/N 707 Unknown Unknown Unknown Unknown Unknown N/N 708 Normal Normal Normal Unknown None N/N 709 Horseshoe kidney Scoliosis, abnormal left thumb Absent Unknown None N/N 710 Normal Normal Normal Unknown None N/N 715 Unknown Normal Normal Unknown None N/N 716 Unknown Normal Normal Unknown None N/N 717 Unknown Unknown Unknown Unknown Unknown N/N 739 Normal Normal Normal Unknown None N/N CH92-138 Normal Mild scoliosis Normal 46,XX autosomal translocation None N/N N, no mutations. Login to comment
54 One patient was heterozygous for the DF508 mutation, and another was heterozygous for the W1282X mutation. Login to 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
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

PMID: 12825202 [PubMed] de Semir D et al: "Suitability of oligonucleotide-mediated cystic fibrosis gene repair in airway epithelial cells."

No. Sentence Comment

10 In addition, a methodology allowing the relative quantification of the percentage of W1282X mutation repair in a heterozygous background using the PCR/oligonucleotide ligation assay (PCR/OLA) was developed. Login to comment
14 Moreover, regardless of the corrector oligonucleotide structure applied to our CF bronchial epithelial cells, of compound heterozygous genotype (F508del/W1282X), the percentage of their resulting wild-type allele in the W1282X (exon 20) locus of the CFTR gene was not significantly different from that of the control untreated cells by our PCR/OLA assay (confidence interval at 95% ± 4 allele wild-type). Login to comment
17 Copyright  2003 John Wiley & Sons, Ltd. Keywords W1282X mutation correction; chimeraplasts; non-viral vectors; PCR/OLA Introduction Cystic fibrosis (CF) is the most common autosomal recessive inherited disease in Caucasian populations. Login to comment
20 However, other minority pathologic mutations may occur at higher frequencies in selected populations, as exemplified by the W1282X mutation on 60% of Ashkenazic CF chromosomes. Login to comment
34 In this study, we further sought to validate the chimeraplasty and the use of short single-stranded oligonucleotide technologies for the correction of the W1282X nonsense mutation in CF airway epithelial cells. Login to comment
46 Chimeric RNA/DNA oligonucleotides (CSO-1, CSO-1C, CSO-2 and CSO-3) (A) and short single-stranded oligonucleotides (CSO-4 and CSO-4C) (B) were designed to target either the transcribed or the non-transcribed strand of the W1282X mutation locus within exon 20 of the CFTR gene (C). Login to comment
47 Correction of the point mutation W1282X requires replacement of the mutant A residue with a G residue in the transcribed strand, or of the corresponding complementary residues in the non-transcribed strand. Login to comment
91 Three oligonucleotide probes were used for the analysis of the W1282X mutation in the IB3.1 cells. Login to comment
92 A combination of two upstream (allelic) probes: WT (5 -TATCACTCCAAAGGCTTTCCTC-3 ) for detection of the wild-type allele, and M (5 -TATCACTCCAAAGGCT- TTCCTT-3 ) for detection of the W1282X allele, in which non-complementary 5 -poly(A) extensions (ranging from none to 8A) were added for sizing, plus one common, downstream, 5 -phosphorylated and 3 -FAM-labeled reporter probe: W1282X-CR (5 - CACTGTTGCAAAGTTATTGAATCC-3 ). Login to comment
95 A portion of the OLA reaction was run on an ABI PRISM 310 genetic analyzer (Applied Biosystems, Foster City, CA, USA), and the fluorescent OLA products from W1282X or wild-type alleles were automatically quantified by recording the corresponding peak areas or peak heights of the electropherograms with the GeneScan software, v. Login to comment
110 Statistical analysis General linear models were used to estimate the relationship between peak areas corresponding to wild-type and W1282X mutant alleles and the percentage of wild-type allele within exon 20 of the CFTR gene from IB3.1 cells. Login to comment
118 This widely used and physiologically relevant human CF bronchial epithelial cell line has been well characterized at the molecular level as a compound heterozygote with genotype F508del/W1282X. Login to comment
119 Our initial genetic screening of the CFTR gene confirmed the above genotype but revealed a consistent imbalance between both alleles, the F508del allele being slightly more frequent than the W1282X allele (Figure 2A). Login to comment
126 (A) Genomic DNA isolated from IB3.1 cells was screened for 31 of the most common CFTR gene mutations (together accounting for 77% of the CF chromosomes worldwide), including the deletion F508 (within exon 10), and the transversion W1282X (within exon 20), by multiplex PCR/OLA and sequence-coded separation using the Genotyper software (CF multiplex PCR/OLA kit from PE Applied Biosystems). Login to comment
127 The unbalanced heterozygous nature of the F508del and W1282X mutations is clearly visible in the CFTR gene fingerprint from IB3.1 cells. Login to comment
130 Thus, the above findings are relevant when attempting to undertake and quantify oligonucleotide-mediated correction of the W1282X nonsense mutation in our cellular model. Login to comment
146 Adaptation of the PCR/OLA assay for the assessment of the W1282X mutation correction frequency on IB3.1 cells To assess the percentage of oligonucleotide-directed W1282X mutation correction in the IB3.1 cells, of heterozygous genotype in that locus, we adapted a molecular diagnostic assay, previously employed for the analysis of CFTR gene mutations [28,29], which uses fluorescence-based oligonucleotide ligation technology (OLA). Login to comment
147 As a first step, we optimized the detection of allelic W1282X (G-3978 → A) or wild-type variants within exon 20 of the CFTR gene from genomic DNA of IB3.1 cells, on the exponential phase of their amplification. Login to comment
152 Adjustment of two parameters was found to be essential to allow a reliable quantification of the OLA products reflecting the percentage of W1282X and wild-type alleles from the exon 20 locus of the CFTR gene in the treated and untreated IB3.1 DNA samples: the nature of the thermostable DNA ligase and the size of the allelic OLA probes. Login to comment
153 Specificity of the ligation reaction proved to be critical for a correct quantification of the relative percentage of both the wild-type and the W1282X alleles in a given IB3.1 DNA sample. Login to comment
156 Optimization of the PCR/OLA assay for the relative quantification of the W1282X mutation repair in IB3.1 airway epithelial cells (I). Login to comment
158 Electropherogram displays represent fluorescence detection of oligonucleotide ligation products (single signal, or dual signal with peaks differing at least 2 bp, depending on the poly-A tails appended to the discriminating allelic probes) formed after hybridization over normal or W1282X mutant CFTR target sequences, and analyzed by capillary electrophoresis in an entangled polymer network in 8 M urea. Login to comment
161 Up to 16% of non-specific OLA product resulting from cross-hybridization ligation was detected using Taq DNA ligase but not Tsc DNA ligase W1282X mutation (data not shown). Login to comment
163 This DNA ligase proved to be highly specific for discriminating the wild-type and the W1282X alleles and gave no or insignificant cross-ligation background of mutant allele when a normal DNA from a non-CF individual was tested (Figure 4). Login to comment
164 To analyze whether the above PCR/OLA assay could be used for an accurate assessment of the proportion of either W1282X or wild-type allele present in the exon 20 locus of the CFTR gene from a DNA sample, we mixed different ratios of genomic DNA isolated from a normal non-CF individual, and from a CF homozygous patient for the W1282X mutation. Login to comment
169 The optimized extensions ''5 -AAAA`` for the wild-type discriminating OLA probe (WT + 4A), and ''5 -AAAAAA`` for the W1282X mutant discriminating OLA probe (M + 6A), gave the best regression (R2 = 0.996) in our PCR/OLA assay. Login to comment
170 Thus, this optimized methodology proved to be suitable for the assessment of the W1282X mutation correction frequency on IB3.1 cells. Login to comment
171 Lack of appreciable oligonucleotide-mediated repair on IB3.1 CF airway epithelial cells To ascertain whether chimeraplasts and/or short single-stranded oligonucleotides would mediate the permanent correction of the W1282X mutation at physiologically relevant frequencies, capable of yielding a measurable reversion of the CF phenotype [30], we investigated the percentage of oligonucleotide-mediated wild-type allele augmentation on chimeraplast- or short single-stranded oligonucleotide-treated IB3.1 cells with respect to the background wild-type allele already present in the heterozygous untreated IB3.1 cells. Login to comment
172 We tested different chimeraplast structures (see Figure 1), ranging from the standard 68 nt initial design (CSO-1) [31], and its homologous counterpart targeting the complementary strand of the W1282X DNA locus (CSO-1C), to a 80 nt, CSO-1-related, chimeraplast with an extended targeting region comprising two runs of 12nt of 2 -O-methyl RNA, separated by a 7 nt stretch of DNA (CSO-2). Login to comment
176 However, none of the above chimeraplast designs seemed to elicit targeted W1282X point mutation repair on the IB3.1 chromosomes, at least at a level above the sensitivity of our PCR/OLA method of detection (see standard curve from Figure 5B), because, in all cases, the difference between the percentage of the wild-type allele in the transfected IB3.1 cells and that of the wild-type allele present in either untransfected cells or transfected with an irrelevant chimeraplast was not statistically significant (Table 2, and see Figure 6 as an example). Login to comment
178 Therefore, we tested two additional 25 nt single-stranded oligonucleotide structures (CSO-4 and CSO-4C) complementary to both template strands of the W1282X locus, to discriminate any strand bias for gene correction. Login to comment
182 Again, no significant W1282X mutation correction in the IB3.1 cells was obtained using CSO-3, CSO-4 or CSO-4C oligonucleotides under the different conditions tested (Table 2). Login to comment
183 We conclude that the oligonucleotide-mediated targeted repair of the W1282X nonsense mutation within the CFTR gene is an inefficient process in the IB3.1 CF bronchial epithelial cells. Login to comment
185 Lack of appreciable oligonucleotide-mediated CFTR (W1282X) mutation repair on IB3.1 airway epithelial cells Treatment Oligo conc. Login to comment
187 of the W1282X chromosomal point mutation in CF airway epithelial cells. Login to comment
192 Although these cells have a compound heterozygous genotype for the CFTR gene (F508del/W1282X), the presence of a G → A transversion in nearly half of their chromosomes makes them amenable to attempt chimeraplast- and short single-stranded oligonucleotide-directed gene repair. Login to comment
194 Notably, it has been shown in the latter case that aminoglycoside antibiotics were able to suppress the W1282X premature stop mutation from IB3.1 cells because of the reappearance of cAMP-activated chloride currents, restoration of CFTR protein at the apical plasma membrane, and increase in the abundance of CFTR mRNA levels from the W1282X allele. Login to comment
202 Optimization of the PCR/OLA assay for the relative quantification of the W1282X mutation repair in IB3.1 airway epithelial cells (II). Login to comment
203 Sensitivity assessment of the PCR/OLA methodology for the relative quantification of W1282X mutant and wild-type alleles within exon 20 locus of the CFTR gene, from DNA of treated or untreated IB3.1 cells. Login to comment
204 (A) OLA electropherograms are shown using DNAs from a CF-affected individual homozygous for the W1282X mutation (1), from a normal non-CF individual (7), and from graded mixtures of the above DNAs (2 to 6). Login to comment
205 (B) Standard curves from these samples using different allelic probe combinations such as those shown allowed optimization of the 5 allelic probe length for the best accurate estimation of the frequency of the W1282X mutation correction as a function of the peak areas from both alleles. Login to comment
208 The tables below the standard curves represent the predicted values of % wild-type allele matching the corresponding ratios of non-CF normal DNA (allele wt) to W1282X homozygous DNA (allele W1282X), according to the linear regression model obtained, and their respective lower and upper limits of confidence Figure 6. Login to comment
209 Oligonucleotide-mediated W1282X mutation repair is inefficient in IB3.1 airway epithelial cells. Login to comment
210 Example of the outcome of the repair experiments performed: genomic DNA from IB3.1 cells either untransfected (control) or transfected with a chimeraplast (CSO-3), or a short single-stranded oligonucleotide (CSO-4), both targeted towards accomplishment of the W1282X CFTR A to G transversion, was subjected to the PCR/OLA assay for the relative quantification of the percentage of W1282X mutation correction. Login to comment
211 The electropherograms obtained show well-defined, independent peaks differing in 2 bp, which correspond to the wild-type and W1282X mutant alleles, respectively. Login to comment
216 Thus, our results indicate that CF airway epithelial cells are competent to support chimeraplast-mediated targeted repair, and that it is not inconsistent to attempt in vivo oligonucleotide-mediated correction of the W1282X mutation in our cellular model since the limits of targeted gene repair are not yet known. Login to comment
226 The heterozygous nature of our CF airway epithelial cell model for the W1282X mutation required a special effort to optimize a quantitative methodology to determine the frequencies of targeted gene repair. Login to comment
227 Because our results showed more than 50% of wild-type exon 20 from the F508del- containing chromosomes in the IB3.1 cells, this high background of the 'corrected` allele in the W1282X locus previous to the repair process prevented the use of classical quantitative gene mutation detection such as allele-specific hybridization techniques [14,15,47]. Login to comment
228 Thus, we took advantage of a powerful DNA diagnostic technology, the fluorescent PCR/OLA, already employed for identification of normal and mutant CF alleles [28,29], to develop an easy, fast, sensitive and specific molecular assay for the relative quantification of the W1282X mutation repair at the genomic level in a diploid setting. Login to comment
229 Nevertheless, the sensitivity of our relative W1282X single-nucleotide allele discrimination/quantification method (confidence interval at 95% near ±4% allele wild-type) may be lower than that achieved by the above indicated allele-specific hybridization-based assays, although it would allow the reliable detection of the minimum percentage of corrected, wild-type allele in lung epithelial cells (5-10%) that seems to be required for at least partial phenotypic correction of CF, e.g., to favorably increase CFTR-mediated chloride conductance overall [48]. Login to comment
230 To our knowledge, our adapted PCR/OLA assay is unique in our attempts for a relative quantification of the percentages of the W1282X mutation repair in the heterozygous background of IB3.1 cells. Login to comment
232 Although oligonucleotide synthesis and delivery, and the mutation detection assay, have all been optimized for an effective oligonucleotide-mediated repair, we have not been able to detect any significant oligonucleotide-induced in vivo repair activity of the W1282X chromosomal mutation in the CFTR gene from IB3.1 cells. Login to comment
245 Nevertheless, we have not observed any significant repair activity for the W1282X mutation above the background levels of our detection assay with any of the corrective-oligonucleotides tested. Login to comment
248 However, using this methodology, we have been unable to validate oligonucleotide-mediated targeted gene repair as an effective approach for the correction of the W1282X mutation within the CFTR gene in the repair-competent IB3.1 CF airway epithelial cells. 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
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: 12878584 [PubMed] Cannon CL et al: "Pseudomonas aeruginosa-induced apoptosis is defective in respiratory epithelial cells expressing mutant cystic fibrosis transmembrane conductance regulator."

No. Sentence Comment

37 IB3 cells are bronchial epithelial cells from a ⌬F508/W1282X patient that are adeno-12-SV40 immortalized (17). Login to comment
78 Similar flow cytometry experiments were performed using the cell line IB3, an adeno-12-SV40 immortalized bronchial epithelial cell line derived from a ⌬F508/W1282X patient, and the S9 derivative of the IB3 cells generated by transfection with a recombinant adeno-associated viral vector encoding WT CFTR. Login to comment

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

No. Sentence 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
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

PMID: 12885347 [PubMed] Flotte TR et al: "Phase I trial of intranasal and endobronchial administration of a recombinant adeno-associated virus serotype 2 (rAAV2)-CFTR vector in adult cystic fibrosis patients: a two-part clinical study."

No. Sentence Comment

63 30 ml more than once per week W1282X 4. Login to comment

PMID: 12906319 [PubMed] Wallis C et al: "Atypical cystic fibrosis--diagnostic and management dilemmas."

No. Sentence Comment

80 The most common mutation is the absence of a three base pair sequence resulting in the loss of a phenylalanine residue at position 508-designated deltaF508.22 The remaining mutations are individually rare or unique, although some alleles tend to segregate within specific ethnic groups-for example, 36.2% of CF chromosomes in the Ashkenazi Jewish community carry the mutation W1282X, a gene with a frequency of 51% in the UK.22 4 J O U R N A L O F T H E R O Y A L S O C I E T Y O F M E D I C I N E S u p p l e m e n t N o . 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."

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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

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
122 Ashkenazi Jews have a low incidence of F508 but have an increased frequency (60%) of the nonsense mutation W1282X (Shoshani et al. 1992). 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

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

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

55 All patients had severe CFTR genetic mutations (W1282X). Login to comment
90 Moreover, five of our 10 patients carry the W1282X mutation (stop mutation). Login to 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: 14522463 [PubMed] Fink J et al: "Pro-inflammatory effects of Burkholderia cepacia on cystic fibrosis respiratory epithelium."

No. Sentence Comment

50 The IB3 cell line is adenovirus 12-SV40 hybrid-transformed human bronchial epithelial cells from a CF patient (vF508/W1282X). Login to comment

PMID: 14532265 [PubMed] Zhang XM et al: "Organic solutes rescue the functional defect in delta F508 cystic fibrosis transmembrane conductance regulator."

No. Sentence Comment

43 Cell Culture-The IB3-1 (IB3) cell line is an SV40-transformed line derived from the bronchial epithelium of a cystic fibrosis patient with the ⌬F508/W1282X genotype (X ϭ stop mutation). Login to comment
44 The W1282X mutation produces an unstable mRNA (16). Login to comment
136 Gentamicin enhances read-through of the W1282X deletion (24). Login to comment
143 Because IB3 cells have a W1282X allele that could complicate the data because of potential gentamicin-mediated read-through, we used another cell line. Login to comment
157 Although there could be enhanced read-through of the W1282X allele of the CFTR gene in these cells, the major effect of treatment with organic solutes seemed to be an increase in the ratio of the band C compared with the amount of band B. Login to comment

PMID: 14534332 [PubMed] Lukacs GL et al: "Pharmacologic approaches to correcting the basic defect in cystic fibrosis."

No. Sentence Comment

31 However, almost 60 percent of Ashkenazi Jewish patients with cystic fibrosis carry at least one copy of a nonsense gene alteration (e.g., R553X, G6542X, or W1282X). 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
34 immunofluorescence microscopy of primary human airway cells Primarynasalepithelialcellsfromtwopatientswith cystic fibrosis who were compound heterozygotes for the W1282X and the ∆F508 mutations and who participated in the gentamicin study were obtained by scraping before and after treatment with gentamicin and were then spread on microscope slides. 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
63 The 3849+10kbC˚T mutation can lead to the inclusion of a cryptic 84-bp exon, which contains a stop codon.24 Another eight patients were heterozygous for stop mutations: six were ∆F508/W1282X, one was G85E/ W1282X, and one was W1282X/unknown. Login to comment
89 detection of full-length cftr protein The effect of intranasal gentamicin treatment on the "read through" of premature nonsense codons was further analyzed in two of the patients with the ∆F508/W1282X genotype who had a response to gentamicin. Login to comment
107 Furthermore, staining the cells with an antibody against CFTR, which recognizes a region in CFTR beyond the W1282X mutation, showed an increase in the numberofcellswithsurfacestaining,indicatingthe delivery of full-length CFTR proteins to the apical membrane. Login to comment
108 These results provide direct evidence that gentamicin treatment of patients with cystic fibrosis and the stop mutation W1282X can induce the synthesis of full-length CFTR. This correction of the abnormal potential difference and the appearance of full-length CFTR on the cell surface support the findings of previous studies,whichshowedthatgentamicincanpromote "read through" of stop mutations. Login to comment
117 An Example of Immunostaining for the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) in a Negative Control Involving Nonimmune Mouse CFTR IgG (Panel A) and in a Patient with the W1282X/∆∆∆∆F508 Mutation before (Panel B) and after (Panel C) Gentamicin Treatment (¬100). Login to comment
158 ShoshaniT,AugartenA,GazitE,etal.Association of a nonsense mutation (W1282X), themostcommonmutationintheAshkena- zi Jewish cystic fibrosis patients in Israel, with presentation of severe disease. Login to comment

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

No. Sentence Comment

38 The other 21 common mutations are often found in higher frequency in particular ethnic groups, such as the W1282X mutation in Askenazi Jewish populations (16), G551D in French Canadians (17), and 3,120 ϩ 1G → A in African/Mediterranean populations (18). Login to comment

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

No. Sentence Comment

4 Results: Among the 98 patients studied, 12 (12.2%) had CFTR gene mutations: 2 of the 34 patients (5.9%) with acute pancreatitis, 9 of the 46 (19.6%) with chronic pancreatitis, and 1 of the 18 (5.6%) with pancreatic cancer. All the mutations were found in heterozygosis (2 ⌬F508, 1 W1282X, and 9 T5 allele). Login to comment
45 RESULTS Among the 98 patients studied, 12 (12.2%) had CFTR gene mutations: 2 of the 34 patients (5.9%) with acute pancreatitis, 9 of the 46 (19.6%) with chronic pancreatitis, and 1 of the 18 (5.6%) with pancreatic cancer. All mutations were found in heterozygosis; the CFTR mutations identified were 2 ⌬F508, 1 W1282X, and 9 T5 allele. Login to comment
52 The mutations identified were ⌬F508 in 2 patients, W1282X in 1 and the T5 allele in 6; 1 of these 6 patients had autoimmune pancreatitis. Login to 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: 14583596 [PubMed] Wright JM et al: "Gene expression profile analysis of 4-phenylbutyrate treatment of IB3-1 bronchial epithelial cell line demonstrates a major influence on heat-shock proteins."

No. Sentence Comment

44 IB3-1 (⌬F508/W1282X) bronchial epithelial cells (25) were cultured in LHC-8 as described previously (40). Login to comment
96 IB3-1 cells (⌬F508/W1282X) express only ⌬F508 protein because the W1282X mRNA is unstable (17, 18). 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

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

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

48 1 3 TD 37 M 1 3 24 M ⌬F508/W1282X 1 4 NTD 19 M 1 4 25 M W1282X/N1303K 1 5 NTD 40 F 1 5 20 M ⌬F508/⌬F508 1, 2, 3, 5 6 COPD 60 M 1, 3, 4, 5 6 41 M ⌬F508/⌬F508 1, 2, 4, 5 7 NTD 23 M 2, 3 7 10 M ⌬F508/⌬F508 2 8 TD 36 F 2, 3 8 37 M Not genotyped 2 9 TD 21 M 2 9 28 M ⌬F508/⌬F508 2, 3, 4, 5 10 NTD 45 M 2 10 18 F ⌬F508/⌬F508 2, 4, 5 11 NTD 42 M 2 11 29 M ⌬F508/621ϩ1GϾT 3 12 NTD 22 M 2 12 47 F Not genotyped 3 13 COPD 57 M 3, 4 13 42 M ⌬F508/? Login to comment

PMID: 14701827 [PubMed] Zsembery A et al: "Extracellular zinc and ATP restore chloride secretion across cystic fibrosis airway epithelia by triggering calcium entry."

No. Sentence Comment

42 MATERIALS AND METHODS Cell Cultures-IB3-1 cells2 are CF human bronchial epithelial cells carrying two different mutations of the CFTR gene (⌬F508/W1282X) (13). Login to comment

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

No. Sentence Comment

39 In the Ashkenazi Jewish population, the W1282X mutation is remarkably frequent (45% of carriers), improving the screening sensitivity in this ethnic group [6]. 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: 14744818 [PubMed] Derand R et al: "Activation of VPAC1 receptors by VIP and PACAP-27 in human bronchial epithelial cells induces CFTR-dependent chloride secretion."

No. Sentence Comment

25 IB3-1 (delF508/W1282X) were generously given by Dr P. Zeitlin (Zeitlin et al., 1991) and routinely cultured at 371C in 5% CO2 incubators in LHC-8 medium (Biofluids, Inc., Rockville, MO, U.S.A.) supplemented with 10% fetal bovine serum and 100 IU mlÀ1 penicillin/ streptomycin (Bulteau et al., 2000). Login to comment
174 Specificity of VIP and PACAP-27 towards CFTR In this part of the study, we used the human airway epithelial IB3-1 cells (Zeitlin et al., 1991) derived from a CF patient (delF508/W1282X) because CFTR is absent from the plasma membrane due to its abnormal trafficking (Zeitlin et al., 1991; Dormer et al., 2001). 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
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
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: 15000840 [PubMed] De Semir D et al: "Misleading gene conversion frequencies due to a PCR artifact using small fragment homologous replacement."

No. Sentence Comment

53 We wished to improve the conditions to obtain maximal correction of the CFTR mutation F508del in our cellular model, the adeno-SV40-transformed bronchial epithelial cell line IB3.1, isolated from a CF patient with genotype F508del/W1282X (Zeitlin et al., 1991). Login to comment
57 Similarly as performed with the detection of the oligonucleotide-mediated W1282X correction frequency in IB3.1 cells (De Semir et al., 2003), we optimized the analysis of the percentage of F508del mutation repair in a heterozygous background using exponential PCR and genotyping. 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

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: 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

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: 15097853 [PubMed] Casals T et al: "Different CFTR mutational spectrum in alcoholic and idiopathic chronic pancreatitis?"

No. Sentence Comment

51 The most common mutation in the CFTR gene, F508del, was found in 3 ACP patients (8%), another common CF mutation, W1282X, was identified in 1 ACP patient. Login to comment
63 Time Years BMI Alcohol Alcohol Time Years Tobacco Pancreatic Features Hepatobiliary Disease CFTR Genotype Sweat Test mmol/L FEV1/FVC % Predicted Male Fertility Alcoholic Chronic Pancreatitis (n = 15) 1 M/52 15 24.5 110g/d 27 yes AP, P, Ps, DM, PI Chronic hepatitisa F508del/S1235R 18 105/107 yes 2 M/72 15 23.4 85g/d 22 yes AP, P, C, PS no F508del/1716G/A 72 90/104 yes 3 M/53 10 21.9 135g/d 20 yes P, C, DM, PI no F508del/- 54 71/89 yes 4 M/64 18 20.7 250g/d 27 yes AP, P, C, Ps, DM, PI cirrhosis, lithiasis W1282X/- 68 71/78 unproved 5 M/44 13 22.0 95g/d 6 yes AP, P, C, Ps, DM, PI lithiasis R170C/- 16 105/111 yes 6 M/62 12 22.1 >60g/d >5 yes AP, P, C, Ps, DM, PS no R258G/- 82 73/82 yes 7 M/38 9 18.0 210g/d 15 yes AP, P, C, Ps, PS no M281T/- 62 132/126 yes 8 M/40 11 - >60g/d >5 yes AP, P, C, Ps, PS lithiasis R297Q/- 46 103/99 yes 9 M/42 2 21.4 150g/d 20 yes AP, P, C, Ps, PS no 1716G/A/- 19 93/102 yes 10 M/44 3 22.2 95g/d 22 yes AP, P, DM, PS no R668C/- 58 105/102 yes 11 M/59 6 21.8 90g/d 18 yes PS lithiasis L997F/- 85 69/84 nd 12 M/72 16 - >60g/d >5 no P, C, DM, PI lithiasis R1162L/- - - yes 13 M/35 8 21.0 90g/d 7 yes AP, P, C, PS no 5T-12TG-V470/- 13 106/114 unproved 14 M/60 14 28.0 80g/d 20 no AP, P, C, Ps, DM, PI no 5T-11TG/- 28 80/77 yes 15 M/65 12 24.4 100g/d 23 yes AP, P, C, DM, PS no 5T-11TG/ 40 86/110 yes Idiopathic Chronic Pancreatitis (n = 12) 16 M/21 5 - no - yes AP, P, PS no 1716G/A/R170H 40 normal yes 17 M/59 4 24.2 no - no PS chronic hepatitisb 1716G/A/- 40 146/128 yes 18 M/63 14 21.4 no - no DM, PI no 1716G/A/- 34 144/126 yes 19 M/70 18 19.9 no - yes AP, P, DM, PI chronic hepatitisa 1716G/A/- 60 36/47 yes 20 M/65 1 27.7 no - yes P, Ps, DM, PI no 1716G/A/- 38 79/78 yes 21 M/76 8 24.1 no - no AP, P, DM, PS no 1716G/A/- 60 81/109 yes 22 M/25 2 25.0 no - yes AP, P, PS no 1716G/A/- 48 94/86 nd 23 F/42 10 22.6 no - yes P, C, PS lithiasis P205S/- 72 111/109 - 24 F/81 21 34.6 no - no P, C, DM, PI lithiasis D443Y+G+R*/- 42 121/108 - 25 F/72 8 23.3 no - yes AP, C, PS no L997F/- 40 100/93 - 26 M/9 2 19.2 no - no AP, P, PS no 5T-11TG/- 30 101/110 nd 27 M/63 6 - no - no C, DM, PI cirrhosis 5T-11TG/- - - yes a C virus hepatitis. Login to comment
90 Common CF mutations, F508del and W1282X, were found exclusively in ACP (11%). 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: 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
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: 15176679 [PubMed] Decaestecker K et al: "Genotype/phenotype correlation of the G85E mutation in a large cohort of cystic fibrosis patients."

No. Sentence Comment

137 In patients carrying mutations like F508del, N1303K and W1282X, which correlate with a severe phenotype, w95% have PI [21]. Login to comment

PMID: 15191910 [PubMed] Lim M et al: "Modulation of deltaF508 cystic fibrosis transmembrane regulator trafficking and function with 4-phenylbutyrate and flavonoids."

No. Sentence Comment

4 We sought to determine (i) the effect of apigenin, genistein, kaempferol, and quercetin on CFTR processing in IB3-1 cells (F508/ W1282X) and (ii) whether sequential treatment with 4-phenylbutyrate (4-PBA) to increase CFTR processing and flavonoid to directly stimulate CFTR would increase Cl-conductance. Login to comment
33 Materials and Methods Cell Culture IB3-1 (⌬F508/W1282X) bronchial epithelial cells (20) were cultured on uncoated T-75 flasks in LHC-8 supplemented with glutamine (gentamicin-free formulation; Biofluids, Rockville, MD), 5% bovine serum albumin (BSA) (Biofluids), penicillin-streptomycin (Gibco, BRL, Gaithersburg, MD), 1% fungizone (Biofluids), and 1% tobramycin (Eli Lily, Indianapolis, IN). Login to comment
77 The IB3-1 cell line contains one ⌬F508 allele and one W1282X allele. Login to comment

PMID: 15233679 [PubMed] Choudari CP et al: "Risk of pancreatitis with mutation of the cystic fibrosis gene."

No. Sentence Comment

45 ( F508, G551D, R553X, W1282X, N1303K, R117H, Delta I507, 621+1G- >T, R560T, 1717-1G->A, 711+1G->T, and R1162X; Nichols Institute, Nichols Institute Reference Laboratories, California). Login to comment
79 Sex Mutant Allele Poly T Genotype Age at Onset of Pancreatitis Age at Entry into Study 1. M F508 - 13 17 2. M R117H - 51 53 3. F 621+1(G-T) 7T/7T 48 52 4. F R117H 9T/7T 47 49 5. M F508 - 27 30 6. M F508 7T/7T 30 42 7. M F508 - 46 50 8. F F508 - 20 30 9. M F508 - 16 18 10. F F508 - 61 61 11. M F508 7T/7T 29 31 12. F F508 - 23 26 13. M W1282X 9T/7T 10 18 14. M R117H - 40 45 15. F R117H - 70 76 16. F F508 - 23 28 17. F R117H - 20 26 18. M F508 9T/7T 14 18 19. M F508 - 65 67 Of the 210 control patients, 198 were Caucasian and 12 were African-American. Login to comment
83 Four different mutations were detected: F508 in 12 patients, R117H in five patients, 621+1(G-T) in one, and W1282X in one patient. 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: 15246977 [PubMed] van Heeckeren AM et al: "Role of Cftr genotype in the response to chronic Pseudomonas aeruginosa lung infection in mice."

No. Sentence Comment

220 However, this will not explain the results in IB-3 cells, which are compound heterozygous cystic fibrosis cells containing W1282X and ⌬F508 (6). Login to comment
217 However, this will not explain the results in IB-3 cells, which are compound heterozygous cystic fibrosis cells containing W1282X and ⌬F508 (6). Login to comment

PMID: 15266396 [PubMed] Cardoso H et al: "A low prevalence of cystic fibrosis in Uruguayans of mainly European descent."

No. Sentence Comment

38 *G542X, R1162X, G85E, N1303K, R334W, R75Q, R74W, D1270N, W1282X, ∆I507, 2789+5G->A, R1066C, -816C/T, and R553X. Table 1. Login to comment
56 *G542X, R1162X, G85E, N1303K, R334W, R75Q, R74W, D1270N, W1282X, ∆I507, 2789+5G->A, R1066C, -816C/T, R553X. Table 2. Login to comment

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

No. Sentence Comment

62 The 5T variant produces a lower level of normal CFTR mRNA transcripts than the 7T and 9T alleles and is associated with disseminated bronchiectasis, CBAVD and epididymal obstruction [5].Arduino et al. have described a CBAVD patient with a compound heterozygosity in the CFTR gene for a stop mutation W1282X and a new missense mutation P499A. 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
68 A (1), DF508/N1303K (1), W1282X/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
76 Likewise, among the 8 patients homozygous for the W1282X mutation, 4 presented with gastrointestinal manifestations at diagnosis, while 4 did not. Login to comment

PMID: 15336656 [PubMed] Virella-Lowell I et al: "Effects of CFTR, interleukin-10, and Pseudomonas aeruginosa on gene expression profiles in a CF bronchial epithelial cell Line."

No. Sentence Comment

38 The cell lines used were IB3-1 (CFTR genotypeDF508/W1282X) and cells derived from IB3-1 that were either stably transduced to achieve low-level expression of full-length wild-type CFTR (S9) or transiently transfected with a high-expressing IL-10 construct. Login to comment
42 RESULTS General Oservations about Similarity of Gene Expression Profiles among Infected and Uninfected Cell Lines To characterize primary and secondary effects of CFTR mutation on gene expression, we extracted mRNA from cultures of the CF bronchial epithelial cell line IB3-1 (DF508/W1282X), the CFTR-corrected S9 line (DF508/ W1282X + wild-type CFTR), and IB3-1 cells with vector-mediated IL-10 expression. 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: 15358638 [PubMed] Zaman MM et al: "Interleukin 8 secretion from monocytes of subjects heterozygous for the deltaF508 cystic fibrosis transmembrane conductance regulator gene mutation is altered."

No. Sentence Comment

49 Although the majority of CF subjects were homozygous for ⌬F508, mutations on the other allele (compound heterozygotes) included 621 ϩ 1G-T, N1303K, C276X, W1282X, and 1717-1GϾA. 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

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
104 Among these studies, only eight mutations were identified; the most common being W1282X. 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
41 W1282X was most frequently detected by both programs with a carrier frequency of Ϸ1 in 50 (or Ϸ0.020). 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
56 Five individuals from four families in the DY program were found to be compound heterozygotes for D1152H and W1282X (2 families), ⌬F508 (1), or 3849ϩ10kb CϾT (1). Login to comment
57 Two individuals with the D1152H/W1282X genotype had digestive problems and growth retardation without significant pulmonary problems. 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
97 However, the two individuals identified at MSSM were found to be negative for the 3199del6 mutation that presumably is the disease-causing mutation in cis with the I148T variant.18-20 Of the five individuals identified by DY who were compound heterozygotes for D1152H and W1282X, ⌬F508 or 3849ϩ10kb CϾT, anecdotal information from the two individuals from one family with the D1152H/W1282X genotype indicated a mild form of CF. Login to comment
101 Of interest, W1282X, which was the most prevalent mutation seen in the 100% AJ cohort (46.4% of CFTR mutations), was observed in 32.3% of the population with Ͻ 100% AJ descent. 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: 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

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

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: 15472711 [PubMed] Nissim-Rafinia M et al: "Restoration of the cystic fibrosis transmembrane conductance regulator function by splicing modulation."

No. Sentence Comment

61 The analysis showed no forskolin-stimulated chloride efflux, indicating that the CFTR channels in these cells are inactive, as found in CFP22a cells (DF508/DF508) and IB3 cells (W1282X/DF508). Login to comment

PMID: 15507145 [PubMed] Blaisdell CJ et al: "CLC-2 single nucleotide polymorphisms (SNPs) as potential modifiers of cystic fibrosis disease severity."

No. Sentence Comment

57 We examined human CLC-2 protein expression using lysates from primary nasal cells obtained from elective Table 1: Primers used to amplify CLC-2 polymorphisms Primer oligomer expected size (bp) rat hpolE1 dTCC GGG TCA ATA TCC TTC ACA TCG 2128 hClC-2 promoter dCGC CCG TGG CTC CAT CCC TTC 15F dGTC CCA GGA GTA GAC TTC C 760 bp 16R dCAC TGC CCT CTG GCC TC 17F dTCC CCT CCG GCC TAC CCC TTC CGG T 147 + 300 bp 18R dGGA AGG ATT CGG AGA GGG TTG GGG C Intron 1F dCGC TGC AGC ACG AGC AGA C 2273 Intron 1R dCCC AAG GTC CTG AGT GTA CC Exon 20F dGCC TCT TCT GTG GCA GTC C 481 Exon 20R dCTT CAG GGC TCA TCT CGC C ClC-2 expression by Western blot of nasal polyp lysatesfrom CF adults with the following genotypesFigure 1 ClC-2 expression by Western blot of nasal polyp lysates from CF adults with the following genotypes: Lanes 1,3,6 dF508/dF508; Lane 2: dF508/d559T; Lane 4: unknown; Lane 5: S549N/R553X; Lane 7,9: dF508/unknown; Lane 8: F508/ W1282X.; Lane 10, IB3-1 cell line, genotype F508/W1282X. Login to comment
63 In addition, the expression of ClC-2 protein was diminished in transformed bronchial epithelial IB3-1 cells [11] (lane 10, figure 1), which were derived from primary nasal epithelial cells of a subject with delF508/ W1282X (lane 8, figure 1). Login to comment

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

No. Sentence Comment

51 In the Ashkenazi Jewish population, the W1282X mutation is the most common CF-causing mutation, and together with other nonsense mutations, accounts for 64% of all CFTR alleles [8,9]. Login to comment
83 Subsequently, the same group has shown that the functional CFTR was restored to the apical membrane and the relative level of mRNA increased in bronchial cell line IB3-1 expressing the W1282X mutation. Login to comment
117 In this double-blind, crossover, placebo-controlled trial [27••] as well as in our previous pilot study [25], all patients in the stop mutation group carried at least one W1282X allele. 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: 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
14 One patient was heterozygous for W1282X who inherited the defective allele from her mother (Fig. 1). 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: 15638824 [PubMed] Castaldo G et al: "Comprehensive cystic fibrosis mutation epidemiology and haplotype characterization in a southern Italian population."

No. Sentence Comment

14 Most mutations are "private," but some are frequent in specific regions or ethnic groups (Estivill et al. 1997): 2143delT in Germany (Dork et al. 1992), W1282X among Ashkenazim (Shoshani et al. 1992), Y122X in Reunion Island (Chevalier-Porst et al. 1992), 2183AA>G and R1162X in northeast Italy and T338I in Sardinia (Rendine et al. 1997). Login to 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
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
85 Present study case (n) Mutation references* Haplotype (n. of repeats) Other studies case (n) W1282X 16 17-7-17 26 1, 2, 3 1259insA 11 16-33-13 852del22 11 16-33-13 4016insT 11 16-30-13 I502T 8 16-30-13 L1065P 4 16-30-13 2522insC 4 23-30-13 2789+5G>A 2 17-7-17 9 1, 2, 3 D1152H 2 16-7-13 2711delT 1 16-45-13 2 3 D110H 1 16-32-13 Y849X 1 16-30-13 * References: 1: Morral et al., 1996 2: Claustres et al., 1996 3: Hughes et al., 1996b peculiar to Sardinia, is absent in our population (Rendine et al. 1997). 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: 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: 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

98 AUGARTEN et al. [24] previously investigated 15 CF patients carrying the 3849+10kbC-.T allele and compared their clinical status with that of an unmatched group of 57 patients who were compound heterozygous or homozygous for the DF508 or W1282X mutations. 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: 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

8 Two controls (3.3%) carried a single CF mutation ( F508 in one primary biliary cirrhosis patient; W1282X in one hepatitis C patient). Login to 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
74 Analysis of the individual groups identified one patient (5%) in the PBC group with the F508 mutation, one patient (5%) in the hepatitis C group with the W1282X mutation, and no patient in the autoimmune hepatitis group with any CF mutation. Login to comment
91 CFTR Mutations in Patients with PSC and in Control Patients PSC Controls (n = 59) (n = 60) P-Value CF Mutations F508/+* 1 1 0.74 W1282X/+* 0 1 0.52 CFTR variants 5T/7T 2 6 0.27 Codon 470 Genotypes M/M 10 10 0.9 M/V 28 26 0.67 V/V 21 24 0.59 CF = cystic fibrosis; CFTR = cystic fibrosis transmembrane conductance regulator; PSC = primary sclerosing cholangitis. 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

141 and Class III mutations such as W1282X, F508, and G551D result in little or no functional CFTR channel activity, and are usually associated with the classic CF phenotype of pulmonary disease, elevated sweat chlorides, pancreatic insufficiency, and male infertility. Login to 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
168 COMPLEX ALLELES While phenotypic expression of autosomal recessive disorders typically results from the presence of a causative mutation in each allele of the pair, for example, F508 mutation on one chromosome and W1282X on the other, CF screening has unmasked a diagnostic and counseling challenge in the form of complex alleles. Login to comment

PMID: 15800050 [PubMed] Liang L et al: "RNA interference targeted to multiple P2X receptor subtypes attenuates zinc-induced calcium entry."

No. Sentence Comment

32 IB3-1 is a CF human bronchial epithelial cell line that is compound heterozygous for two different CFTR mutations (⌬F508 and W1282X) (22). Login to comment

PMID: 15800694 [PubMed] Grigorescu M et al: "Genetic factors in pancreatitis."

No. Sentence Comment

98 More than 1200 CFTR gene polymorphism have been reported which can be divided into six classes, based on the functional consequences of the polymorphisms on channel function: - class I-III mutations are severe (CFTRsev ), comprising: class I: defective protein synthesis (R553X, W1282X, 3950 del T); class II: abnormal processing trafficking (del 508, N1303K); class III: defective activation (G551D) and all result in functional loss of CFTR from the epithelial cell surface; - class IV mutations (R117H, R347P, D1152H) are mild-variable mutations (CFTRm-v ) and result in reduction but not absence of channel ion conductance; - class V mutations (3849+10KbC >T) diminish protein synthesis or stability and - class VI mutations may affect the regulatory function of CFTR on other ion channels (71-73). Login to comment

PMID: 15828773 [PubMed] Chen Y et al: "Parallel single nucleotide polymorphism genotyping by surface invasive cleavage with universal detection."

No. Sentence Comment

170 508 of the protein product.23 The CF mutations chosen in this study, ∆F508, G551D, W1282X, N1303K, R117H, R560T, 3849+10kbCT, V520F, R334W, and I148T, are a subset of the standard panel. Login to comment
174 Among the six unrelated CF carriers, one was found to be homozygous for 3849+10kbCT, one homozygous for ∆F508, one heterozygous for both R117H and ∆F508, one heterozygous for W1282X/WT, one heterozygous for V520F/WT, and one heterozygous for G551D/WT. 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

15 The genetic analysis detected 4 affected (F508del/F508del; F508del/1717-1G > A; 2183AA > G/711 þ 5G > A; W1282X/R117H; CF incidence 1/ 2,500) and 294 heterozygous infants (carrier frequency 1/34) (Table I). Login to 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: 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."

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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
70 In the Ashkenazi Jewish population, W1282X is the most common CF-causing mutation, and together with other nonsense mutations accounts for 64% of all CFTR alleles.78 The phenotype of patients carryingstop mutations is severe, similarto thatof the DF508 mutation.89 It has been known for many years that aminoglycoside antibiotics, in addition to their antimicrobial activity, can suppress premature termination codons by disrupting translational fidelity and allowing the incorporation of an amino acid, thus permitting translation to continue to the normal termination of the transcript.10,11 The susceptibility to suppression by aminoglycosides depends on the stop codon itself and on the sequence context surrounding it. 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
102 In this double-blind, crossover, placebo-controlled trial,20 as well as in a previous pilot study,18 all patients in the stop mutation group carried at least one W1282X allele. 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
24 The W1282X allele is highly prevalent in the Ashkenazi Jewish population; in Israeli CF patients, its allele frequency is >50% [6,7]. 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

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

No. Sentence Comment

62 G, R1162X, 3659delC, W1282X, 3905insT, N1303K, 1078delT, R347P, R347H and R334W labelled with TET (green) and A455E, 1898þ1G.A, 2183AA.G, 2789þ5G.A, G85E, 621þ1G.T, R117H, Y122X and 711þ1G.T labelled with HEX (yellow). 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: 15937068 [PubMed] Zabner J et al: "CFTR DeltaF508 mutation has minimal effect on the gene expression profile of differentiated human airway epithelia."

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236 Using microarray technology in a matched pair of cell lines expressing wild-type (IB3a) (11) and mutant ⌬F508/W1282X CFTR (IB3-1) (34), Srivastava et al. Login to comment

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

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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
35 The founder mutations in the Ashkenazi patients accounted for 98.5% of the CF-bearing chromosomes; the major mutation was W1282X representing 43% of the CF mutations while DF508 mutation represented 33.5%. 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
43 We tested 12 CF chromosomes of Tunisian origin, eight (66.7%) possessed the 405 þ 1G!A mutation, three DF508 and one had the W1282X mutation. 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
54 Both had the I1234V mutation while the second mutation was DF508 in one patient and W1282X in the other. 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: 15964894 [PubMed] Medjane S et al: "Impact of CFTR DeltaF508 mutation on prostaglandin E2 production and type IIA phospholipase A2 expression by pulmonary epithelial cells."

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59 The human bronchial epithelial cell line IB3 and C38 cell lines, obtained from ATCC, were grown in minimum essential medium with Earle`s salt and L-glutamine supplemented with 10% FCS at 37°C in 5% CO2/95% air. IB3 express mutant CFTR (⌬F508/W1282X), and C38 is derived from IB3 cells stably transfected with wild-type CFTR (33). 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: 16078047 [PubMed] van de Vosse E et al: "Susceptibility to typhoid fever is associated with a polymorphism in the cystic fibrosis transmembrane conductance regulator (CFTR)."

No. Sentence Comment

8 A few other mutations in CFTR are present at high frequency in specific subpopulations (e.g. W1282X in Ashkenazi Jews (Kornreich et al. 2004) and 1677delTA around the Black Sea (Angelicheva et al. 2005)). Login to comment
12 A CFTR null allele (S489X) in mice was found to confer resistance to cholera toxin (Gabriel et al. 1994), however, this particular mutation is very rare in humans (found in one patient) and may not be comparable to F508del, W1282X and 1677del TA in survival in a population. 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
50 In effect, virtually no func- Table 2 Unusually Common Cystic Fibrosis Mutations in Specific Populationsa Total Exon/ Number Number Frequency Mutation Intron Ethnic Origin Observed Screened (%) 296+12T→C intron 02 Pakistani 02 24 8.33 E60X exon 03 Belgian 06 394 1.52 G91R exon 03 French 04 266 1.50 394delTT exon 03 Scandinavian 78 1588 4.91 457TAT→G exon 04 Austrian 04 334 1.20 Y122X exon 04 Réunion Island 14 29 48.27 I148T exon 04 French Canadian 06 66 9.09 711+5G→A intron 05 Italian (North East) 06 225 2.67 1078delT exon 07 Celtic 27 475 5.68 1161delC exon 07 Pakistani 02 24 8.33 T338I exon 07 Italian, Sardinian 04 86 4.65 Q359K/T360K exon 07 Georgian Jews 07 8 87.50 R347H exon 07 Turkish 04 134 2.98 1609delCA exon 10 Spanish 03 96 3.12 1677delTA exon 10 Bulgarian 05 222 2.25 S549I exon 11 Arabs 02 40 5.00 Q552X exon 11 Italian (North East) 03 225 1.33 A559T exon 11 African-American 02 79 2.53 1811+1.2kbA→G intron 11 Spanish 22 1068 2.06 1898+5G→T intron 12 Chinese 03 10 30.00 1949del84 exon 13 Spanish 02 136 1.47 2143delT exon 13 Russian 04 118 3.39 2183AA→G exon 13 Italian (North East) 21 225 9.33 2184insA exon 13 Russian 03 118 2.54 3120+1G→A intron 16 African-American 14 112 12.50 3272-26A→G intron 17a Portugese, French 06 386 1.55 R1066C exon 17b Portugese 05 105 4.76 R1070Q exon 17b Bulgarian 04 166 2.41 Y1092X exon 17b French Canadian, 11 725 1.52 French M1101K exon 17b Hutterite 22 32 68.75 3821delT exon 19 Russian 03 118 2.54 S1235R exon 19 French (South) 04 340 1.18 S1251N exon 20 Dutch, Belgian 11 792 1.39 S1255X exon 20 African-American 02 79 2.53 3905insT exon 20 Swiss 45 982 4.58 Amish, Arcadian 13 86 15.12 W1282X Exon 20 Jewish-Ashkenazi 50 95 52.63 R1283M exon 20 Welsh 03 183 1.64 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: 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: 16177360 [PubMed] Reiniger N et al: "Influence of cystic fibrosis transmembrane conductance regulator on gene expression in response to Pseudomonas aeruginosa infection of human bronchial epithelial cells."

No. Sentence Comment

42 IB3-1 (CF-IB3-1) and S9 (WT CFTR S9) are both human bronchial epithelial cell lines with the compound heterozygous background of ⌬F508/ W1282X alleles of CFTR (12). Login to comment
138 Cell lysates from WT CFTR S9 and CF- IB3-1 (⌬F508/W1282X CFTR) cells both uninfected and infected with P. aeruginosa strain PAO1 for 3 h were assayed to determine their levels of IL-6, IL-8, CXCL1, and ICAM-1. Login to comment
233 Aminoglycosides are known to cause read-through of stop mutations, such as the W1282X mutation present in CF-IB3-1 cells (4, 18). Login to comment

PMID: 16189704 [PubMed] McGinniss MJ et al: "Extensive sequencing of the CFTR gene: lessons learned from the first 157 patient samples."

No. Sentence Comment

76 Meconium peritonitis;pseudocyst; volvulus 6 p.W1282X/p.S492F 2 months M IRT positive 57, 78, 75, 80, 81 Dx of CF, symptomatic 7 DF508/p.F1099Lb 2 months M IRT positive 48, 52 Asymptomatic at this point 8 DF508/[p.R352W; pP750L]c 1.5 months M IRT positive 1 nl, 44 Followed in CF clinic, being treated prophylactically, neg. elastase 9 DF508/c.1154insTC 4 days M Meconium ileus at birth Not done CF, two affected sibs 10 DF508/c.2789+2insA 2 months F IRT positive 58,57,53 Dx of CF a Concentrations >60 mmol/l on repeated analysis are diagnostic for cystic fibrosis b Novel CFTR mutation c Complex CFTR allele with two different mutations Table 4 Complex CFTR alleles observed in a series of 157 patient samples after extensive sequencing Subject Genotype Phenotype Age Sweat chloride concentration (mmol/l) 1 [p.G576A;p.R668C]/wta Chronic cough, sinusitis, and recurrent pneumonia 3 years Normal 2 p.R1158X/[p.V562I;p.A1006E] Mild CF 40 years 115 3 DF508/[p.R352W;p.P750L] Abnormal newborn screen 49 days 44 4 [c.1198_1203delTGGGCT;c.1204G>A]/wt Mild CF (respiratory symptoms) 12 years 110, 115 a This complex allele has been previously described in a patient with disseminated bronchiectasis with L997F on the other allele (Pignatti et al. 1995) Table6NovelCFTRvariantsfoundinaseriesof157patientsamplesafterextensivesequencing SubjectMutation type LocationNucleotidechangeEffectonproteinCFTRdomaina Mutationonother allele Phenotype 1MissenseExon4c.605G>Cp.S158TL1Nonedetected4-month-oldmale,abnormalnewbornscreen; 3borderlinesweattestresults 2ComplexalleleExon7[c.1198_1203delTGGGCT; c.1204G>A] [p.W356_A357del; p.V358I] AfterTM6and beforeNBD1 Nonedetected12-year-oldmale,meconiumilleusatbirth, respiratorysymptomsofCF;positivesweatchlorides (110,115mmol/l).Motheralsocarriescomplexallele 3MissenseExon9c.1484G>Tp.G451VNBD1DF50819-year-oldmale,diagnosisofCF 4MissenseExon10c.1573A>Gp.K481ENBD1Nonedetected15-year-oldmale,atypicalCF,asthma,2borderline sweatchlorides(low60s) 5MissenseExon10c.1604G>Cp.C491SNBD1NonedetectedNoabnormalsymptoms;sisterofCFpatientthat carriesp.P67L/DF508.Probablebenign variantascertainedduring singleexonsequencingofexon10 6DeletionExon10c.1641AG>Tp.K503NfsX23NBD1p.H609R22-year-oldmale,classicCF,PI,positivesweat chloride(>100mmol/l) 7DeletionExon15c.2949_2953delTACTCp.H939fsX32L3DF5083-month-oldfemale,diagnosisofCF,positivesweat chloride(105mmol/l) 8MissenseExon15c.2978A>Tp.H949LL3Nonedetected, but5Tpositive 12-year-oldmale,atypicalCF,sinusproblems. Login to comment
72 The two deletions Table 2 Atypical CF or nonclassic patients in whom extensive sequencing revealed two CFTR mutations Patient Genotype Phenotype Sex Age (years) Sweat chloride concentration (mmol/l) 1 p.S912L/DF508 Chronic lung and sinus disease F 52 Not done 2 p.R1070W/p.N1303K Recurrent respiratory infections F 4.5 2X intermediate 3 p.G551D/c.2789+2 InsA Pancreatic insufficiency, little lung involvement F 50 92, 96 4 c.3849+10kb C>T/p.L732X Failure to thrive, chronic cough, chronic sinusitis M 5.5 70,73 5 p.W1282X/p.R170H Chronic pancreatitis, CBVAD M 44 Borderline (c.1641 AG>T, and c.2949-2953 del TACTC) are expected to be severe disease-associated mutations, since they change the CFTR reading frame; the two patients harboring these novel deletions had a diagnosis of CF with elevated sweat chloride levels and carried a second, previously described, CF mutation. 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
56 §Eight cases of DF508/DF508, 1 case of DF508/312011G>A, 1 case of DF508/3849110kbC>T, 1 case of DF508/W1282X, 1 case of DF508/ R347P, 1 case of DF508/278915G>A, 1 case of DF508/I148T. Login to comment

PMID: 16202789 [PubMed] Parad RB et al: "Diagnostic dilemmas resulting from the immunoreactive trypsinogen/DNA cystic fibrosis newborn screening algorithm."

No. Sentence Comment

65 Two infants with DF508/5T and borderline sweat chloride values were not included in the count of the true positive cohort, however follow-up continues Group IRT (mg/ml) IRT % CFTR Allele 1 CFTR Allele 2 [Cl2 ] mEq/L Sex I 64 97 DF508 R117H-7T 34 F 179 100 DF508 R117H-7T 33 F 79 99 DF508 R117H-7T 49 M 97 99 W1282X 3849110kb 54 M II 176 99.8 DF508 R117H-7T 24 F 129 99.7 G85E R117H 21 F 84 99 G551D R117H-7T 27 M III 94 99.1 DF508 unknown 58 M* 142 100 G85E R117C 33 F 72 98 G551D R117C 46 F 100 99.2 DF508 L206W 35 M IV 141 100 G85Ey R117C 41 M *Identified twin sibling has [Cl2 ] > 60 mEq/L. 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

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

No. Sentence Comment

56 T (i) 19 3905insT, W1282X, S1251N 20 N1303K 21 TABLE 2. 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

79 Three different types of transformed human bronchial epithelial cells were used in the present study: IB3-1 cells that express mutant CFTR (genotype ⌬F508/W1282X); C38 cells, the "corrected" CFTR-complemented cell line with a functional CFTR that is derived from IB3-1 cells and stably transfected with an episomal, truncated of CFTR; and BEAS-2B cells that express wild-type CFTR (46, 71). 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

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: 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
94 Case 4-5 In two subjects, one oligospermic male and a child suspected of CF because of a borderline sweat test, no signal could be obtained ateither the wild-type or the mutated site, with the allele-specific probes W1282X and 3905insT localized in exon 20 of CFTR gene (Fig. 1D). Login to comment
96 This nucleotide change occurred 24 bp downstream from the W1282X site, and we postulated that it prevented amplification of the fragment by affecting the annealing of the reverse PCR primer. 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: 16429425 [PubMed] Mussaffi H et al: "Cystic fibrosis mutations with widely variable phenotype: the D1152H example."

No. Sentence Comment

54 Age (y)/gender Age (y) at diagnosis Ethnic origin (all Jewish) Other CF mutation Sweat ClÀ (meq/l)2 Presentation 1 54/m 46 Ashkenazi W1282X 120 Bronchiectasis 2 39/m 33 Turkey/Iraq D1152H 49 CBAVD 3 46/f 41 Ashkenazi DF508 54 Bronchiectasis 4 49/m 44 Ashkenazi DF508 113 Bronchiectasis 5 51/f 49 Ashkenazi DF508 50 Pancreatitis 6 1.5/m 0.5 Iran/Turkey/Bulgaria D1152H 53 Lung disease 7 2/m 1.3 Iran/Bulgaria W1282X 70 Lung disease 8 1/f Prenatal Ashkenazi DF508 80 Prenatal dilated bowel 9 0.8/m Prenatal Tunis/Ashkenazi DF508 28 Prenatal screening 1 Patients 4 and 5 are siblings. 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: 16512671 [PubMed] Singh OV et al: "Pharmacoproteomics of 4-phenylbutyrate-treated IB3-1 cystic fibrosis bronchial epithelial cells."

No. Sentence Comment

21 IB3-1 cells (∆F508/W1282X CF bronchial epithelial cells)22 were grown on uncoated 75 cm2 tissue culture flasks (Falcon, Franklin Lakes, NJ) in a 5% CO2 incubator at 37 °C for 48-72 h to reach 80% confluency. Login to comment
76 We studied the immortalized CF bronchial epithelial cell line IB3-1,22 (CFTR genotype ∆F508/W1282X). Login to comment
77 IB3-1 expresses the ∆F508 CFTR protein only, because the W1282X mutation produces an unstable, and therefore untranslated, mRNA.26,27 We have previously published the dose response curve for 4-PBA mediated rescue of ∆F508 CFTR processing in IB3-1 cells. Login to comment

PMID: 16612392 [PubMed] Poschet JF et al: "Endosomal hyperacidification in cystic fibrosis is due to defective nitric oxide-cylic GMP signalling cascade."

No. Sentence Comment

25 A pair of previously characterized (Egan et al, 1992), genetically matched CF and CFTR-corrected bronchial epithelial cell lines was used: IB3-1 (from a compound heterozygote CF patient with CFTR DF508/W1282X alleles) and S9 (IB3-1 cells corrected with a full-size functional CFTR complementary DNA). Login to comment

PMID: 16621797 [PubMed] Vij N et al: "Selective inhibition of endoplasmic reticulum-associated degradation rescues DeltaF508-cystic fibrosis transmembrane regulator and suppresses interleukin-8 levels: therapeutic implications."

No. Sentence Comment

57 Cell Culture, Transfection, and Metabolic Labeling-IB3-1 cells (⌬F508/W1282X, low level expression of ⌬F508-CFTR and no W1282X-CFTR protein), CF tracheal epithelial (CFTE) cells (homozygous for ⌬F508-CFTR), and S9 cells (IB3-1 cells corrected with adeno-associated virus-CFTR) were maintained in LHC-8 medium (BIOSOURCE) containing 100 units/ml penicillin, 100 ␮g/ml streptomycin, 0.25 ␮g/ml amphotericin B, and 10% fetal bovine serum (all from Invitrogen). Login to comment
110 The efficiency of VCP shRNA (⌬VCP)-mediated inhibition of VCP protein levels in IB3-1 cells (⌬F508/W1282X CF bronchial epithelial line) (13) was evaluated by immunoblotting of whole cell lysates (Fig. 1B, upper panel). 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

125 Other mutations are often found in higher frequency in particular ethnic populations, such as the W1282X mutation in Ashkenazi Jewish populations and G551D in French Canadians.71 Such information is useful in designing mutation panels suitable for screening programs in different populations. 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: 16763223 [PubMed] Velsor LW et al: "Mitochondrial oxidative stress in the lungs of cystic fibrosis transmembrane conductance regulator protein mutant mice."

No. Sentence Comment

49 These cells possess heterozygous mutations (⌬F508 and W1282X) for the CFTR gene. Login to comment

PMID: 16946273 [PubMed] Emam A et al: "Laboratory and clinical Pseudomonas aeruginosa strains do not bind glycosphingolipids in vitro or during type IV pili-mediated initial host cell attachment."

No. Sentence Comment

30 IB3-1 (ATCC CRL-2777) is a compound heterozygote cell line containing the DF508 mutation, and a nonsense mutation, W1282X, with a premature termination signal. 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: 16990428 [PubMed] Schneider M et al: "Detection of exon deletions within an entire gene (CFTR) by relative quantification on the LightCycler."

No. Sentence Comment

34 We used DNA samples from 3 healthy control individuals and from 2 CF patients with only 1 known variation, 1 with a W1282X and 1 with a 5T sequence variant in intron 8. Login to comment
40 Origin of sample Sample details/characterization of deletion Division of Human Geneticsa CF normal control individuals (calibrator) ● 2 healthy individuals in whom no CFTR pathogen sequence variant could be detected by our single-strand conformation polymorphism/heteroduplex screening method Normal control individuals ● 3 healthy control individuals ● 2 CF patients with only 1 (W1282X/5T) detected pathogen sequence variant but multiple homozygous sequence variants Individuals with known large deletions ● CFTRindel2 ● CFTRdele2-3 (21 kb)b ● 3 CF patients with CFTRdele14b-17b (c.2752-674_3499 ϩ 198del9858)b ● 3 CF patients with CFTRdele17a-17b (c.3121-977_3499 ϩ 248del2515)b Blinded analysis ● 61 patients with classic or atypical CF symptoms with only 1 detected pathogen sequence variant in the CFTR gene Positive controls (from individuals with known large deletions) Audrezet et al. (Brest, France) (2) ● CFTRindel4 (c.274-5938_489 ϩ 2011del8165ins41) ● CFTRindel4-6a (c.273 ϩ 7983_743 ϩ 362del18654insACCTCG) ● CFTRindel11-16 (c.1584 ϩ 10TϾC; c.1584 ϩ 12_2988 ϩ 403del47.5 kbins35 bp; homozygous) ● CFTRdele22-23 (c.3864-78_4242 ϩ 577del1532) Chevalier-Porst et al. (Lyon, France) (1) ● CFTRdele2-10 (c.53 ϩ 4533_1585-7322del95738) ● CFTRdele4-10 (c.274-10538_1393 ϩ 277del39572) ● CFTRindel16-17b (c.2909-636_3368-1611del6965ins32) ● CFTRdele17a-18 (3120 ϩ 1 kbdel8.6 kb)c ● CFTRindel22-24 (c.3964-3890-4413 ϩ 3143del9454ins5) a Division of Human Genetics, Children`s University Hospital, Inselspital, Bern, Switzerland. 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

83 Patients With SPINK1 and CFTR Mutations SPINK Mutation 1 SPINK Mutation 2 SPINK1 Mutation 3 CFTR Mutation 1 CFTR Mutation 2 No. of Patients 5¶UTR-147 A9G W1282X 1 5¶UTR-41 G9A 5¶UTR-41 G9A D1445N 1 5¶-41 G9A D1270N R74W 1 5¶UTR-81 C9T deltaF508 5T 1 IVS3+184 T9A S1235R 1 IVS3+184 T9A 5T 1 IVS3+184 T9A deltaF508 5T 1 IVS-72delCT R75X 1 L12F IVS3+90 A9T 296+28 A9G 1 L12F IVS3+90 A9T 4375-20 A9G 1 M1R 5¶UTR-147 A9G 5T 1 N34S IVS3-66-65insTTTT N37S Q1352H 1 N34S IVS3-66-65insTTTT L997F 1 N34S 5T 1 N34S IVS3-66-65insTTTT 5T 3 N34S IVS3-66-65insTTTT IVS1-37T 9C deltaF508 R117H 1 N34S IVS3-66-65insTTTT IVS1-37T9C R117H 5T 1 N34S IVS3-66-65insTTTT 621+83 A9G 1 N34S IVS3-66-65insTTTT IVS1-37T9C deltaF508 S1235R 1 Total patients 21 CFTR mutations in boldface would not have been detected by the ACOG/ACMG mutation panel. Login to comment

PMID: 17020467 [PubMed] Giannattasio S et al: "Molecular basis of cystic fibrosis in Lithuania: incomplete CFTR mutation detection by PCR-based screening protocols."

No. Sentence Comment

60 CFTR GENOTYPE CHARACTERIZED IN 32 NON-p.F508del HOMOZYGOTE LITHUANIAN CF PATIENTS Patient CFTR mutationa (TG)ma Tna M470V 1 F508del/R553X 10/10 9/7 MM 2 F508del/R553X 10/12 9/7 VV 3 F508del/R553X 10/10 9/7 VV 4 F508del/R553X 10/10 9/7 VV 5 F508del/3944delGT 10/11 9/7 VV 6 F508del/W1282X 10/10 9/7 VV 7 F508del/G314R 10/12 9/7 MV 8 F508del/N1303K 10/11 9/7 MV 9 F508del/CFTRdele2,3(21kb) 10/11 9/7 MV 10 F508del/CFTRdele2,3(21kb) 10/11 9/7 MV 11 F508del/- 10/10 9/7 VV 12 F508del/- 10/11 9/7 MV 13 F508del/- 10/10 9/7 VV 14 F508del/- 10/10 9/9 VV 15 F508del/- 10/10 7/7 MV 16 F508del/- 10/11 9/7 MV 17 F508del/- 10/10 9/7 VV 18 N1303K/- 10/10 7/7 MM 19 R75Q/- 10/11 7/7 MV 20 -/- 11/11 7/7 VV 21 -/- 10/12 7/7 MM 22 -/- 11/11 9/7 MV 23 -/- 11/11 7/7 MV 24 -/- 10/10 7/7 MV 25 -/- 10/12 9/7 MV 26 -/- 10/11 7/7 MM 27 -/- 11/11 9/7 VV 28 -/- 12/12 7/7 MV 29 -/- 11/11 9/9 MM 30 -/- 10/11 9/9 MV 31 -/- 11/11 5/7 MV 32 -/- 10/11 9/9 MM aFor each patient, (TG)m and Tn alleles are indicated in phase with each other but not with CFTR mutations identified. Login to comment
3 Seven CFTR mutations, p.N1303K (2.0%), p.R75Q (1.0%), p.G314R (1.0%), p.R553X (4.2%), p.W1282X (1.0%), and g.3944delGT (1.0%), accounted for 10.1% of Lithuanian CF chromosomes. Login to comment
32 The following CFTR mutations were found: p.N1303K (2.0%), p.R75Q (1.0%), p.G314R (1.0%), p.R553X (4.2%), p.W1282X (1.0%), and g.3944delGT (1.0%). Login to comment
46 CFTR GENE MUTATIONS IDENTIFIED BY PCR SCREENING METHODS IN 98 UNRELATED LITHUANIAN CF CHROMOSOMES Number of chromosomes CFTR allele (relative frequency) p.F508del 51 (52.0%) p.R553X 4 (4.2%) p.N1303K 2 (2.0%) CFTRdele2,3(21kb)a 2 (2.0%) p.R75Q 1 (1.0%) p.G314R 1 (1.0%) p.W1282X 1 (1.0%) g.3944delGT 1 (1.0%) Uncharacterized 35 (35.8%) Total 98 (100%) aDork et al. 2000. 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: 17178710 [PubMed] Wang W et al: "Curcumin opens cystic fibrosis transmembrane conductance regulator channels by a novel mechanism that requires neither ATP binding nor dimerization of the nucleotide-binding domains."

No. Sentence Comment

6 Consequently, this compound potently activated CF mutant channels that are defective for the normal ATP-dependent mode of gating (e.g. G551D and W1282X), including channels that lack NBD2. Login to comment
44 CFTR constructs that are robustly activated by curcumin include two of the more common CF mutants, G551D (mutation in NBD1 (21)) and W1282X (nonsense mutation deleting most of NBD2 (22)). Login to comment
53 HeLa cells stably transfected with W1282X-CFTR were provided by J. P. Clancy at the University of Alabama at Birmingham. Login to comment
114 The activation of ⌬1198-CFTR channels by curcumin did not require bath ATP; in fact, ATP substantially reduced the curcumin response for this construct (see Fig. 4 and W1282X-CFTR below). Login to comment
146 We next determined whether W1282X-CFTR channels also can be activated by curcumin. Login to comment
147 W1282X is a fairly common nonsense mutation in certain CF populations including Ashkenazi Jews, for whom it is the most frequent CF mutation (22). Login to comment
149 W1282X-CFTR channels are targeted to the cell surface, albeit less efficiently than ⌬1198-CFTR channels (see biotinylation results in Fig. 2B). Login to comment
150 Like ⌬1198-CFTR channels, W1282X-CFTR channels exhibit low (but detectable activity) in excised patches either in the absence or presence of bath ATP (Fig. 2F). Login to comment
151 W1282X-CFTR channels were also robustly stimulated by curcumin under either condition (Fig. 2F), although the effect of curcumin is more pronounced in the absence of bath ATP (see also Fig. 4). Login to comment
152 Gating Properties of Curcumin-activated Channels; Curcumin Increases the Opening Rates of G551D-CFTR Channels and the NBD2 Deletion Mutants-To explore how curcumin influences the gating properties of these mutant constructs, we tested its effects on G551D-CFTR, ⌬1198-CFTR, and W1282X-CFTR channels in excised micropatches containing small numbers of channels (less than eight). Login to comment
156 Individual records for G551D-CFTR, ⌬1198-CFTR, and W1282X-CFTR channels are shown in Fig. 3 (A, B, and D). Login to comment
165 Curcumin Activation of ⌬1198-CFTR Channels Is Inhibited by ATP Binding to NBD1-Fig. 4 shows another striking feature of the effect of curcumin on the NBD2 deletion constructs (both ⌬1198-CFTR and W1282X-CFTR), namely strong inhibition of this activating effect by bath ATP. Login to comment
183 D, W1282X-CFTR;-60mV.E,representativepatchshowingdynamicsofopeningandclosingof⌬1198-CFTRchannelsduringthereversibleandpersistentphases of curcumin activation. Login to comment
208 A similar PKA dependence of the curcumin effect was observed for G551D-CFTR, W1282X-CFTR, and wild type channels (results not shown). Login to comment
214 DISCUSSION Our data indicate that curcumin strongly activates mutant CFTR channels that normally have very low activities because of defects in ATP binding and/or NBD heterodimerization (e.g. G551D-CFTR and W1282X-CFTR channels). Login to comment
216 That the stimulatory effect of curcumin does not require heterodimerization of the two NBDs is best exemplified by its potent activation of channels that lack all (⌬1198-CFTR) or part (W1282X-CFTR) of NBD2. Login to comment
244 NBD1 Is a Plausible Interaction Site for Curcumin-ATP strongly inhibits the activation of channels that lack NBD2 (⌬1198-CFTR and W1282X-CFTR) by curcumin. Login to comment
253 Tight ATP binding to NBD1 is less likely for mutants that are disrupted for ATP binding and/or the dimerization of the two NBDs (e.g. G551D, W1282X, and ⌬1198-CFTR), given that dimerization would be expected to stabilize ATP binding to NBD1 (9-11). Login to comment
267 Acknowledgments-We thank J. P. Clancy for the HeLa cells stably transfected with W1282X-CFTR and M. J. Welsh for the ⌬R/S660A-CFTR construct. Login to comment

PMID: 17197571 [PubMed] Dechecchi MC et al: "MPB-07 reduces the inflammatory response to Pseudomonas aeruginosa in cystic fibrosis bronchial cells."

No. Sentence Comment

47 MATERIALS AND METHODS Cell Lines and Bacteria IB3-1 is a human bronchial epithelial cell line, immortalized with adeno- 12/SV40, derived from a patient with CF with a ⌬F508/W1282X mutant genotype (32). 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: 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

10 Our results demonstrate differences in NMD efficiency of CFTR transcripts carrying the W1282X mutation among different epithelial cell lines derived from the same tissue. Login to comment
13 Downregulation of NMD in cells carrying the W1282X mutation increased the level of CFTR nonsense transcripts and enhanced the CFTR chloride channel activity in response to gentamicin. Login to comment
21 We have recently administered gentamicin to the nasal epithelium of CF patients, all of whom carried the same W1282X nonsense mutation (29). Login to comment
36 Variability in the NMD efficiency was found for CFTR transcripts carrying the W1282X mutation as well as for several physiologic NMD substrates, ribosomal protein L3 (RPL3), splicing component 35 kDa (SC35) 1.6 kb, SC35 1.7 kb, asparagine synthetase (ASNS), and cysteinyl-tRNA synthetase (CARS). Login to comment
46 (C) A summary of the W1282X transcript levels in the W1282X/ΔF508 patients. Login to comment
48 (D) An example of real-time PCR of the CFTR and the RPS9 genes, of RNA from 2 patients (nos. 8 and 9) homozygous for W1282X and a control individual with normal CFTR alleles. Login to comment
51 (F) An example of GeneScan analysis of RT-PCR products of the CFTR and the KRT18, in a patient homozygous for the W1282X mutation (patient 6). Login to comment
55 The levels in C, E, and G, are 685 scripts carrying the W1282X mutation, we obtained RNA samples from nasal epithelial cells from patients who had participated in our double-blind, placebo-controlled, crossover trial (29). Login to comment
56 The level of nonsense CFTR mRNA was analyzed in pretreatment samples from these patients. Five of the patients were heterozygous for the W1282X and the ΔF508 mutations (Figure 1A). Login to comment
58 Thus, the level of mRNA transcribed from W1282X alleles could be distinguished and compared to those transcribed from the ΔF508 allele. Login to comment
59 The results showed that the level of the W1282X mRNA among these patients was reduced to between 62% ± 0.05% and 68% ± 0.02% of that transcribed from the ΔF508 allele (Figure 1, B and C). Login to comment
60 The other 5 patients carried 2 alleles with CFTR nonsense mutations, of which at least 1 was the W1282X (Figure 1A). Login to comment
62 The level of the normalized CFTR nonsense mRNA in each patient was compared to the normalized level obtained from a control individual with normal CFTR alleles. The results revealed that in 3 patients (nos. 6, 7, and 8), the level of CFTR nonsense mRNA was between 60% ± 0.10% and 84% ± 0.12% of that found in a control individual with normal CFTR alleles, similar to the level found in the W1282X/ΔF508 patients (Figure 1, D and E). Login to comment
64 We further analyzed 1 patient heterozygous for the W1282X and the ΔF508 mutations (patient 3) by both GeneScan and real-time PCR analyses for comparisons of the results obtained by the different mRNA quantification methods. Login to comment
66 Furthermore, 2 of the patients homozygous for W1282X (nos. 8 and 9) are sisters whose parents are first-degree cousins. Login to comment
67 Although they carry identical CFTR alleles, there was a large difference in their levels of W1282X transcripts. Login to 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
91 Variable NMD efficiency of endogenous CFTR transcripts carrying the W1282X mutation. Login to comment
92 Previous studies showed that the level of W1282X transcripts is markedly reduced in epithelial samples derived from CF patients and in a bronchial epithelial cell line, IB3-1, heterozygous for the W1282X and the ΔF508 mutations (5, 45). Login to comment
93 These results raised the possibility that transcripts carrying the W1282X mutation are subject to NMD. Login to comment
95 Since the last CFTR exon-exon junction is located more than 55 nucleotides downstream to the W1282X mutation, transcripts carrying the W1282X mutation have the potential to be subject to NMD. Login to comment
96 In order to investigate this possibility, we analyzed nasal epithelial cell lines (CFP15a and CFP15b) derived from polyps of 2 unrelated CF patients, both heterozygous for the W1282X and the 3849+10 kb C→T mutations. Login to comment
101 These results suggest that endogenous CFTR W1282X transcripts might be subject to NMD with variable efficiencies. Login to comment
117 Together, the results suggest that NMD efficiency for transcripts carrying the W1282X mutation is different among different cell lines even derived from the same tissue. Login to comment
157 Previous studies have shown that the level of the W1282X transcripts in these cells is markedly reduced in comparison to the level of transcripts derived from the ΔF508 allele (5). Login to comment
213 It is worth noting that the role of posttranscriptional mechanisms in regulating the response to gentamicin cannot be excluded, except for alternative splicing of CFTR exon 20, which we found not be upregulated by the W1282X mutation (Supplemental Results and Supplemental Figure 4). Login to comment
216 It is interesting to note that we and others are currently investigating the effect of a newly developed small molecule, PTC124, on CF patients carrying the W1282X mutation (64). 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
232 The level of the nonsense CFTR mRNA in samples of W1282X/ΔF508 patients was analyzed by RT-PCR with primers in exons 10 and 11, flanking the ΔF508 mutation. Login to comment
234 Thus, the level of mRNA transcribed from W1282X alleles could be distinguished and compared to those transcribed from the ΔF508 allele. Login to comment
237 The PCR products of the ΔF508 transcripts and the W1282X transcripts were 254 and 257 bp, respectively. Login to comment
241 The level of the W1282X transcripts was determined as the peak area of the signal of the W1282X PCR product divided by the peak area of the signal of the ΔF508 PCR product. Login to comment
253 CFTR primer pair used here was the same as that used for the reactions with samples from the W1282X/ΔF508 patients. Login to comment
265 In order to analyze the splicing pattern 691 of the W1282X region, we performed RT-PCR reactions with primers in exons 18 and 21: forward GTAAACTCCAGCATAGATGTGG, reverse CCACTGTTCATAGGGATCCAA. Login to comment
382 Association of a nonsense mutation (W1282X), the most common mutation in the Ashkenazi Jewish cystic fibrosis patients in Israel, with presentation of severe disease. 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: 17329263 [PubMed] Ratbi I et al: "Detection of cystic fibrosis transmembrane conductance regulator (CFTR) gene rearrangements enriches the mutation spectrum in congenital bilateral absence of the vas deferens and impacts on genetic counselling."

No. Sentence Comment

50 CFTR mutations were detected in 387 out of 444 alleles (87.2%), most of them being previously described in patients with CF of varying severity, CBAVD or other CFTR diseases: 45% of identified alleles consisted of severe CF mutations (e.g. F508del, W1282X, 2183AA.G); 13.8% of mild or variable CF mutations (e.g. L206W, 3272-26A.G, R117H, D1152H); 36.7% of mild CFTR defects which are currently not considered CF-causing (e.g. IVS8(T)5, Q1352H, the complex alleles [D443Y;G576A;R668C] and [R74W;D1270N]) and 4.5% of rare missense mutations whose effect is difficult to predict (e.g. A959V, G1069R, V1153E). Login to comment
143 Three of the five carried a mutation on the other chromosome: L997F, S977F and W1282X. Login to comment
144 Although V562I has been considered a severe CF mutation, a series of arguments question its severe deleterious effect: its presence in trans of the severe W1282X mutation, the case of a V562I homozygous CF patient who carried in cis the frameshift 2347delG (Girodon et al., unpublished data), and the fact that residue V562 is not conserved in other proteins containing the ATP-binding cassette motif. 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
212 The majority of premature stop subjects were homozygous for stop mutations (n ϭ 11/19), and all possessed at least one copy of the W1282X CFTR mutation. Login to comment
213 In contrast, no subject in our study had two copies of premature stop mutations, and only 1 of 11 subjects carried the W1282X CFTR mutation. Login to comment
215 Furthermore, in vitro studies completed in our laboratory have demonstrated that W1282X CFTR can retain partial function that is enhanced after stop codon suppression (28). Login to comment
216 Thus, increased activity of W1282X CFTR might be predicted in the context of higher expression levels. Login to comment
220 Thus, genetic differences in NMD between the Israeli and American populations with CF may account in part for differences in treatment effects (particularly in the context of the W1282X CFTR mutation). 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: 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
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
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
203 Indeed, a considerable variability in the level of CFTR nonsense transcript was found among the patients carrying the W1282X mutation and receiving a topical administration of nasal gentamicin, with a significant correlation between the amount of CFTR nonsense transcripts and the modification of CFTR function after treatment [24]. 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
52 The father was found to be a carrier of a cystic fibrosis mutation (W1282X), but the mother was mutation-negative. Login to comment
75 Inability to demonstrate the gallbladder on ultrasound scans may also be the result of 'technical difficulties` such as, aberrant location of the Table1-Clinicalcharacteristicsof17caseswithisolatednonvisualizedfetalgallbladder(INVFGB) Case InitialU/S scan(weeks) Subsequent scans(weeks) Subsequent findings Amniotic fluidMME* KaryotypeCFmutationanalysis Pregnancy outcome Gallbladder detectedDiagnosis 11617,19NoneNormal46,XXNormalDeliveryYesThyroidaplasia 21517NoneNormal47,XXXPaternalcarrier(W1282X)TOPYesTripleX 31517,21NoneNormal46,XXNormalDeliveryYesNormal 41517NoneNormal46,XYNormalDeliveryYesNormal 51517,20NoneNormal46,XXNormalDeliveryYesNormal 61517,21FEBAlllow46,XXFetusaffectedTOPYes (atrophic) Cysticfibrosis 71622NoneNormal46,XYPaternalcarrier(D1152H)DeliveryYesNormal 81519NoneNormal46,XYNormalDeliveryNoNormal 91517,23NoneNormal46,XYMaternalcarrier(F508)DeliveryYesNormal 101517NoneNormal46,XYNormalDeliveryYesNormal 111517NoneNormal46,XXNormalDeliveryYesNormal 121517,19,24NoneLowiALKP46,XYFetuscarrier(5T)DeliveryNoNormal 131517,22NoneHighGGTPandAMP NormaliALKP 46,XYNormalDeliveryYesNormal 141520,22SmallVSDNormal46,XXNormalDeliveryYesNormal 151518NoneNormal46,XXNormalDeliveryYesNormal 161518NoneNormal46,XXNormalDeliveryYesNormal 171524NoneNormal46,XXNormalDeliveryYesNormal *lowlevels:<1stpercentile,highlevels>99thpercentile. Login to comment

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

No. Sentence Comment

32 In Ashkenazi Jews, W1282X accounts for nearly 50% of mutated CFTR alleles and this is the only significant population in which phe508del is not the dominant CF-causing mutation [12]. Login to comment

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

No. Sentence Comment

0 Restoration of W1282X CFTR Activity by Enhanced Expression Steven M. Rowe, Karoly Varga, Andras Rab, Zsuzsa Bebok, Kevin Byram, Yao Li, Eric J. Sorscher, and John P. Clancy Departments of Medicine, Pediatrics, and Physiology and Biophysics, the Gregory Fleming James Cystic Fibrosis Research Center; and Department of Cell Biology, University of Alabama at Birmingham, Birmingham, Alabama Cystic fibrosis results from mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Login to comment
3 We studied two well-described premature termination codons found in the distal open reading frame of CFTR, W1282X and R1162X, expressed in polarizing and nonpolarizing cells. Login to comment
4 Our findings indicate that W1282X CFTR-expressing cells demonstrate significantly greater CFTR activity when overexpressed compared with R1162X CFTR cells, even when truncated protein is the predominant form. Login to comment
6 These findings provide evidence that W1282X CFTR exhibits membrane localization and retained chloride channel function after enhanced expression, and suggest that patients harboring this mutation may be more susceptible to CFTR rescue. Login to comment
16 Importantly, all subjects with nonsense mutations in both of these studies carried at least one copy of W1282X CFTR, a PTC that is particularly common in this population (found in up to 40% of Israeli patients with CF) (5, 16, 17). Login to comment
21 Based on the promising clinical findings in patients possessing W1282X CFTR, coupled with variable in vivo responses to premature stop suppression, we designed experiments to examine the effects of stop codon site on two common PTCs found in CFTR (R1162X and W1282X). Login to comment
22 Our results indicate CLINICAL RELEVANCE Evidence that W1282X cystic fibrosis transmembrane conductance regulator (CFTR) retains chloride channel function improves our understanding of CFTR biology, and may explain why subjects harboring W1282X CFTR appear more susceptible to the strategy of premature termination codon suppression. Login to comment
24 E-mail: smrowe@ uab.edu Am J Respir Cell Mol Biol Vol 37. pp 347-356, 2007 Originally Published in Press as DOI: 10.1165/rcmb.2006-0176OC on May 31, 2007 Internet address: www.atsjournals.org that enhanced expression is sufficient to restore measurable activity to W1282X CFTR but not R1162X CFTR. Login to comment
26 MATERIALS AND METHODS Development of Stable Cell Lines Expressing W1282X and R1162X CFTR W1282X and R1162X CFTR cDNA were stably introduced into HeLa and CFBE41o-cells using TranzVector (Tranzyme, Inc., Birmingham, AL). Login to comment
50 SPQ Studies of Halide Efflux in HeLa Cells HeLa cells stably expressing W1282X, R1162X, or wild type CFTR were studied with the halide quenched dye 6-methoxy-N-(3-sulfopropyl)- quinolinium (SPQ; Molecular Probes, Inc., Eugene, OR) as previously described (27, 29). Login to comment
63 Briefly, CFBE41o2 cells expressing W1282X or R1162X CFTR were seeded on Costar 0.4-mm permeable supports (5 3 105 cells/filter, 6.5 mm diameter; Bethesda, MD) after coating with fibronectin as previously described (32). Login to comment
72 The CFBE41o2 W1282X and CFBE41o2 R1162X cells were handled in exactly the same fashion during our studies. Login to 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
88 We limited our comparisons to R1162X and W1282X CFTR in readily comparable model systems widely used in CF research. Login to comment
89 These two mutants occur in the distal portion of CFTR (immediately after TMD-2 for R1162X CFTR, and approximately one third through NBD-2 for W1282X CFTR). Login to comment
91 Figure 1 summarizes functional studies in HeLa cells expressing R1162X CFTR and W1282X CFTR. Login to comment
94 In Figure 1A, increasing concentrations of NaBu exposure led to dramatic increases in halide transport in W1282X CFTR-transduced cells. Login to comment
99 W1282X CFTR-expressing cells had significantly increased agonist-stimulated Isc relative to R1162X CFTR-expressing cells at baseline (no NaBu treatment). Login to comment
102 Halide transport in W1282X and R1162X CFTR transduced HeLa cells. Login to comment
103 (A) Fluorescence-based halide efflux (SPQ) activity of W1282X CFTR HeLa cells after treatment with increasing concentrations of NaBu or control (vehicle media) for 24 h. Closed arrowhead represents basal CFTR activity after switch to dequenched buffer, and the open arrowhead signifies fluorescence after the addition of CFTR agonists forskolin (20 mM) and genistein (50 mM). Login to comment
104 * Halide efflux of W1282X compared with R1162X CFTR transduced cells was significantly increased after treatment with NaBu (P , 0.001, 6 SEM). Login to comment
107 with NaBu, further enhancement of agonist-stimulated Isc was demonstrated in W1282X CFTR-transduced cells relative to R1162X CFTR. Login to comment
109 Together, the studies in both HeLa and CFBE41o2 cell lines demonstrate similar results: NaBu treatment has unique effects on halide transport only in W1282X CFTR-expressing cells. Login to comment
111 NaBu treatment results in increased Isc in W1282X expressing cells. Login to comment
114 (A) Representative tracings in CFBE41o2 cells expressing W1282X CFTR (left) and R1162X CFTR (right) after treatment with NaBu (500 mM) or control conditions for 24 h. Login to comment
115 Experiments show increased Isc in W1282X CFTR-transduced CFBE41o2 cells pretreated with NaBu after forskolin (forsk, 20 mM) and genistein (gen, 50 mM) stimulation. Login to comment
118 (B) Summary data of CFBE41o-cells expressing W1282X (solid bars) or R1162X CFTR (open bars) exposed to various concentrations of NaBu versus control (vehicle media) for 24 h, then studied in modified Ussing chambers under voltage clamp conditions. Login to comment
119 Short-circuit currents were greater in W1282X compared with R1162X CFTR-transduced cells under control and NaBu-treated conditions. Login to comment
121 *P , 0.05 compared with W1282X control, ‡P , 0.05 compared with R1162X at same condition, ‡‡P , 0.01 compared with R1162X at same condition, (6 SEM). Login to comment
122 Enhancement of R1162X and W1282X CFTR Expression by Sodium Butyrate NaBu has been shown to deacetylate the CMV promoter and enhance expression of transgenes in other model systems (34-36). Login to comment
123 To better understand the mechanism of the activating effects of NaBu in HeLa and CFBE41o2 cells expressing W1282X CFTR, we measured mutant CFTR expression at the mRNA and protein level. Login to comment
124 Figure 3 demonstrates that under basal conditions, W1282X and R1162X CFTR-transduced cells exhibit slightly greater CFTR mRNA levels relative to endogenous CFTR in Calu-3 cells (Figure 3A); however, protein expression across the three cell lines are qualitatively similar, probably due to differences in processing efficiency between the native and transduced genes (32). Login to comment
125 Figure 4 summarizes real-time PCR studies comparing R1162X and W1282X CFTR expression in HeLa and CFBE41o2 cells. Login to comment
126 Figure 4A shows dose-response studies with NaBu in transduced HeLa cells, and Figure 4B shows similar studies in CFBE41o2 cells expressing R1162X or W1282X CFTR. Login to comment
127 NaBu led to dose-dependent increases in both R1162X and W1282X CFTR mRNA levels in HeLa cells, with similar enhancing effects seen in CFBE41o2 cells. Login to comment
132 Relative expression of R1162X and W1282X CFTR in transduced HeLa cells is similar to the Calu-3 type. Login to comment
133 (A) R1162X and W1282X CFTR transduced HeLa cells grown to confluence and then assayed by RT-PCR after RNA isolation showed mRNA expression within 3-fold compared with endogenously expressing Calu-3 cells. Login to comment
138 Relative transcript levels of R1162X and W1282X CFTR in transduced HeLa (A) and CFBE41o2 (B) cells. Login to comment
141 W1282X CFTR mRNA levels under control conditions were 72% of R1162X CFTR expression. Login to comment
146 R1162X CFTR mRNA levels under control conditions were 83% of W1282X expression levels. Login to comment
149 Together, the results from Figures 1-6 provide evidence that NaBu enhanced the expression of truncated CFTR (without significantly increasing the level of full-length protein) in both W1282X and R1162X CFTR-expressing cells; moreover only W1282X CFTR-expressing cells demonstrated increased agonist stimulated ion transport after NaBu treatment. Login to comment
150 Synergistic Effects of Stop Codon Suppression and Enhanced Expression in R1162X and W1282X CFTR-Expressing Cells We next examined the effects of NaBu combined with G418 (an aminoglycoside and previously described potent suppressor of premature stop mutations) on full-length CFTR production in HeLa and CFBE41o2 cells transduced with either of the two CFTR premature stop codons of interest. Login to comment
152 Treatment with the combination of NaBu and G418 for 16 hours led to increased full-length core glycosylated (band B) and fully glycosylated (band C) CFTR production in HeLa (Figure 6A) and CFBE41o2 (Figure 6B) cells transduced with R1162X or W1282X CFTR. Login to comment
156 To confirm the presence of truncated W1282X CFTR at the cell surface compared with R1162X-expressing cells, immunofluorescence studies were performed. Login to comment
158 A high proportion of cells positive for surface-localized truncated W1282X CFTR was detectable after treatment with NaBu alone (55% of cells, P , 0.001 versus control, probed with anti-NBD-1 antibody). Login to comment
160 In contrast, R1162X CFTR-transduced cells demonstrated overall lower surface expression of both full-length and truncated protein (controlled for treatment condition), reflecting less efficient surface localization of truncated protein relative to W1282X CFTR (P , 0.001 by logistic regression analysis). Login to comment
162 Full-length CFTR expression after NaBu, G418, and combination treatment in W1282X or R1162X CFTR-transduced HeLa (A) and CFBE41o2 (B) cells. Login to comment
163 (A) Immunoprecipitation with C-terminus-specific antibody (24-1) followed by in vitro phosphorylation of W1282X and R1162X CFTR-transduced HeLa cells is shown. Login to comment
169 Detection of truncated R1162X and W1282X CFTR in HeLa (A) and CFBE41o2 (B) cells. Login to comment
170 (A) HeLa Cells were selectively probed for truncated CFTR using an antibody directed against NBD-1 in W1282X and R1162X CFTR-transduced cells. Login to comment
174 NaBu treatment significantly enhanced W1282X (z 140 kD, left panel) or R1162X (z 110 kD, right panel) CFTR protein expression. Login to comment
177 The synergistic effects of G418 and NaBu on W1282X and R1162X CFTR activity were also measured by SPQ (Figure 8). Login to comment
178 The top portion shows examples of experiments in W1282X CFTR-expressing cells, and the bottom portion summarizes results from multiple paired studies comparing R1162X and W1282X CFTR-expressing cells. Login to comment
180 G418 treatment had positive effects on halide transport in both R1162X and W1282X CFTR-expressing cells (reflecting readthrough of PTCs), and NaBu treatment had significantly stronger effects on agonist stimulated halide transport in the W1282X CFTR-expressing cells relative to cells transduced with R1162X CFTR. Login to comment
181 Combination treatment with G418 and NaBu dramatically increased halide efflux in cells expressing W1282X CFTR, with smaller synergistic effects seen in the R1162X CFTR-transduced cells. Login to comment
182 Together, the results from Figures 6-8 provide evidence for synergistic effects on CFTR activity and surface localization produced by enhanced expression (NaBu treatment) coupled with stop codon suppression (G418 treatment) in W1282X and R1162X CFTR-transduced cells, and further emphasize apparent differences in the relative susceptibility of these CFTR mutations to functional rescue. Login to comment
184 We identified distinct differences in the responses of R1162X and W1282X CFTR to treatment designed to enhance transgene expression (NaBu). Login to comment
186 However immunohistochemical detection using anti-NBD-1 antibody revealed significantly greater cell surface localization of W1282X CFTR Figure 7. Login to comment
187 NaBu increases surface-localized truncated CFTR expression in W1282X CFTR-expressing cells as detected by immunofluorescence. Login to comment
188 (A) Immunofluorescence staining of W1282X (left) and R1162X CFTR (right)-expressing HeLa cells after 24 h exposure to NaBu (2.5mM), NaBu 1 G418 (500 mg/ml), or untreated (vehicle control) conditions. Login to comment
190 W1282X CFTR-transduced cells demonstrate significantly greater number of cells with surface localized truncated CFTR after 24 h treatment with NaBu compared with R1162X cells (55.2% versus 10.4% of cells with surface staining, respectively; P , 0.001). Login to comment
191 A significant number of cells with surface localized full-length CFTR is detected in both cell lines after the addition of G418, although a greater percentage was seen in W1282X-transduced cells (29.1% of W1282X cells exhibit surface staining after G418 1 NaBu versus 0.5% under control conditions, P , 0.001; 5.4% and 0.06% surface staining was seen in R1162X cells, respectively, P , 0.01). Login to comment
195 *P , 0.05 versus control condition for each cell type; †P , 0.001 comparing W1282X versus R1162X cells at exact same treatment condition. Login to comment
197 Furthermore, W1282X (but not R1162X) CFTR activity was partially restored in both cell lines after treatment with NaBu alone (Figures 1, 2, and 8). Login to comment
199 Together, our results suggest that increasing the expression of W1282X CFTR was sufficient to restore partial CFTR activity, and this effect was likely due to retained function of truncated W1282X CFTR that localizes to the plasma membrane. Login to comment
203 Because mRNA levels were similar after NaBu treatment for both mutations, enhanced efficiency of cellular processing and localization of W1282X CFTR relative to R1162X likely account for the observed differences. Login to comment
207 As R1162X CFTR is truncated immediately after the TMD-2 domain and W1282X CFTR is truncated within the NBD-2 domain, our results suggest that critical sequences between R1162X and W1282X may be responsible for functional differences between the mutations. Login to comment
209 Our findings are also in agreement with single channel studies recently reported by Wang and colleagues, in which low-level activity was retained in W1282X CFTR expressing HeLa cells without treatments to enhance protein expression (43). Login to comment
210 Moreover, surface localization of W1282X CFTR in HeLa cells was confirmed using a biotinylation assay. Login to comment
213 CFTR-mediated halide transport in W1282X and R1162X CFTR-transduced HeLa cells studied by SPQ. Login to comment
214 Top: representative experiments in W1282X CFTR-transduced cells at various conditions. Login to comment
215 Bottom: change in halide transport after stimulation with forskolin (20 mM) and genistein (50 mM) in W1282X or R1162X CFTR-transduced HeLa cells. Login to comment
217 Results demonstrate CFTR activity in W1282X CFTR-transduced cells after treatment with NaBu that is not present in R1162X CFTR-transduced cells. Login to comment
218 *P , 0.001 for treated conditions compared with untreated controls, †P , 0.001 for W1282X versus R1162X under identical conditions, n 5 30 cells/condition, 6 SEM. Login to comment
224 The similar findings between the two cell types studied here (airway and nonairway) suggest that fundamental differences in cellular processing of R1162X and W1282X CFTR are retained across both model systems. Login to comment
225 Studies examining PKA-dependent and independent regulation of the two mutations will be needed to determine if cellular differences are also seen in regards to cAMP activation of truncated W1282X CFTR (as is seen with DF508 CFTR expressed in these two cell types) (32). Login to comment
230 In the context of adequate expression, W1282X CFTR function could be demonstrated at the cell membrane of both polarizing and nonpolarizing cell types. Login to comment
231 While our studies demonstrate distinct differences in truncated protein activity between R1162X and W1282X CFTR, they do not rule out the possibility that NaBu treatment leads to enhanced levels of background translational readthrough of W1282X CFTR relative to R1162X CFTR. Login to comment
232 In fact, this is suggested by a higher proportion of W1282X cells with detectable full-length CFTR at the cell surface of NaBu-treated HeLa cells (13.6 versus 3.7% of cells, respectively; Figure 7). Login to comment
233 Background readthrough is not likely to account for all the findings presented here, as combination treatment with NaBu and G418 led to similar levels of total (surface and nonsurface) full-length CFTR in cell lines expressing either R1162X or W1282X CFTR (Figures 6A and 6B), but NaBu alone led to much larger increases in truncated W1282X CFTR activity (Figures 1 and 2). Login to comment
234 Further studies directly comparing protein expression and function from CFTR cDNAs containing premature stop codons with and without distal CFTR open reading frames will be necessary to definitively determine the contribution of low-level background readthrough to the activity of W1282X CFTR. Login to comment
237 To date, the strongest suppressive and corrective effects have been seen in studies completed within the Israeli population (16, 17, 20), which is enriched with patients possessing a limited repertoire of premature stop mutations (particularly W1282X CFTR). Login to comment
238 At least three interpretations may be responsible for the treatment effects seen in these studies relative to others in patients with CF, including (1) enhancement of truncated but functionally active W1282X CFTR expression through inhibition of mRNA degradation by aminoglycoside-induced suppression of nonsense-mediated decay; (2) inherent, CFTR-independent population differences influencing CFTR mRNA stability among different study populations; or (3) differences in the relative suppressibility of Israeli subjects (particularly those subjects harboring W1282X CFTR). Login to comment
239 For example, although both W1282X and R1162X CFTR are caused by an abnormal UGA stop codon, W1282X is flanked by an adenine (as opposed to guanine in R1162X), a factor that enhances susceptibility to translational readthrough (8). Login to comment
240 Regardless of the contributor(s), the differences between R1162X and W1282X CFTR activity after enhancement of expression should be considered when interpreting the results of related clinical trials designed to restore CFTR function through suppression of premature stop mutations. Login to comment
241 In summary, the results reported here demonstrate that W1282X CFTR function can be partially restored after enhancement of transcription relative to R1162X CFTR. Login to comment
243 The results suggest W1282X may be more susceptible to corrective therapies than other mutations, and should be considered in the interpretation of clinical trials examining agents to suppress premature stop codons as a treatment strategy for genetic diseases. 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

250 Association of a nonsense mutation (W1282X), the most common mutation in the Ashkenazi Jewish cystic fibrosis patients in Israel, with presentation of severe disease. 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: 17586695 [PubMed] Poschet JF et al: "Pharmacological modulation of cGMP levels by phosphodiesterase 5 inhibitors as a therapeutic strategy for treatment of respiratory pathology in cystic fibrosis."

No. Sentence Comment

39 IB3-1 is a bronchial epithelial cell line derived from a CF patient with a DF508/W1282X CFTR mutant genotype (55). 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: 17625509 [PubMed] Linde L et al: "The efficiency of nonsense-mediated mRNA decay is an inherent character and varies among different cells."

No. Sentence Comment

2 This variability was found for CF transmembrane conductance regulator (CFTR) transcripts carrying the W1282X PTC, as well as for several NMD physiologic substrates. Login to comment
4 To investigate this possibility, we analyzed the NMD efficiency of both a CFTR constructs carrying the W1282X PTC and b-globin constructs carrying the NS39 PTC, in HeLa and MCF7 cells. Login to comment
13 Tel: þ 49 972 2 6585689; Fax: þ 49 972 2 6584810; E-mail: kerem@cc.huji.ac.il European Journal of Human Genetics (2007) 15, 1156-1162 & 2007 Nature Publishing Group All rights reserved 1018-4813/07 $30.00 www.nature.com/ejhg In a recent study, we have shown that NMD efficiency considerably varies among three cell lines derived from nasal epithelium of cystic fibrosis (CF) patients.7 We found variability in NMD efficiency for CF transmembrane conductance regulator (CFTR) transcripts carrying a disease-causing PTC, the W1282X mutation. Login to comment
21 Variability in NMD efficiency was found for two different transcripts carrying disease-causing PTCs: CFTR constructs carrying the W1282X nonsense mutation and b-globin transcripts carrying the NS39 nonsense mutation. Login to comment
30 The CFTR mutant construct was generated using the same cloning approach on DNA extracted from an individual homozygous for the W1282X mutation. Login to comment
31 Both constructs were sequenced and asides from the W1282X mutation no variation was identified in all exons and 199 bp of each intron. Login to comment
41 For quantification of CFTR W1282X transcript levels in HeLa and MCF7 cells, which had been transfected with the CFTR constructs, we performed real-time PCR in the LightCycler (software version 3.5), using a FastStart DNA Master SYBR Green I kit (Roche Diagnostics). Login to comment
43 The level of mRNA transcribed from the WT or W1282X CFTR construct was normalized to the mRNA level of GFP. Login to comment
59 We analyzed the efficiency of NMD for two different transcripts carrying disease-causing PTCs: CFTR constructs carrying the CF-causing PTC W1282X and the b-globin constructs carrying the b-thalassemia-causing PTC NS39. Login to comment
61 In our previous study, we analyzed the efficiency of NMD for endogenous CFTR transcripts carrying the W1282X nonsense mutation, in nasal epithelial cells derived from CF patients. Login to comment
62 As HeLa and MCF7 cells do not express CFTR gene, we transfected them with CFTR constructs carrying the W1282X PTC, which is located 455 nucleotides upstream to the final exon-exon junction, or the normal sequence (WT) (Figure 1a). Login to comment
63 We examined the levels of transfected W1282X transcripts following treatment with CHX, a general inhibitor of translation elongation and as NMD is a translation-dependent mechanism, CHX treatment leads indirectly to inhibition of NMD.13 A GFP plasmid was used as a reference for transfection efficiency in each cell line. Login to comment
64 The levels of mRNA transcribed from the WT or W1282X CFTR construct was normalized to the mRNA level of GFP. Login to comment
67 These results suggest that in MCF7 cells, the NMD of CFTR transcripts carrying the W1282X PTC is inefficient, as the transcript level showed only a marginal increase following the NMD indirect inhibition. Login to comment
70 The levels of the a b Figure 1 Effect of CHX treatment on the level of CFTR mRNA transcribed from constructs carrying the W1282X PTC. Login to comment
71 (a) A scheme of the WT (upper panel) and W1282X (lower panel) constructs, which contained all CFTR exons (marked in the boxes by numbers) and part of the intronic sequences between exons 20-22. Login to comment
74 The level of mRNA transcribed from CFTR constructs carrying either the normal sequence or the W1282X PTC was normalized to the mRNA level of GFP. Login to comment
76 The fold increase in the level of CFTR W1282X transcripts is shown as mean7SEM. Login to comment
81 Following CHX treatment, no increase in the level of NS39 transcripts was observed in MCF7 cells, whereas in HeLa cells a significant increase (4.470.20-fold) was observed (Figure 2b), similar to the variable effect of CHX on the level of CFTR W1282X transcripts in these cell lines. 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

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

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

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

PMID: 17827250 [PubMed] Hybiske K et al: "Effects of cystic fibrosis transmembrane conductance regulator and DeltaF508CFTR on inflammatory response, ER stress, and Ca2+ of airway epithelia."

No. Sentence Comment

27 This has been observed repeatedly for the IB3 (CF, ⌬F508/W1282X) and C38 or S9 (CFTR-corrected; see Refs. 12, 50, and 59) pairs and also for the 9HTEo- /pCep [wild-type (wt) CFTR] vs. 9HTEo- /pCepR (overexpress R domain and do not secrete Cl- ; see Refs. 7, 34, and 59) pairs. Login to comment
24 This has been observed repeatedly for the IB3 (CF, ⌬F508/W1282X) and C38 or S9 (CFTR-corrected; see Refs. 12, 50, and 59) pairs and also for the 9HTEo- /pCep [wild-type (wt) CFTR] vs. 9HTEo- /pCepR (overexpress R domain and do not secrete Cl- ; see Refs. 7, 34, and 59) pairs. 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

145 2 223CϾT R31C 3 355CϾT R75X 386GϾA G85E 4 482GϾA R117H 575TϾC I148T 621 ؉ 1GϾTb 5 711 ؉ 1GϾT 7 1078delT 1132CϾT R334W 1150delA 1172GϾC R347P 8 1341 ϩ 18AϾCc 9 1496CϾA A455E 10 1651-1653del I507del 1653-1655del F508deld 11 1717 - 1GϾA 1756GϾT G542Xe 1784GϾA G551Db 1789CϾT R553Xf 1811GϾC R560T 12 1898 ؉ 1GϾA 13 2184delA 14b 2789 ؉ 5GϾAe 16 3120 ؉ 1GϾA 18 3500 - 2AϾTg 19 3616CϾT R1162X 3659delC Intron 19 3849 ؉ 10kbCϾTe 20 3978GϾA W1282X 21 4041CϾG N1303K 22 4178GϾA G1349Dc a Disease-causing variants recommended for genotyping by the ACMG (4) are in bold. Login to comment
8 The melting patterns of most heterozygotes were unique (37 of 40 pairs within the same amplicon), the exceptions being p.F508del vs p.I507del, p.G551D vs p.R553X, and p.W1282X vs c.4002A>G. Login to comment
17 Several common mutations are specific to ethnic groups, such as p.W1282X among Ashkenazi Jews and c.3120 ϩ 1GϾA among native Africans. Login to comment
162 The exceptions included 3-bp deletions, p.I507del/p.F508del, and 2 single-base variant pairs (p.G551D/p.R553X and p.W1282X/ c.4002AϾG). Login to comment
166 Fig. 5 in the online Data Supplement describes a small amplicon assay to distinguish the disease-causing variant p.W1282X from the benign variant c.4002AϾG. Login to comment
205 The substitutions were 5 bp (p.G551D and p.R553X) and 24 bp (p.W1282X and c.4002AϾG) apart, and the variants within each pair were of the same type (16). Login to comment

PMID: 18043508 [PubMed] Weiner SA et al: "Rectal potential difference and the functional expression of CFTR in the gastrointestinal epithelia in cystic fibrosis mouse models."

No. Sentence Comment

16 In addition, gentamicin, an aminoglycoside antibiotic, has been shown to suppress premature termination codons and restore CFTR function in patients with the W1282X mutation (15). Login to comment

PMID: 18223673 [PubMed] Schmidt A et al: "Prolonged treatment of cells with genistein modulates the expression and function of the cystic fibrosis transmembrane conductance regulator."

No. Sentence Comment

246 In support of this idea, Lim et al. (2004) demonstrated that concentrations of genistein exceeding 5 mM caused a dose-dependent loss of the viability of IB3-1 cells ((F508del/W1282X) bronchial epithelial cells) after 72 h of treatment, while Li et al. (2004) reported similar results with Madin Darby canine kidney epithelial cells using genistein (100 mM). Login to comment

PMID: 18285607 [PubMed] Singh OV et al: "Chemical rescue of deltaF508-CFTR mimics genetic repair in cystic fibrosis bronchial epithelial cells."

No. Sentence Comment

30 EXPERIMENTAL PROCEDURES Cell Culture-IB3-1 cells (CF genotype ⌬F508/W1282X, bronchial epithelial derivation) (16) and S9 (genetically repaired CF, IB3-1 corrected by adeno-associated virus-wtCFTR) (17) were grown in LHC-8 medium (BIOSOURCE, Rockville, MD) as described previously (Ref. 10; see supplemental Material SM.1). 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
46 of patients W1282X/3849 + 10 kb 15 W1282X/5T 15 DF508/5T 7 DF508/D1152H 6 DF508/3849 + 10 kb 5 W1282X/D1152H 5 W1282X/I1234V 2 3849 + 10 kb/405 + 1G- > A 2 R334W/R334W 2 5T/5T 2 D1152H/D1152H 1 D1152H/5T 1 D1152H/3849 + 10 kb 1 DF508/UKN 13 W1282X/UKN 11 5T/UKN 7 D1152H/UKN 3 1717/UNK 1 G85E/UKN 1 Q359K/T360K/UKN 1 S549R/UKN 1 3849 + 10 kb/UKN 1 UKN/UKN 36 CF, cystic fibrosis; CFTR, cystic fibrosis transmembrane regulator. Login to comment
69 Table 3 The clinical characteristics of the PS patients who became PI Age at CF diagnosis Presenting symptom Age at first pancreatitis event Age at transition PS-PI Genetic profile Sweat Clmmol/l 19 years Pulmonary 19 yearsa 22 years W1282X/G85E 66 6 months Affected sibling 3 yearsa 14 years W1282X/I1234V 82 1 month Affected sibling (None) 12 years DF508/G85E 32 28 years Pancreatitis 28 yearsa 34 years D1152H/5T 30 CF, cystic fibrosis; PI, pancreatic insufficient; PS, pancreatic sufficient. Login to comment

PMID: 18304008 [PubMed] Riordan JR et al: "CFTR function and prospects for therapy."

No. Sentence Comment

529 This study focused on a single stop mutation common in the Israeli population (W1282X), and the nasal potential difference measurements, all made at a single center, were statistically quite uniform. Login to comment
533 However, effectiveness even in patients with the W1282X mutation alone would represent a highly significant accomplishment if long-term delivery of an appropriate compound, producing clinical benefit without major side effects, can be achieved. 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: 18360295 [PubMed] Segal I et al: "Cystic fibrosis transmembrane conductance regulator ion channel function testing in recurrent acute pancreatitis."

No. Sentence Comment

13 Mutation analysis revealed W1282X/5T, D1152H/5T, and W1282X/ À in 3 patients with abnormal NPD and 1 W1282X allele was found in 1 patient with normal NPD. Login to comment
71 One patient in the normal PD group was found to be heterozygous for the W1282X mutation, whereas 3 of the 7 patients in the pathologic PD group were found to have mutations in the CFTR gene: 1 patient was compound heterozygous W1282X/5T, 1 patient heterozygous for W1282X, and another patient with compound heterozygous D1152H/5T (Table 3). Login to comment
79 Demographics, Clinical, and Laboratory Data of 33 Patients With Recurrent Acute Pancreatitis Mean age 20 ± 12 years (range: 7-49) Sex 15 females, 18 males Symptoms 27: recurrent pancreatitis 3: recurrent pancreatitis+mild asthma 1: recurrent pancreatitis+ulcerative disease 1: recurrent pancreatitis+infertility 1: recurrent 1: recurrent pancreatitis+polycystic kidneys Mean sweat chloride 41 ± 14 mmol/L (range: 18-64) CFTR mutations 2: W1282X/ À 1: W1282X/5T 1: D1152H/5T TABLE 2. Summary of NPD Measurements Normal PD Abnormal PD Patients no. Login to comment
90 In our study, we found 2 patients heterozygous for CF mutations, and 2 more patients with carriage of mild mutations and 5T allele (W1282X 3/33: 9%; D 1152H 1/33: 3%, 5T 2/33: 6%). Login to comment
92 The reported prevalence of these mutations in the CF Israeli Jewish population is W1282X 46.3%, and D1152H 5.3%.22 We confirm the findings of Bishop et al10 that ion transport studies correlates with the number and severity of CFTR mutations. Login to comment
99 Sex Age (y) CFTR Genotype Sweat Chloride (mmol/L) NPD DClÀ free+iso (mV) Exp (DClÀ free+iso/DAmil) 1 M 40 W1282X/ À 60 1 1.09 2 M 9 W1282X/5T 44 0 1 3 F 15 À / À 43 À 4 0.83 4 F 14 À / À 45 À 9 0.81 5 F 10.5 À / À 27 À 1 0.96 6 F 7 À / À 61 2 1.09 7 M 34 D1152H/5T 30 4 2.72 0 0.7 1.4 2.1 2.8 3.5 ΔΔ FIGURE 2. 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

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

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

No. Sentence Comment

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
37 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: 18508776 [PubMed] Cebotaru L et al: "Cystic fibrosis transmembrane regulator missing the first four transmembrane segments increases wild type and DeltaF508 processing."

No. Sentence Comment

194 IB3-1 are CF bronchial epithelial cells containing two mutant alleles of CFTR, ⌬F508/W1282X. Login to comment
195 There are low levels of ⌬F508 CFTR protein expression but no expression of W1282X protein (25). 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: 18574003 [PubMed] Roque T et al: "Proinflammatory effect of sodium 4-phenylbutyrate in deltaF508-cystic fibrosis transmembrane conductance regulator lung epithelial cells: involvement of extracellular signal-regulated protein kinase 1/2 and c-Jun-NH2-terminal kinase signaling."

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8 Sodium 4-phenylbutyrate (4-PBA) restores chloride conductance by promoting trafficking of mature ⌬F508-CFTR to the cell membrane in the IB3-1 lung epithelial cell line (expressing the heterozygous ⌬F508/ W1282X mutation), the CFBE41o- lung epithelial cell line (expressing the homozygous ⌬F508/⌬F508 mutation), and This work was supported in part by grants from Institut National de la Sante´ et de la Recherche Me´dicale, the French Cystic Fibrosis Foundation Vaincre La Mucoviscidose (France) and Universite´ Pierre et Marie-Curie-Paris 06 (Grant BQR 2007). Login to comment
40 IB3-1 was a bronchial epithelial cell line derived from a CF patient (CFTR genotype ⌬F508/W1282X), and it was purchased from American Type Culture Collection (LGC Promochem SARL, Strasbourg, France). Login to comment
95 Results The effect of 4-PBA was investigated on two cultured CFBE41o- and IB3-1 lung epithelial cell lines (expressing the homozygous ⌬F508/⌬F508 mutation and heterozygous ⌬F508/W1282X, respectively). Login to comment

PMID: 18635816 [PubMed] Bartling TR et al: "Oxidative stress causes IL8 promoter hyperacetylation in cystic fibrosis airway cell models."

No. Sentence Comment

60 IB3 bronchial epithelial cells (DF508/ W1282X) and S9 cells (IB3-1 cells stably transfected with the full-length wild-type CFTR as controls) were a gift from Pamela L. Zeitlin (Johns Hopkins University, Baltimore, MD). 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

96 * Non-⌬F508 gene mutations include G542X, 3905insT, R347P, 711ϩ1GϾT, 3120ϩ1GϾA, W1282X, and 1161delC. 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."

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35 CFTR mutations may Table 1 Methods for CFTR gene mutation detection most frequently used in Europe Methods for the detection of known mutations Mutations detected Advantages Limits and pitfalls Heteroduplex analysis (strictly speaking a scanning method) Mainly F508del and I507del Other microinsertions/deletions (2 bp minimum): 394delTT (Northern Europe), 1677delTA (Black Sea countries), 1609delCA (Spain) Simple and rapid Migration pattern not specific for a given mutation Restriction enzyme analysis (restriction sites can be natural or created by the use of modified primers) Mainly specific individual mutations Possibly a small number of mutations can be combined in one assay Simple and rapid Useful for cascade carrier testing in case of rare mutations Not specific, especially if site abolition (eg, G551D and R553X abolish the same Hinc II site, and W1282X and R1283M the same Mnl I site) Reverse dot blot hybridization Up to 20 mutations per multiplex Appropriate for large series Innogenetics (Inno LiPA)a 36 mutations Good specificity ARMS (amplification refractory mutation system) Up to 20 mutations Appropriate for large series Design of primers is difficult Results are based on the absence of PCR product Tepnel (Elucigene)a 28-30 mutations Good specificity OLA (oligonucleotide ligation assay) Appropriate for large series Abbott Molecular (Cystic Fibrosis Genotyping Assay)a 32 mutations Good specificity Methods for the detection of unknown mutations DGGE (denaturing gradient gel electrophoresis) DGGE, DHPLC, SSCP and Sequencing: High sensitivity (495%) Difficult to set up; difficult automation Can miss isostable mutations in the homozygous state DHPLC (denaturing high performance liquid chromatography) Aiming to detect all mutations of small bp in the coding regions and intronic boundaries High sensitivity (495%) Generally miss homozygous mutations Need sequencing of polymorphism-rich regions SSCP (single strand conformation polymorphism) Simple and rapid to set up Sensitivity 80-85% Sequencing (as a first-line method or confirmation after a scanning technique) Close to 100% sensitivity Quantitative fluorescent multiplex PCR MLPA (multiple ligation-dependent probe amplification) Aiming to detect deletions, insertions, and duplications All coding regions Simple and rapid Sensitive to extraction methods Duplications may be difficult to evidence a Commercially available methods are indicated in italics be missed by scanning techniques, especially when homozygous, and even direct sequencing cannot identify 100% of mutations. Login to 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: 18790990 [PubMed] Manson ME et al: "cAMP-mediated regulation of cholesterol accumulation in cystic fibrosis and Niemann-Pick type C cells."

No. Sentence Comment

61 IB3-1 cells (⌬F508/W1282X) and S9 cells (IB3-1 cell stably transfected with the full-length wild-type CFTR as controls) were developed by Pamela L. Zeitlin (Johns Hopkins University, Baltimore, MD). Login to comment
219 We have shown that Cftr-/- mice exhibit cholesterol processing defects (41), and we have demonstrated that cholesterol processing in IB3 (W1282X/⌬F508) is restored in CFTR-corrected IB3 cells (S9 cells) (40). Login to comment
58 IB3-1 cells (⌬F508/W1282X) and S9 cells (IB3-1 cell stably transfected with the full-length wild-type CFTR as controls) were developed by Pamela L. Zeitlin (Johns Hopkins University, Baltimore, MD). Login to comment
216 We have shown that Cftr-/- mice exhibit cholesterol processing defects (41), and we have demonstrated that cholesterol processing in IB3 (W1282X/⌬F508) is restored in CFTR-corrected IB3 cells (S9 cells) (40). 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: 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: 18987251 [PubMed] Liang L et al: "Spiperone, identified through compound screening, activates calcium-dependent chloride secretion in the airway."

No. Sentence Comment

57 IB3-1 is a CF human bronchial epithelial cell line that is heterozygous with two different CFTR mutations (⌬F508 and W1282X). 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: 19168701 [PubMed] Yu H et al: "Defective acid sphingomyelinase pathway with Pseudomonas aeruginosa infection in cystic fibrosis."

No. Sentence Comment

34 MATERIALS AND METHODS Cell Lines The IB3-1 cell line, the CFTR-defective (DF508/W1282X) immortalized bronchial epithelial cell line from a patient with CF (21), and S9 cell line, a stable IB3-1 subclone transduced with the recombinant AAV-CFTR vector, which expresses a functional Cl-channel (22-24), were used in this study. 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: 19212293 [PubMed] Coman T et al: "[The diagnosis of cystic fibrosis in adults: lessons from a family story]."

No. Sentence Comment

44 L`existence de deux mutations fréquentes de CFTR (génotype W1282X : 3849+10kbC->T) est mise en évidence. Login to comment
77 Une recherche des 33 mutations les plus fréquentes du gène CFTR identifie la mutation W1282X, présente chez son fils, sans autre mutation. Login to comment
78 Un séquençage complet du gène CFTR met en évidence une seconde mutation (D1152H), confirmant le diagnostic de mucoviscidose (génotype W1282X :D1152H). Login to comment
82 Les deux sœurs de Monsieur X étaient asymptomatiques et l`analyse génétique a montré une simple hétérozygotie (génotype W1282X :N). Login to comment
122 Monsieur X Mère de Monsieur X Frère de Monsieur X Âge au diagnostic 39 ans 74 ans 40 ans Âge de début des symptômes respiratoires 46 ans 12 ans Absence de symptômes Manifestations cliniques et atteinte d`organes Déshydratation aiguë Stérilité par agénésie des canaux spermatiques Dilatation des bronches Polypose nasosinusienne Dilatation des bronches Hémoptysie Insuffisance pancréatique exocrine et endocrine Anémie ferriprive Polypose nasosinusienne Colonisation bronchique P. aeruginosa souche muqueuse S. aureus P. aeruginosa souche muqueuse Aucune Chlorure sudoral (mmol/l) 74 25 31 Différence de potentiel nasal avec tests pharmacologiques Tracé caractéristique de mucoviscidose Tracé en partie anormal, évoquant une dysfonction de CFTR Tracé en partie anormal, évoquant une dysfonction de CFTR Génotype CFTR W1282X :3849+10kbC->T W1282X :D1152H* 3849+10kbC->T :D1152H* * Obtenu après séquençage complet du gène CFTR ; DPN : différence de potentiel transépithélial nasal. 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

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

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: 19386787 [PubMed] Bajmoczi M et al: "Cystic fibrosis transmembrane conductance regulator and caveolin-1 regulate epithelial cell internalization of Pseudomonas aeruginosa."

No. Sentence Comment

10 To investigate the molecular bases for the hypersusceptibility of CF patients to P. aeruginosa, we used the IB3-1 cell line with two defective CF transmembrane conductance regulator (CFTR) genes (⌬F508/W1282X) to generate isogenic stable, clonal lung epithelial cells expressing wild-type (WT)- CFTR with an NH2-terminal green fluorescent protein (GFP) tag. Login to comment
12 P. aeruginosa internalization, a component of effective innate immunity, required functional CFTR and caveolin-1, as shown by: 1) direct correlation between GFP-CFTR expression levels and P. aeruginosa internalization; 2) enhanced P. aeruginosa internalization by aminoglycoside-induced read through of the CFTR W1282X allele in IB3-1 cells; 3) decreased P. aeruginosa internalization following siRNA knockdown of GFP-CFTR or caveolin-1; and 4) spatial association of P. aeruginosa with GFP-CFTR and caveolin-1 at the cell surface. Login to comment
34 To explore in detail the properties of CFTR that are essential to mount a rapid innate immune response to P. aeruginosa and to identify the spatial interactions of CFTR, caveolin-1, and P. aeruginosa throughout the course of bacterial attachment and internalization, we have developed a series of nominally isogenic, clonal bronchial epithelial cell lines stably expressing a green fluorescent protein (GFP)-NH2-terminal- labeled WT-CFTR, using as a parental cell line the IB3-1 cells initially obtained from a CF patient with ⌬F508/W1282X cftr alleles. Login to comment
51 IB3-1 cells (⌬F508/W1282X), derived from the bronchial epithelium of a CF patient, have been immortalized by stable infection with adeno-12-SV-40 (78). Login to comment
151 A series of stable transfectants (C clones), each originating from a single transfected cell, was derived by introducing a GFP-CFTR expression vector into the human CF bronchial epithelial cell line IB3-1 (⌬F508/W1282X) and selecting for resistance to the G418 aminoglycoside antibiotic. Login to comment
248 Treatment of IB3-1 cells with an aminoglycoside (G-418 or gentamicin) increases levels of W1282X-CFTR mRNA, with increased production of CFTR due to read through of the W1282X stop mutation and parallel induction of cAMP-dependent Cl-efflux in treated cells (6, 40). Login to comment
254 In IB3-1 cells, the G-418-induced increase in functional CFTR correlated with a statistically significant increase in P. aeruginosa invasion levels (Supplemental Fig. 5B), providing further evidence for the importance of functional CFTR in mediating the efficient uptake of P. aeruginosa in IB3-1 cells. Although G-418 was included in the medium for the routine growth of C clones, the antibiotic was removed 3-4 days before experimentation to minimize unintended expression of endogenous CFTR protein from the native W1282X allele at the time of the experiment. Login to comment
277 DISCUSSION We have examined the mechanism of P. aeruginosa entry into an isogenic set of clonal cell lines derived from the human CF bronchial epithelial cell line IB3-1 (⌬F508/W1282X). Login to comment
8 To investigate the molecular bases for the hypersusceptibility of CF patients to P. aeruginosa, we used the IB3-1 cell line with two defective CF transmembrane conductance regulator (CFTR) genes (⌬F508/W1282X) to generate isogenic stable, clonal lung epithelial cells expressing wild-type (WT)- CFTR with an NH2-terminal green fluorescent protein (GFP) tag. Login to comment
32 To explore in detail the properties of CFTR that are essential to mount a rapid innate immune response to P. aeruginosa and to identify the spatial interactions of CFTR, caveolin-1, and P. aeruginosa throughout the course of bacterial attachment and internalization, we have developed a series of nominally isogenic, clonal bronchial epithelial cell lines stably expressing a green fluorescent protein (GFP)-NH2-terminal- labeled WT-CFTR, using as a parental cell line the IB3-1 cells initially obtained from a CF patient with ⌬F508/W1282X cftr alleles. Login to comment
49 IB3-1 cells (⌬F508/W1282X), derived from the bronchial epithelium of a CF patient, have been immortalized by stable infection with adeno-12-SV-40 (78). Login to comment
149 A series of stable transfectants (C clones), each originating from a single transfected cell, was derived by introducing a GFP-CFTR expression vector into the human CF bronchial epithelial cell line IB3-1 (⌬F508/W1282X) and selecting for resistance to the G418 aminoglycoside antibiotic. Login to comment
246 Treatment of IB3-1 cells with an aminoglycoside (G-418 or gentamicin) increases levels of W1282X-CFTR mRNA, with increased production of CFTR due to read through of the W1282X stop mutation and parallel induction of cAMP-dependent Cl- efflux in treated cells (6, 40). Login to comment
252 In IB3-1 cells, the G-418-induced increase in functional CFTR correlated with a statistically significant increase in P. aeruginosa invasion levels (Supplemental Fig. 5B), providing further evidence for the importance of functional CFTR in mediating the efficient uptake of P. aeruginosa in IB3-1 cells. Although G-418 was included in the medium for the routine growth of C clones, the antibiotic was removed 3-4 days before experimentation to minimize unintended expression of endogenous CFTR protein from the native W1282X allele at the time of the experiment. Login to comment
275 DISCUSSION We have examined the mechanism of P. aeruginosa entry into an isogenic set of clonal cell lines derived from the human CF bronchial epithelial cell line IB3-1 (⌬F508/W1282X). Login to comment

PMID: 19411311 [PubMed] Bartling TR et al: "Loss of CFTR results in reduction of histone deacetylase 2 in airway epithelial cells."

No. Sentence Comment

73 IB3 bronchial epithelial cells (⌬F508/W1282X) and S9 cells (IB3-1 cells stably transfected with the full-length wild-type CFTR as controls) were developed by Dr. Pamela L. Zeitlin (Johns Hopkins University, Baltimore, MD). Login to comment

PMID: 19420138 [PubMed] Barriere H et al: "Revisiting the role of cystic fibrosis transmembrane conductance regulator and counterion permeability in the pH regulation of endocytic organelles."

No. Sentence Comment

45 The IB3 cells have ⌬F508/W1282X genotype (Zeitlin et al., 1991). Login to comment
55 IB3 bronchial epithelia, expressing endogenous ⌬F508 and W1282X CFTR at undetectable levels, were stably transfected with the pCEP4 expression plasmid encoding the wt or G551D CFTR-3HA. Login to comment
201 IB3 and CFBE cells were derived from the bronchial epithelia of CF patients with ⌬F508/W1282X and ⌬F508/⌬F508 CFTR genotypes, respectively (Zeitlin et al., 1991; Cozens et al., 1994) and have no detectable CFTR expression by immunoblotting (Figure 3A). 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: 19447965 [PubMed] Erlich Y et al: "DNA Sudoku--harnessing high-throughput sequencing for multiplexed specimen analysis."

No. Sentence Comment

214 To estimate the value of DNA Sudoku for the analysis of rare variants in individuals, we presented the process with a population in which two prevalent cystic fibrosis (CF) risk alleles were segregating, CFTR mutations DF508 (MIM: 602421.0001) and W1282X (MIM: 602421.0009). Login to comment
225 The case of W1282X was more complex since pools that essentially contain no carriers may report a presence of a carrier because of sequencing error. Login to comment
215 To estimate the value of DNA Sudoku for the analysis of rare variants in individuals, we presented the process with a population in which two prevalent cystic fibrosis (CF) risk alleles were segregating, CFTR mutations DF508 (MIM: 602421.0001) and W1282X (MIM: 602421.0009). Login to comment
226 The case of W1282X was more complex since pools that essentially contain no carriers may report a presence of a carrier because of sequencing error. Login to comment

PMID: 19617352 [PubMed] Caohuy H et al: "Rescue of DeltaF508-CFTR by the SGK1/Nedd4-2 signaling pathway."

No. Sentence Comment

100 IB3-1 cells (bronchial; ⌬F508/W1282X genotype (25)) were maintained at 37 °C in LHC-8 (Invitrogen) medium in a 5% CO2 environment. Login to comment

PMID: 19617399 [PubMed] Myerburg MM et al: "AMPK agonists ameliorate sodium and fluid transport and inflammation in cystic fibrosis airway epithelial cells."

No. Sentence Comment

48 CF HBE cells were obtained from 13 patients with CF and the following CFTR mutations: DF508, W1282X, 1717 G-.A, 278915 G-.A, N1303K, and four unknowns. Login to comment

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

No. Sentence Comment

52 Materials and Methods Cell lines and cultures Human CF bronchial epithelial cell line IB3-1, carrying F508del/W1282X CFTR mutation, isogenic stably rescued C38, normal bronchial epithelial 16HBE, or lung carcinoma A549 cell lines (LGC Standards) were cultured as recommended by American Type Culture Collection. Login to 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
135 Results PIASy-mediated TG2 SUMOylation increases TG2 protein levels in CF airway epithelial cells To investigate whether posttranslational modifications could result in the persistence of high levels of TG2 protein, we first analyzed IB3-1 CF epithelial cell lines carrying F508-del/W1282X CFTR mutations and the isogenic stably rescued C38 cells. Login to comment
53 Materials and Methods Cell lines and cultures Human CF bronchial epithelial cell line IB3-1, carrying F508del/W1282X CFTR mutation, isogenic stably rescued C38, normal bronchial epithelial 16HBE, or lung carcinoma A549 cell lines (LGC Standards) were cultured as recommended by American Type Culture Collection. 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
136 Results PIASy-mediated TG2 SUMOylation increases TG2 protein levels in CF airway epithelial cells To investigate whether posttranslational modifications could result in the persistence of high levels of TG2 protein, we first analyzed IB3-1 CF epithelial cell lines carrying F508-del/W1282X CFTR mutations and the isogenic stably rescued C38 cells. 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: 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: 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: 19812525 [PubMed] de Cid R et al: "Independent contribution of common CFTR variants to chronic pancreatitis."

No. Sentence Comment

38 Scanning Methodology Applied in CFTR Gene Analysis Amplicon Name Fragment Size, bp Control Set (n = 93) Patient Set 1 (n = 68) Patient Set 2 (n = 68) Control Sequence Exon 1 192 SSCP/HD SSCP/HD dHPLC 125G9C Exon 2 334 SSCP/HD SSCP/HD dHPLC 296+3insT Exon 3 309 DGGE DGGE dHPLC G85V Exon 4 436 SSCP/HD SSCP/HD dHPLC R117H Exon 5 466 DGGE DGGE dHPLC R170H Exon 6a 345 SSCP/HD SSCP/HD dHPLC L206W Exon 6b 331 SSCP/HD SSCP/HD SSCP/HD TTGA 6/7 Exon 7 410 SSCP/HD SSCP/HD dHPLC R334W Exon 8 328 DGGE DGGE dHPLC 1341+28C9T Exon 9 375 DGGE DGGE DGGE 7T/9T Exon 10 493 SSCP/HD SSCP/HD SSCP/HD F508del; 1540A/A Exon 11 322 DGGE DGGE dHPLC S549R Exon 12 426 DGGE DGGE dHPLC G576A Exon 13a 532 SSCP/HD SSCP/HD dHPLC R668C Exon 13b 498 SSCP/HD SSCP/HD dHPLC I807M Exon 14a 284 DGGE DGGE DGGE 2694T9G Exon 14b 211 DGGE DGGE dHPLC 2789+5G9A Exon 15 487 DGGE DGGE dHPLC D924N Exon 16 294 SSCP/HD SSCP/HD dHPLC 3041-71G9C Exon 17a 294 SSCP/HD SSCP/HD dHPLC L997F Exon 17b 463 DGGE DGGE dHPLC 3272-26A9G Exon 18 451 DGGE DGGE dHPLC N1148K Exon 19 588 SSCP/HD SSCP/HD SSCP/HD 3601-65C9A Exon 20 471 DGGE DGGE dHPLC W1282X Exon 21 477 DGGE DGGE DGGE 4029G9A Exon 22 339 SSCP/HD SSCP/HD dHPLC Q1352H Exon 23 249 DGGE DGGE dHPLC 4374+13A9G Exon 24 362 SSCP/HD SSCP/HD SSCP/HD 4521G9A Control set, general population series analyzed; patient set 1, previous patient series reported in 2004; and patient set 2, new patient series analyzed in this study. Login to comment

PMID: 19833837 [PubMed] Oca F et al: "Amniotic fluid digestive enzyme analysis is useful for identifying CFTR gene mutations of unclear significance."

No. Sentence Comment

89 CFTR mutation Cases, n Outcome/follow-up CF/CF mutation (n ϭ 38) F508del/F508del 21 TOPa (n ϭ 20); birth, severe CF (n ϭ 1) F508del/unidentified severe mutationb 3 TOP (n ϭ 3) F508del/G551D 2 TOP (n ϭ 2) F508del/4005ϩ1GϾA 1 TOP F508del/2711delT 1 Birth, severe CF F508del/297-3CϾT 1 TOP F508del/3120ϩ1GϾA 1 TOP F508del/405ϩ1GϾA 1 TOP F508del/711ϩ1GϾT 1 TOP F508del/Q1042X 1 TOP F508del/dele22-23 1 TOP F508del/2789ϩ5GϾA 1 Birth, severe CF dele19/dele19c 1 Birth, severe CF W1282X/dele2-6b 1 TOP 1078delT/394delTT 1 TOP CF/unknown variant (n ϭ 4) F508del/G622D 1 Birth, no clinical sign of CF F508del/N1224K 1 Birth, no clinical sign of CF F508del/L73F 1 Birth, no clinical sign of CF 3849ϩ10kbCϾT/G1127E 1 Birth, no clinical sign of CF CF/CFTR-related disorder (n ϭ 1) F508del/S1235R 1 Birth, no clinical sign of CF (del22q11 ϩ imperforate anus)d a TOP, termination of pregnancy. 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: 19880661 [PubMed] Ierano T et al: "The lipid A of Burkholderia multivorans C1576 smooth-type lipopolysaccharide and its pro-inflammatory activity in a cystic fibrosis airways model."

No. Sentence Comment

4 The structure of B. multivorans lipid A was attained by chemical, mass spectrometry and nuclear magnetic resonance analyses whereas its biological activity was assessed on the intestinal epithelial cell line CACO-2 cells, on the airway epithelial IB3-1 cells, carrying the ÁF508/W1282X CFTR mutation and on an ex vivo model of culture explants of nasal polyps. Login to comment
15 The structure of B. multivorans lipid A was attained by chemical, mass spectrometry (MS) and nuclear magnetic resonance (NMR) analyses whereas its biological activity was assessed on the intestinal epithelial cell line CACO-2 cells, on the IB3-1 cells, carrying the ÁF508/W1282X CFTR mutation and on an ex vivo model of culture explants of nasal polyps. Login to comment
43 Patients and ex vivo cultures of nasal polyp mucosal biopsies Five consecutive cystic fibrosis patients carrying the common CFTR mutations (F508del/F508del, F508del/W1282X) with idiopathic polyposis underwent surgical treatment. Login to comment
47 Cell culture Human cystic fibrosis bronchial epithelial cell line IB3-1, carrying the F508del/W1282X CFTR mutation, or intestinal CACO-2 cell line (LGC Promochem, Milan, Italy) were cultured as recommended by the American Type Culture Collection (ATCC). Login to comment
130 Effects of B. multivorans lipid A on cystic fibrosis airways To investigate whether B. multivorans lipid A was effective in triggering an inflammatory response in cystic fibrosis airways, we used an epithelial cell line carrying a common ÁF508/W1282X CFTR mutation. Login to comment
129 Effects of B. multivorans lipid A on cystic fibrosis airways To investigate whether B. multivorans lipid A was effective in triggering an inflammatory response in cystic fibrosis airways, we used an epithelial cell line carrying a common ÁF508/W1282X CFTR mutation. Login to comment

PMID: 19885835 [PubMed] McWilliams RR et al: "Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations and risk for pancreatic adenocarcinoma."

No. Sentence Comment

55 Interestingly, 10% of carriers among cases carried W1282X compared with 1% of controls. Login to comment
56 This is a mutation overrepresented in the Ashkenazi Jewish population.19 However, of the 5 cases with W1282X mutations detected, only 2 reported Jewish heritage, and neither responded whether they were Ashkenazi. Login to comment

PMID: 19890354 [PubMed] Mueller C et al: "In vitro and in vivo functional characterization of gutless recombinant SV40-derived CFTR vectors."

No. Sentence Comment

47 CFTR-mutant IB3-1 cells (genotype DF508/ W1282X) were infected with rSV40-CFTR at an MOI of 100. 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
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

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

No. Sentence Comment

405 Table 1 Classification of CFTR mutations. Class Mutation example Cellular/molecular phenotype I W1282X Absent CFTR production due to nonsense mutations, frameshift mutations, or abnormal mRNA splicing II ΔF508 Improper intracellular processing of CFTR with less than normal amounts of CFTR protein at the apical plasma membrane III G551D Defective regulation of CFTR channels at the apical plasma membrane IV R117H Defective permeation of anions through CFTR channels at the apical plasma membrane V 3849+10KbCNT Reduced synthesis of normal CFTR VI Q1412X Altered apical membrane residence time of CFTR channels with truncated c-termini 4. 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

46 cHomogeneity test between the two previous PR and SC results and RS35: mutations p.N1303 K, p. R1162X, p.W1282X and p.R553X and the mutations p.G85E, c.2183AA4G and 'other` were grouped for the test. 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
45 bHomogeneity test between the PR and SC19 and PR and SC11: mutations p.G85E and p.R334W, and the mutations c.2183AA4G, p.W1282X, p.R553X and p.G551D were grouped for the test. 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
59 aMutations p.R1162X, c.1717-1G4A, p.W1282X, p.R553X and 'others` were grouped for the test. Login to comment
60 bMutations p.N1303 K, c.2183AA4G, p.R1162X, c.1717-1G4A, p.W1282X, p.R553X and 'others` were grouped for the test. 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: 20037649 [PubMed] Cigana C et al: "Pseudomonas aeruginosa exploits lipid A and muropeptides modification as a strategy to lower innate immunity during cystic fibrosis lung infection."

No. Sentence Comment

215 Cell Cultures of CF Origin IB3-1 cells, an adeno-associated virus-transformed human bronchial epithelial cell line derived from a CF patient (DF508/ W1282X) and C38 cells, the rescued cell line which expresses a plasmid encoding a copy of functional CFTR, have been obtained from LGC Promochem [50,51]. Login to comment

PMID: 20044437 [PubMed] Hampton TH et al: "A novel approach to analyze gene expression data demonstrates that the DeltaF508 mutation in CFTR downregulates the antigen presentation pathway."

No. Sentence Comment

33 The lack of similar findings among these studies may be due to experimental differences, including the type of tissue examined (i.e., nasal brushings, stable clones of airway epithelial cells, airway epithelial cells in primary culture, and stable bronchial epithelial cell lines), the genotype of the cells used (i.e., ⌬F508/⌬F508 vs. ⌬F508/W1282X), and because no two studies used the same statistical approach to identify differentially expressed genes. Login to comment
49 Virella-Lowell et al. (44) used immortalized bronchial epithelial cells expressing the ⌬F508/ W1282X mutation (IB3-1 cells isolated from a single individual) and IB3-1 cells rescued with wild-type (wt)-CFTR (S9). Login to comment
66 Summary of the experimental designs used by the original authors CF Genotype Tissue N Affymetrix Platform Reference ⌬F508/W1282X Isogenic bronchial cells (IB3-1 and S9) 1/1 U95Av2 Virella-Lowell et al. (44) ⌬F508/⌬F508 Tracheal and bronchial cells in primary culture 10/10 HGU133A Zabner et al. (50) ⌬F508/⌬F508 Nasal brushings 12/11* HGU-133A,B Wright et al. (47) ⌬F508/⌬F508 Fetal tracheal cells (CFT-2 and NT-1) 1/1 HGU-133Plus2 Verhaeghe et al. (43) Most studies compared nonisogenic samples from cystic fibrosis (CF) and non-CF patients bearing a homozygous ⌬F508 mutation. Login to comment

PMID: 20051483 [PubMed] Kelly M et al: "Cystic fibrosis transmembrane regulator inhibitors CFTR(inh)-172 and GlyH-101 target mitochondrial functions, independently of chloride channel inhibition."

No. Sentence Comment

3 In the present study, we investigated the effects of the two compounds on reactive oxygen species (ROS) production and mitochondrial membrane potential in several cell lines: the CFTR-deficient human lung epithelial IB3-1 (expressing the heterozygous F508del/ W1282X mutation), the isogenic CFTR-corrected C38, and HeLa and A549 as non-CFTR-expressing controls. Login to comment
49 The IB3-1 human CF bronchial epithelial cell line (mutations F508del/ W1282X) and the stably rescued cell line C38 expressing CFTR were grown on fibronectin-coated culture flasks in Laboratory of Human Carcinogenesis basal medium 8 supplemented with 1% heat-inactivated fetal calf serum (FCS). Login to comment

PMID: 20059346 [PubMed] Whitcomb DC et al: "Genetic aspects of pancreatitis."

No. Sentence Comment

154 Other recent case reports and small studies have associated pancreatitis with the following CFTR mutations: D1152H/D1152H (54), W1282X/5T, D1152H/5T, W1282X/- (55), and in Hispanics, S531P/S531P (56). Login to comment
155 Other recent case reports and small studies have associated pancreatitis with the following CFTR mutations: D1152H/D1152H (54), W1282X/5T, D1152H/5T, W1282X/- (55), and in Hispanics, S531P/S531P (56). 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: 20147297 [PubMed] Henderson MJ et al: "Ubiquitin C-terminal hydrolase-L1 protects cystic fibrosis transmembrane conductance regulator from early stages of proteasomal degradation."

No. Sentence Comment

42 EXPERIMENTAL PROCEDURES Cell Lines and Culture-The CF bronchial epithelial cell line IB3-1 (⌬F508/W1282X; low level expression of ⌬F508-CFTR and no W1282X protein) (35), a CF tracheal epithelial cell line CFTE (⌬F508-homozygous) (36), and a CF line with wild type phenotype S9 (IB3-1 corrected by AAV-CFTR) (37) were maintained in LHC-8 medium with 10% fetal bovine serum, 100 units/ml penicillin, 100 ␮g/ml streptomycin, and 0.25 ␮g/ml amphotericin B at 37 °C in the presence of 5% CO2. Login to comment
86 Whole cell protein lysates (30 ␮g) from IB3-1 (⌬F508/W1282X), CFTE (⌬F508/⌬F508), and S9 (⌬F508/W1282X ϩ AAV-WT CFTR) were resolved by SDS-PAGE and immunoblotted with antibodies to UCH-L1 (upper panel), UCH-L3 (middle panel), and actin (lower panel). Login to comment
110 To validate these earlier observations, we performed Western blot analysis on cell lysates from IB3-1 (⌬F508/W1282X) and S9 (CF corrected - ⌬F508/W1282X ϩ AAV-WT-CFTR) cells and a second CF cell line homozygous for ⌬F508 (CFTE). 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

38 IB3-1 cells are human bronchial epithelial cells derived from a compound heterozygote individual with cystic fibrosis (∆F508/W1282X) expressing only ∆F508 CFTR protein, owing to the instability of the W1282X mutation15. Login to 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: 20190016 [PubMed] Faa' V et al: "A synonymous mutation in the CFTR gene causes aberrant splicing in an italian patient affected by a mild form of cystic fibrosis."

No. Sentence Comment

25 As the patient`s parents were not available, to define the phase of the W1282X and 2811 GϾT mutations, extra-long PCR was performed in patient`s cDNA using GeneAmp XL PCR kit (Applera), according to the manufacturer`s instructions. Login to comment
28 Results After an extensive second level molecular screening (ie, direct sequencing for searching of point mutations and multiplex ligation-dependent probe amplification for detection of large rearrangements) was performed at the DNA level on 441 unrelated Italian CF patients, we selected one patient in which we detected the W1282X mutation and the synonymous mutation 2811 GϾT. Login to comment
37 As patient`s parents were not available, we performed, in patient`s cDNA, extra-long PCR spanning exons 14b-21 in order to define the phase of the 2811GϾT and W1282X mutations. Login to comment
39 Sequence analysis showed the presence of the W1282X mutation in the 1124-bp fragments. Login to comment
41 These results indicate that the 2811GϾT and W1282X mutations are in trans. 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

65 Half of Ashkenazi Jewish carriers of cystic fibrosis have the W1282X mutation (rarely found in non-Jewish carriers), whereas less than one-third have the [⌬F508] mutation. Login to 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: 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

40 Screening for frequent mutations in another laboratory identified W1282X in the father and the fetus. Login to 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
50 Table 2 Phenotype and genotype data in fetuses carrying at least one large CFTR deletion Ultrasound findings Case Year of the study Gestational age (weeks) HB LD GB Ascites Other Amniotic fluid digestive enzymes Outcome Allele 1a Allele 2 (short name) Geographic origin for the deletion 1 1998 20 + À À À À Normal Birth, CF dele19 dele19 Turkey 2 2004 20 + + NV À À Abnormally low TOP W1282X dele2_6b Denmark 3 2005 30 + À Sludge + À Abnormally high TOP F508del dele22_23 France 4 2008 25 + + NV À À NP Birth, CF 2347delG dele14b_15 Brittany/Germany 5 2009 32 À À À + Polyhydramnios NP Birth, CF F508del dele6a_6b Portugal GB: gallbladder; HB: hyperechogenic bowel; LD: loop dilatation; NP: not performed; NV: not visualized; TOP: termination of pregnancy. Login to comment
72 Table 3 Genotype data of the deletions found in CF fetuses Case Allele 1a Allele 2 a Short name of the deletion Motif sequence at the breakpoints 1 3601-2880_3849+2150del5279 bpb (c.3469-2880_3717+2150del5279 bp) 3601-2880_3849+2150del5279 bpb (c.3469-2880_3717+2150del5279bp) dele19 AACT (direct) 2 W1282X 185+2909_1002-1620del55429ins17bpc (c.53+2909_870-1620del55429ins17 bp) dele2_6b CAGCTCTAGTT (direct) 3 F508del IVS21-78_IVS23+577del1532 bp (c.3964-78_4242+577del1532 bp) dele22_23 ACT (direct) 4 2347delG 2751+1355_3040+243del7613bp (c.2619+1355_2908+243del7613 bp) dele14b_15 GTGGG-CTG (5') and GTGGG-CTG (3') (direct) 5 F508del 746_1002-1547del3273bp (c.614_870-1547del3273 bp) dele6a_6b TCCTTTG (inverted) aMutation names were given according to the international consortium mutation database (www.genet.sickkids.on.ca/cftr). 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: 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

154 BASELINE PATIENT CHARACTERISTICS Characteristic N 5 30 Age, median, yr (range) 12 (6 to 18) Sex, n Male 16 Female 14 BMI, median % predicted*(range) 35 (,1 to 97) Sweat test chloride concentration, median, mEq/L† (range) 104 (84 to 140) TEPD Total chloride transport, median, mV‡ (range) 20.3 (24.6 to 114.6) Pulmonary function, mean % predictedx FEV1 (range) 90 (40 to 133) FVC (range) 99 (52 to 131) Pathologic bacterial/fungal colonization, n 30 Staphylococcus aureus 26 Pseudomonas aeruginosa 9 Hemophilus influenzae 3 Alcaligenes xylosoxidans 1 Stenotrophomonas maltophilia 1 Pancreatic insufficiency, n 30 Exocrine 30 Endocrine 2 Liver enzyme abnormalities, n 15 Alkaline phosphatase 7 Lactate dehydrogenase 6 g-Glutamyltransferase 4 Alanine aminotransferase 4 Aspartate aminotransferase 2 Bilirubin 1 Nonsense mutation genotype (premature stop codon type), n G542Xk (UGA) 14 W1282X (UGA) 4 Q493X (UAG) 3 R553X (UGA) 2 E1104X (UGA) 2 R1162Xk (UGA) 2 W846X (UGA) 1 W882X (UAG) 1 Q1313X (UAA) 1 Definition of Abbreviations: BMI 5 body mass index; TEPD 5 transepithelial potential difference. 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
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
24 As previously noted, the most common mutation in the Caucasian population is DF508, and the most common mutation in the Ashkenazi Jewish population is W1282X followed by DF508.18 Although Hispanics exhibit a relatively high incidence of disease, the sensitivity of carrier testing remains only 57% to 72% because detectable alleles account for only slightly more than half of the CF mutations observed in this population. 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

PMID: 20706124 [PubMed] Lucarelli M et al: "A new complex allele of the CFTR gene partially explains the variable phenotype of the L997F mutation."

No. Sentence Comment

57 W1282X (c.3846GϾA) is a nonsense mutation that produces a truncated CFTR form. Login to comment
59 F508del, W1282X, G85E,35 and S549R(AϾC)36 are considered classic CFTR mutations that cause a severe CF form when in homozygosity or compound heterozygosity with another classic mutation. Login to comment
78 By contrast, the sweat test values in the two subjects with apparently the same W1282X/L997F genotype (Subjects 9 and 10) were more similar (96 mEq/L and 80 mEq/L, respectively). Login to comment
92 Because the other allele in the two subjects with the W1282X mutation (Subjects 9 and 10) was characterized by the presence of the complex allele, no evaluation of the effect of simple compound heterozygosity was possible. 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

17 ReSulTS Human and mouse CF airway epithelia have defective autophagy We cultured human CF airway epithelial IB3-1 or CFBE41o-cells, carrying F508del/W1282X and F508del/F508del mutations, respectively, 1 European Institute for Research in Cystic Fibrosis, San Raffaele Scientific Institute, Milan 20132, Italy. 2 Department of Chemical Engineering, Federico II University, Naples 80125, Italy. 3 Institute of Pediatrics, University of Foggia, Foggia 71100, Italy. 4 Telethon Institute of Genetics and Medicine (TIGEM), Naples 80131, Italy. 5 Department of Pediatrics, Federico II University, Naples 80131, Italy. 6 Department of Laboratory Medicine, University of Foggia, Foggia 71100, Italy. 7 Departments of Neurosciences, University of California, San Diego, La Jolla, CA 92093-0624, USA. Login to 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: 20797923 [PubMed] Farra C et al: "Mutational spectrum of cystic fibrosis in the Lebanese population."

No. Sentence Comment

5 Of the 44 alleles studied, the most common mutations were: F508del (34%), N1303K (27%), W1282X (7%), and S4X (7%). 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
41 The most common mutations were; F508del detected in 34% of the 44 alleles, N1303K in 27%, W1282X in 7%, and S4X in 7% of the alleles. Login to comment
45 Ethnic distribution of CF mutations The mutations 4010del4, S4X, and W1282X were only present in Christian families, of Maronite and Greek-catholic origins. 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
53 By combining the results of our study on 22 Lebanese families with those of Desgeorges et al. from 20 families, and considering these two studies as one whole Lebanese population (total identified CF alleles=80), we can deduce that the three most frequent mutations in Lebanese families are F508del, N1303K, and W1282X accounting for 70.1% of CF alleles (Table 2). Login to comment
63 In populations from Saudi Arabia, United Arab Emirates, Oman, Qatar, Kuwait, and Jordan the most commonly reported mutations were 1548delG, I123V, F508del, 3120+1G→A, and H139L; while F508del (7.4%-15%) and N1303K (1.5%-14%) are not common, and the mutation W1282X is absent from these populations (Table 2) [1,3,24-26]. Login to comment
70 In Israel, the most common mutations reported were also F508del, W1282K, and N1303K, with W1282X being the most common (31.3%-36.2%) [21,30]. 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

104 The reasons for failure are not completely clear, but include the challenge of NPD studies in multicenter trials (a critique that has been subsequently addressed by improvement in the testing method [72]), relative susceptibility of the W1282X mutation found commonly in Israel [73], and genetic founder effects, including the degree of CFTR mRNA expression at baseline [70 ,74]. 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: 21059651 [PubMed] Wang G et al: "The inhibition mechanism of non-phosphorylated Ser768 in the regulatory domain of cystic fibrosis transmembrane conductance regulator."

No. Sentence Comment

268 Role of Curcumin in Normal CFTR Gating-A previous study (21) showed that curcumin activates mutant CFTR channels, such as G551D, W1282X, ⌬1198, and A462F. Login to comment

PMID: 21060690 [PubMed] Frossard JL et al: "Recurrent Acute Pancreatitis and Therapy for Ulcerative Colitis."

No. Sentence Comment

32 Genetic testing revealed the presence of the CFTR mutation, W1282X, that is known to increase the risk of chronic pancreatitis and idiopathic pancreatitis [7]. Login to comment

PMID: 21148790 [PubMed] Tamanini A et al: "Trimethylangelicin reduces IL-8 transcription and potentiates CFTR function."

No. Sentence Comment

39 IB3-1 cells, derived from a CF patient with a F508del/W1282X mutant genotype, were grown as previously described (3, 8, 15, 16, 32); non-CF Calu-3, a cell line obtained from a human lung adenocarcinoma derived from submucosal gland of proximal bronchial airways, and CF CuFi-1 cell line, obtained from human bronchial epithelium derived from a CF patient with a F508del/ F508del mutant genotype, were cultured on Transwell membranes (41). Login to comment
42 IB3-1 cells, derived from a CF patient with a F508del/W1282X mutant genotype, were grown as previously described (3, 8, 15, 16, 32); non-CF Calu-3, a cell line obtained from a human lung adenocarcinoma derived from submucosal gland of proximal bronchial airways, and CF CuFi-1 cell line, obtained from human bronchial epithelium derived from a CF patient with a F508del/ F508del mutant genotype, were cultured on Transwell membranes (41). 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

155 - HE TOP, MI [W1282X]? 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

91 Three nonsense mutation genotypes were represented, with W1282X being the most common. Login to 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

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: 21420913 [PubMed] Legendre C et al: "Impaired expression of hypoxia-inducible factor-1alpha in cystic fibrosis airway epithelial cells - a role for HIF-1 in the pathophysiology of CF?"

No. Sentence Comment

30 Cell culture IB3-1 (ATCC CRL-2777) is a bronchial epithelial cell line derived from a CF patient with CFTR ΔF508/W1282X alleles (CF-affected cells). 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: 21499205 [PubMed] Lucidi V et al: "The etiology of acute recurrent pancreatitis in children: a challenge for pediatricians."

No. Sentence Comment

46 Genetic Findings Observed in Our Study Population and Related Clinical Features CFTR PRSS1 SPINK1 Clinical CharacteristicsMutations IVS8 F508del/UN 9T/9T S181G/- NEG No respiratory symptoms 3849+10KbC9T/UN 7T/7T NEG NEG No respiratory symptoms UN/UN 7T/7T NEG N34S/- UN/UN 5T/7T NEG NEG No respiratory symptoms 1899-136T/C/UN 5T/7T NEG NEG No respiratory symptoms F508del/UN 5T/9T NEG NEG No respiratory symptoms D1152H/D1152H NEG NEG No respiratory symptoms R75Q/UN 5T/7T NEG NEG No respiratory symptoms L997F/UN 7T/9T NEG NEG No respiratory symptoms UN/UN 7T/7T NEG N34S/- W1282X/I148T 7T/9T NEG NEG No respiratory symptoms NEG N34S/- R75Q/F1052V NEG NEG No respiratory symptoms F508del/D1152H NEG NEG Bronchiectasis-CF 406-6T/C/E528E 7T/7T NEG NEG No respiratory symptoms F508del/UN 7T/9T Mild respiratory symptomsYCF L967S/L997F NEG NEG No respiratory symptoms E528E/UN 5T/7T Crohn disease, food allergy 1716 G/A/UN 7T/7T NEG NEG No respiratory symptoms 1898+1G9A/UN 7T/7T No respiratory symptoms R31C/UN No respiratory symptoms R75Q/UN 7T/7T NEG NEG No respiratory symptoms N29T;V212I; D217Y NEG F508del/UN 7T/9T NEG NEG Pancreas divisum S1235R/UN 7T/9T NEG NEG Duodenal stenosis Entries in bold font undelines the detection of mutations or polymorphisms in the studied genes. 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: 21518732 [PubMed] Kelly-Aubert M et al: "GSH monoethyl ester rescues mitochondrial defects in cystic fibrosis models."

No. Sentence Comment

281 Cell culture The IB3-1 cell line was derived from bronchial epithelial cells from a patient with CF (F508del/W1282X) and was immortalized by viral transformation. Login to comment
279 Cell culture The IB3-1 cell line was derived from bronchial epithelial cells from a patient with CF (F508del/W1282X) and was immortalized by viral transformation. Login to comment

PMID: 21525008 [PubMed] Suaud L et al: "ERp29 regulates DeltaF508 and wild-type cystic fibrosis transmembrane conductance regulator (CFTR) trafficking to the plasma membrane in cystic fibrosis (CF) and non-CF epithelial cells."

No. Sentence Comment

17 Sodium 4-phenylbutyrate (4PBA) improves ⌬F508-CFTR intracellular trafficking in CF epithelial cells such as the IB3-1 CF human bronchiolar epithelial cell line (genotype ⌬F508/ W1282X) as early as 4-8 h after exposure and restores CFTR function at the plasma membrane without altering CFTR mRNA expression (16). Login to comment
48 EXPERIMENTAL PROCEDURES Cell Culture-IB3-1 CF epithelial cells (genotype ⌬F508/ W1282X) (68) were cultured as described previously (4, 18). 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
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

PMID: 21544602 [PubMed] Thomsen KF et al: "Increased elongase 6 and Delta9-desaturase activity are associated with n-7 and n-9 fatty acid changes in cystic fibrosis."

No. Sentence Comment

39 IB3 cells are compound heterozygotes which contain one DF508 allele and one nonsense mutation, W1282X, with a premature termination signal [23]. Login to comment
119 The IB3 cell line consists of immortalized bronchial epithelial cells from an actual CF patient that carried a compound heterozygous genotype (DF508/W1282X) [23]. Login to comment

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

No. Sentence Comment

58 The template for these PCR reactions is DNA from HT-29 cells, carrying normal CFTR alleles, or DNA from KM cells, homozygous for the W1282X mutation. Login to comment
185 The DNA mix for the CFTR transfections contains 2 μg DNA per 6 well of WT or W1282X CFTR constructs together with 0.2 μg DNA of GFP. Login to 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
239 W - the W1282X mutation; 3849 - the 3849+10 kb C→T mutation. Login to comment
241 The level of RNA transcribed from the WT or W1282X CFTR constructs is normalized to the RNA level of GFP (which is used as a reference for transfection efficiency). Login to comment
248 Then, the level of the normalized transcripts following NMD Fig. 10.2. Effect of CHX treatment on the level of CFTR mRNA transcribed from constructs carrying the W1282X PTC. Login to comment
249 (a) A scheme of the wild-type (WT) (upper panel) and W1282X (lower panel) constructs, which contain all CFTR exons (marked in the boxes by numbers) and part of the intronic sequences between exons 20 and 22. Login to comment
252 The level of mRNA transcribed from CFTR constructs carrying either the normal sequence or the W1282X PTC was normalized to the mRNA level of GFP. Login to comment
254 The fold increase in the level of CFTR W1282X transcripts is shown as mean ± SEM (reproduced from (9)). Login to comment

PMID: 21625641 [PubMed] Del Porto P et al: "Dysfunctional CFTR alters the bactericidal activity of human macrophages against Pseudomonas aeruginosa."

No. Sentence Comment

59 49% CF11 27 F F508del/F508del P.a. 28% CF12 45 F F508del/F508del P.a. 44% CF13 30 M W1282X/W1282X P.a. 43% CF14 28 M F508del/F508del S.a. 66% CF15 36 F F508del/F508del S.a. 76% a S.a.: Staphylococcus aureus; P.a.: Pseudomonas aeruginosa; C.a.: Candida albicans; A.t.: Aspergillus terreus; S.m.: Stenotrophomonas maltophilia; P.f.: Pseudomonas fluorescens; - unknown; doi:10.1371/journal.pone.0019970.t001 antibody (Developmental Studies Hybridoma Bank, University of IOWA, IOWA City, IA) and the Alexa Fluor-488 F(ab)2 goat anti-mouse IgG. 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
67 Specific mutations appear to be enriched within ethnic groups.53 For example, the nonsense mutation, W1282X (a PTC in place of tryptophan residue 1282) accounts for slightly .1% of worldwide mutations but for approximately 50% of the those in the Israeli Ashkenazi Jewish population where nonsense mutations nearly exceed the frequency of F508del.54 Ultimately, the majority of CF mutations are rare and have not been functionally characterized. Login to comment
70 In particular, nonsense mutations, a single point alteration in DNA that creates an in-frame PTC (UAA, UGA, or UAG) in the protein-coding region, have been reported to cause approximately 30% of all human inherited diseases.57 The designation for nonsense mutation ends with an X (eg, W1282X). Login to comment
71 The Table1-OverviewoftheFiveClassesofCFTRMutations Class ApproximateWorldwide Frequency Predominant MutationType Common Representative Mutations CFTRDomain Location Associated Phenotype Severity CFTRProtein Outcome Functional Consequence RelevantAgentsin ClinicalTrials I?10%(Ashkenazi,50%)Nonsense,spliceG542X,W1282X, 62111G→T NBD1,NBD2, MSD1 HighNoCFTRNoCl2transportPTCread-through (eg,ataluren) II70%MissenseF508del,N1303KNBD1,NBD2HighDefectiveprocessingNoCl2transportCorrectors(eg,VX-809) III2%-3%MissenseG551D,R560TNBD1,NBD1HighDefectiveregulationNoCl2transportPotentiators (eg,VX-770) IVUncertain,,2%MissenseR117H,R347PMSD1,MSD1ReducedAlteredconductanceMinimalexpression&Cl2 transport Potentiators VUncertain,,1%Missense,splice3349110kbC→GIntronReducedReducedsynthesisReducedexpression&Cl2 transport Uncertain CFTR5cysticfibrosistransmembraneconductanceregulator;Cl25chloride;MSD5membranespanningdomain;NBD5nucleotide-bindingdomain;PTC5prematureterminationcodon. Login to comment
127 Although NPD changes were not detected, the promising data for VX-809 provide support for more clinical trials.105 Potentiators of Mutant CFTR Protein Potentiator compounds increase chloride ion flow of PKA-activated mutant CFTR proteins that are Ataluren, developed by PTC Therapeutics, Inc (South Plainfield, New Jersey), is an orally bioavailable small molecule that proved superior to gentamicin in in vitro assays at inducing ribosomal read-through of in-frame nonsense PTCs to produce full-length proteins.76 Ataluren does not exhibit any antibiotic activity, and studies in transgenic CF mouse possessing hG542X- CFTR revealed that ataluren is capable of enhancing production of the full-length CFTR protein.84 Ataluren also passed requisite tolerability studies in healthy non-CF human volunteers apart from a mild elevation of hepatic transaminases with repeated dosing.85 In a subsequent phase II prospective trial in Israel where nonsense CFTR mutations are prevalent (eg, W1282X), 23 adult patients with CF exhibiting mainly heterozygous nonsense mutations were administered ascending doses of ataluren in two 2-week cycles (with a 2-week interval washout). 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
63 Specific mutations appear to be enriched within ethnic groups.53 For example, the nonsense mutation, W1282X (a PTC in place of tryptophan residue 1282) accounts for slightly .1% of worldwide mutations but for approximately 50% of the those in the Israeli Ashkenazi Jewish population where nonsense mutations nearly exceed the frequency of F508del.54 Ultimately, the majority of CF mutations are rare and have not been functionally characterized. Login to comment
66 In particular, nonsense mutations, a single point alteration in DNA that creates an in-frame PTC (UAA, UGA, or UAG) in the protein-coding region, have been reported to cause approximately 30% of all human inherited diseases.57 The designation for nonsense mutation ends with an X (eg, W1282X). Login to comment
123 Although NPD changes were not detected, the promising data for VX-809 provide support for more clinical trials.105 Potentiators of Mutant CFTR Protein Potentiator compounds increase chloride ion flow of PKA-activated mutant CFTR proteins that are Ataluren, developed by PTC Therapeutics, Inc (South Plainfield, New Jersey), is an orally bioavailable small molecule that proved superior to gentamicin in in vitro assays at inducing ribosomal read-through of in-frame nonsense PTCs to produce full-length proteins.76 Ataluren does not exhibit any antibiotic activity, and studies in transgenic CF mouse possessing hG542X- CFTR revealed that ataluren is capable of enhancing production of the full-length CFTR protein.84 Ataluren also passed requisite tolerability studies in healthy non-CF human volunteers apart from a mild elevation of hepatic transaminases with repeated dosing.85 In a subsequent phase II prospective trial in Israel where nonsense CFTR mutations are prevalent (eg, W1282X), 23 adult patients with CF exhibiting mainly heterozygous nonsense mutations were administered ascending doses of ataluren in two 2-week cycles (with a 2-week interval washout). Login to comment

PMID: 21658632 [PubMed] Becq F et al: "Pharmacological therapy for cystic fibrosis: from bench to bedside."

No. Sentence Comment

31 Class I mutations: defective protein production Some CF mutations (e.g. W1282X) are nonsense mutations that introduce stop signals known as premature termination codons (PTCs) into the CFTR gene. Login to comment
128 For further information, see the text. *Cellular model used: Primary cells/tissues: HBE, human bronchial epithelial cells from normal subjects; HBEC-CF primary, human bronchial epithelial cells from CF patients. Cell-lines (immortalized) expressing endogeneous CFTR: CF15 cells (human nasal airway, F508del/F508del); CFBE41o- (human bronchial origin, F508del/F508del); CFPAC-1 (human pancreatic duct origin, F508del/F508del); CFT1 (human tracheal origin, F508del/F508del); CuFi-1 (human bronchial origin, F508del/F508del); NuLi-1 (human bronchial origin, wild-type CFTR); IB3-1 (human bronchial origin, F508del/W1282X); LLC-PK1 (pig kidney epithelial cell line, wild-type CFTR). Login to comment

PMID: 21765932 [PubMed] Liang L et al: "A novel role of protein tyrosine kinase2 in mediating chloride secretion in human airway epithelial cells."

No. Sentence Comment

174 Materials and Methods Cell and monolayer cultures IB3-1 is a CF human bronchial epithelial cell line that has two different CFTR mutations (DF508 and W1282X) [30]. Login to comment

PMID: 21778412 [PubMed] Parker D et al: "Induction of Type I Interferon Signaling by Pseudomonas aeruginosa is Diminished in Cystic Fibrosis Epithelial Cells."

No. Sentence Comment

41 Materials and methods Cell culture IB3 (∆F508/ W1282X) or C38 (corrected) cystic fibrosis epithelial cell lines were grown between passage 22 and 60 in LHC-8 media, 10% fetal bovine serum, penicillin, streptomycin and L-glutamine. Login to comment
81 Decreased type I IFN responses in cells with CFTR mutations - To determine if mutations in CFTR affect induction of the type I IFN cascade, we compared the effects 5 of P. aeruginosa or LPS on the Ifnb expression in the matched C38 (corrected) and IB3 (∆F508/W1282X) (containing the episomal vector) cell lines (41) (Figure 3A&B). Login to comment
128 Using data obtained from well characterized CF (∆F508/W1282X) plus vector and corrected cell lines we suggest that CFTR mutation may affect epithelial induction of IFN-β expression by airway cells in response to P. aeruginosa, the most proximal step in the mucosal response to inhaled airway pathogens. Login to comment
92 (A) Confluent monolayers of IB3 (ΔF508/ W1282X) or C38 (corrected) epithelial cell lines were infected with P. aeruginosa (P.a.; 107 CFUs; n ¼ 3) or LPS (n ¼ 2) for 2 or 4 hours, and concentrations of Ifnb were quantified by quantitaive RT-PCR. Login to comment
116 Decreased Type I IFN Responses in Cells with CFTR Mutations To determine if mutations in CFTR affect the induction of the type I IFN cascade, we compared the effects of P. aeruginosa or LPS on the expression of Ifnb in matched C38 (corrected) and IB3 (DF508/W1282X, containing the episomal vector) cell lines (39) (Figures 3A and 3B). Login to comment
185 Using data obtained from well-characterized CF (DF508/ W1282X) plus vector and corrected cell lines, we suggest that CFTR mutations may affect the epithelial induction of IFN-b expression by airway cells in response to P. aeruginosa, the most proximal step in the mucosal response to inhaled airway pathogens. 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

4 In a fluorescence-based halide efflux assay, NB54 partially restored halide efflux in a CF bronchial epithelial cell line (CFTR genotype W1282X/F508del), but not in a CF epithelial cell line lacking a PTC (F508del/F508del). Login to 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
39 Growth of stable cell lines expressing recombinant CFTR CFTR-W1282X cDNA were stably transfected into HeLa and CFBE41o-cells using the TranzVector™ (Tranzyme, Inc., Birmingham, AL) as described [22]. Login to comment
46 SPQ studies of halide efflux in heterologous cells HeLa cells stably transfected with a lentiviral system carrying a CFTR-W1282X cDNA were studied with the halide quenched dye 6-methoxy-N-(3-sulfopropyl)-quinolinium (SPQ, Molecular Probes Inc., Eugene, OR) as described by the manufacturer and previously published [23, 26, 27]. Login to comment
78 Results Translational readthrough screen of synthetic aminoglycosides in human epithelial cell lines To determine whether the synthetic aminoglycosides NB30 and NB54 induce enough translational readthrough of CFTR PTCs to partially restore CFTR function using a stimulated halide transport assay, we first tested the compounds using HeLa cells stably transduced with a lentiviral system driving CFTR-W1282X expression. Login to comment
82 To confirm the effects of aminoglycosides on readthrough in a more physiologically relevant cell type with endogenous CFTR expression, we next examined the IB3-1 bronchial epithelial cell line (CFTR genotype W1282X/ F508del) in comparison to a CF epithelial cell line derived from nasal polyps from a homozygous CFTR-F508del donor (CFNPE cells). Login to comment
93 Fig. 2 Fluorescence-based halide efflux assay of cells expressing CFTR-W1282X following treatment with gentamicin, NB30, or NB54. Login to comment
94 a HeLa cells expressing CFTR-W1282X were grown on glass coverslips were treated with 500 μg/ml of the indicated aminoglycoside (gentamicin, NB30, or NB54) for 24 h, or mock treated with vehicle, and studied by fluorescence-based halide efflux (SPQ). Login to comment
99 b IB3-1 cells (endogenous CFTR genotype W1282X/F508Del) were incubated with the aminoglycosides NB30, NB54, or gentamicin at the concentrations indicated for 24 h, and halide efflux was quantified by percentage change in fluorescence over basal compared to control following activation with forskolin (20 μM) and genistein (50 μM). Login to comment
105 In CFBE41o-cells stably transduced with a CFTR-W1282X cDNA, NB54 treatment (500 μg/ml) increased ISC 0.38 μA/cm2 more than in cells treated with vehicle alone. 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
117 a Representative short-circuit current tracings obtained from CFBE41o- expressing W1282X CFTR mounted in modified Ussing chambers and studied under voltage clamp conditions. 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
197 We found that NB30 and NB54 treatment restored a level of cAMP-stimulated halide transport that was comparable to gentamicin in both HeLa cells stably transduced with a lentiviral system expressing CFTR-W1282X and in the IB3-1 bronchial epithelial cell line (W1282X/F508del, Fig. 2). 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
238 Shoshani T, Kerem E, Szeinberg A, Augarten A, Yahav Y, Cohen D, Rivlin J, Tal A, Kerem B (1994) Similar levels of mRNA from the W1282X and the delta F508 cystic fibrosis alleles, in nasal epithelial cells. Login to comment
272 Mol Ther 2:47-55 23. Rowe SM, Varga K, Rab A, Bebok Z, Byram K, Li Y, Sorscher EJ, Clancy JP (2007) Restoration of W1282X CFTR activity by enhanced expression. Login to comment

PMID: 21809164 [PubMed] Rittenhouse DW et al: "Subject Review: Pancreatic Ductal Adenocarcinoma in the Setting of Mutations in the Cystic Fibrosis Transmembrane Conductance Regulator Gene: Case Report and Review of the Literature."

No. Sentence Comment

4 Patients and Methods We report a case of a patient with PDAwho underwent resection, who is a carrier for the W1282X nonsense mutation in the CFTR gene. Login to comment
10 W1282X mutation Introduction Cystic fibrosis (CF) is the most common lethal autosomal recessive inherited disease amongst Caucasians.1 The gene responsible for CF is on chromosome 7 and encodes the cystic fibrosis transmembrane conductance regulator (CFTR) protein, which functions as a chloride channel regulated by cyclic AMP.2 Much work has been accomplished over the past 20 years identifying over 1,300 different mutations in the CFTR gene. Login to comment
19 A less common mutation in the CFTR gene is the W1282X, where a G to A base pair substitution at nucleotide 3978 leads to a substitution of a tryptophan amino acid residue with generation of a premature stop codon. Login to comment
20 Albeit far less common than the ΔF508 mutation, the W1282X mutation has been shown to occur with a tenfold higher frequency in patients with PDAwhen compared to controls.8 We recently operated on a patient with PDA who had a family history of CF. Login to comment
21 The patient underwent genetic testing and was found to harbor a heterozygous W1282X mutation in the CFTR gene. Login to comment
45 Genetic analysis revealed the patient to harbor a heterozygous W1282X mutation in the CFTR gene. Login to comment
56 The four most prevalent genotypes were the ΔF508 mutation (n=47), 5T allele (n=44), W1282X mutation (n=6), and R117H mutation (n=5). Login to comment
57 The present case is the sixth W1282X mutation in the setting of PDA to have been reported in the English literature, and only the second publication to note this association. Login to comment
60 b Intraductal papillary mucinous neoplasm with mild dysplasia in the mucinous cells lining cyst wall (hematoxylin and eosin stain, ×200 original magnification) patient underwent genetic testing and was found to be heterozygous for the W1282X CFTR gene mutation. Login to comment
61 The W1282X mutation is a class I CFTR gene nonsense mutation that occurs with a frequency of 1% in the population and has only been reported in one publication with five other patients with PDA.8 Below, we discuss the significance of CFTR gene mutation carrier status in the risk of developing PDA and what this means in terms of cancer screening and surveillance. Login to comment
71 None of the patients tested in the McWilliams study had the W1282X mutation. Login to comment
84 Klapman et al. suggested screening those patients that have two or more first degree relatives with PDA as Year Author Number of patients Average age (years) Pathology Genotype 2001 Malats 9 66.5 PDA 3 ΔF508 6 5T Allele 2003 Pezzilli 1 73.8 PDA 5T Allele 2003 Matsubayashi 42 Not reported PDA 6 ΔF508 36 5T Allele 2006 Piepoli 3 63 PDA 3 ΔF508 2010 Rebours 1 52 IPMN with PanIN-2 2789+G>A/5T Allele 2010 McWilliams 50 67 PDA 35 ΔF508 5 R117H 5 W1282X G551D N1303K R347 P S549R Δ1507 2011 Present Study 1 77 PDA W1282X Table 2 Patients with pancreatic tumors and heterozygous mutations in the CFTR gene CFTR cystic fibrosis transmembrane regulator, PDA pancreatic ductal adenocarcinoma, ΔF508 Delta F508, IPMN intraductal papillary mucinous neoplasm, PanIN-2 pancreatic intraepithelial neoplasia-2 well as those with a family history of any of the known hereditary pancreatic cancer syndromes such as familial adenomatous polyposis, hereditary nonpolyposis colorectal cancer syndrome, hereditary pancreatitis, hereditary breast/ ovarian cancer syndrome, Peutz-Jeghers syndrome, and familial atypical multiple mole and melanoma syndrome.24 It might be worthwhile for those patients with a family history of CF and who have other risk factors such as smoking and obesity, who are known carriers of any of the more disease-associated mutations (i.e., ΔF508, W1282X) to be screened for PDA. Login to comment
85 The W1282X mutation, found in our proband, is approximately 66 times less common than the ΔF508 mutation in the general population. Login to comment
88 The patient was found to harbor a rare nonsense mutation in the CFTR gene (W1282X) that has an increased prevalence in the Ashkenazi Jewish population. 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

38 Cell lines Cell lines utilized were the following: CFBE41o2 , (kind gift from DC Gruenert, California Pacific Medical Center Research Institute, San Francisco, CA, USA) [10], 16HBE14o- (kindly provided by P. Davis, Case Western Reserve University School of Medicine, Cleveland, OH, USA) [11], the bronchial epithelial cell line IB3-1 derived from a CF patient with genotype W1282X/ F508del (kind gift of Pamela Zeitlin, Johns Hopkins Hospital, Baltimore, USA) [12], pancreatic cell lines Suit-2 derived from a liver metastasis of a human pancreatic adenocarcinoma [13] and CFPAC-1 [14]. Login to comment
130 CFBE41o2 (CFBE) (F508del/F508del) cells express a single band corresponding to a core-glycosylated CFTR (band B, ACL-006 and 24-1 antibodies) while CFTR expression level in IB3-1 (W1282X/F508del) is below the detection limit of the assay for ACL-006 antibody but display a band using the 24-1 antibody. Login to 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: 9616231 [PubMed] DiMango E et al: "Activation of NF-kappaB by adherent Pseudomonas aeruginosa in normal and cystic fibrosis respiratory epithelial cells."

No. Sentence Comment

6 IB3 cells, which express mutations in cystic fibrosis transmembrane conductance regulator (CFTR) (⌬F508/W1282X), were noted to have significantly greater amounts of endogenous nuclear NF-␬B, but not the transcription factor C/EBP, than CF cells corrected by episomal copies of normal CFTR (C-38) or IB3 cells grown at a permissive temperature (25ЊC). Login to comment
44 IB3 cells, an adeno-associated virus-transformed human bronchial epithelial cell line derived from a CF patient (⌬F508/W1282X), and C-38 cells, the rescued cell line which expresses a plasmid encoded copy of a functional CFTR, obtained from P. Zeitlin (Johns Hopkins University, Baltimore, MD) (25), were grown in LHC-8 media (Biofluids, Rockville, MD) supplemented with 10% FBS. 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

53 In the 10 non-508/non-508 normal α1-AT phenotype group, one patient had each of the following: G551D/G551D, W1282X/2711delT, N1303K/unknown, 977ins/unknown, S549?/unknown, ∆I507/unknown; in four patients both mutations were unknown at the time of the study. Login to comment

PMID: 9630075 [PubMed] Arduino C et al: "Congenital bilateral absence of vas deferens with a new missense mutation (P499A) in the CFTR gene."

No. Sentence Comment

4 0 Munksgaard, 1998 We describe a congenital bilateral absence of the vas deferens (CBAVD) patient with a compound heterozygosity in the cystic fibrosis transmembrane regulator ( C n R ) gene for a stop mutation W1282X and a new missense mutation P499A.The P499A is interpreted as a mild mutation whose phenotypic effects, in this case limited to the development of wolffian duct derivatives,are revealed only in combination with a severe CFTR mutation. Login to comment
11 The present study reports a CBAVD patient with a compound heterozygosity in the CFTR gene for a stop mutation (W1282X) and a new missense mutation (P499A). Login to comment
42 The P499A behaves as allelic to W1282X. Login to comment
49 The CFTR genotype of our patient is represented by a severe mutation (W1282X) and by a new missense substitution P499A. 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
88 For example, the stop mutation W1282X is present on approximately 50% of Ashkenazi Jewish chromosomes, making it the most common mutation in this particular population. 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

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

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: 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
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

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: 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
118 2 W1282X/405 ϩ 1G3A 1 5T/W1089X 2 ⌬F508/? Login to comment
120 3 W1282X/? 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: 9922378 [PubMed] Schultz BD et al: "Pharmacology of CFTR chloride channel activity."

No. Sentence Comment

367 In thisThese studies were subsequently repeated with similar results using NIH 3T3 cells expressing DF508 CFTR or nomenclature system, tyrosine phosphatases (PTP) are classified separately, whereas neither acid nor alkalinewild-type CFTR as well as with the human airway cell line IB3-1 derived from a DF508/W1282X CF patient (151). 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
45 Screening of further two mutations, p.R1162X and p.W1282X (exons 19 and 20, respectively) increases the detection power to 57%, whereas a laborious search for other rare mutations all over the CFTR coding region only increases the detection level another 6% (12 different mutations) (Table 1). 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
63 Nevertheless, taken by regions, some of them account for a high proportion of the mutations, like p.R1162X (5% in Bolívar), p.W1282X (4.2% in Valle) or c.2185_2186insC (5% in the other Departments) (Table 1), and analysis of more patients should confirm their relative frequency in those particular regions. 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

11 For example, the frequency of p.W1282X mutation is about 1-2% in Caucasians but is as high as 60% in Ashkenazi Jews [8, 9]. 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

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
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

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: 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

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: 9393813 [PubMed] Kammouni W et al: "Altered cytokine production by cystic fibrosis tracheal gland serous cells."

No. Sentence Comment

53 Three tracheal explants from healthy donors and CF patients were used, all from patients showing severe pancreatic insufficiency and with the following genetic status: one ⌬F508/⌬F508, one ⌬F508/W1282X, and one ⌬F508/unknown. Login to comment

PMID: 15927881 [PubMed] Clark H et al: "The genetics of neonatal respiratory disease."

No. Sentence Comment

155 Conversely, in individuals of Ashkenazi Jewish origin, W1282X accounts for approximately 60% of the total.67 Genotype-phenotype correlations in cystic fibrosis have been well documented.67,69e71 The R117H mutation is generally associated with pancreatic sufficiency and a milder phenotype. 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: 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

138 After screening for the Phe508 deletion (Kerem et al., 1989), most CFTR mutations were investigated by restriction analysis of PCR products (R334W, R347P, A455E, G551D, R553X, R1162X, W1282X) (Cutting et al., 1990; Dean et al., 1990; Gasparini et al., 1991; Kerem et al., 1990; Vidaud et al., 1990). Login to comment

PMID: 23069118 [PubMed] Thursfield RM et al: "Cystic Fibrosis: therapies targeting specific gene defects."

No. Sentence Comment

31 Examples of class I mutations include Trp1282X (previously W1282X) and Gly542X. Login to comment
39 Trp1282X previously termed W1282X] II Trafficking mutations: Misfolded protein fails to traffic to the apical cell surface and instead is degraded by intracellular processes [eg. Login to comment

PMID: 22874563 [PubMed] Luciani A et al: "Targeting autophagy as a novel strategy for facilitating the therapeutic action of potentiators on DeltaF508 cystic fibrosis transmembrane conductance regulator."

No. Sentence Comment

15 For this, we developed an assay in which airway epithelial cells carrying ΔF508/ΔF508 or ΔF508/W1282X CFTR mutations (parental CFBE41o- and IB3-1 cells, respectively),7,29,38 which we refer to as "CF cells," were first incubated with PRs or the CFTR correctors Corr-4a or Vrx-32526 at 37°C for 18 h and then washed and re-cultured for up to 12 h in the presence of cycloheximide (CHX, 100 μg ml-1 , refreshed every 6 h) to inhibit protein neosynthesis.29 CHX toxicity in this system was excluded by a 3-[4,5-dimethylthia- zol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) cell viability assay.39 The efficacy of protein synthesis inhibition by CHX was validated by the absence of ΔF508-CFTR band B, an immature form of neosynthesized ΔF508-CFTR that is retained in the endoplasmic reticulum and prematurely destroyed, after 12 h of incubation with CHX (Fig. S1A and S1B). Login to comment
16 For this, we developed an assay in which airway epithelial cells carrying ƊF508/ƊF508 or ƊF508/W1282X CFTR mutations (parental CFBE41o- and IB3-1 cells, respectively),7,29,38 which we refer to as "CF cells," were first incubated with PRs or the CFTR correctors Corr-4a or Vrx-32526 at 37&#b0;C for 18 h and then washed and re-cultured for up to 12 h in the presence of cycloheximide (CHX, 100 bc;g ml-1 , refreshed every 6 h) to inhibit protein neosynthesis.29 CHX toxicity in this system was excluded by a 3-[4,5-dimethylthia- zol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) cell viability assay.39 The efficacy of protein synthesis inhibition by CHX was validated by the absence of ƊF508-CFTR band B, an immature form of neosynthesized ƊF508-CFTR that is retained in the endoplasmic reticulum and prematurely destroyed, after 12 h of incubation with CHX (Fig. S1A and S1B). 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: 22859523 [PubMed] Quinton P et al: "beta-Adrenergic Sweat Secretion as a Diagnostic Test for Cystic Fibrosis."

No. Sentence Comment

42 DIAGNOSTIC CHARACTERISTICS OF PARTICIPANTS IN THE VALIDATION COHORT Group Age (yr) Sex Genotype Sweat Cl2 (mmol/L) Cholinergic b-Adrenergic Ratio b/Chol Healthy 38 M 2/2 15 64.45 72.79 1.13 Healthy 39 M 2/2 18 81.61 86.08 1.05 Healthy 54 F 2/2 29 48.90 47.30 0.97 Healthy 64 F 2/2 28 50.64 57.54 1.14 Healthy 54 F 2/2 11 68.63 52.30 0.76 Hetero. 64 M F508del/2 16 68.21 36.78 0.54 Hetero. 56 M F508del/2 53 82.44 59.57 0.72 Hetero. 27 F F508del/2 11 78.30 46.30 0.59 Hetero. 29 F F508del/2 16 65.63 26.13 0.40 Hetero. 51 F G551D/2 62 39.13 16.50 0.42 CFTR-RD CBAVD 41 M W1282X/5T 55 84.61 20.69 20.01 CFTR-RD CBAVD 52 M F508del/R117H (7T) 57 70.39 20.61 20.01 CFTR-RD CBAVD 41 M F508del/5T 40 68.00 22.29 20.03 CFTR-RD CBAVD 47 M G551D/R117H (7T) 57 65.93 10.08 0.15 CFTR-RD CBAVD 40 M L206W/W216C 42 67.80 17.00 0.25 CFTR-RD CBAVD 26 M 36599delC15T/7T 55 91.55 0.18 0.00 CFTR-RD Sinopulm 65 F F508del/c.876-9_876-6delGATT 51 74.30 32.20 0.43 CFTR-RD Sinopulm 39 F R764X/2 12 24.64 3.49 0.14 CFTR-RD Sinopulm 17 F 5T/2 50 52.95 14.24 0.27 CFPS 21 M F508del/2 97 46.19 0.56 0.01 CFPS 33 M F508del/3849110kbC.T 50 76.22 22.94 20.04 CFPS 58 M 71111G.T/A455E 72 70.19 23.06 20.04 CFPS 41 M G551D/3849110kbC.T 88 87.37 0.08 0.00 CFPS 54 F F508del/R117C 59 36.74 1.06 0.03 CFPS 23 F F508del/A455E 82 64.85 3.46 0.05 CFPS 30 F D1152H/D1152H 31 41.52 23.54 20.09 CFPS 55 F G551D/2 99 67.62 21.78 20.03 CFPS 42 F F508del/1002-2A.G 94 27.64 2.63 0.10 CFPS 46 F 3849110kbC.T/3849110kbC.T 53 24.43 21.16 20.05 CFPS 14 F R1162X/3849110kbC.T 46 50.19 20.49 20.01 CFPI 32 M F508del/F508del 108 73.93 1.41 0.02 CFPI 28 M F508del/F508del 84 95.13 3.45 0.04 CFPI 24 F F508del/F508del 109 60.48 4.06 0.07 CFPI 34 F F508del/F508del 115 79.24 0.99 0.01 CFPI 35 F F508del/F508del 87 79.79 23.02 20.04 CFPI 44 F F508del/F508del 112 80.60 1.23 0.02 CFPI 23 F F508del/G551D 90 45.80 0.80 0.02 Definition of abbreviations: CBAVD ¼ congenital bilateral absence of vas deference; CF ¼ cystic fibrosis; CFPI ¼ pancreatic-insufficient patients with CF; CFPS ¼ pancreatic-sufficient patients with CF; CFTR ¼ CF transmembrane regulator; CFTR-RD ¼ CFTR-related disorder; hetero ¼ heterozygotes; sinopulm ¼ chronic sinopulmonary disease. Login to comment
82 Four men with congenital bilateral absence of vas deference (CBAVD) (W1282X/5T, F508del/R117H [7T], F508del/5T, and 36599delC17T/5T) showed no b-adrenergic secretory response; one woman with chronic sinopulmonary disease (F508del/c.876-9_876-6delGATT) responded comparably with heterozygotes; two men with CBAVD (G551D/ R117H and L206W/W216C) and two women with chronic sinopulmonary disease (5T/2 and R764X/2) demonstrated b-adrenergic sweat secretion that was reduced compared with heterozygotes (Figure 3A, Table 1). Login to comment
43 DIAGNOSTIC CHARACTERISTICS OF PARTICIPANTS IN THE VALIDATION COHORT Group Age (yr) Sex Genotype Sweat Cl2 (mmol/L) Cholinergic b-Adrenergic Ratio b/Chol Healthy 38 M 2/2 15 64.45 72.79 1.13 Healthy 39 M 2/2 18 81.61 86.08 1.05 Healthy 54 F 2/2 29 48.90 47.30 0.97 Healthy 64 F 2/2 28 50.64 57.54 1.14 Healthy 54 F 2/2 11 68.63 52.30 0.76 Hetero. 64 M F508del/2 16 68.21 36.78 0.54 Hetero. 56 M F508del/2 53 82.44 59.57 0.72 Hetero. 27 F F508del/2 11 78.30 46.30 0.59 Hetero. 29 F F508del/2 16 65.63 26.13 0.40 Hetero. 51 F G551D/2 62 39.13 16.50 0.42 CFTR-RD CBAVD 41 M W1282X/5T 55 84.61 20.69 20.01 CFTR-RD CBAVD 52 M F508del/R117H (7T) 57 70.39 20.61 20.01 CFTR-RD CBAVD 41 M F508del/5T 40 68.00 22.29 20.03 CFTR-RD CBAVD 47 M G551D/R117H (7T) 57 65.93 10.08 0.15 CFTR-RD CBAVD 40 M L206W/W216C 42 67.80 17.00 0.25 CFTR-RD CBAVD 26 M 36599delC15T/7T 55 91.55 0.18 0.00 CFTR-RD Sinopulm 65 F F508del/c.876-9_876-6delGATT 51 74.30 32.20 0.43 CFTR-RD Sinopulm 39 F R764X/2 12 24.64 3.49 0.14 CFTR-RD Sinopulm 17 F 5T/2 50 52.95 14.24 0.27 CFPS 21 M F508del/2 97 46.19 0.56 0.01 CFPS 33 M F508del/3849110kbC.T 50 76.22 22.94 20.04 CFPS 58 M 71111G.T/A455E 72 70.19 23.06 20.04 CFPS 41 M G551D/3849110kbC.T 88 87.37 0.08 0.00 CFPS 54 F F508del/R117C 59 36.74 1.06 0.03 CFPS 23 F F508del/A455E 82 64.85 3.46 0.05 CFPS 30 F D1152H/D1152H 31 41.52 23.54 20.09 CFPS 55 F G551D/2 99 67.62 21.78 20.03 CFPS 42 F F508del/1002-2A.G 94 27.64 2.63 0.10 CFPS 46 F 3849110kbC.T/3849110kbC.T 53 24.43 21.16 20.05 CFPS 14 F R1162X/3849110kbC.T 46 50.19 20.49 20.01 CFPI 32 M F508del/F508del 108 73.93 1.41 0.02 CFPI 28 M F508del/F508del 84 95.13 3.45 0.04 CFPI 24 F F508del/F508del 109 60.48 4.06 0.07 CFPI 34 F F508del/F508del 115 79.24 0.99 0.01 CFPI 35 F F508del/F508del 87 79.79 23.02 20.04 CFPI 44 F F508del/F508del 112 80.60 1.23 0.02 CFPI 23 F F508del/G551D 90 45.80 0.80 0.02 Definition of abbreviations: CBAVD &#bc; congenital bilateral absence of vas deference; CF &#bc; cystic fibrosis; CFPI &#bc; pancreatic-insufficient patients with CF; CFPS &#bc; pancreatic-sufficient patients with CF; CFTR &#bc; CF transmembrane regulator; CFTR-RD &#bc; CFTR-related disorder; hetero &#bc; heterozygotes; sinopulm &#bc; chronic sinopulmonary disease. Login to comment
83 Four men with congenital bilateral absence of vas deference (CBAVD) (W1282X/5T, F508del/R117H [7T], F508del/5T, and 36599delC17T/5T) showed no b-adrenergic secretory response; one woman with chronic sinopulmonary disease (F508del/c.876-9_876-6delGATT) responded comparably with heterozygotes; two men with CBAVD (G551D/ R117H and L206W/W216C) and two women with chronic sinopulmonary disease (5T/2 and R764X/2) demonstrated b-adrenergic sweat secretion that was reduced compared with heterozygotes (Figure 3A, Table 1). Login to comment

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

No. Sentence Comment

290 2007. Restoration of W1282X CFTR activity by enhanced expression. Login to comment
285 2007. Restoration of W1282X CFTR activity by enhanced expression. Login to comment

PMID: 22340520 [PubMed] Schwarzer JU et al: "Significance of CFTR gene mutations in patients with congenital aplasia of vas deferens with special regard to renal aplasia."

No. Sentence Comment

26 The 3272-26A>G mutation was detected in two related patients with CBAVD, and L1388Q, W1282X and G551D in one patient each. Login to comment
45 Table 1 Frequency of CFTR mutations detected in 110 patients with CBAVD Mutation: DF508 R117H IVS8-5T 3272-26A>G L1388Q W1282X G551D Patients with CBAVD 61 (55)a 22 (22) 22 (22) 2 (2) 1 (1) 1 (1) 1 (1) a Percentages in brackets refer to total number of patients with CBAVD (110). Login to comment

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

No. Sentence Comment

979 For instance, the W1282X, a stop codon mutation, accounts for 48% of CF chromosomes in Ashkenazi Jews [65] and 23% of French Canadian CF chromosomes carry the 621+ 1G>T variant [66,67]. Login to 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: 22999299 [PubMed] Tucker TA et al: "The DeltaF508-CFTR mutation inhibits wild-type CFTR processing and function when co-expressed in human airway epithelia and in mouse nasal mucosa."

No. Sentence Comment

79 The IB3-1 cell line (derived from a CF human bronchus expressing the ΔF508 and W1282X mutant forms of CFTR) was grown in LHC-8 media without gentamycin (Biofluids) supplemented with 5% heat-inactivated fetal bovine serum, 6 ml of penicillin-streptomycin 100x solution (penicillin 100U/ml and streptomycin 100 μg/ mg final), 6 ml of 200 mM L-glutamine 100X solution (2 mM final), and 2 ml of fungizone solution (amphotericin B, 1ug/ml final). Login to comment
74 The IB3-1 cell line (derived from a CF human bronchus expressing the ƊF508 and W1282X mutant forms of CFTR) was grown in LHC-8 media without gentamycin (Biofluids) supplemented with 5% heat-inactivated fetal bovine serum, 6 ml of penicillin-streptomycin 100x solution (penicillin 100 U/ml and streptomycin 100 bc;g/mg final), 6 ml of 200 mM L-glutamine 100X solution (2 mM final), and 2 ml of fungizone solution (amphotericin B, 1 ug/ml final). Login to comment

PMID: 22821996 [PubMed] Hampton TH et al: "Does the F508-CFTR mutation induce a proinflammatory response in human airway epithelial cells?"

No. Sentence Comment

32 For example, studies on IB3-1 (⌬F508/W1282X) and S9 cells (IB3-1 cells complemented with wt-CFTR) demonstrate that P. aeruginosa elicits a more robust increase in IL-8 production in IB3-1 CF cells than in wt-CFTR-corrected S9 cells (1, 10), whereas studies on other matched cell lines reveal that, when challenged with P. aeruginosa, CF cells actually produce less IL-8 than non-CF cells, contrary to the generally accepted view that CF mutations enhance the inflammatory response of airway epithelial cells to P. aeruginosa (16, 22, 31). Login to comment
101 This experiment involved IB3-1 cells, which have a relatively uncommon CF genotype, ⌬F508/W1282X (41). Login to comment
165 Reanalysis of microarray gene expression identifies a proinflammatory phenotype in IB3-1 cells (⌬F508/W1282X) compared with S9 cells (⌬F508/W1282X/wt-CFTR). Login to comment
220 Second, the genotype of the cells is different (i.e., IB3-1 cells have the ⌬F508/ W1282X genotype and CFBE cells are ⌬F508/⌬F508). Login to comment
229 Gene array data from S9 (wt-CFTR) and IB3-1 (⌬F508/W1282X) cells exposed to P. aeruginosa. Login to comment
28 For example, studies on IB3-1 (èc;F508/W1282X) and S9 cells (IB3-1 cells complemented with wt-CFTR) demonstrate that P. aeruginosa elicits a more robust increase in IL-8 production in IB3-1 CF cells than in wt-CFTR-corrected S9 cells (1, 10), whereas studies on other matched cell lines reveal that, when challenged with P. aeruginosa, CF cells actually produce less IL-8 than non-CF cells, contrary to the generally accepted view that CF mutations enhance the inflammatory response of airway epithelial cells to P. aeruginosa (16, 22, 31). Login to comment
97 This experiment involved IB3-1 cells, which have a relatively uncommon CF genotype, èc;F508/W1282X (41). Login to comment
161 Reanalysis of microarray gene expression identifies a proinflammatory phenotype in IB3-1 cells (èc;F508/W1282X) compared with S9 cells (èc;F508/W1282X/wt-CFTR). Login to comment
216 Second, the genotype of the cells is different (i.e., IB3-1 cells have the èc;F508/ W1282X genotype and CFBE cells are èc;F508/èc;F508). Login to comment
225 Gene array data from S9 (wt-CFTR) and IB3-1 (èc;F508/W1282X) cells exposed to P. aeruginosa. 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: 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

PMID: 22495179 [PubMed] Wally V et al: "Spliceosome-mediated trans-splicing: the therapeutic cut and paste."

No. Sentence Comment

69 IB3-1 cells, which are compound heterozygous for the CFTR hotspot mutation delF508 and a nonsense mutation W1282X, were transduced with two RTMs delivering the 50 - and the 30 -halves of CFTR, the 50 - and 30 - donor and acceptor splice sites, respectively, and a hybridization domain. Login to comment

PMID: 22825912 [PubMed] Gavina M et al: "Nebulized Hyaluronan Ameliorates lung inflammation in cystic fibrosis mice."

No. Sentence Comment

113 HA Controls Oxidative Stress and TG2 Activation in CF Epithelia Lung inflammation with increased levels of reactive oxygen species (ROS) characterizes CF airway epithelia as a consequence of defective CFTR function.29 We have reported that a complex alteration of redox balance drives a sequential cascade of events involving upregulation of TG2, autophagy inhibition and lung inflammation in human and mouse CF airways.29-31 To unravel whether the effects of exogenous HA in damping down lung inflammation in vivo was linked to the ability to control the ROS-mediated events, we cultured airway epithelial IB3-1 and CFBE41o cells, carrying DF508/W1282X or DF508/DF508 CFTR mutations respectively,29-31 below referred as ''CF cells,`` with or without 100 mg/ml HA for 24 hr in presence or absence of PA-LPS stimulation (1 mg/ml). 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: 22591852 [PubMed] Scott A et al: "Functional analysis of synonymous substitutions predicted to affect splicing of the CFTR gene."

No. Sentence Comment

121 Evidence of altered splicing was identified in two of the five variants (variants 2 and 5; Fig. 2A), and results were replicated in IB3-1 cells (a mutant CFTR lung epithelial cell line with the CFTR genotype of D508/ W1282X) (Fig. 2B). Login to comment
120 Evidence of altered splicing was identified in two of the five variants (variants 2 and 5; Fig. 2A), and results were replicated in IB3-1 cells (a mutant CFTR lung epithelial cell line with the CFTR genotype of D508/ W1282X) (Fig. 2B). Login to comment

PMID: 22191729 [PubMed] Lobna HL et al: "Analysis of cystic fibrosis transmembrane regulator and azoospermia factor polymorphisms in infertile men in relation to other abnormalities."

No. Sentence Comment

35 Table 1 Summary of reported compound genetic abnormalities in CFTR patients References CFTR Karyotype Y-del SA Exam FSH Testis histology Current study (2011) )/), 5T/5T 46,XY AZFa+b Azoo Bil Vas NA NA Current study (2011) )/), 6T/6T 46,XY AZFa+b Azoo Bil Vas NA NA Current study (2011) )/), 5T/5T 46,XY AZFa+b+c Azoo Bil Vas NA NA Karpman et al. (2007) W1282X/), WT/WT 46,XY AZFb+c Azoo Bil Vas 4 Late, incomplete maturation Karpman et al. (2007) I148T/), WT/WT 46,XY AZFb+c OAT Bil Vas 19 NA Schulz et al. (2006) F508/), WT/WT 45,XY, der(14;22) None OAT Bil Vas NA NA Dohle et al. (2002) F508/), 7T/9T 46,XY AZFc OAT Hpogonadism 7.3 NA Dohle et al. (2002) R117/H/) 47,XXY None Azoo Hpogonadism 11 NA Meng et al. (2001) F508/), 7T/9T 46,XY AZFb Azoo CBAVD NA Sertoli cell only Black et al. (2000) )/), 5T/9T 46,XY, inv(6)(p12q21) None Azoo CBAVD 8.8 Late, incomplete maturation Azoo, azoospermia; Bill Vas, bilateral vas deferens present; CBAVD, congenital bilateral absence of the vas deferens; CFTR, cystic fibrosis transmembrane receptor; FSH, follicle stimulating hormone, NA, not available; OAT, oligoasthenoteratozoospermia; SA, semen analysis; WT, wild type; AZF, Azoospermia factor. Login to comment

PMID: 22495616 [PubMed] Dreux S et al: "Relationship of non-visualization of the fetal gallbladder and amniotic fluid digestive enzymes analysis to outcome."

No. Sentence Comment

35 Non-visualization of the gallbladder was associated with hyperechogenic bowels in four cases (F508del homozygous in three; del508F/405+1G->A), with dilated bowel in one case (F508del homozygous) and with both signs in two cases (2347delG/CFTRdele14b-15; W1282X/del2->6b). Login to comment

PMID: 22496330 [PubMed] Trinh NT et al: "Improvement of defective cystic fibrosis airway epithelial wound repair after CFTR rescue."

No. Sentence Comment

33 Cell culture Several non-CF and CF cell lines have been used: NuLi-1 (non-CF) and CuFi-1 (homozygous F508/F508) (gifted by Dr. J. Zabner, University of Iowa, [20]), IB3 (ΔF508/W1282X, ATCC) and S9 (wt-CFTR genetically repaired CF IB3 cells, ATCC), CFBE41o- transduced with wt-CFTR (CFBE-wt) or F508-CFTR (CFBE-F508) [21] (kindly provided by Dr. J. Hanrahan, McGill University). 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
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
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
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

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
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

PMID: 22135344 [PubMed] Chaudhary N et al: "Cystic fibrosis transmembrane conductance regulator regulates epithelial cell response to Aspergillus and resultant pulmonary inflammation."

No. Sentence Comment

58 IB3 cell line (DF508/W1282X) and CFTR- corrected wild-type (WT) cell line (S9) were purchased from ATCC (Manassas, VA). Login to comment

PMID: 22079487 [PubMed] Kivlehan F et al: "Three-dimensional hydrogel structures as optical sensor arrays, for the detection of specific DNA sequences."

No. Sentence Comment

45 Detection of complementary target sequences down to nanomolar concentrations was observed, allowing for low detection limits of target sequences that contain mutations p.W1282X and p.F508del relative to the cystic fibrosis transmembrane conductance regulator gene (CFTR; OMIM ID: 602421). Login to comment
50 Probe sequences used in the detection of p.W1282X and p.F508del mutations were provided by The Wellcome Trust Centre, University of Oxford, and are also described in Table 1. Login to comment
61 Name Oligonucleotide sequence (50 to 30 ) Length Probe 1-Cy5 + NH2 Cy5-TACAGGCTTACCGTCATAGGT-C7-Aminolinka 21 Probe 1-NH2 C6-Aminolinkb -TACAGGCTTACCGTCATAGGT 21 Target 1-Cy5 Cy5 Ester-ACCTATGACGGTAAGCCTGTA 21 Probe 2-Cy5 + NH2 Cy5-GCCTAAGCCCTCTTTCTCAGT-C7-Aminolinka 21 Probe 2-NH2 C6-Aminolinkb -GCCTAAGCCCTCTTTCTCAGT 21 Target 2-Cy5 Cy5 Ester-ACTGAGAAAGAGGGCTTAGGC 21 W1282X-wt AAAGGCTTTCCTCCACTGTTGCGATCATGTCGAAGGA 22 W1282X-mut AAGGCTTTCCTTCACTGTTGCGATCATGTCGAAGGA 23 DF508-wt AAATATCATCTTTGGTGTTTCCTATGGATCATGTCGAAGGA 26 DF508-mut AAAGAAAATATCATTGGTGTTTCCTATGGATCATGTCGAAGGA 28 a Primary amino group at the end of seven carbon spacer. Login to comment
75 Cy5-labeled p.W1282X and p.F508del PCR primers (Metabion International AG) were used in standard PCR. Login to comment
76 Concentrations of 280-300 and 200-250 nM were recorded using the 2100 Bioanalyzer system for the 87-bp p.W1282X and 105- bp p.F508del PCR products, respectively, using an Agilent DNA 1000 kit. Login to comment
118 Two mutations in the CFTR gene associated with cystic fibrosis were selected: the p.W1282X mutation where a tryptophan group at position 1282 of the CFTR gene is replaced by a stop codon as a result of a nucleotide change from G to A at position 3978 [33], and the more commonly known p.F508del mutation, which consists of a 3 base deletion of CTT at position 508 of the gene. Login to comment
125 Fluorescence intensities obtained resulted in a ratio of 3.6 for wild-type over mutant for the p.W1282X probes, and a ratio of 2.9 for wild-type over mutant for the p.F508del probes (as was expected). Login to comment
126 Results obtained from hybridization reactions with the heterozygous (wt/mut) PCR products correctly showed an equal level of Cy5 fluorescence between the probes in each pair, resulting in ratios of 0.93 for the p.W1282X probes, and 1.05 for the p.F508del probes. Login to comment
128 The detection of these mutations and successful discrimination between wild-type and mutant allele sequences was achieved down to lower target concentrations of $1 nM, an example of which is shown in Fig. 7 for the detection of p.W1282X homozygous target. Login to comment
132 Fig. 8 shows that we were able to replicate the same fluorescence intensity ratios for hybridization of p.W1282X heterozygous target, with a time period ranging from 2 h down to 15 min. Login to comment
140 Hybridization between p.W1282X-wt and -mut probes immobilized within 25% (v/v) hydrogel spots (4 lM) and denatured p.W1282X PCR wt/wt homozygous products of (i) 78.6 nM, (ii) 7.2 nM, (iii) 1.08 nM, and (iv) 0.72 nM. Login to comment
170 Hybridization between p.W1282X-wt and -mut probes immobilized within 25% (v/v) hydrogel spots (4 lM) and denatured W1282X ($49 nM) PCR wt/mut heterozygous products, (i) prehybridization reaction for W1282X-wt, (ii) posthybridization reaction and washes for W1282X-wt, (iii) prehybridization reaction for W1282X-mut; (iv) posthybridization reaction and washes for W1282X-mut. Login to comment
187 Acknowledgments We acknowledge the financial support of Enterprise Ireland for funding of this project (Grant PC-2008-030), support from Wellcome Trust grant # 075491/Z/04 to J.R. for providing the p.W1282X and p.F508del probes in this work, and Suzanne Crotty from the Electron Microscopy Facility Biosciences Institute in UCC for her help with the confocal microscopy work. Login to comment

PMID: 22137130 [PubMed] Cordovado SK et al: "CFTR mutation analysis and haplotype associations in CF patients."

No. Sentence 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
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
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

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: 22056837 [PubMed] Saint-Criq V et al: "Azithromycin fails to reduce inflammation in cystic fibrosis airway epithelial cells."

No. Sentence Comment

33 Cell culture IB3-1 is a bronchial epithelial cell line derived from a cystic fibrosis patient with a F508del/W1282X CFTR genotype. Login to comment

PMID: 21983161 [PubMed] Spicuzza L et al: "Mild cystic fibrosis in patients with the rare P5L CFTR mutation."

No. Sentence Comment

4 The P5L variant was associated with ΔF508 in 5 patients and with W1282X in two patients. Login to comment
57 Five patients also carried the ΔF508 mutation in the second allele while two carried the W1282X mutation. Login to comment

PMID: 21917531 [PubMed] Handschick M et al: "Frequency of the hyperactive W493R ENaC variant in carriers of a CFTR mutation."

No. Sentence Comment

53 A. Caucasians a F508del 378 2184delA 2 CFTRdele2,3(21 kb) 4 2789+5 G-A 1 R117H 1 I1005R 1 405+1 G-A 1 L1077P 1 H199Y 1 Y1092X 1 L206W 1 3601-111 G-C 1 R347P 3 3849+10 kb C-T 1 Q414X 1 3850-3 T-G 1 G551D 4 W1282X 1 R553X 8 N1303K 2 1717-1 G-A 1 4374+1 G-T 1 2143delT 1 Unknown 9 B. Turks K68N 1 1525-1 G-A 1 G85E 1 F508del 2 E92K 1 1677delTA 1 CFTRdele2(ins186) 2 2184delA 1 CFTRdele2,3(21 kb) 2 3601-2 A-G 1 435insA 1 Unknown 1 a The subjects were born in Austria (N=9 subjects), Belgium (2), France (4), Germany (374), Greece (4), Italy (12), The Netherlands (7), Poland (2), Spain (5), Sweden (2) and United Kingdom (5). 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

92 In contrast, for the 28 individuals in the ''CF suspicion`` group who showed lumen-negative responses, i.e., normal CFTR function (Isc-CCH(IBMX/Fsk) = 2153.38615.33 mA/ cm2 vs Isc-CCH(IBMX/Fsk) = 2162.07619.64 mA/cm2 in the non-CF control group) we could only detect one CF-causing mutation (F508del) in one individual (being thus a CF-carrier) and 2 other mutations in two individuals who were thus compound heterozygous: W1282X/4428insGA and F508del/D1152H, respectively (Table S1). Login to comment

PMID: 22649552 [PubMed] Tang A et al: "Inflammasome-mediated IL-1beta production in humans with cystic fibrosis."

No. Sentence Comment

170 IB3-1 cells were derived from a patient expressing the DF508 and W1282X mutations and CuFi-1 were derived from a DF508 homozygous patient. Login to comment
169 IB3-1 cells were derived from a patient expressing the DF508 and W1282X mutations and CuFi-1 were derived from a DF508 homozygous patient. Login to comment

PMID: 22069317 [PubMed] Suaud L et al: "4-Phenylbutyrate stimulates Hsp70 expression through the Elp2 component of elongator and STAT-3 in cystic fibrosis epithelial cells."

No. Sentence Comment

21 Sodium 4-phenylbutyrate (4PBA) improves ⌬F508-CFTR intracellular trafficking in CF epithelial cells such as the IB3-1 CF human bronchiolar epithelial cell line (genotype ⌬F508/ W1282X) as early as 4 h after exposure, and restores CFTR function at the plasma membrane without altering CFTR mRNA expression (16). 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
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
42 ARMS PCR program for W1282X mutation began with a 1 min incubation at 95°C, and Proceeded with 32 cycles, each with 1 min of denaturation at 95°C, 30 s of annealing at appropriate temperature and 45 s of extension at 72°C; with a 5 min incubation at 72°C completing the amplification.PCR conditions for amplification of above DNA samples stood as described earlier [21]. 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
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: 21605700 [PubMed] Njoroge SW et al: "Increased Delta5- and Delta6-desaturase, cyclooxygenase-2, and lipoxygenase-5 expression and activity are associated with fatty acid and eicosanoid changes in cystic fibrosis."

No. Sentence Comment

214 The IB3 cell line consists of immortalized bronchial epithelial cells from a CF patient with a compound heterozygous genotype (ΔF508/W1282X) [49]. 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
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
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
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

PMID: 22156145 [PubMed] Peleg L et al: "The D1152H cystic fibrosis mutation in prenatal carrier screening, patients and prenatal diagnosis."

No. Sentence Comment

173 Carrier rate Total individuals screened 49,940 Total CF carriers 1524 1:33 D1152H carriers 195 1:255 Table 3 D1152H in conjunction with CF-related symptoms No. Mutations Age Sex Reason for referral 1 D1152H/ W1282X 30 F Mild asthma during childhood that disappeared in adulthood. Login to comment
176 No pancreatic insufficiency. 6 D1152H/ D1152H 40 M CBAVD, no respiratory symptoms or pancreatic insufficiency. 7 D1152H/ W1282X 30 F Recurrent pneumonia during childhood. Login to comment
178 No pancreatic insufficiency. 8 D1152H/ W1282X 21 M CBAVD, no respiratory symptoms or pancreatic insufficiency. 9 D1152H/ D1152H 17 M Bronchiectasis, recurrent lung infections, lately with Aspergillus, nasal polyps, no pancreatic insufficiency. Login to 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: 21966101 [PubMed] Prasad R et al: "Molecular basis of cystic fibrosis disease: an Indian perspective."

No. Sentence Comment

107 W1282X and 621?1G-T, that occur with a frequency greater than 1% in Non-Hispanic Caucasians [42] were also not detected. 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: 19389632 [PubMed] Park HJ et al: "A soluble sulfogalactosyl ceramide mimic promotes Delta F508 CFTR escape from endoplasmic reticulum associated degradation."

No. Sentence Comment

213 The cystic fibrosis cell line IB3-1 (DF508/W1282X) and the S9 (IB3 cells transfected with wtCFTR) were maintained in LHC-8 serum free medium supplemented with 5% FBS and 1% antibiotics as described previously (Emam et al., 2006). Login to comment
214 The cystic fibrosis cell line IB3-1 (DF508/W1282X) and the S9 (IB3 cells transfected with wtCFTR) were maintained in LHC-8 serum free medium supplemented with 5% FBS and 1% antibiotics as described previously (Emam et al., 2006). 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: 18815075 [PubMed] Dechecchi MC et al: "Anti-inflammatory effect of miglustat in bronchial epithelial cells."

No. Sentence Comment

46 Cell lines and bacteria IB3-1 is a human bronchial epithelial cell line, immortalised with adeno12/SV40, derived from a CF patient with a F508del/ W1282X mutant genotype [20]. Login to comment
228 Moreover, CuFi-1 cells are homozygous for the F508del-CFTR mutation whereas IB3-1 cells are compound heterozygous for the F508del-CFTR mutation (genotype F508del/W1282X). Login to comment
231 Moreover, CuFi-1 cells are homozygous for the F508del-CFTR mutation whereas IB3-1 cells are compound heterozygous for the F508del-CFTR mutation (genotype F508del/W1282X). 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: 18455968 [PubMed] Farra C et al: "Cystic fibrosis: a new mutation in the Lebanese population."

No. Sentence Comment

46 Recently, a panel of 11 common mutations accounting overall for 70% of all Arab CF chromosomes have been reported : ΔF508del, 3120+1G"A, N1303K, W1282X, G115X, 711+1G"A, S549R, I1234V, 1548delG , H139L and 4010del4 [9]. Login to comment
63 Of all the CF alleles reported in the Lebanese population by Desgeorges et al. [4], four were included in the 11 most common Arab CF alleles: ΔF508del, N1303K, W1282X and 4010del4 accounting for around 60% of the reported Lebanese CF alleles. 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

63 Continued Exon Primer Sequences GC length Amplicon length (bp) Introns Number of heterozygous- positive controls Number of homozygous- positive controls Recommended control 16 LSCFE16Fmod 5Ј-CCGCTGAATGCGTCTACTGTGATCCA-3Ј 3 299 bp 77 6 G970R LSCFE16Rmod 5Ј-CCGTAGACAGGACTTCAA CCCTCAATCAA-3Ј 3 87 3120ϩ1GϾA 17a LSCFE17AFmod 5Ј-CCGCCGGACACACTTTG TCCACTT-3Ј 6 286 bp 49 13 3121-1GϾA LSCFE17ARmod 5Ј-CCGCCGTCAAATAGCTCTTATAGCTTTTTT ACAAGATG-3Ј 6 25 I1027T 17b LSCF17BAFmod 5Ј-CCGCCGCCCCGCCGTCAGGTACA AGATATTATG-3Ј 14 56 11 3272-26AϾG LSCF17BARmod 5Ј-CCGCCGCCGCAGTGTTGACAGGT ACAAGAAC-3Ј 7 247 bp A1067T LSCF17BBFmod 5Ј-CCGCCCTTACTTTGAAACTCTGTT CCACAAAGC-3Ј 4 247 bp T1095T LSCF17BBRmod 5Ј-CCGCCGTTGATAACCTATAGAATG CAG-3Ј 6 62 E1104X 18 LSCFE18Fmod 5Ј-CCGCCGAGTCGTTCACAGAAGA GAGAAATAAC-3Ј 6 236 bp 34 2 D1152H LSCFE18Rmod 5Ј-CCGCCGCCGCGGTACTTTGTT ACTTGTCTGAATTTTTTT-3ЈCATAA 12 25 3547delA 19 LSCF19i5mod 5Ј-CCGCCGCCGCGCATCAAACTA ATTGTGAAATTGTCTGCC-3Ј 10 408 bp 73 10 S1235R LSCF19i3mod 5Ј-CCGCCGCCGCACACATTGCT TCAGGCTACTGGGA-3Ј 11 49 R1162L 20 LSCF20i5mod 5Ј-CCGCCGCCGCCGCTACTGAATTATGT TTATGGCATGG-3Ј 13 323 bp 44 13 W1282X LSCF20i3mod 5Ј-CCGCCGCCGCTCTTGAGTACAAGTA TCAAATAGCAG-3Ј 10 50 4005ϩ33GϾA 21 LSCFe21F 5Ј-CCGCCGCCGCGCAAGTTATTCATA CTTTCTTCTTCTTT-3Ј 12 217 bp 15 5 1 N1303K LSCFe21R 5Ј-CCGCCGCCGCTATATCAGCCA TTTGTG-3Ј 8 47 Q1313X 22 LSCFe22FmodC LSCFe22 RmodD 5Ј-CCGCCGAGAATGTCAAC TGCTTGAGTGT-3Ј 6 311 bp 41 2 R1358S 5Ј-CCGCCGGCAGGCATAATGA TTCTGTTCCCAC-3Ј 10 51 I1366T 23 LSCFE23Fmod 5Ј-CCGCCGCCGCAAGGTAAAT ACAGATCAT-3Ј 9 259 bp 44 3 4374ϩ1GϾT 4374ϩ13AϾG LSCFE23Rmod: 5Ј-CCGGCAGGAACTATCACAT GTGAGATTG-3Ј 3 53 24 LSCFE24FmodB 5Ј-CCGCCGCTTTGAGCCTGT GCCAGTTTCTGT-3Ј 6 378 bp 58 5 1 Q1463Q LSE24RmodB 5Ј-CCGCCGACGAGCTCCAATTC CATGAGGTGA-3Ј 6 62 Y1424Y the same technique: the majority of our samples were extracted by a classical saline technique or an automated extraction and their quality was adequate. 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
103 In the 13 patients who had a W1282X mutation as the only type of nonsense mutation (homozygous W1282X or W1282X/ΔF508), the amount of W1282X transcript was associated with the most electrically negative value for total chloride transport after either treatment phase (r=0·57, R²=0·32, p=0·046). 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
153 These results accord with in vitro data that show that PTC124 does not modify mRNA transcription or stability.8 Preclinical work has previously shown that it is possible to alter translational fidelity at the site of a premature stop codon without modifying the surveillance mechanism that is responsible for degrading mutatedmRNAthroughtheprocessofnonsense-mediated decay.31,32 Our pharmacological strategy was based on the assumption that sufficient mRNA containing a nonsense mutation must be present to provide a template for protein production during drug-induced ribosomal read-through.7,33 We tested this presumption in the largest subset of patients in our study with a single CFTR genotype-W1282X. 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: 18372427 [PubMed] Boncoeur E et al: "Cystic fibrosis transmembrane conductance regulator controls lung proteasomal degradation and nuclear factor-kappaB activity in conditions of oxidative stress."

No. Sentence Comment

44 Cell Culture and Oxidative Stress Conditions The CF patient-derived lung epithelial cell system that we used was IB3-1 cells (CFTR genotype ⌬F508/W1282X), and the IB3-1-derived cell line S9 that was stably transduced to achieve low-level expression of full-length WT CFTR. 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: 17825628 [PubMed] Fichou Y et al: "Estimating the age of CFTR mutations predominantly found in Brittany (Western France)."

No. Sentence Comment

22 doi:10.1016/j.jcf.2007.07.009 W1282X and N1303K) have frequencies N1% in the CF population [5]. 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

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

PMID: 18047834 [PubMed] Taminelli GL et al: "CISD1 codifies a mitochondrial protein upregulated by the CFTR channel."

No. Sentence Comment

18 IB3-1 cells (ATCC CRL-2777) are bronchial epithelial cells derived from a CF patient (DF508/W1282X genotype) [24]. Login to comment

PMID: 17936667 [PubMed] Boncoeur E et al: "Oxidative stress induces extracellular signal-regulated kinase 1/2 mitogen-activated protein kinase in cystic fibrosis lung epithelial cells: Potential mechanism for excessive IL-8 expression."

No. Sentence Comment

1 We here report the effects of oxidative stress (hyperoxia, 95% O2) on the expression of pro-inflammatory interleukin (IL)-8 and CXCR1/2 receptors in two human CF lung epithelial cell lines (IB3-1, with the heterozygous F508del/W1282X mutation and CFBE41o- with the homozygous F508del/F508del mutation) and two control non-CF lung epithelial cell lines (S9 cell line derived from IB3-1 after correction with wtCFTR and the normal bronchial cell line 16HBE14o-). Login to comment
46 Cell culture and hyperoxia-mediated oxidative stress IB3-1 is a bronchial epithelial cell line derived from a CF patient with a CFTR genotype of F508del/W1282X. Login to comment

PMID: 17572159 [PubMed] Loumi O et al: "CFTR mutations in the Algerian population."

No. Sentence Comment

78 In our study, we identified 9 homozygous CF patients: four F508del/F508del, one N1303K/N1303K, two 711+1G→T/ 711+1G→T, one 1609delCA/1609delCA and one W1282X/ W1282X. 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

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

PMID: 17204267 [PubMed] Conner GE et al: "The lactoperoxidase system links anion transport to host defense in cystic fibrosis."

No. Sentence Comment

80 All three individuals had one DF508 allele, one had a second W1282X allele (nonsense mutation), while the second alleles in the other two patients were unidentified. Login to comment
82 Transport rates for cultures from each CF individual were: D F508/W1282X, 1.69 ± 0.32 (n = 8) and 2.41 ± 0.72 (n = 5) as well as 3.65 ± 2.34 (n = 3) for the other two. Login to comment
84 Transport rates for cultures from each CF individual were: D F508/W1282X, 1.69 &#b1; 0.32 (n = 8) and 2.41 &#b1; 0.72 (n = 5) as well as 3.65 &#b1; 2.34 (n = 3) for the other two. 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
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
120 It is interesting to note that p.W1282X and c.1717-1G> A mutations, two of the most common in Buenos Aires study, were not found in our patients. 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
118 It is interesting to note that p.W1282X and c.1717-1G> A mutations, two of the most common in Buenos Aires study, were not found in our patients. Login to comment

PMID: 16472777 [PubMed] Nguyen TD et al: "Novel short chain fatty acids restore chloride secretion in cystic fibrosis."

No. Sentence Comment

29 Airway IB3-1 cells, compound heterozygotes for the CFTR mutations DF508 and W1282X, were used as in vitro model for DF508-CFTR correction since the W1282X mutation results in a truncated protein that is not expressed [8]. Login to comment
31 Gentamycin (and amphotericin B contained in the same mixture) was omitted from the culture medium when the effect of aminoglycosides on the W1282X mutation was studied. Login to comment
74 Because IB3-1 cells are DF508/W1282X compound heterozygotes for the CFTR gene, effects of SCFAD on the W1282X mutation rather than the DF508-CFTR should be considered. Login to comment
136 However, because these cells are compound heterozygotes for W1282X, a premature CFTR stop mutation that can be suppressed with aminoglycosides, a possible SCFAD effect on this mutation was considered [11]. Login to comment
139 However, the much smaller response observed with W1282X-CFTR read-through, as induced by aminoglycosides, suggests that the larger response observed with SCFAD is mediated via DF508-CFTR correction, as previously asserted [2,3]. Login to comment

PMID: 16647268 [PubMed] Chan MM et al: "Increased NaCl-induced interleukin-8 production by human bronchial epithelial cells is enhanced by the DeltaF508/W1282X mutation of the cystic fibrosis transmembrane conductance regulator gene."

No. Sentence Comment

2 The objectives of this study were: (i) to determine the relative contribution of three potential cis-regulatory elements in the regulation of NaCl-induced IL-8 production in BEAS-2B human bronchial epithelial cells, (ii) to compare NaCl-induced IL-8 expression in IB3-1 bronchial epithelial cells, which have the DF508/W1282X mutation of the CF transmembrane conductance regulator (CFTR) gene, with that in C38 cells, which are IB3-1 cells stably transfected with a truncated but functional CFTR gene, and (iii) to compare equal osmolar concentrations of NaCl and D-sorbitol in the induction of IL-8 in all three cell types. Login to comment
4 Human bronchial epithelial cells with the DF508/W1282X CFTR mutation produce an exaggerated amount of basal and NaCl-induced IL-8. Login to comment
49 IB3-1 epithelial cells were derived from a CF patient with a compound heterozygous mutation of CFTR (DF508/W1282X) [30]. Login to comment
125 IB3-1 epithelial cells with the DF508/W1282X CFTR mutation produces more IL-8 basally and with osmotic stimulation than cells rescued with a functioning CFTR Since epithelial cells in CF individuals have a defect in the CFTR membrane protein, we investigated whether a Clÿ channel defect affects IL-8 production in response to NaCl or D-sorbitol. Login to comment
127 The IB3-1 cells exhibit the DF508/W1282X CFTR mutation. Login to comment
134 Discussion In this study, we showed that: (i) NaCl increased IL-8 protein expression in human bronchial epithelial cells, (ii) BEAS-2B cells were more sensitive to NaCl stimulation in that IL-8 expression was increased and toxicity occurred at lower concentrations compared to equivalent osmolarity of D-sorbitol, (iii) the binding sites for NFkB, AP-1, and NF-IL-6 play important regulatory roles in the induction of IL-8 by NaCl, (iv) bronchial epithelial cells with defective CFTR (DF508/ W1282X) produced significantly more IL-8 constitutively and in response to NaCl stimulation than cells with functioning CFTR, and (v) in contrast to BEAS-2B cells, IB3-1 and C38 human bronchial epithelial cells were more sensitive to D-sorbitol than to equiosmolar concentrations of NaCl. Login to comment
179 (A) IB3-1 cells with defective CFTR due to a DF508/W1282X mutation and C38 cells in which wild-type CFTR has been stably transfected were stimulated with NaCl at the indicated concentrations for 48 h and the cell supernatants assayed for IL-8. Login to comment
192 Indeed, airway epithelial cells with either the DF508/DF508 or the DF508/W1282X CFTR mutation produce more IL-8 in response to TNFa [46] or to infection with Pseudomonas aeruginosa [47,48]. 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

54 Patient CFTR mutation found 1 AG DF508/IVS8-5T 5 AG DF508/IVS8-5T 6 AG DF508 IVS8-5T 7 AG DF508/IVS8-5T 8 AG DF508/IVS8-5T 9 AG DF508/IVS8-5T 12 AG R117H/R117H 16 AG DF508/R1162X 18 AG N1303K/R1162X 21 AG DF508/IVS8-5T 23 AG R347H/R117H 24 AG N1303K/R117H 25 AG DF508/W1282X 27 AG N1303K/IVS8-5T 29 AG DF508/IVS8-5T 30 AG N1303K/W1282X 32 AG DF508/IVS8-5T 34 AG R347H/R117H 36 AG DF508/N1303K 38 AG IVS8-5T/IVS8-5T 39 AG DF508/R117H 40 AG DF508/N1303K Concerning the most prevalent mutation in our study, DF508, we found a higher proportion in our patients than that found in Argentine patients (Levy et al., 2004), 35% vs. 20.8%. 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
159 These are c.1525-1GϾA found in Pakistan, c.1649TϾC found in Lebanon, c.3170CϾT found in Turkey, and c.3661AϾT found in Bahrain.39 - 42 Two mutations that were common in the rest of the world, p.G551D and p.W1282X, were not found in this group of Iranian CF patients.43,44 This suggests that there has been some divergence in the CFTR mutation spectrum in recent human history and has implications for mutation screening in West Asia and North Africa. 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: 15890513 [PubMed] Eaker S et al: "Detection of CFTR mutations using ARMS and low-density microarrays."

No. Sentence 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

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

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
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

PMID: 16378926 [PubMed] Marcus-Soekarman D et al: "Hyperechogenic fetal bowel: counseling difficulties."

No. Sentence 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

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

53 Table 1. Continued CFTR location Amino acid change Nucleotide change 141 IVS 16 Splicing defect 3120 ϩ 1GϾA 142 IVS 16 Splicing defect 3121 - 2AϾG 143 IVS 16 Splicing defect 3121 - 2AϾT 144 E 17a Frameshift 3132delTG 145 E 17a I1005R 3146TϾG 146 E 17a Frameshift 3171delC 147 E 17a Frameshift 3171insC 148 E 17a del V1022 and I1023 3199del6 149 E 17a Splicing defect 3271delGG 150 IVS 17a Possible splicing defect 3272 - 26AϾG 151 E 17b G1061R 3313GϾC 152 E 17b R1066C 3328CϾT 153 E 17b R1066S 3328CϾA 154 E 17b R1066H 3329GϾA 155 E 17b R1066L 3329GϾT 156 E 17b G1069R 3337GϾA 157 E 17b R1070Q 3341GϾA 158 E 17b R1070P 3341GϾC 159 E 17b L1077P 3362TϾC 160 E 17b W1089X 3398GϾA 161 E 17b Y1092X (TAA) 3408CϾA 162 E 17b Y1092X (TAG) 3408CϾG 163 E 17b L1093P 3410TϾC 164 E 17b W1098R 3424TϾC 165 E 17b Q1100P 3431AϾC 166 E 17b M1101K 3434TϾA 167 E 17b M1101R 3434TϾG 168 IVS 17b 3500 - 2AϾT 3500 - 2AϾT 169 IVS 17b Splicing defect 3500 - 2AϾG 170 E 18 D1152H 3586GϾC 171 E 19 R1158X 3604CϾT 172 E 19 R1162X 3616CϾT 173 E 19 Frameshift 3659delC 174 E 19 S1196X 3719CϾG 175 E 19 S1196T 3719TϾC 176 E 19 Frameshift and K1200E 3732delA and 3730AϾG 177 E 19 Frameshift 3791delC 178 E 19 Frameshift 3821delT 179 E 19 S1235R 3837TϾG 180 E 19 Q1238X 3844CϾT 181 IVS 19 Possible splicing defect 3849 ϩ 4AϾG 182 IVS 19 Splicing defect 3849 ϩ 10 kb CϾT 183 IVS 19 Splicing defect 3850 - 1GϾA 184 E 20 G1244E 3863GϾA 185 E 20 G1244V 3863GϾT 186 E 20 Frameshift 3876delA 187 E 20 G1249E 3878GϾA 188 E 20 S1251N 3884GϾA 189 E 20 T1252P 3886AϾC 190 E 20 S1255X 3896CϾA and 3739AϾG in E19 191 E 20 S1255L 3896CϾT 192 E 20 Frameshift 3905insT 193 E 20 D1270N 3940GϾA 194 E 20 W1282R 3976TϾC 195 E 20 W1282X 3978GϾA 196 E 20 W1282C 3978GϾT 197 E 20 R1283M 3980GϾT 198 E 20 R1283K 3980GϾA 199 IVS 20 Splicing defect 4005 ϩ 1GϾA 200 E 21 Frameshift 4010del4 201 E 21 Frameshift 4016insT 202 E 22 Inframe del E21 del E21 203 E 21 N1303K 4041CϾG 204 E 24 Frameshift 4382delA Genomic and Synthetic Template Samples Where possible, native genomic DNA was collected. 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: 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

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
186 Table 3. Continued CFTR mutations Alleles Relative mutation frequency (%) (of 317) G567A 1 Ͻ1 S573C 1 Ͻ1 E585X 1 Ͻ1 T604S 1 Ͻ1 F693L 1 Ͻ1 V754 mol/L 1 Ͻ1 2108delA 1 Ͻ1 2184delA 1 Ͻ1 2215insG 1 Ͻ1 2585delT 1 Ͻ1 2752 - 6TϾC 1 Ͻ1 E831X 1 Ͻ1 D836Y 1 Ͻ1 Y913X 1 Ͻ1 S945L 1 Ͻ1 L967S 1 Ͻ1 3171delC 1 Ͻ1 3199del6 1 Ͻ1 3271 ϩ 8AϾG 1 Ͻ1 R1066H 1 Ͻ1 R1070W 1 Ͻ1 Y1092X 1 Ͻ1 W1098C 1 Ͻ1 3500 - 2AϾT 1 Ͻ1 4016insT 1 Ͻ1 4374 ϩ 13AϾG 1 Ͻ1 D1152H 1 Ͻ1 R1158X 1 Ͻ1 R1162X 1 Ͻ1 W1282X 1 Ͻ1 N1303K 1 Ͻ1 Q1313X 1 Ͻ1 P1372L 1 Ͻ1 R1438W 1 Ͻ1 Total 317 100 Table 3. 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

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

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

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
69 of chromosomes (frequency %) p.E1104X 17b 2 (0.47) p.R1158X 19 3 (0.70) p.R1162X 19 2 (0.47) c.3659delC 19 1 (0.23) c.3737delA 19 2 (0.47) p.I1234V 19 1 (0.23) c.3849+10kbCNT intron 19 4 (0.93) c.3850-1GNA intron 19 1 (0.23) p.G1244E 20 1 (0.23) p.W1282X 20 2 (0.47) p.N1303H 21 1 (0.23) p.N1303K 21 13 (3.02) p.Q1313X 21 1 (0.23) c.4382delA 24 1 (023) Mutations described for the first time by our laboratory appear in bold. 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
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: 15271383 [PubMed] Farinha CM et al: "A comparison of 14 antibodies for the biochemical detection of the cystic fibrosis transmembrane conductance regulator protein."

No. Sentence Comment

37 Although not shown, analyses were also performed in the following cell lines: the human bronchial epithelial cell line IB3-1 (CFTR genotype F508del/W1282X) [18], the human colonic cell line HT29, endogenously expressing wt-CFTR [19], and the human tracheal cell line SCFTE29o- (CFTR genotype F508del/F508del) [20]. Login to comment
99 CFTR was not detected in non-transfected BHK cells (Fig. 2A, lane 1) or in F508del/W1282X IB3-1 cells (not shown). Login to comment
113 CFTR was not detected by IP in non-transfected BHK cells (Fig. 3A, lane 1), nor in F508del/ W1282X IB3-1 cells (not shown). Login to comment
96 CFTR was not detected in non-transfected BHK cells (Fig. 2A, lane 1) or in F508del/W1282X IB3-1 cells (not shown). Login to comment
110 CFTR was not detected by IP in non-transfected BHK cells (Fig. 3A, lane 1), nor in F508del/ W1282X IB3-1 cells (not shown). Login to comment

PMID: 15236173 [PubMed] Coates SW Jr et al: "Inhibition of neutral sodium absorption by a prostaglandin analogue in patients with cystic fibrosis."

No. Sentence Comment

39 Results Of the 5 patients with CF studied with a balanced electrolyte solution, 4 are homozygous for the ⌬F508 mutation and the remaining patient is homozygous for the W1282X mutation. Login to comment
57 Sex/age (yr) CFTR mutation analysis Meconium ileus Body mass indexa Forced vital capacity (% predicted) Forced expiratory volume in 1 second (% predicted) Work/school statusb Sweat chloride concentrationc Balanced electrolyte solution 1 M/34 ⌬F508/⌬F508 No 22 64 45 1 120 2 F/20 ⌬F508/⌬F508 No 21 81 91 1 110 3 M/28 ⌬F508/⌬F508 Yes 18 35 23 2 77 4 F/38 ⌬F508/⌬F508 No 22 58 39 3 70 5 F/21 W1282X/W1282X Yes 22 77 76 1 111 Bicarbonate-free solution 1 F/20 ⌬F508/N1303K No 21 28 20 3 100 2 F/22 ⌬F508/⌬F508 No 17 30 22 2 87 3 F/33 ⌬F508/1898ϩ1G-A No 23 112 106 1 113 4 F/27 ⌬F508/⌬I507 No 22 77 56 3 105 5 M/28 ⌬F508/⌬F508 Yes 18 35 23 2 77 6 M/18 ⌬F508/M1101K Yes 21 94 96 1 81 7 M/18 ⌬F508/M1101K Yes 22 98 96 1 96 NOTE. Login to comment
99 The response of the patient who is homozygous for the W1282X mutation was similar to the responses of 4 patients who are homozygous for the ⌬F508 mutation. Login to comment
120 Four of the 5 patients were homozygous for the ⌬F508 mutation (circles), and one was homozygous for the W1282X mutation (triangle). 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

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: 15463893 [PubMed] Braunstein GM et al: "Purinergic signaling underlies CFTR control of human airway epithelial cell volume."

No. Sentence Comment

54 Cell culture The bulk of experiments were performed with the IB3-1 CF human bronchial epithelial cell line that is compound heterozygous for the DF508 and W1282X CFTR mutations. Login to comment
119 IB3-1 cells express the DF508-CFTR and W1282X-CFTR mutations endogenously [35,49]. Login to comment
116 IB3-1 cells express the DF508-CFTR and W1282X-CFTR mutations endogenously [35,49]. 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

87 Examples of carcinoma cells expressing DF508 cDNA was re- common mutations in this class are: W1282X, duced [34]. Login to 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
198 Rubens- Once DF508 CFTR escapes the ER and passes tein and Zeitlin [46] looked at IB3-1 cells (genotype through the Golgi, there are additional barriers to DF508/W1282X) grown in 0.05-5 mM 4-PBA for 2 cross to reach the plasma membrane. 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

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

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

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
25 Finally, mutation W1282X is common in most Mediterranean countries, reaching its highest frequency (36.2%) in Israel (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
55 We used PHYLIP (Felsenstein 1989) to produce maximum-likelihood population trees of allele frequencies of five polymorphisms (no data were available for IVS1CA, for chromosomes carrying G551D or W1282X) of normal and CF chromosomes. 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
61 Table 4 Frequencies, Normal Chromosomes, of Haplotypes 7-16/17-2-7-1, Associated with CF Mutations G551D and W1282X Population Mean Frequency ‫ע‬ SE (%) Tanzanians 3.2 ‫ע‬ 2.2 Biaka 9 ‫ע‬ 2.6 Mbuti 12 ‫ע‬ 4 Saharawi 20.8 ‫ע‬ 3.9 Druze 15.1 ‫ע‬ 3.2 Yemenites 7.5 ‫ע‬ 2.9 Basques 11.2 ‫ע‬ 2.1 Catalans 16.7 ‫ע‬ 2.9 Finns 16.1 ‫ע‬ 4.7 Russians 15 ‫ע‬ 4.6 Adygei 17.3 ‫ע‬ 3.8 Kazakhs 6.7 ‫ע‬ 3.2 Yakut 2.6 ‫ע‬ 1.8 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
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
85 The situation is very different for the two other frequent mutations (G551D and W1282X). 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
96 The current widespread distribution of haplotypes related to G551D and W1282X is compatible with an origin in Europe, although a geographic distribution that would allow us to identify the birthplace of these mutations is not evident. 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

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
45 In addition to these alleles, only three other CF mutations were detected: 621+1 G>T, S549N, and W1282X. Login to comment
57 The three additional mutations found (W1282X, 621+1G>T, and S549N) represent only 1.5% of the CF allele occurrence in this analysis. 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

6 The father was an asthmatic, and a heterozygote for the cystic fibrosis transmembrane regulator (CFTR) mutation W1282X. Login to comment
18 The father of this patient is an asthmatic and a heterozygote for the cystic fibrosis transmembrane regulator (CFTR) mutation W1282X. Login to comment
22 Sweat chloride was 101 mEq/L, and her gene mutations were W1282X and G542X. Login to comment
82 He has a normal sweat test and is heterozygous for the W1282X mutation for cystic fibrosis. Login to comment
102 Although their underlying diseases are different (the father is an asthmatic and the child has CF), they both carry the W1282X mutation for CFTR. 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
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

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

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
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
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

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

PMID: 10228103 [PubMed] Jorissen MB et al: "Genotype-phenotype correlations for the paranasal sinuses in cystic fibrosis."

No. Sentence 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
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: 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

PMID: 9799593 [PubMed] Chiba-Falek O et al: "The molecular basis of disease variability among cystic fibrosis patients carrying the 3849+10 kb C-->T mutation."

No. Sentence Comment

39 These patients were compound heterozygous for the 3849ϩ10 kb C3T mutation and one of the following CFTR mutations: 4 patients carried the ⌬F508 mutation, 2 carried the W1282X mutation, 3 carried the 405ϩ1 G3A mutation, and 1 carried the G85E mutation (Welsh et al., 1995) (Table 1). Login to comment
108 Sex Other mutation Current age (years) Age at diagnosis (years) Sweat chloride (meq/L) Pancreatic status FVC (% predicted) FEV1 (% predicted) Aberrant transcript (% of total) 1 F ⌬F508 25 8 84 PS 92 88 0 2 F W1282X 13 13 95 PS 100 90 3 Ϯ 1 3 M G85E 11 0.3 54 PS-ϾPI 92 68 9 Ϯ 0.5 4 M ⌬F508 11 11 40 PS 51 44 22 Ϯ 1 5a M 405ϩ1 G3A 31, 32 10 63 PS 52, 40 30, 25 23 Ϯ 2, 28 Ϯ 2 6 M W1282X 19 13 97 PS 73 64 17 Ϯ 1 7b M 405ϩ1 G3A 22 5 112 PS 84 65 12 Ϯ 1 8b M 405ϩ1 G3A 21 4 74 PS 44 37 21 Ϯ 2 9b M ⌬F508 18 16 40 PS 78 46 26 Ϯ 1 10b F ⌬F508 10 8 37 PS 104 99 2 Ϯ 0.5 11c F Unknown 32 25 56 PS 25 18 46 Ϯ 2 a This patient was analyzed twice, at a year`s interval. Login to comment
38 These patients were compound heterozygous for the 3849110 kb C3T mutation and one of the following CFTR mutations: 4 patients carried the DF508 mutation, 2 carried the W1282X mutation, 3 carried the 40511 G3A mutation, and 1 carried the G85E mutation (Welsh et al., 1995) (Table 1). 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: 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
224 In NBD2, a few key mutations have been found that include missense mutations (G1349D, D1370N, K1250M, K1250Q, G1244E, S1255P) and several nonsense mutations (W1282X, S1255X, W1316X). 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: 9545412 [PubMed] Grody WW et al: "Diversity of cystic fibrosis mutation-screening practices."

No. Sentence Comment

32 Three laboratories do not include the prevalent W1282X Ashkenazi Jewish mutation, which would seem essential for any test panel directed at a North American urban population. Login to comment
33 Some of the laboratories included written comments that their panels cannot distinguish between mutations DF508 and DI507 (both 3-nucleotide deletions of adjacent codons) or G551D and R553X (two of the more common point mutations), which our ACMG/CAP committee already suspected, based on the results of our earlier CF challenges. 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

27 For the identification of N1303K, W1282X, V520F, C524X and R334W, mutation detection methods based on the analysis of PCR products by appropriate restriction enzymes were used as previously described (Osborne et al. 1992; Shoshani et al. 1992; Picci et al. 1992; Jones 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
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
86 W1282X 20 Trp→Stop at 1282 G→A at 3978 1 (0.82) Vidaud et al. 1990 16. 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

56 However, some genotypes (DF508/L206W, DF508/R347H, DF508/D1152H, DF508/R117H, W1282X/D1152H and even DF508/5T) can induce both CF and CBAVD phenotypes. Login to 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: 9482579 [PubMed] Malone G et al: "Detection of five novel mutations of the cystic fibrosis transmembrane regulator (CFTR) gene in Pakistani patients with cystic fibrosis: Y569D, Q98X, 296+12(T>C), 1161delC and 621+2(T>C)."

No. Sentence Comment

10 Most of these are of low overall frequency, although certain ethnic groups or geographic areas exhibit elevated frequencies of particular mutations, the most notable of these being the W1282X mutation, which is present at a frequency of 60% in Ashkenazi Jewish CF patients (Shoshani et al., 1992). 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

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

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

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: 9374717 [PubMed] Jiang X et al: "Glycosylation differences between a cystic fibrosis and rescued airway cell line are not CFTR dependent."

No. Sentence Comment

216 13), and treatment with 0.1 mg/ml geneticin, which can promote read through from the W1282X allele present in IB3-1 cells (M. Howard and M. Gondor, personal communication). Login to comment

PMID: 9311495 [PubMed] Ho LP et al: "Correlation between nasal potential difference measurements, genotype and clinical condition in patients with cystic fibrosis."

No. Sentence Comment

60 Data analysis Patients were divided into two groups, according to genotype: 1) mutations that fail to generate significant apical membrane protein (∆F508/∆F508, ∆F508/ W1282X, ∆F508/Q493X) and 2) mutations where gene product is present in the apical membrane (∆F508/G551D, ∆F508/ A455E, ∆F508/R117H, G551D/G551D) [12]. 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

88 This study L997F G→C at 3123 exon 17a 1 A2 Fanen et al. (1992) Y1032C A→G at 3227 exon 17a 1 B3 This study 3272-26 A→G A→G at 3272-26 intron 17a 2 D3 Fanen et al. (1992) D1152H G→C at 3586 exon 18 3 C2, A2 Highsmith et al. (pers. comm.) V1153E T→A at 3590 exon 18 1 B3 This study 3659delC deletion of C at 3659 exon 19 1 C2 Kerem et al. (1990) W1282X G→A at 3978 exon 20 1 D3 Vidaud et al. (1991) N1303K C→G at 4041 exon 21 1 B1 Osborne et al. (1991) K1351E A→G at 4183 exon 22 1 A2 This study D1377H G→C at 4261 exon 22 1 C1 Costes et al. (1995) L1388Q T→A at 4295 exon 23 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

71 The first was comprised of 40 patients homozygous or compound heterozygous for the W1282X and ⌬F508 mutations, both associated with severe disease presentation.2,3 In the second group were 20 patients carrying the 3849ϩ10kb C-ϾT mutation, which is associated with higher frequency of PS and a milder phenotype.7,8 Statistical Analysis Mean values of continuous variables were compared using analysis of variance and Student`s t test. Login to comment
76 Six patients were homozygous for the G85E mutation and 6 were compound heterozygote for the G85E and the ⌬F508, W1282X or the 3849ϩ10kb C-ϾT mutations. Login to comment
92 Comparison of the patients carrying the G85E mutation with patients carrying the ⌬F508 and/or W1282X mutations previously associated with PI and the more severe disease (group 1) or with patients carrying the 3849ϩ10kb C-ϾT previously associated with higher frequency of PS and a milder disease (group 2), revealed that the mean age at diagnosis and age at assessment in the group of patients carrying the G85E mutation were not significantly different from those in group 1, but significantly lower than in group 2 (P ϭ .001 for age of diagnosis, P ϭ .04 for age at assessment; Table 2). Login to comment
94 Thus, it seems that patients carrying the G85E mutation have similarly severe disease as patients carrying the ⌬F508 and/or W1282X mutations. Login to comment
98 Genotype Sex Age at Diagnosis Sweat Chloride meq/l Mode of Presentation Current Age Pancreatic Status FEV1 % Predicted Weight Percentile Sputum Culture 1* G85E/G85E F 9 mo 143 Respir ϩ GI Died 13 y PI NA Ͻ3 Klebsiela 2* G85E/G85E M 2 mo 184 Respir Died 10 y PI NA Ͻ3 H influenzae 3* G85E/G85E M 12 y 54 Liver 13 y PS 82 Ͻ3 H influenzae 4 G85E/G85E F 6 mo 157 Respir ϩ GI Died 6 y PI 20 Ͻ3 P aeruginosa 5 G85E/G85E F 2 mo 90 Respir ϩ GI 4 mo PI NA Ͻ3 H influenzae 6 G85E/G85E F 3 mo 97 Respir ϩ GI 6 yr PS 86 35 H influenzae ϩ Staph 7† G85E/⌬F508 M 6 mo 158 GI Died 11 y PI NA 3 NA 8† G85E/⌬F508 M 10 y 108 Screening 12 y PS 83 80 Staph 9 G85E/⌬F508 M 5 mo NA Respir ϩ GI 18 y PI 50 Ͻ3 P aeruginosa ϩ Staph 10 G85E/W1282X F 7 mo 117 Respir 20 y PI 65 50 P aeruginosa 11 G85E/W1282X F 19 y 82 Pancreatitis ϩ Respir 34 y PI 22 50 P aeruginosa 12 G85E/3849 ϩ 10KB M 5 mo 54 Respir 10 y PI 65 97 P aeruginosa * and † Patients are siblings, respectively. Login to comment
101 Comparison of Clinical Data Between CF Patients Carrying the G85E Mutations and Patients Homozygous or Compound Heterozygous for Two Severe Mutations (W1282X and ⌬F508) and Those Carry a Milder Mutation (3849ϩ10kb C-ϾT) Variable G85E W1282X/W1282X ⌬F508/⌬F508 W1282X/⌬F508 3849 ϩ 10kb C-ϾT n 12 40 21 Age at diagnosis* 3.7 Ϯ 6.3 0.7 Ϯ 1.8࿣ 13.2 Ϯ 7.8 Sweat chloride (mmol/L)* 119 Ϯ 38 111 Ϯ 12࿣ 71 Ϯ 18¶ Died, n 4 2 2 Pancreatic sufficiency, %§ 25 0 79 Meconium ileus, %§ 0 33 0 Current age, y† 12.8 Ϯ 8.5 10.8 Ϯ 7.0 19.8 Ϯ 8.8 Weight (percentile)‡ 28 Ϯ 34 24 Ϯ 24 50 Ϯ 34 Forced expiratory volume in 1 second (% predicted) 55 Ϯ 26 (n ϭ 7) 66 Ϯ 28 (n ϭ 24) 55 Ϯ 21 (n ϭ 19) * P Ͻ .0001, † P Ͻ .001, ‡ P Ͻ .01 analysis of variance for three means. Login to 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
129 Severe: ⌬F508/⌬F508, W1282X/W1282X, ⌬F508/W1282X. Login to comment

PMID: 9254864 [PubMed] Desgeorges M et al: "Cystic fibrosis in Lebanon: distribution of CFTR mutations among Arab communities."

No. Sentence Comment

6 Three mutations, ∆F508 (37.5%), W1282X (15.6%), and N1303K (9.4%) accounted for 62.5% of CF alleles. Login to comment
32 Distribution of CFTR mutations A total of ten different CFTR mutants accounting for 87.5% of independent CF alleles was identified, among them three mutations that are common in Caucasian populations, ∆F508 (37.5%), W1282X (15.6%), and N1303K (9.4%), accounted for 62.5% of alleles (Table 1). Login to comment
50 Although the numbers of chromosomes were insufficient for definite conclusion, we noted that the most common CF mutations (W1282X, ∆F508) shared an identical haplotype background among the different communities. Login to comment
61 W1282X was the second most frequent mutation in our sample; it accounts for 60% of CF alleles in Ashkenazim Jews (Shoshani et al. 1994) but is rare in other, non-Jewish different patient groups (1.2% worldwide; The Cystic Fibrosis Genetic Analysis Consortium 1994). Login to comment
62 In our sample of Arab chromosomes, all mutants W1282X were found to be associated with the same haplotype in Maronites, Greeks or Shi- ites, suggesting that they may all be derived from the same origin. 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: 9216449 [PubMed] Heinonen P et al: "Simple triple-label detection of seven cystic fibrosis mutations by time-resolved fluorometry."

No. Sentence Comment

27 Clinical Chemistry 43:7 1142-1150 (1997) Molecular Pathology 1142 (3905insT), W1282X, and N1303K mutations after PCR amplification of the CFTR gene exons 10, 11, 20, and 21. 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
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: 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

51 In cases in which family members were not available, the assignment was performed by the complete correlation between the 9T allele and the AF508 and the N1303K, and between the 7T allele and the W1282X, G85E, D1152H, and W1089X mutations. Login to 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
143 16 Pneumonia F/3 1.5 71 - - - - - NF ND 5T/W1282X 17 Bronchiectasis M/28 0.5 32 - - + + + NF 28 Fertile 5T/ Recurrent pneumonia since age 6 mo of age. 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
113 Further, in populations that have large subpopulations with high frequencies of a particular mutation, for example, Ashkenazi Jews (⌬F508 (27%) and W1282X (51%)),9 inclusion of other mutations to the second tier screen may be warranted. 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
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
160 For example, South Austra- lia15 has a very small Jewish population and, consequently, analysis for the W1282X mutation was not included in the DNA screen. Login to comment
108 Further, in populations that have large subpopulations with high frequencies of a particular mutation, for example, Ashkenazi Jews (DF508 (27%) and W1282X (51%)),9 inclusion of other mutations to the second tier screen may be warranted. 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
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
155 For example, South Austra- lia15 has a very small Jewish population and, consequently, analysis for the W1282X mutation was not included in the DNA screen. 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
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
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: 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
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: 9135734 [PubMed] Porteous DJ et al: "Evidence for safety and efficacy of DOTAP cationic liposome mediated CFTR gene transfer to the nasal epithelium of patients with cystic fibrosis."

No. Sentence Comment

32 Table 1 Anthropometric data Group Patient Gender Age Genotype FEV1 No (% predicted) Placebo 03 Female 33 ⌬F508/R117H 57 06 Male 27 ⌬F508/⌬F508 55 08 Female 29 ⌬F508/A455E 97 11 Female 42 ⌬F508/Q493X 24 15 Male 30 ⌬F508/R560T 20 16 Female 20 ⌬F508/⌬F508 70 18 Female 27 ⌬F508/⌬F508 21 21 Female 20 ⌬F508/⌬F508 20 Mean (s.d.) 6F, 2M 28.5 (7.1) 51.9 (28.1) Treated 01 Male 31 ⌬F508/G551D 45 05 Female 30 ⌬F508/⌬F508 91 09 Male 32 G551D/G551D 37 10 Female 29 ⌬F508/⌬F508 63 13 Male 16 ⌬F508/⌬F508 55 14 Female 37 ⌬F508/G551D 66 19 Male 23 ⌬F508/W1282X 37 23 Female 21 ⌬F508/G551D 53 Mean (s.d.) 4F, 4M 27.4 (6.8) 55.9 (17.8) and illustrative results shown in Figure 3. Login to comment

PMID: 8981951 [PubMed] Rave-Harel N et al: "The molecular basis of partial penetrance of splicing mutations in cystic fibrosis."

No. Sentence Comment

37 1991a), 3 carried the AF508 mutation (Kerem et al. 1989a), 1 carried the N1303K mutation (Osborne et al. 1991), and 1 carried the W1282X mutation (Vidaud et al. 1990) (table 1). Login to comment
51 Biopsies from epithelial epididymis were obtained Table 1 Levels of Normally Spliced RNA Transcribed from the 5T Allele in Nasal and Epididymal Epithelium, and Clinical and Genetic Features NASAL EPITHELIUM EPIDIDYMAL EPITHELIUM (% Normal RNA) (% Normal RNA) PATIENT SEx/AGE DIAGNOSIS GENOTYPE FEV, From ST From Total From 5T From Total 607b M/41 CBAVD ST/ST 88 37 37 24 24 1549 F/19 Healthy ST/ST 83 31 31 ... ... 658b M/36 CBAVD ST/G85E 78 28 14 ... ... 1703 F/33 Healthy ST/G85E 92 62 31 1474b M/17 CF ST/G85E 40 16 8 660 M/29 CBAVD ST/AFS08 91 72 36 20 10 666 M/31 CBAVD ST/AFS08 83 52 26 32 16 662 M/33 CBAVD ST/AFS08 71 24 12 628 M/35 CBAVD ST/N1303K 57 12 6 12 6 642 M/39 CBAVD ST/W1282X 72 12 6 ... ... 610 M/36 CBAVD ST/(unknown mutation) 86 S0 25 ... ... aValues are means of repeated experiments (n = 2-6); variability between experiments was <10% of the mean. Login to comment
80 In cases in which family members were not available the assignment was performed by the complete correlation between the 9T allele and the AF508 and N1303K mutations and between the 7T allele and the W1282X and G85E mutations. 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: 9259194 [PubMed] Friedman KJ et al: "Rapid characterization of the variable length polythymidine tract in the cystic fibrosis (CFTR) gene: association of the 5T allele with selected CFTR mutations and its incidence in atypical sinopulmonary disease."

No. Sentence Comment

102 The fourth man, who presented with azoospermia and chronic lung and sinus disease, was heterozygous for W1282X and was 5T,7T. Login to comment
144 Although the CF mutations W1282X and 3849 + 10kb C>T are prevalent in Ashkenazi Jews (Abeliovich et al., 1992; Shoshani et al., 1992), the frequency of 5T in this population has been reported to be 6% (Kerem et al., 1995), comparable to its frequency elsewhere. 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: 9222762 [PubMed] Jordanova A et al: "SSCP analysis: a blind sensitivity trial."

No. Sentence Comment

22 List of Mutations Included in the Experiment and Original Method of Detection Used by the Referring Laboratory Referring Probe Original method laboratory no.a Mutation Exon of detection Original SSCP conditions Institut de 1 1677delTA 10 Heteroduplexes Recerca 1 1859G/C 12 DDGE Oncologica, 3 W1282X 20 SSCPb 6% 19:1 (AA:bisAA) 4°C 5h 30W Department 4 delF508 10 Heteroduplexes de Genetica 4 Q1313X 20 SSCPb 6% 19:1 (AA:bisAA) 4°C 5h 30W Molecular, 5 1609delCA 10 SSCPb 6% 19:1 (AA:bisAA) RT 28h 10W10% glycerol Barcelona, 7 T582R 12 DGGE Spain 8 1898+3G→A ivs 12 DGGE Molecular 910085 1161delC 7 SSCP/Heteroduplexes 9% 49:1 (AA:bisAA) 4°C 20 h 10V/cm Genetics 860176 1138insG 7 SSCP/Heteroduplexes 9% 49:1 (AA:bisAA) 4°C 20 h 10V/cm Laboratory, 930215 1154insTC 7 SSCP/Heteroduplexes 9% 49:1 (AA:bisAA) 4°C 20 h 10V/cm Royal 930838 delF508 10 SSCP/Heteroduplexes 9% 49:1 (AA:bisAA) 4°C 20 h 10V/cm Manchester 930127 delI507 10 SSCP/Heteroduplexes 9% 49:1 (AA:bisAA) 4°C 20 h 10V/cm Children`s 931205 Q493X 10 SSCP/Heteroduplexes 9% 49:1 (AA:bisAA) 4°C 20 h 10V/cm Hospital, 900592 V520F 10 SSCP/Heteroduplexes 9% 49:1 (AA:bisAA) 4°C 20 h 10V/cm UK G12984 S489X 10 SSCP/Heteroduplexes 9% 49:1 (AA:bisAA) 4°C 20 h 10V/cm 910143 G551D 11 ARMS 930274 S549N 11 SSCP/Heteroduplexes 10% 49:1 (AA:bisAA) 4°C 20 h 10V/cm 920132 1811+1G→C ivs 11 SSCP/Heteroduplexes 10% 49:1 (AA:bisAA) 4°C 20 h 10V/cm 930140 1898+1G→A ivs 12 SSCP/Heteroduplexes 930334 W1282X 20 SSCP/Heteroduplexes 7.25% 49:1 (AA:bisAA) 4°C 20 h 10V/cm 140735 3850-1G→A 20 SSCP/Heteroduplexes 7.25% 49:1 (AA:bisAA) 4°C 20 h 10 V/cm Laboratoire 293 G551D 11 SSCPb 5% 19:1 (AA:bisAA) 4°C 5 h 50W and de Biochimie 5% 19:1 (AA:bisAA) RT 18h 8W 10%glycerol Genetique, 324 S549R 11 ASO Hybridization Centre 649 1898+1G→A ivs 12 DGGE Hospitalier 583 E585X 12 DGGE Universitaire 710 L967S 15 DGGE Montpellier, 325 S945L 15 SSCPb 5% 19:1 (AA:bisAA) 4° 5h 50W and France 5% 19:1 (AA:bisAA) RT 18h 8W 10%glycerol 473 N1303H 21 SSCPb 5% 19:1 (AA:bisAA)4°C 5h 50W and 5% 19:1 (AA:bisAA) RT 18h 8W 10%glycerol 216 300delA 3 SSCP 5% 19:1 (AA:bisAA)4°C 5h 50W and 5% 19:1 (AA:bisAA) RT 18h 8W 10%glycerol 287 394delTT 3 SSCP 5% 19:1 (AA:bisAA)4°C 5h 50W and 5% 19:1 (AA:bisAA) RT 18h 8W 10%glycerol 559 R74W 3 SSCP 5% 19:1 (AA:bisAA)4°C 5h 50W and 5% 19:1 (AA:bisAA) RT 18h 8W 10%glycerol 237 P67L 3 DGGE 1023 R75X 3 DGGE 885 1215delG 7 DGGE 113 Y122X 4 DGGE, SSCP 356 621+1G→T ivs 4 SSCP 5% 19:1 (AA:bisAA)4°C 5h 50W and 5% 19:1 (AA:bisAA) RT 18h 8W 10%glycerol 709 621+2T→G ivs 4 SSCP 5% 19:1 (AA:bisAA)4°C 5h 50W and 5% 19:1 (AA:bisAA) RT 18h 8W 10%glycerol 802 I148T 4 DGGE 1016 Q98R 4 DGGE V75 R117H 4 SSCP 5% 19:1 (AA:bisAA) 4°C 5 h 50W and 5% 19:1 (AA:bisAA) RT 18h 8W 10%glycerol a Identification numbers given by referring laboratories. Login to comment
57 Type of Mutations Detected by SSCP Analysis in This Study Type of mutation Mutation Mutation characteristics Detected by SSCP analysis Deletions 1677delTA deletion of TA from 1677 Yes delF508 deletion of 3 bp from 1655 Yes delI507 deletion of 3 bp from 1648 Yes 1609delCA deletion of CA from 1609 Yes 1161delC deletion of C at 1161 Yes 300delA deletion of A at 300 Yes 394delTT deletion of TT from 394 Yes 1215delG deletion of G at 1215 No Insertions 1138insG insertion of G after 1138 Yes 1154insTC insertion of TC after 1154 Yes Base 1859G/C Yes substitutions W1282X G→A at 3978 Yes Q1313X C→T at 4069 Yes T582R C→G at 1877 Yes 1898+3G→A A→G at 1898+3 Yes Q493X C→T at 1609 Yes V520F G→T at 1690 Yes S489X C→A at 1598 Yes G551D G→A at 1784 No S549N G→A at 1778 Yes 1811+1G→C G→C at 1811+1 Yese 1898+1G→A G→A at 1898 Yes 3850-1G→A G→A at 3850-1 Yes S549R T→G at 1779 Yes E585X G→T at 1885 Yes L967S C→T at 2966 Yes S945L C→T at 2966 No N1303H A→C at 4039 Yes R74W C→T at 352 Yes P67L C→T at 332 Yes R75X C→T at 355 Yes Y122X T→A at 498 No 621+1G→T G→T at 621+1 No 621+2T→G T→G at 621+2 No I148T T→C at 575 Yes Q98R A→G at 425 Yes R117H G→A at 482 Yes FIGURE 1. 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

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 Ƞ6;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
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 Ƞ6;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
136 These cases were mostly observed in Groups 1 and 2, despite a ∆F508 mutation either homozygote or associated with a nonsense mutation (E827X, W846X and W1282X). 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

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

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

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

87 Multiplex PCR has also been used to identify the AF508 and W1282X mutations in the Jewish population from oocytes and single blastomeres (Avner et al., 1994). Login to comment
88 However this procedure requires further analysis including heteroduplex formation and restriction enzyme digest to obtain a result, whereas the ARMS (which can also detect the W1282X in the standard plus kit) does not. 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

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
83 W1282X, R1283M N1303K. 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

84 M, G W1282X 17-07-17 5 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
105 CFTR Haplotypes for Diallelic and Multiallelic DNA Markers for 94 CF Mutations" J44-GATT- 8CA-17BTA- No. of T854-TUB20 17BCA Mutation chromosomes % Normal Laboratory Reference 2-7-1-2 17-47-13 (55.4%) 17-46-13 17-45-13 17-34-13 17-32-13 17-31-14 17-31-13 17-29-14 17-28-13 16-48-13 16-46-14 16-46-13 16-45-13 16-44-13 16-35-13 16-33-13 16-32-13 16-31-14 16-31-13 16-30-13 16-29-13 16-26-13 16-25-13 16-24-13 14-31-13 1-7-2-1 17-7-17 (16.8%) R334W R334W 3860ins31 G1244E R1162X R1162X R1162X G91R MllOlK R347P R334W R117C E92K 3849+lOkbC+T 3293delA 1811+1.6kb A-tG 1811+1.6kb A-tG 2184insA P205S 3659delC G673X 11005R I336K W58S R347P W846X 405+1-A G178R 3905insT R1162X R347H 3100insA E60X 1078delT 4005+1-A K710X 1677delTA H199Y 3601-2AjG 3850-3T+G 3272-26A-tG 3850-1-A 1812-1-A R117H L1059X S492F Y1092X Y569H 3732delA C866Y 711+1G+T 711+1-T G85E 1949del84 2789+5-A H1085R W1282X R1066C 2043delG V456F 2 1 1 1 2 1 6 2 2 1 2 1 1 2 1 1 4 1 1 1 3 2 1 1 1 1 1 1 2 7 1 1 1 1 2 1 1 3 19 3 3 1 1 2 1 1 5 1 1 1 1 3 6 3 5 1 13 2 1 1 - 0.48 0.48 - - - 0.24 - - - 2.65 2.40 1.93 2.65 1.68 2.65 0.72 13.94 13.46 1.93 - 0.72 0.24 3.37 - b b fP fP fP t b,fb.fP h fb t h t h h fP fP b.h b h h b h h h h h fb fb,fP.t fP fP fP9t fP b t fPh b h fb b.fb,h fb*fP b,fP h h t h fb fb,fp,h.t fP fP fb t b.fP,t b,fb,h,t b f b h h fb b,fb.fP,h fP h h Gasparini et al. (1991b) Chilldn et al. (1993a) Devoto et al. (1991) Gasparini et al. (1991b) Dork et al. (1993a) Guillermit et al. (1993) Zielenski et al. (1993) Dean et al. (1990) Dork et al. (1994a) Nunes et al. (1993) Highsmith et al. (1994) Ghanem et al. (1994) Chilldn et al. (1995) Dork et al. (1994a) Dork et al. (1993a) Chilldn et al. (1993b) Kerem et al. (1990) Dork et al. (1994a) Dork et al. (1994a) Cuppenset al. (1993) Fanen et al. (1992) Maggio et al. (personal communication) Audrezet et al. (1993) Vidaud et al. (1990) Dork et al. (1993b) Zielenski et al. (1991a) Chilldn et al. (1994b) Malik et al. (personal communication) Cremonesi et at. Login to comment
135 However, it is difficult to evaluate the age for other mutations that have relative frequencies of between 0.6 and 1.6% (G551D, 1717-1G-+A,and W1282X), but are associated with a single haplotype (17-7-17), since the numberof repeatsat IVS17BTAis very low and less susceptibleto variation. 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

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

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: 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
35 106), for exons5,8, and 18by denaturing gradient gel electrophoresis (DGGE), for exons 3 and 7 by single-stranded conformational polymorphism (SSCP), for W1282X and N1303K by AS0 hybridization to dot-blots (Table 4, p. 106), and for R553X by restriction endonuclease digestion of PCR products. Login to comment
41 AF508 N CACCAAAGATGATATTTTC M AACACCAATGATATTTTCTT 1717-l(G>A) N TGGTAATAGGACATCTC M TGGTAATAAGACATCTC 1898+ l(G>A) N CAAAGAACATACCTTTCAA M TGAAAGATATGTTCTTTG W1282X N CAACAGTGGAGGAAAGCCTT M CAACAGTGAAGGAAAGCCTT N1303K N TAGAAAAAACTTGGATCC M TAGAAAAAAGTTGGATCC PolyT(intron8) 5T TGTGTGTGTTTTTAACAG 7T TGTGTGTTTTTTTAACAG 9T GTGTGTTTTTTTTTAACAG 42-44 42-44 42-44 424 42,44,46 36,40,42 36 36,40,42 aPosthybndlzatlon washes are camed out m 2X SSC, 0 1% SDS solution at incremental temperatures as shown (see Notes 9 and 10). Login to comment
42 Screening in Cystic Fibrosis 107 Table 5 CF Mutations Detectable by Restriction Endonuclease (RE) Digestion of PCR Products Mutation PCR primers0 RE RE digestion product sizes, bpbJ Normal Mutant G85E 621+ 1 (G`V 1154insTC R334W R347P G551D R553X R560T S549N 3849+ IOkb CC ` T) W1282X 3i5 and 313 4i5 and 4i3 Hinff MseI 105 + 204 33,35,71, 118, 181 7i5 and 7i3 MspI, RsaI 50,68,74 + 21V 715 and 7i3 MspI 192 + 218 7i5 and 7i3 CfoI 151+ 259 1li5 and 1113 Mb01 425 1115 and lli3 HzncII 186 + 239 lli5 and lli3 Mae11 425 lli5 and lli3 DdeI 13, 174 + 238 i19F and i19R HphI 88 + 349 2Oi5 and 2Oi3 Mnfl 185 + 288 309 33,35,54,71, 118, 127 50,68,76 + 21gc 410 410 182+243 425 215 + 210 13 + 412 88,127 + 222 473 'See Table 2 bThe expected digestion product sizes for both normal and mutant sequences are shown CTheseproducts may be d1stmgmshedby PAGE 1.2.3. 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

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

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

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

3 The W1282X mutation was not detected at all. 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

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
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

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

PMID: 7541313 [PubMed] Schwiebert EM et al: "CFTR regulates outwardly rectifying chloride channels through an autocrine mechanism involving ATP."

No. Sentence Comment

227 IB3-1 cells are a CF human bronchial epithelial cell line derived from a CF patient compound heterozygous for the AF508 mutation (~F508/W1282X) (Zeitlin et al., 1991; Egan et al., 1992). Login to comment
231 IB3-1 cells are a CF human bronchial epithelial cell line derived from a CF patient compound heterozygous for the AF508 mutation (~F508/W1282X) (Zeitlin et al., 1991; Egan et al., 1992). 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
65 Each family had at least one male with CBAVD and one brother Table I CFTR Mutations and Haplotypes in Israeli Patients with CBAVD CFTR HAPLOTYPESb CFTR ETHNIC ORIGIN AND PATIENT MUTATIONSa XV2C/KM19C GATT TUB18 24M XV2C/KM19c GATT TUB18 24M Ashkenazi Jews: 104-1, 104-10, 610 ................. N1303K/N B 2 1 2 A 1 1 2 613, 645,635 ......................... AF508/N B 2 1 2 C 1 12 643 ......... ............... W1282X/R117H B 1 2 1 C 1 1 2 609,611,615,620,642 ......... W1282X/N B 1 2 1 C 1 1 2 631 ......... ............... W1282X/N B 1 2 1 A 1 1 2 630 ......... ............... D1152H/D1152H C 1 1 2 C 1 1 2 633 ......... ............... D1152H/D1152H D 1 1 2 D 1 1 2 612 ......... ............... N/N B 1 2 1 D 1 2 1 632 ......... ............... N/N B (2) 1 2 A (1) 1 2 640 ......... ............... N/N A/B 2 1 2 D/C 2 1 2 614,624 ........................ N/N A 1 1 2 C 1 12 616 ......... ............... N/N A 1 (2) 2 C 1 (1) 2 644 ........................ N/N A 1 1 (1)C 1 1 (2) 605,636 ........................ N/N C 1 1 2 C 1 12 Non-Ashkenazi Jews: 602 ......... ............... AF508/R117H B 2 1 2 B 1 1 2 604 ........................ AFS08/N B 2 1 2 C 2 2 1 629 ........................A AF508/N B 2 1 2 C 1 1 2 608 ......... ............... N/N B (2) 1 1 D (1) 1 2 628-1, 628-4 ........................ N/N B 2 1 2 C 1 1 2 625,637 ........................ N/N C 1 1 2 C 1 12 603-1, 603-4 ........................ N/N A 2 2 1 A 2 2 1 Arabs: 627 ......... ............... D1152H/D1152H C 1 1 2 C 1 1 2 626, 607-1 ........................ N/N C 1 1 2 C 1 1 2 607-4, 638 ........................ N/N A 1 1 2 C 1 1 2 639 ......... ............... N/N B/A 1 (2) (1) C/D 1 (1) (2) a The data in the column "CFTR mutations" are in the same order (left to right) as in the column "CFRT haplotypes." Login to comment
103 Five mutations-AF508, W1282X, N1303K, D1152H, and R117H-were identified. Login to comment
104 The AF508, W1282X, and N1303K mutations were found on chromosomes carrying the same haplotype as previously found in chromosomes of CF patients carrying these mutations (Sereth et al. 1993). Login to comment
105 The R117H mutation 626 XV2C KM19 GAir M470V a: 1525-61A/G F T854T 'L IVS17B CA 0 TUB18 24M W30 I121 2 2 .2 2 2 2 1 1 1 1 2 1 1 1 1 2 2 1 ;2 11 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 2 2 2 22 2 2 2 1 1 1 1 1 1 1 1 1 222 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 12 5 5 5 5 55 55 55 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 3 72 4 7 U4 7 U4 7 2 3 2 3 4 3 2 3 2 3 4 3 ;U4 Figure 2 Haplotype analysis of the CFTR locus in pedigree 626. 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
66 Each family had at least one male with CBAVD and one brother Table I CFTR Mutations and Haplotypes in Israeli Patients with CBAVD CFTR HAPLOTYPESb CFTR ETHNIC ORIGIN AND PATIENT MUTATIONSa XV2C/KM19C GATT TUB18 24M XV2C/KM19c GATT TUB18 24M Ashkenazi Jews: 104-1, 104-10, 610 ................. N1303K/N B 2 1 2 A 1 1 2 613, 645,635 ......................... AF508/N B 2 1 2 C 1 1 2 643 ......... ............... W1282X/R117H B 1 2 1 C 1 1 2 609,611,615,620,642 ......... W1282X/N B 1 2 1 C 1 1 2 631 ......... ............... W1282X/N B 1 2 1 A 1 1 2 630 ......... ............... D1152H/D1152H C 1 1 2 C 1 1 2 633 ......... ............... D1152H/D1152H D 1 1 2 D 1 1 2 612 ......... ............... N/N B 1 2 1 D 1 2 1 632 ......... ............... N/N B (2) 1 2 A (1) 1 2 640 ......... ............... N/N A/B 2 1 2 D/C 2 1 2 614,624 ........................ N/N A 1 1 2 C 1 1 2 616 ......... ............... N/N A 1 (2) 2 C 1 (1) 2 644 ........................ N/N A 1 1 (1) C 1 1 (2) 605,636 ........................ N/N C 1 1 2 C 1 1 2 Non-Ashkenazi Jews: 602 ......... ............... AF508/R117H B 2 1 2 B 1 1 2 604 ........................ AFS08/N B 2 1 2 C 2 2 1 629 ........................A AF508/N B 2 1 2 C 1 1 2 608 ......... ............... N/N B (2) 1 1 D (1) 1 2 628-1, 628-4 ........................ N/N B 2 1 2 C 1 1 2 625,637 ........................ N/N C 1 1 2 C 1 1 2 603-1, 603-4 ........................ N/N A 2 2 1 A 2 2 1 Arabs: 627 ......... ............... D1152H/D1152H C 1 1 2 C 1 1 2 626, 607-1 ........................ N/N C 1 1 2 C 1 1 2 607-4, 638 ........................ N/N A 1 1 2 C 1 1 2 639 ......... ............... N/N B/A 1 (2) (1) C/D 1 (1) (2) a The data in the column "CFTR mutations" are in the same order (left to right) as in the column "CFRT haplotypes." 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

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/712-1G→;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

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: 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

49 Association of a nonsense mutation (W1282X), the most common mutation in the Askenazi Jewish cysticfibrosis patients in Israel, withpre- sentation of severe disease. 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: 7530908 [PubMed] Egan ME et al: "Differential expression of ORCC and CFTR induced by low temperature in CF airway epithelial cells."

No. Sentence Comment

33 Genotypically the cell line is a compound heterozygote containing the AF508 mutation and a nonsense mutation with a premature termination signal W1282X (unpublished observations). Login to comment

PMID: 8825494 [PubMed] Zielenski J et al: "Cystic fibrosis: genotypic and phenotypic variations."

No. Sentence Comment

596 Finally, variable mRNA splicing has been shown for W1282X. Login to comment
597 Although the W1282X-bearing transcripts are often rapidly degraded, some CF patients can apparently retain the mutant mRNA at a much higher level (160). 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
1274 AssoCIation of a nonsense mutation (W1282X), the most common mutation in the Ashkenazi Jewish cystic fibrosis patients in Israel, with presentation of severe disease. Login to comment
1278 Similar levels of mRNA from the W1282X and thedelta F508cysticfibrosisalleles, in nasal epithelial cells. 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

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

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

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

58 a Detection of mutations in exon 20 (HphI fragment): 3850-3 T-eG (lane 3), S1251N (lane 4), W1282X (lane 5), 4002 A---~G(lane 6). 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

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

PMID: 7530726 [PubMed] Avner R et al: "Preimplantation diagnosis of cystic fibrosis by simultaneous detection of the W1282X and delta F508 mutations."

No. Sentence Comment

12 The two major mutations in the CF Israeli population are AF5O8 (A) (30% of CF mutations in all ethnic groups) and the point mutation W1282X (W) (60% of CF Ashkenazi Jews) (Shoshani et al., 1992). Login to comment
24 W1282X external set (amplified product 473 bp) (Zielenski etal., 1991): 20i-5: 5'GGTCAGGATTGAAAGTGTGCA3' 20i-3: 5'CTATGAGAAAACTGCACTGGA3' 4. Login to comment
25 W1282X internal set (amplified product 270 bp) (Zielenski etal., 1991): Wl: 5TACCTATATGTCACAGAAGT3' (44 bp upstream exon 20) W2: 5'GTACAAGTATCAAATAGCAG3' (70 bp downstream exon 20) Locus-specific amplification The independent amplifications of the W1282X locus and the AF508 locus were performed under the same conditions in both cases using a two-step PCR procedure. Login to comment
40 Schematic representation of multiplex polymerase chain reaction (PCR) for simultaneous amplification of the AF508 and W1282X mutations from a single cell. Login to comment
53 Efficiency of amplification at the CFTR locusa in single cells Type of cells analysed Number of cells amplified at: Single locus W Single locus A Both loci W and A simultaneously Double signal Single W signal Single A signal Oocytes Blastomeres Total 60/98 43/64 103/162 75/110 60/78 135/188 33/65 14/35 57/100 6/65 2/35 8/100 14/65 2/35 8/100 W = W1282X; A = AF508. Login to comment
55 Identification of the W1282X (W) and AF508 (A) mutations simultaneously amplified from genomic DNA. Login to comment
61 Simultaneous amplification and analysis ofAF508 and W1282X Genomic DNA analysis The simultaneous amplification of both sites of mutations, A and W, was performed as described above. Login to comment
82 The simultaneous amplification products of single blastomeres at the W1282X locus (W) and at the AF508 locus (A) were visualized in a 2% agarose ethidium bromide-stained gel. Numbers indicate the expected sizes of the amplified products. Login to comment
85 Analysis of mutations W1282X (W) and AF508 (A) simultaneously amplified in single blastomeres. Login to comment
94 W1282X and AF508 are the two most common mutations in the CF Israeli population. 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

18 PCR-amplified DNA containing mutations R117H, S1255P, W1282X, and 3905insT was kindly supplied by the European Concerted Action on Cystic Fibrosis. Login to comment
25 Polym. Frameshift Polym. Frameshift Y1092X S1255P W1282X Frameshift N1303K Polym. Login to comment

PMID: 7519398 [PubMed] Schwiebert EM et al: "Heterotrimeric G proteins, vesicle trafficking, and CFTR Cl- channels."

No. Sentence Comment

145 Similar results were observed in several CF cell lines [ZCFSMEo- cells, compound heterozygous for CFTR AF508/unknown mutation (lo), IB3-1 cells, compound heterozygous for CFTR AF508/ W1282X (33)] and in CF nasal epithelial cells (AF508 CFTR homozygous) in primary culture (data not shown). 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

PMID: 7525964 [PubMed] Miedzybrodzka ZH et al: "Evaluation of laboratory methods for cystic fibrosis carrier screening: reliability, sensitivity, specificity, and costs."

No. Sentence 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

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
37 somes with W1282X, apart from one on haplotype D, are from haplotype B). Login to comment
47 In our study, W1282X has a higher frequency than in the rest of France (CFGAC). 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
130 28 Shoshani T, Augarten A, Gazit E, 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. 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

53 All studied DNA samples had a mutation on one CF allele except for the DNA sample with W1282X, which is from a homozygous CF patient. Login to 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: 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

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

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

69 1 Kerem et al. 1990 1 394 del TT 3 0.05 Claustres et al. 1993 1 E60X 3 0.05 unpublished data 1 621 + 1 G---~T intron 5 0.05 Zielenski et a1.1991 1 876 - 14 del 12 NT 6a 0.05 Audr6zet et a1.1993 1 Q493X 10 0.05 Kerem et al. 1990 1 1507 10 0.05 Kerem et al. 1990, Schwartz et al. 1991 1 1717 - 1 G---~A intron 10 0.05 Kerem et al. 1990, Guillermit et al. 1990 1 K710X 13 0.05 Fanen et al. 1992 1 L610S 13 0.05 This study 1 E83 IX 14a 0.05 This study 1 W846X 14a 0.05 Vidaud et al. 1990 1 $945L 15 0.05 Claustres et al. 1993 1 Y1092X 17b 0.05 unpublisheddata 1 3359 del CT 17b 0.05 Mercier et al. 1993 1 RI066C 17b 0.05 Fanen et al. 1992 1 W1204X 19 0.05 Costes et al. 1993 1 R1162X 19 0.05 Gasparini et al. 1991 1 W1282X 20 0.05 Vidaud et al. 1990 175 Identified 96.1 6 Unidentified 3.9 15 No blood left to perform the complete analysis 196 Total The affected child has a pancreatic insufficiency. Login to comment
75 For example, G551D in exon 11 is consistent with a Celtic origin and W1282X is the most common mutation in the Ashkenazi Jews in Israel (Shoshani et al. 1992). 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
64 In contrast, when 16 W1282X homozygotes and 22 W1282X/AF508 heterozygotes were compared, no difference was found in the disease phenotype (Shoshani et al. 1992). 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

6 Among Ashkenazi Jewish CF patients one major mutation, W1282X, was found in 60% of the CF chromosomes (3). Login to comment

PMID: 7520797 [PubMed] Cuppens H et al: "CFTR haplotype backgrounds on normal and mutant CFTR genes."

No. Sentence 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
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
84 The 875+40A-G mutation was found on the W1282X chromosome. Login to comment
96 The 1717-1G-A and W1282X mutations shared the same haplotype at the centromeric site of the CFTR gene, but differed in the intragenic regions of the CFTR gene, except for the M470V locus. 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
180 These conclusions were drawn from the observation that of the 7 studied mutations that shared the same haplotype background at the centromeric region of the CFTR gene, 2 of them, 1717- 1G- A and W1282X, shared a different intragenic haplotype. Login to comment
181 We also found here that of the mutations that shared haplotype background 122 (XV2c/KM19/D9), the 1717- 1G-A, 2183AA-G and W1282X CFTR genes did not share identical alleles at several intragenic polymorphic loci. Login to comment
184 In fact, within the group of 122 (XV2c/KM19/D9) mutant CFTR genes, of all 6 intragenic polymorphic loci tested, this was the only common allele that was even shared by the 1717- 1G-A and W1282X mutant CFTR genes. Login to comment

PMID: 7514288 [PubMed] Santis G et al: "Recent advances in cystic fibrosis."

No. Sentence Comment

17 For example, the W1282X mutation accounts for 48% of CF chromosomes in the Ashkenazi Jewish population, and the 621 + lG-*T mutation for 23% of French Canadian CF chromosomes.78 Knowledge of the ethnicdistribution of CFTR mutations is therefore essential for prenatal diagnosis and heterozygote screening. 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
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
64 Three other mutations-R553X, W1282X, and N1303K-are rare in many populations, and any deviation from expected frequencies cannot be determined from our study. 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
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
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

PMID: 7517189 [PubMed] Rosenfeld MA et al: "Gene transfer to freshly isolated human respiratory epithelial cells in vitro using a replication-deficient adenovirus containing the human cystic fibrosis transmembrane conductance regulator cDNA."

No. Sentence Comment

33 A C F respiratory epithelial cell line, IB3-1 [originally derived from the bronchial epithelium of an individual with C F (a compound heterozygote with the common AF508 C F mutation and the W1282X mutation); (Zeitiin et al., 1991; G. Cutting, Johns Hopkins University, personal communication)] was a gift of P. Zeitiin (Dept. 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

10 The cycling parameters were: initial denaturation at 94°C for 5 min. followed by 30 cycles of 94°C 30 sec, 57°C 30 sec, 72°C 1 min. and a final step at 72°C for 7 min. SSCP analysis of exon 20 was performed on 14% acrylamide gels with several different mutations used as heterozygous controls (W1282X, 4005 +1 G - A , 3850 - 1 G - A , G1244E, P1290P) (Fig. 1A). Login to comment
24 Lane 1, normal individual N/N; lane 2, W1282X/N; lane 3, 3850-1 G-A/N; lane 4, 4005 + 1 G-A/N; lane 5, P1290P/N; lane 10, G1244V/N; lane 11, G1244E/N; lanes 6, 7, 8, 9, 12 investigated patients without mutations in exon 20. 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
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

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: 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

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
112 The 875 + 40A --~ G polymorphism was found on a W1282X allele. 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
111 The 875 + 40A --~ G polymorphism was found on a W1282X allele. 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

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
77 Two mutations associated with the B haplotype, W1282X and 1717-1G--->A, were found to be associated with a completely different intragenic haplotype, 121, in 56 of 57 (98%) of the chromosomes carrying these mutations. Login to comment
78 One chromosome, carrying the W1282X mutation, was associated with the haplotype 221, which varies from the rest of the chromosomes at the GATT repeat site. 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
86 All chromosomes carrying the W1282X and the 1717-1G--~A mutations and associated with the intragenic haplotype 121 were associated with allele 2 at the exon 14a polymorphic site and all the rest of the studied chromosomes, associated with the intragenic haplotype 212, were associated with allele 1 at this polymorphic site. Login to comment
87 The three chromosomes (one with the W1282X mutation, one with the Q359K/T360K mutation, and one with the AF508 mutation) associated with a different allele at the repeat site were identical at the 14a polymorphic site to the rest of the chromosomes carrying the same mutation. Login to comment
88 Note that the number of haplotyped chromosomes carrying the W1282X mutation does not represent the frequency of this mutation in the Israeli CF population (Shoshani et al. 1992a). Login to comment
89 Since the W1282X mutation is associated with a rare intragenic haplotype, 121, in cases of unavailable or noninformative parents, patients heterozygous for this mutation were frequently heterozygous for the intragenic haplotype, and, therefore, their haplotype could not be phased. Login to comment
95 The chromosomes associated with the extended haplotype B121 carry two mutations, W1282X and 1717-1G-+A. Login to comment
96 The W1282X mutation accounts for 60% of CF chromosomes of Ashkenazi origin (Shoshani et al. 1992a). Login to comment
100 The association of a completely different intragenic haplotype with the W1282X and the 1717-1G--+A mutations indicates that the common region is not part of most of the CFTR locus itself. 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: 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

19 Furthermore, different ethnic groups also have varying frequencies of CF mutations; for instance W1282X, a nonsense mutation in exon 20, accounts for 60% of all Ashkenazi Jewish CF chromosomes, but only 2% of the Sepharadic Jewish CF chromosomes (7). Login to 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
14 In contrast, Shoshani et al"5 showed that the most common CF mutation in the Ashkenazi Jewish population, W1282X, which is located in exon 20, is clearly associated with a severe phenotype. We previously classified the only known homozygous R553X patient as being moderately severely affected. Login to comment
110 Transcription studies of patients homozygous for the stop mutation W1282X within exon 20 of the CFTR gene (that is, its 3' end), which is associated with a severe phenotype,'5 as well as mRNA analysis of other patients homozygous for nonsense mutations will help to come to a better understanding of the relationship between the location of nonsense mutations, and their influence on the mRNA level and the clinical phenotype. We thank C Stewart and B Gerrard, PRI/ DynCorp, Frederick, Maryland, for technical assistance. Login to comment
147 Association of a nonsense mutation (W1282X), the most common mutation in the Ashkenazi Jewish cystic fibrosis patients in Israel, with presentation of severe 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
68 In nine patients the mutation identified was W1282X, a nonsense mutation on exon 20, predicting the production of truncated polypeptides. 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

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
49 Mutations I148T A120T E92K 621+1G->T R334W 1078delT CFSOKBdeUM G551D G54 AJ507 lDuIKJt AF5O8 2X If*A Iv 1OA 28691m '10X }f)a\OA (G 3601-111G->C R1162X 3860)ns31 R1158X 3€€7deM I W1282X 141303K | | 1 2 3 Exons Markers 6 7 8 8 • b 10 11 12 13 14 15 • t> 16 17 18 19 20 21 22 23 24 IVS8CA IVS17BTA / IVS17BCA 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
138 CFTR mjcrosatellhe haplotypes for 19 CF mutations Haplotypes 8CA 16 17 23 14 16 17 16 16 16 17 17 16 21 22 17BTA 7 7 7 31 31 31 44 43 46 45 46 - 31 30 17BCA 17 17 17 13 13 13 13 13 13 13 13 - 13 13 Mutation 1609delCA (0.9) AI507 (0.6) G551D (0.5) 3667del4 (0.1) W1282X (0.7) R1158X(0.1) I148T (0.1) 1949del84 (0.3) K710X (0.3) 1078ddT (0.1) R1162X (1.6) 2869insG (0.7) 3601-111G-C (2.1) E92K (0.1) 3860ins31 (0.1) R334W (0.2) CF50KBdel#l (0.3) Chromosomes CF Number 8 5 4 1 5 1 1 3 2 1 7 5 1 18 1 1 2 3 621 + 1G-T (0.2)1 A120T (0.1) 1 % Normal 14.5 2.9 0.6 - 10.0 1.1 1.9 - 3.0 - 0.2 - 0.4 - CF cystic fibrosis; ( ) frequency of mutation in the population. Login to comment
187 Other mutations which are also relatively common (3601 -111G-C, 1609delCA, Rl 162X, W1282X, and AI5O7) were always found associated with the same respective haplotype, which suggests that they have arisen quite recently in the population. This association allows us to use microsatellite haplotypes as frameworks for mutation analysis in populations with a high level of mutation heterogeneity. 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
200 Several mutations were analysed by digestion with restriction enzymes: R1162X/£WeI, 1609delCA/£WeI, N13O3K/D<ieI, KllOX/Xmnl, 3667del4/AfariI, R1158X/§SJNI, G551D/tfincII, W1282X/M/iII, 2869insG/AftoI, 3601-lllG-C/Afa«III, E92K/£coNI, R334W/AftpI and 621 + 1G-T/Miefl. Login to comment

PMID: 7689013 [PubMed] Reiss J et al: "A comprehensive CFTR mutation analysis of German cystic fibrosis patients."

No. Sentence Comment

6 In exon 20, the mutation W1282X (7) was found three times and the mutation 39O5insT (8) was detected once by direct fluorescence sequencing of PCR products using a 37OA (Applied Biosystems, Foster City, USA) and the 'dye primer' or 'dye terminator' protocol, respectively. Login to comment

PMID: 7686577 [PubMed] Lissens W et al: "Mild pulmonary, but severe hepatic disease in a cystic fibrosis patient homozygous for a frameshift mutation in the regulatory domain of the CFTR."

No. Sentence Comment

27 '-' However, on the basis of the large variation in lung function in patients homozygous for the most common CF mutation, AF508, and W1282X homozygotes,5 it was concluded that most CF patients have a common phenotype, but that other genetic and environmental factors may be important for the clinical phenotype.7 We describe a patient, homozygous for a frameshift mutation in the regulatory (R) domain of the CFTR, who presented with mild lung disease but severe hepatic and pancreatic involvement. Login to comment
65 6 Shoshan T, Augarten A, Gazit E, 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. 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
48 The second alteration was confined to 3 DNA samples ( 1.9% of CF chromosomes) and was identified as mutation W1282X (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
71 lnd«p*nd«nt Hybridizations E A ( B ^ 0 E A ( C* 0 E + )Conlrols * ) C o n l r o l « GS42X GSS1D R553X I W1282X N1303K 1 « Pool 1 Probss 2 3 4 • • 9 • 5 • • A( + ) B B A( + ) B A( + ) B A C ) A 807 R1 17H • 21 + 1 8S4tN RS«0T 1 # f Pool 2 Probes 2 3 4 i 5 » 6 A( B B B A( B A(- 1717-1 Figure 3. 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
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
86 of the less common CF mutations were seen in significantly greater frequency in CAVD patients: W1282X had a frequency of 12% compared to <2% among CF patients, and Rl 17H had a frequency of 8% compared to < 1% in CF patients. Login to comment
89 Table I shows that of the eight mothers tested in the CAVD-CF+ group of patients, five were found to be carriers (one for Rl 17H, one for W1282X, and three for Delta F508). Login to comment
92 Cystic fibrosis (CF) mutation frequency in patients with CF and isolated bilateral congenital absence of vas deferens (CAVD) CF mutation Frequency in CF patients Frequency in CAVD CF positive patients R117H W1282X DF508 0.3% (3/812)a 1.6% (9/578) 73% (593/812) 8% (4/52) 12% (6/52) 31% (16/52) a (3/812) indicates three R117H alleles among 812 CF alleles (in 406 patients). 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
145 R117H is one of the transmembrane regions of CFTR, Delta F508, W1282X and R553X are in nucleotide binding regions, and 1717G-A is at the splice border of intron 10 (Kerem et al., 1990; Cutting et al., 1990; Dean et al, 1990). Login to comment
147 Indeed, 1717G-A, Delta F508 and W1282X are associated with the pancreatic insufficient CF phenotype (Kerem et al., 1990) which tends to be a more severe phenotype, whereas Rl 17H has been found only in mildly affected individuals (Dean et al, 1990). Login to comment
148 Four of the six patients with the W1282X mutation were Jewish Ashkenazi and this is in agreement with a previous report where W1282X was found to be the most common CF mutation in this ethnic group (Shashani et al., 1992). 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
266 Association of a nonsense mutation (W1282X), the most common mutation in the Ashkenazi Jewish cystic fibrosis patients in Israel, with presentation of severe disease. 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
67 The W1282X mutation is the most common Ashkenazi mutation in Israel (Shoshani et al. 1992). 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
38 Mutation W1282X was detected by oligonucleotide 1282X (5'-CAACA- GTGAAGGAAAGCCTT-3'), while the oligonucleotide 1282NL (5'-CAACAGTGGAGGAAAGCCTT- 3'), was used to detect the normal allele. 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
43 The W1282X mutation was also identified by cleavage of the PCR product with MnlI (Vidaud et al. 1990). 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
58 In the non-Ashkenazi Jews, the AF508 mutation accounted for 43% of the CF mutations; however, the W1282X (3%) mutation was identified on only one CF chromosome, leaving 54% of the CF mutations unidentified. 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
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
84 In this sample, 13 individuals were detected as heterozygotes for either the W1282X mutation or the AF508 mutation. 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

PMID: 1279852 [PubMed] Tsui LC et al: "The spectrum of cystic fibrosis mutations."

No. Sentence Comment

60 In contrast, while only 22% of the CF chromosomes in the Ashkenazic Jewish population in Jerusalem carry AF508, the frequency for W1282X is 60% (Ref. 15). 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
25 A mutation in exon 20, W1282X, is present in approximately 60% of CF chromosomes in the AshkenaziJewish population (Vidaud et al. 1990). Login to comment
50 Reaction mixes for the other mutations and linked markers were similar, with the following modifications: for exon 11, 150 jM each dNTP and 0.4 jM each primer; for N1303K, 200 jM each dNTP and 1 jM each primer; for XV2c, 100 jM each dNTP and 0.3 jM each primer; for KM19, 200 jM each dNTP and 0.4 jM each primer; and, for W1282X, 200 jiM each dNTP and 0.6 jM each primer. Login to comment
55 C. Restriction Digestion of Amplified Samples For exon 1 1, 12 gI PCR product were digested with 30 U HincII and/or 30 U MboI in a 30-gl reaction mix containing the recommended reaction buffer. Electrophoresis was in a 1.8% agarose gel. For KM19, 12 gI PCR product were digested with 30 U PstI in a 30-il reaction mix containing the recommended buffer. Electrophoresis was in a 1.2% agarose gel. For XV2C, 20 jl PCR product were digested with 30 U TaqI in a 30-pl reaction mix containing the recommended buffer. Electrophoresis was in a 1.8% gel. For W1282X, 20 jgl PCR product were digested with 8 U MnlI in a 30-glreaction mix containing the recommended buffer. Electrophoresis was in a 2.0% gel. Login to comment
78 Direct mutation analysis of the CFTR gene in the patients revealed no copies of AF508, GSS1D, R553X, N1303K, or W1282X. Login to comment
49 The reaction mix for AF508 contained 200 gM each dNTP, 0.6 gM each primer, 1 jg DNA, 2.5 U Promega Taq polymerase, and 5 jl Promega 10 X reaction buffer (500 mM KCl, 100 mM Tris-HCl pH 8.8, 15 mM MgCl2, 1% Triton X-100) in a total volume of 50 pl. Reaction mixes for the other mutations and linked markers were similar, with the following modifications: for exon 11, 150 jM each dNTP and 0.4 jM each primer; for N1303K, 200 jM each dNTP and 1 jM each primer; for XV2c, 100 jM each dNTP and 0.3 jM each primer; for KM19, 200 jM each dNTP and 0.4 jM each primer; and, for W1282X, 200 jiM each dNTP and 0.6 jM each primer. Login to comment

PMID: 1281033 [PubMed] Harris A et al: "Cystic fibrosis gene."

No. Sentence Comment

87 One of these is sufficiently common to warrant specific mention, it is a 'stop' mutation at amino acid 1282 (W1282X).46 Another common mutation in this region is found in exon 21, the substitution of aspargine 1303 by lysine (N1303K)/» IMPLICATIONS OF DISTRIBUTION OF MUTATIONS Clearly the analysis of mutations within CFTR has potential power in shedding light on functionally important regions of the CFTR protein. Login to comment

PMID: 1281032 [PubMed] Super M et al: "Milestones in cystic fibrosis."

No. Sentence 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

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
5 Furthermore, W1282X is the most common CFTR mutation in the Ashkenazi Jewish population, where it is present on 60% of CF chromosomes (6). 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
17 The ASOs are as indicated; the dots are in duplicate. The W1282X/AF508 cDNA is derived from a nasal polyp cell culture; the AF508/unknown cDNA is derived from a tracheal cell culture. Login to comment
33 For the W1282X mutation, cDNA was amplified using Exon 18-5' and Exon 24-3' (3); genomic DNA was amplified using 20i-5 and 2CH-3 (5). Login to comment
35 Figure lb shows the ASO hybridization results from one homozygote and two heterozygotes for the W1282X 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
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
46 Comparison of CF patients homozygous for the W1282X mutation with patients who are compound heterozygotes for the W1282X and AF5O8 mutations revealed that both groups were severely affected (6). 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

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

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

PMID: 1379414 [PubMed] Ferrie RM et al: "Development, multiplexing, and application of ARMS tests for common mutations in the CFTR gene."

No. Sentence 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
142 W1282X: CCCATCACTTTTACCTTATAGGTGGGCCTC. 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
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
145 W1282X: CCCATCACTTTTACCTTATAGGTGGGCCTC. 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

PMID: 1380943 [PubMed] Osborne L et al: "Incidence and expression of the N1303K mutation of the cystic fibrosis (CFTR) gene."

No. Sentence Comment

64 The mean age at diagnosis and mean current age was not significantly different in CF patients with the AF508/ N1303K, N1303K/N1303K, W1282X/N1303K and unknown/N1303K genotypes (Table 2). 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
79 For example, the W1282X mutation has been found in approximately 55% of CF chromosomes of Ashkenazi Jewish origin, but in only 1.6% of CF chromosomes from the general CF population (Shoshani et al. 1991). 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

58 We have previously reported the mutation W1282X (Vidaud et al., 1990a). 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

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

109 Screening of the Ashkenazi population in Israel demonstrated that W1282X is the most common CF mutation, accounting for almost 50% of mutations (Lerer et al. 1992). 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
147 One mutation (W1282X) was found in high frequency in Ashkenazi Israelis, probably reflecting founder effect. Login to comment
225 Nucleic Acids Res 15:7155-7175 Shoshani T, Augarten A, Gazit E, Bashan N, Yahav Y, Rivlin Y, Tal A, et al (1992) Association of a nonsense mutation (W1282X), the most common mutation in the Ashkenazi Jewish cystic fibrosis patients in Israel, with presentation of severe disease. 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
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
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
100 The significance of this observation is unclear, and additional studies with larger sample sizes are required, especially since other patients with nonsense mutations (including one homozygous for W1282X) were not found to be associated with meconium ileus. 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
9 Some mutations have a higher frequency among non-AF508 CF chromosomes in specific ethnic populations, such as the W1282X mutation in Ashkenazi Jews (77% ; Shoshani et al. 1992), or the R1162X mutation among Italians (12% ; Gasparini et al. 1991). Login to comment
17 The following additional mutations were screened in different exons or introns of the CFTR gene: 621+lG--~T in intron 4, 1717-1G--~A in intron 10, W1282X in exon 20, and N1303K in exon 21. Login to comment
29 To detect the presence of W1282X mutation, primers flanking exon 20 (Kerem et al. 1990) were used to amplify this region. 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
57 Science 239 :487-491 Sangiuolo F, Novelli G, Murru S, Dallapiccola B (1991) A serine to arginine (AGT to CTG) mutation in codon 549 of the CFTR gene in an Italian patient with severe cystic fibrosis. Genomics 9 :788-789 Shoshani T, Augarten A, Gazit E, Bashan N, Yahav Y, Rivlin Y, Tal A, Seret H, Yaar L, Kerem E, Kerem B-S (1992) Association of a nonsense mutation (W1282X), the most common mutation in the Ashkenazi Jewish cystic fibrosis patients in Israel, with presentation of severe disease. 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

6 The remaining 55 CF chromosomes were subsequently screened for W1282X by ASO (Allele specific oligonucleotide) hybridisations on dot blot preparations of the exon 20 amplified samples. Login to comment
7 The exon 20 W1282X site was amplified by the polymerase chain reaction using the 20i3' and 20i5' primers (7). Login to comment
13 Lane 1 corresponds to the blank, lane 2 to the control W1282X heterozygote DNA, lanes 3-5 to the three unrelated R1283M heterozygote affecteds, lane 6 to a known normal, and lanes 7/8, 9/10, and 11/12 to the parents of each of the three R1283M affecteds. Login to comment
15 This revealed that only the control W1282X heterozygote DNA was identified as positive for the W1282X mutation. Login to comment
16 To confirm the absence of W1282X in our population we performed an Mnll digest on 10 jtl of the PCR products (according to the manufacturers specifications). Login to comment
17 Normal DNA digests generate 185, 183 and 105 bp fragments, whereas the W1282X mutation destroys a restriction site thereby yielding two fragments of 290 and 183 bp. Login to comment
22 To determine if our new mutation was in the same Mnll site as W1282X we performed a double digest with Hinfl. Login to comment
23 Since the same restriction pattern was observed with our new mutants and the W1282X control DNA, it was clear that they were in the same site. Login to comment
25 Sequencing from a primer 87 bp from the site of the W1282X mutation (5'-T GGA TCA GGG AAG AGT ACT TTG-3'), we identified a novel G-T transversion at position 3980. Login to comment
29 To allow the rapid and specific detection of R1283M, we designed some ASOs (Normal: 5'-AGG CTT TCC TCC ACT G-3', Mutant: 5'-CAG TGG ATG 20i5' 473 bp -- 90 bp 15 - * • Hinfl Fokl Hnll W1282X/R1283M 2Oi3' 183 bp 308 bp 105 bp 185 bp 165 bp Figure 2. Login to comment
31 The position of the sequencing primer and the W1282X and R1283M mutations are marked. Login to comment
50 In screening for R1283M by an Mnll restriction digest it is important to note that one would also identify any W1282X mutants in their population; to distinguish between them the use of ASOs or Fokl digestion is required. 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

25 Most CFTR mutations were investigated by restriction analysis of PCR products (R334W, R347P, A455E, G551D, R553X, 2789+5 G---~A,Rl162X, W1282X) (Cutting et al. 1990; Dean et al. 1990b; Gasparini et al. 1991b; Highsmith et al. 1990; Kerem et al. 1990;Vidaud et al. 1990) (see Table 4). 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
134 1) A455E, G551D, 3659delC, W1282X, and N1303K were first detected on chromosomes of Anglo-Saxon or French origin (Cutting et al. 1990; Kerem et al. 1990; Vidaud et al. 1990; Osborne et al. 1991). 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

8 One sequence alteration which is expected to create a termination at residue 1282 (W1282X) was found in 63 chromosomes. Login to comment
11 Patients homozygous for the W1282X mutation (n = 16) and patients heterozygous for the AF508 and W1282X mutations (n = 22) had similarly severe disease, reflected by pancreatic insufficiency, high incidence of meconium ileus (37% and 27%, respectively), early age at diagnosis, poor nutritional status, and variable pulmonary function. Login to comment
12 In conclusion, the W1282X mutation is the most common cystic fibrosis mutation in the Ashkenazi Jewish patient population in Israel. Login to comment
64 One DNA alternation in exon 20 was found in 10 individuals; this was a G--A substitution at nucleotide position 3978, changing the Trp1282 codon to a stop codon (W1282X) and corresponding to a mutation described elsewhere (Vidaud et al. 1990). Login to comment
66 Of the remaining chromosomes carrying unidentified CF mutations, 63 were found to carry the W1282X mutation; 57 (90%) of these 63 were of Ashkenazi origin. Login to comment
67 Thus, the W1282X mutation is the most common mutation (60%) in the Ashkenazi Jewish patient population (table 1). Login to comment
69 The PCR product (473 bp long) has two MnO sites, one of which is destroyed by the W1282X mutation. Login to comment
70 Digestion of normal DNA (N) reveals three bands: 178, 172, and 123 bp in length. DNA digestion of homozygous for the W1282X mutation (M) reveals two bands: 301 and 172 bp in length. DNA digestion ofheterozygotes for the mutation (H) reveals four bands: 301, 178, 172, and 123 bp. 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
73 DNA marker haplotype analysis for informative families showed that chromosomes carrying the W1282X mutation were associated with haplotype B at the H2.3A/ TaqI and El1PstI loci. 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
81 Therefore, the clinical data for the patients homozygous for the W1282X mutation were compared with those for the heterozygous patients carrying both the AF508 mutation and the W1282X mutation. Login to comment
83 Three patients homozygous for the W1282X mutation died (at ages 0.5, 2, and 12 years), and three patients heterozygous for both AF508 and W1282X died (at ages 0.25, 5, and 23 years). Login to comment
90 This indicates similar severity of pulmonary function in patients either homozygous for W1282X or heterozygous for the W1282X and AF508 mutations, as compared with patients homozygous for the AF508 mutation. Login to comment
91 Two patients were heterozygous for two different termination mutations, W1282X and G542X. Login to comment
92 One Table 2 Comparison of Clinical Characteristics and Pulmonary Function: CF Patients Homozygous for W1282X Mutation versus CF Patients Heterozygous for W1282X and AF508 Mutations W1282X/W1282X W1282X/AF508 No. of patients sampled ............... 16 22 No. (%) with meconium ileus ....... 6 (37) 6 (27) Age at diagnosis (years) ............... .9 ± 2.6 .6 ± .8 Sweat chloride (mmol\liter) .......... 113 ± 12 109 ± 11 Current age (years) ..................... 9.3 ± 7.5 11.6±7.5 Current weight (%-ile) ................. 17 ± 17 28 ± 21 Current height (%-ile) ................. 29 ± 29 27 ± 24 FEV, (% predicted) .................... 64 ± 27(n = 11) 69 26(n = 12) FEV2575 (% predicted) ................ 32 ± 20(n = 11) 52 ± 36(n = 12) NOTE. Login to comment
101 In the present study, we have described the most common CF mutation among Ashkenazi Jews, W1282X, accounting for 60% of the CF chromosomes in the studied group. Login to comment
103 The W1282X mutation has been found to be rare in other, non-Jewish different patient groups; in a worldwide survey, only 1.6% ofthe CF chromosomes were found to carry this mutation (Cystic Fibrosis Genetic Analysis Consortium, unpublished data). Login to comment
106 W1282X is a termination mutation. Login to comment
108 Thepresent study showsthatpatients homozygous for W1282X had disease severity similar to that of patients heterozygous for W1282X and AF508. Login to comment
115 Since pulmonary function inpatients carryingsevere CF mutations (i.e., AF508 and W1282X) have high variability, it is difficult to conclude whether the milder form of pulmonary disease shown in these two patients is genetically determined. 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

35 The remains by far the commonest mutation discovered question is whether the heterozygote with the other in all studied populations except in Ashkenazi Jews CFTR gene apparently nxormal may result in these where, interestingly, an exon 20 mutation, W1282X, features or whether a minor mutation, eg in a comprises 60%. Login to comment
45 83 a stop codon or G542X or W1282X), insertions at Al? Login to comment
52 Compound heterozygotes for AFN N1303K 118* 6 0.96% and G551D or W1282X are no better off than DI507 117* 5 0.81% homozygotes for AF5. Login to comment
54 Compound heterozygotes for W1282X 159* 1 0.24% AF5N and R117H however do have milder disease. 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
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: 2210768 [PubMed] Vidaud M et al: "Three point mutations in the CFTR gene in French cystic fibrosis patients: identification by denaturing gradient gel electrophoresis."

No. Sentence Comment

39 Mutations and associated haplotypes in 4 French CF patients CF patient Mutation Haplotype CF52 W846X A Unknown A CF18 Y913C A AF508 B CF91 W1282X B AF508 B CF147 W1282X B Unknown C ence of heteroduplex bands indicates the existence of a point mutation; all mutations are thus easily detected in heterozygotes. Login to comment
53 We characterized a G-to-A substitution at nudeotide 3978 changing a tryptophan to a stop codon (W1282X) and destroying a MnlI recognition site. Login to comment

PMID: 10459902 [PubMed] Alton EW et al: "Cationic lipid-mediated CFTR gene transfer to the lungs and nose of patients with cystic fibrosis: a double-blind placebo-controlled trial."

No. Sentence Comment

28 The genotypes of these patients were: 12 ࢞F508/࢞F508, one ࢞F508/W1282X, and three ࢞F508/other (ie, no mutation detected after screening for mutations present in 92-94% of UK patients with cystic fibrosis).21 All patients met accepted diagnostic criteria for cystic fibrosis, including an abnormal sweat test, and all patients had a forced expiratory volume in 1 s of at least 70% predicted. 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
55 IB3-1 bronchial epithelial cells were derived from a patient with CF (genotype DF508/W1282X); these cells lack functional CFTR (Zeitlin et al. 1991). Login to comment

PMID: 10866434 [PubMed] Super M et al: "CFTR and disease: implications for drug development."

No. Sentence Comment

53 Now M Wilschanski and colleagues14 have found that gentamicin corrects the intranasal electronegativity in cystic-fibrosis patients with the stop mutations including W1282X, which occurs in 60% of cystic-fibrosis patients of Ashkenazi origin. 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
80 of cases IVS8 17bCA 17bTA XV2c KM19 and (%) DF508/DF508 13 - - - - - b DF508/N1303K 4 - - - - - DF508/I148T 1 - - - - - DF508/W1282X 1 - - - - - DF508/R553X 1 - - - - - W1282X/N1303K 1 - - - - - N1303K/71111G . Login to comment
99 In the first case, the female had been identified as a carrier of DF508 (being the sister of a cystic fibrosis carrier), and the partner had been sequentially characterized as a carrier of W1282X even if the familial anamnesis was negative for cystic fibrosis. 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

63 Only one subject in the control group reported a relative with CF. This subject had been previously screened for ࢞F508 and W1282X (because of ethnicity) and does not carry these CF mutations. 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

35 D`autres exemples de disparit&#e9;s r&#e9;gionales et ethniques sont connus : proportion importante des mutations G551D (6,9 %) et W1282X (48 %) chez les patients respectivement celtes et juifs ashk&#e9;nazes [4]. Login to 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

PMID: 11755047 [PubMed] Gomez-Llorente MA et al: "Analysis of 31 CFTR mutations in 55 families from the South of Spain."

No. Sentence Comment

6 A, R117H, DI507 and W1282X) were detected and accounted for 24.7% of the total. Login to comment
27 The patients and their families were referred to us from six Table 1 Listing of the CFTR mutations which are interrogated in the CF assay used in this study Mutation Location Mutation Location Exon/Intron Exon/Intron DF508 E.10 W1282X E.20 F508C E.10 3905insT E.20 DI507 E.10 N1303K E.21 Q493X E.10 G85E E.3 V520F E.10 621 + 1G ! Login to comment
49 A 2.3 I.14b R117H 1.0 E.4 DI507 1.0 E.10 W1282X 1.0 E.20 Known 68.2 Unknown 31.8 M.A. Go &#b4;mez-Llorente et al. / Early Human Development 65 Suppl. Login to comment
54 A, R117H, DI507 and W1282X, which are relatively common in other European populations. 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
63 At micromolar concentrations 4-PBA increases maturation of CFTR in IB3-1 cells (an immortalised CF cell line containing the mutations ࢞F508 and W1282X).14 This maturation was associated with the functional correction of the ࢞F508 transport defect, perhaps due to increased CFTR mRNA synthesis and/or more efficient folding/trafficking. 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
30 doi:10.1016/S1096-7192(03)00033-7 Four other mutant alleles for CF occur at a relative frequency greater than 1%; however, some mutations are unusually common in specific populations, such as W1282X among Ashkenazi Jews [3]. 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
64 W1282X mutation was also detected by RFLP. Login to comment
65 PCR product of exon 20 has two MnlI sites, one of which is destroyed by the W1282X mutation [22]. 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
87 One patient (1.3%) was a compound heterozygote for DF508 and W1282X mutations (DF508/W1282X). 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
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
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
100 Hybridization of pooled PCR products containing the mutant type alleles, obtained by amplification with mutant oligonucleotide probes, for the 621 +1G-+T, A455E, 1717-1G-+A mutations (F), the G458V, R553X, W1282X mutations (G) and the A1507, C551 D mutations (H) . 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
106 (H) and AF508/W1282X (I) individuals. Login to comment

PMID: 1377276 [PubMed] Lerer I et al: "Cystic fibrosis mutations delta F508 and G542X in Jewish patients."

No. Sentence Comment

59 Addendum Since this manuscript was submitted we have found that the nonsense mutation, W1282X at exon 20,31' is the most frequent mutation in Ashkenazi CF chromosomes accounting for 49% (41/84) of the CF mutations. Login to comment
60 The W1282X mutation was found in one CF chromosome of Turkish origin and in one of North African origin. Login to comment

PMID: 14596935 [PubMed] Owsianik G et al: "Rescue of functional DeltaF508-CFTR channels by co-expression with truncated CFTR constructs in COS-1 cells."

No. Sentence Comment

126 This is at variance with previously published reports, which showed that similar CFTR truncates can function as cAMP-activated chloride channels in Xenopus oocytes [29,37,38] and IB3-1 cells [29], a human bronchial epithelial cell line derived from a CF patient compound heterozygous for the vF508 mutation (vF508/W1282X) [39]. Login to comment

PMID: 15298139 [PubMed] Lewis MJ et al: "Cystic fibrosis."

No. Sentence 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
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

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

PMID: 16084692 [PubMed] Tabary O et al: "Calcium-dependent regulation of NF-(kappa)B activation in cystic fibrosis airway epithelial cells."

No. Sentence Comment

2 The hypothesis that Ca2+ signaling may regulate NF-nB activation was tested in a CF bronchial epithelial cell line (IB3-1, CFTR genotype DF508/W1282X) and compared to the CFTR-corrected epithelial cell line S9 using fluorescence microscopy to visualized in situ NF-nB activation at the single cell level. Login to comment
47 Cell lines and culture conditions The airway epithelial cell lines used were IB3-1 (CFTR genotype DF508/W1282X) and cells derived from IB3-1 that were stably transfected to achieve low-level expression of full-length wild-type CFTR (S9 cells). 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

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
63 p.N1303K, p.W1282X and p.R1162X are the next most frequent mutations, with variations from 0.59% to 3.95% (Table 3). 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
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

PMID: 17254580 [PubMed] Karpman E et al: "Compound genetic abnormalities in patients with cystic fibrosis transmembrane regulator gene mutation."

No. Sentence Comment

9 Result(s): Two patients (3.1%) out of 65 were identified in our database to have compound genetic abnormalities. One patient had a W1282X mutation while the other had an I148T mutation. Login to comment
43 This revealed that he was a heterozygous carrier of the W1282X mutation with a normal poly T tract. Login to comment
100 Study Year CFTR,IVS8-T Kayotype Y-del SA Exam FSH Testis histology Current study 2006 W1282X/afa;,WT/WT 46,XY AZF baf9;c Azo Bil Vas 4 Late, incomplete maturation arrest Current study 2006 I148T/afa;, WT/WT 46, XY AZF baf9;c OAT Bil Vas 19 NA Shulz et al. (11) 2006 F508/afa; , WT/WT 45,XY, der(14;22) None OAT Bil Vas NA NA Dohle et al. (9) 2002 F508/afa;, 7T/9T 46,XY AZFc OAT Hypogonadism 7.3 NA Dohle et al. (9) 2002 R117H/afa; 47,XXY None Azo Hypogonadism 11 NA Meng et al. (10) 2001 F508/afa;, 7T/9T 46,XY AZFb Azo CBAVD NA Sertoli cell only Black et al. (8) 2000 afa;/afa;, 5T/9T 46,XY,inv (6)(p12q21) None Azo CBAVD 8.8 Late, incomplete maturation arrest Note: Azo afd; azoospermia; Bil Vas afd; bilateral vas deferens present; CBAVD afd; congenital bilateral absence of the vas deferens; CFTR afd; cystic fibrosis transmembrane receptor; FSH afd; follicle stimulating hormone; NA afd; not available; OAT afd; oligoasthenoteratozoospermia; SA afd; semen analysis; WT afd; wild type. Login to comment
104 1468.e Fertility and Sterility;de; cases had èc;F508 mutations, whereas these new patients were carriers of the W1282X and I148T mutations. Login to comment
105 The W1282X mutation is the most prevalent CFTR mutation noted in patients of Jewish ancestry compared to other ethnic groups, whereas èc;F508 is the most common in the general population (13). Login to comment

PMID: 17324393 [PubMed] Bhattacharyya S et al: "Increased arylsulfatase B activity in cystic fibrosis cells following correction of CFTR."

No. Sentence Comment

38 The IB3-1 cells were derived from a CF patient with compound heterozygous mutations (ƊF508/W1282X) in the gene encoding CFTR [18]. Login to comment

PMID: 17420005 [PubMed] Muselet-Charlier C et al: "Enhanced IL-1beta-induced IL-8 production in cystic fibrosis lung epithelial cells is dependent of both mitogen-activated protein kinases and NF-kappaB signaling."

No. Sentence Comment

31 The IB3-1 cell line (CF cells) is an adeno-12-SV40-immortalized human bronchial epithelial cell line, CFTR-deficient, derived from a CF patient with the heterozygous F508del/W1282X mutation. Login to comment

PMID: 17466952 [PubMed] Verhaeghe C et al: "Role of IKK and ERK pathways in intrinsic inflammation of cystic fibrosis airways."

No. Sentence Comment

369 [41] Chan MM, Chmura K, Chan ED. Increased NaCl-induced interleukin-8 production by human bronchial epithelial cells is enhanced by the DeltaF508/W1282X mutation of the cystic fibrosis transmembrane conductance regulator gene. 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: 19627168 [PubMed] Rowe SM et al: "Pharmaceuticals targeting nonsense mutations in genetic diseases: progress in development."

No. Sentence Comment

477 As an example of this effect, mRNA levels from the W1282X CFTR allele were restored during aminoglycoside treatment, suggesting that the relationships between PTC readthrough and mRNA stabilization may exist in mammalian cells. Login to 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
532 In the oral and parenteral experiments investigating PTC124 in the CF mouse model, correction of X X CFTR with PTC Unstable mRNA Stabilized mRNA Truncated CFTR (partial activity) W1282X Suppressor agents Genetic modifiers Transcription represents the PTC within the mRNA transcript NMD Baseline expression NMD modifiers Degraded mRNA Truncated CFTR (nonfunctional) ࢏ Faithful translation ࢏ Readthrough (+suppressors) + CFTR potentiator X R1162X Full-length CFTR Full-length (nonfunctional) OR S S S S S CFTR potentiator Full-length CFTR Full-length (nonfunctional) OR S S Suppressor agents 1 2 3 3 3 2 +/- +/- + + + + + + represents PTC Fig. 1. Login to comment
541 Again, this truncated CFTR may be functional (e.g. W1282X CFTR) or nonfunctional (e.g. R1162X CFTR). Login to comment
556 In both studies, the vast majority of patients with PTCs harbored at least one copy of the W1282X CFTR allele, a mutation highly prevalent in CF patients of Ashkenazi Jewish descent. Login to comment
567 In in vitro experiments comparing the R1162X (found immediately prior to the second nucleotide binding domain of CFTR) and W1282X CFTR (found within the second nucleotide binding domain) premature termination codons, W1282X CFTR was noted to be more susceptible to readthrough and exhibited partial activity in the truncated state. Login to comment
568 This was seen despite the presence of common UGA PTCs in both mutations and a +4 codon in the R1162X CFTR that would suggest relative susceptibility to readthrough [W1282X PTC is UGA-A, whereas the R1162X PTC is UGA-G]). Login to comment
569 [59] The results suggest that synthesis of both full-length protein (through PTC suppression) and truncated protein (through stabilization of mRNA) could contribute to CFTR rescue in CF patients harboring W1282X CFTR; alternatively, patients with this mutation might be more sensitive to readthrough. 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

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
18 Other common mutations in this region are G542X, N1303K, W1282X, and R1162X (6). 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
64 N1303K, 711+1G>T and W1282X mutations had frequencies of less than 1%. 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
136 A phase IIa study with ataluren in France was intended to evaluate activity, safety and pharmacokinetic observations in children with nonsense mutation (WG542X, W1282X, R1162X). 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: 22561123 [PubMed] Gambari R et al: "Corilagin is a potent inhibitor of NF-kappaB activity and downregulates TNF-alpha induced expression of IL-8 gene in cystic fibrosis IB3-1 cells."

No. Sentence Comment

42 Cell cultures IB3-1 cells [31], derived from a CF patient with a DF508/W1282X mutant genotype and immortalized with adeno12/SV40, were grown in LHC-8 basal medium, supplemented with 5% FBS, at 37 &#b0;C/5% CO2. Login to comment

PMID: 22682487 [PubMed] Ferec C et al: "[Genetics and modifier genes, atypical and rare forms]."

No. Sentence Comment

38 Pour illustrer ceci, on peut rappeler que la mutation W1282X est la mutation la plus fr&#e9;quente dans la population juive ashk&#e9;naze [5] tandis que la mutation G551D rend compte de 5 % des mutations dans les populations d`origine celte [6]. Login to comment
118 [5] Shoshani T, Augarten A, Gazit E, 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. 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: 23185247 [PubMed] Valdivieso AG et al: "The mitochondrial complex I activity is reduced in cells with impaired cystic fibrosis transmembrane conductance regulator (CFTR) function."

No. Sentence Comment

169 The IB3-1 cells were derived from a CF patient exhibiting the most frequent CF mutation (DF508) in one allele and a non-sense mutation (W1282X) in the other allele [39]. 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

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
377 Restoration of W1282X CFTR activity by enhanced expression. 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

35 However, mutations like the W1282X (p.Trp1282X) show a higher frequency than F508del in some populations such as Ashkenazi Jews (Abeliovich et al. 1992; Shoshani et al. 1992). 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

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

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: 23346057 [PubMed] Villella VR et al: "Targeting the Intracellular Environment in Cystic Fibrosis: Restoring Autophagy as a Novel Strategy to Circumvent the CFTR Defect."

No. Sentence Comment

122 Recently, we have reported that overexpression of BECN1, administration of cystamine, or depletion of SQSTM1 by RNA interference, can favor the trafficking of F508del-CFTR protein to the epithelial cell surface in vitro in CF epithelial cell lines (CFBE41o- or IB3-1, carrying F508del/F508del or F508del/W1282X CFTR,respectively),ex vivo in nasal polyp biopsies from CF patients, and in vivo in CftrF508del mice. 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: 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
76 ASL hydration is achieved through establishment of an osmotic gradient by a predominant efflux of chloride ions through CFTR channels, coupled with a moderate influx of sodium ions through epithelial 100 80 60 40 20 0 Sweat chloride mmol&#b7;L -1 Sweat chloride in CF CFTR protein function % 20 0 40 60 80 100 >60 mmol&#b7;L-1 diagnostic cut-off for CF Normal Normal Carriers Carriers CF with pancreatic insufficiency Class I-III (F508del, G551D, W1282X) CF with pancreatic sufficiency Class IV-V (3849+10kbC-T, A455E) CBAVD with two CF mutations (R117H, 5T) CFTR-related disorder (pancreatitis, bronchiectasis, CBAVD) Adults ? Login to comment

PMID: 23503723 [PubMed] Zhou L et al: "Symmetric snapback primers for scanning and genotyping of the cystic fibrosis transmembrane conductance regulator gene."

No. Sentence Comment

86 Another method for genotyping separated loci is to design a bulge into the snapback hairpin, as demonstrated for exon 23 for variants p.W1282X and c.3870Ab0e;G (Fig. 4). Login to comment
127 Another sample had 1 mutation (p.W1282X) and 1 benign variant (c.3870Ab0e;G) in cis, both within a snapback hairpin that required sequencing. Login to comment
166 Two variants (p.W1282X and c.3870Ab0e;G) separated by 23 bases were genotyped with 1 snapback primer by targeting its 5b18; tail to 2 discontinuous regions, thereby inducing a 10-bp secondary bulge in the hairpin. Login to comment
168 (B), Derivative melting curves of the hairpin after dilution and remelting to distinguish wild type (black lines), heterozygous p.W1282X (thick gray line), and heterozygous c.3870A/G (thin gray line). Login to comment
178 Fig. 4 shows an example of a bulge-inducing snapback primer, in which ACMG mutation p.W1282X is separated by 23 bases from the common variant, c.3870Ab0e;G. Deleting 10 bp between the 2 variants in the complementary snapback tail produces a hairpin that induces a 10-bp bulge in the template. 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
54 As shown in Table 3, close to a half of these PGD cycles (180/404) were performed for 122 couples with the same mutation in both parents, including one with both partners carrying 1-3120G>A, two with both partners carrying W1282X, and 119 with both partners carrying the DF508 mutation. 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
60 of mutations in a couple Patients Cycles Transfers Embryos transferred Pregnancies Babies born 1 122: 119 with DF508, 2 with W1282X; 1 with 3120G>A 180 159 317 81 (50.9) (4a ) 84 2 118 180 150 296 74 (49.3) 78 3 25 (18 male + 7 female) 44 36 72 17 (47.2) (2a ) 13 (3 from affected mothers; 10 from affected fathers) Total 265 404 345 685 172 (49.9) (6a ) 175 (50.7) Values are n or n (%) unless otherwise stated. a Ongoing pregnancies. Login to comment

PMID: 23537407 [PubMed] Clarke LA et al: "Changes in transcriptome of native nasal epithelium expressing F508del-CFTR and intersecting data from comparable studies."

No. Sentence Comment

12 Several CF transcriptomics studies have employed microarrays to measure differences in global gene expression caused by the F508del mutation in isogenic bronchial cells [16] (in this case the CFTR genotype was F508del/ W1282X), primary cultures of tracheal and bronchial cells [17], native nasal epithelial and bronchial cells [18,19] and * Correspondence: laclarke@fc.ul.pt 1 BioFIG - Centre for Biodiversity, Functional and Integrative Genomics; FCUL -Faculty of Sciences, University of Lisboa, Lisboa 1749-016, Portugal Full list of author information is available at the end of the article (c) 2013 Clarke et al. Login to comment
108 vs. 5 controls Affymetrix Custom HsAirwaya520108F Virella-Lowell et al., 2004 [16]1 Isogenic bronchial cells (IB3-1 and S9) F508del/W1282X vs. WT-CFTR corrected: 3 technical replicates each Affymetrix U95Av2 Zabner et al., 2005 [17]1 Primary tracheal and bronchial cell cultures 10 CF (F508del homoz.) 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
133 The enrolled 36 CF patients had an overall of 26 different CFTR alleles, with a major prevalence of the mutation F508del (24/36, 66.7%), and, at a lesser extent, N1303K (6/36, 16.7%), 2789+5G.A (5/36, 13.9%) and W1282X (3/36, 8.3%), accordingly with literature (Table 1) [1,5]. Login to comment
135 Some of them are characteristic of certain ethnic groups, such as W1282X in the original Jews of Central Europe, 3659delC in Sweden and, to come to the Italian reality, T338I in Sardinia, 2183AA.G and R1162X in Northern Italy [1,5]. Login to comment

PMID: 23632450 [PubMed] Megiorni F et al: "Elevated levels of miR-145 correlate with SMAD3 down-regulation in cystic fibrosis patients."

No. Sentence Comment

33 CF cases were F508del/F508del homozygotes (11/18) or carried at least one F508del variant: F508del/W1282X (3/18), F508del/N1303K (1/18), F508del/G85E (1/18), F508del/S549R(A N C) (1/18); one individual was homozygote for CFTR mutations different from F508del (R553X/N1303K). 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

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
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: 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

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

PMID: 23873844 [PubMed] Rymut SM et al: "Reduced microtubule acetylation in cystic fibrosis epithelial cells."

No. Sentence Comment

131 IB3 (èc;F508/W1282X) cells and CFTR-corrected S9 cells were examined for Ac-tub content by Western blot (Fig. 1A). Login to comment

PMID: 23891399 [PubMed] Van Goor F et al: "Effect of ivacaftor on CFTR forms with missense mutations associated with defects in protein processing or function."

No. Sentence Comment

22 http://dx.doi.org/10.1016/j.jcf.2013.06.008 surface can also be due to CFTR mutations that either prevent the synthesis of full-length CFTR (e.g., W1282X: class I mutation) or reduce the amount of CFTR synthesis (e.g., 2789+5G࢐A: class V mutation). Login to comment

PMID: 23892095 [PubMed] de Becdelievre A et al: "COMMD1 modulates noxious inflammation in cystic fibrosis."

No. Sentence Comment

90 IB3-1 cells are compound heterozygous [F508del] + [W1282X] and are a standard cystic fibrosis cell model (CF cells). 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: 23977124 [PubMed] Cifani N et al: "Reactive-oxygen-species-mediated P. aeruginosa killing is functional in human cystic fibrosis macrophages."

No. Sentence Comment

50 Nine of them were F508del homozygous, one was W1282X homozygous, and two carried at least one delta F508del allele (F508del/D192G, F508del/P5L). Login to 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: 23977375 [PubMed] Kim S et al: "Normal CFTR inhibits epidermal growth factor receptor-dependent pro-inflammatory chemokine production in human airway epithelial cells."

No. Sentence Comment

56 Cells containing mutant CFTR versus isogenic cells corrected with wild-type CFTR: Human airway epithelial (IB3) cells expressing mutant CFTR (deltaF508/W1282X; [33]) and isogenic airway epithelial (C38) cells complemented with wild-type CFTR [34] were purchased from American Type Culture Collection, and were grown in LHC-8 medium (Invitrogen, Grand Island, NY) containing 5% fetal bovine serum, penicillin (100 U/ml), and streptomycin (100 mcg/ml) at 37uC in a humidified 5% CO2 water-jacketed incubator. 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: 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

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

PMID: 24141140 [PubMed] Caretti A et al: "Anti-inflammatory action of lipid nanocarrier-delivered myriocin: therapeutic potential in cystic fibrosis."

No. Sentence Comment

61 Cell lines and treatments IB3-1 cells, an adeno-associated virus-transformed human bronchial epithelial cell line derived from a CF patient (ƊF508/W1282X) and its isogenic C38 cells, corrected by insertion of CFTR, have been both obtained from LGC Promochem (US) and kindly provided by the Cystic Fibrosis animal Core Facility (CFaCore, San Raffaele Hospital, Milan, Italy). 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
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
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
98 Qualitatively similar results were obtained for the R1162X and W1282X PTCs (Figures 2D and 2E). Login to comment
99 NB124 (100 mM) induced a 2.5-fold increase in readthrough at the highest dose tested with the R1162X readthrough reporter (Figure 2D), and a 1.9-fold increase in readthrough with the W1282X construct. 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
223 (A and B) CFBE41o2 cells stably expressing CFTR-R1162X (A) or W1282X (B) were incubated with synthetic aminoglycosides (250 mg/ml) for 48 hours, followed by Isc measurements in Ussing chambers. 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
4 Results: Out of 800 subjects, 18% [asthma - 24% (n = 250), CP - 29.33% (n = 150) cases and controls - 9.3% (n = 400)] were positive for heterozygous mutation, 0.8% of the (n = 250) asthmatic cases (n = 250) were homozygous for IVS8 T5 polymorphism while no subjects were found positive for W1282X mutation. 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
66 W1282X mutations, known to be the second most common among North Americans (http://www.genet.sickkids.on.ca), were not detected in the present study. 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

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: 24534272 [PubMed] Cant N et al: "CFTR structure and cystic fibrosis."

No. Sentence Comment

2401 CFTR mutations are classified into 5 groups (Prickett and Jain, 2013): Class 1 mutations cause a defect in CFTR protein synthesis, such as the premature stop codon W1282X; Class 2 mutations, including the common F508, are translated into full-length nascent polypeptide chains but are defective in folding and are thus targeted for degradation rather than trafficked to the PM; Class 3 mutants of CFTR are able to reach the PM but have channel gating defects that decrease channel opening time and decrease chloride flux, e.g. the second most common mutation G551D; Class 4 mutants reach the PM, but have decreased channel conductance even when the gate is open; and Class 5 represent a fully functional CFTR at the PM but with reduced abundance due to defective mRNA splicing. Login to comment

PMID: 24556927 [PubMed] Molinski SV et al: "Genetic, cell biological, and clinical interrogation of the CFTR mutation c.3700 A>G (p.Ile1234Val) informs strategies for future medical intervention."

No. Sentence Comment

18 The mutation 1548delG is most common in these seven countries (17.2%),whereas2043delGismostcommoninBahrain(30.8%) and W1282X is most common in Israel (36.1%). 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

76 2 8 I I s s a l C / I I s s a l C l e d 8 0 5 F / l e d 8 0 5 F 1 2 W1282X/4428insGA Class I/Class IV or VI - 137.5 105.5 130.3 105.5 133.9 5 2 . 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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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
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
143 The frequency of Israeli c.3717+12191C.T (l.n.3849+10kbC.T) [4] was significantly elevated in Poland (3.9%) and Slovakia compared to most of the examined populations (Czechs, Germany, Romania, Serbia, Greece, p,0.005), possibly indicating the Ashkenazi-Jewish contribution; in contrast, the frequency of another Israeli mutation, W1282X [4,12], was significantly lower in Poland (0.61%) than in Romania (p,0.006). 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: 24777605 [PubMed] Lee S et al: "Interference with ubiquitination in CFTR modifies stability of core glycosylated and cell surface pools."

No. Sentence Comment

24 CFTR cDNA vectors were studied in immortalized human airway epithelial cells (IB3-1; F508del/W1282X heterozygous mutation in CFTR) (14), which were cultured in LHC-8 medium (Gibco, Grand Island, NY) containing 10% fetal bovine serum (FBS) and 1% antibiotic/antimycotic at 37&#b0;C in 4% CO2. Login to comment

PMID: 24859760 [PubMed] Umunakwe OC et al: "Abnormal n-6 fatty acid metabolism in cystic fibrosis is caused by activation of AMP-activated protein kinase."

No. Sentence Comment

84 The second model, IB3-1, was derived from the bronchial epithelium of a CF patient with a èc;F508/ W1282X CFTR genotype (35). Login to comment

PMID: 24901709 [PubMed] Clauzure M et al: "Disruption of interleukin-1beta autocrine signaling rescues complex I activity and improves ROS levels in immortalized epithelial cells with impaired cystic fibrosis transmembrane conductance regulator (CFTR) function."

No. Sentence Comment

77 Cell Cultures IB3-1 cells (ATCC CRL-2777, a bronchial cell line derived from a cystic fibrosis patient with a DF508/W1282X CFTR genotype) [56] and S9 cells (ATCC CRL-2778, which are IB3-1 cells transduced with an adeno-associated viral vector to stably express wt-CFTR) [57] were purchased from ATCC (www.atcc. 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

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
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

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: 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
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
38 A), R553X (c.1657C.T), R1162X (c.3484C.T), W1282X (c.3846G.A), R117H (c.350G.A), 2184insA (c.2052_2053insA) and 1717-1G.A (c.1585-1G.A). 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
103 [2052_2053insA];[1521 _1523delCTT] 1 100% W1282X/[2] c. 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
89 A 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 (Continued) R553X 0.52% 0.3% W1282X 0.52% - Shwachman-Kulczycki score Excellent or good 57.8% 36.2% 0.005 Mild 26.5% 36.2% Moderate or severe 15.7% 27.6% Deaths 18 31 1 Fecal balance 67.9% 80.0% 0.031 DI - period from 1990 to 2000; DII - period from 2000 to 2010; SpO2 - transcutaneous hemoglobin saturation by oxygen; p - p-value. 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: 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

156 The T465N (p.Thr465Asn) mutation was found in a CF-PI male patient with a W1282X/T465N (p. Login to comment
189 [Phe508del];[Asp529Asn] 4 W1282X/T465N c. Login to comment
198 [1210-14TG[11];1210-12T[5];1684G>A;3017C>A];[2335C>T] F 62 &#b1; 17 - Neonatal screening,familiarity CF-PS 11 W1282X/G1247R(G>C) c. Login to comment
223 The G1247R(G>C) (p.Gly1247Arg) mutation was found in a CF-PS female patient with a W1282X/G1247R(G>C) (p. Login to comment
286 These patients had the following mutations on the other allele: F508del (p.Phe508del) (3 CF-PS and 1 CFTR-RD), W1282X (p.Trp1282*) (2 CF-PS), Q779X (p.Gln779*) (2 CF-PS siblings), D110H (p.Asp110His) (1 CF-PS), D614G (p.Asp614Gly) (1 CF-PS), unknown (1 CBAVD). Login to comment
296 These patients had the following mutations on the other allele: F508del (p.Phe508del) (1 CF-PI), G85E (p.Gly85Glu) (1 CF-PS), R334W (p.Arg334Trp) (2 CF-PS siblings) and W1282X (p.Trp1282*) (2 CF-PS). Login to comment
300 These patients had the following mutations on the other allele: F508del (p.Phe508del) (1 CF-PS, 4 CFTR-RD and 1 CBAVD, including 2 siblings), G85E (p.Gly85Glu) (1 CF-PS), W1282X (p.Trp1282*) (2 CFTR-RD siblings), L320V (p.Leu320Val) (1 CFTR-RD), S549R(A>C) (p.Ser549Arg) (1 CFTR-RD), 711+5G>A (c.579+5G>A) (1 CBAVD) and unknown (1 CBAVD). 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
390 L1077P c.3230T>C CF-PI CF-causing p.Leu1077Pro Y1092X(C>A) c.3276C>A CF-PI CF-causing p.Tyr1092* M1137V c.3409A>G CFTR-RD nd p.Met1137Val D1152H c.3454G>C CF-PI,CF-PS,CFTR-RD varying clinical consequence p.Asp1152His R1162X c.3484C>T CF-PI CF-causing p.Arg1162* D1168G c.3503A>G CFTR-RD nd p.Asp1168Gly 3667ins4 c.3535_3536insTCAA CF-PI CF-causing p.Thr1179IlefsX17 S1206X c.3617C>A uncertain: CF-PI and/or CF-PS nd p.Ser1206* I1234V c.3700A>G CF-PI,CF-PS CF-causing p.Ile1234Val S1235R c.3705T>G CFTR-RD non CF-causing p.Ser1235Arg 3849+10kbC>T c.3717+12191C>T CF-PI,CF-PS CF-causing V1240G c.3719T>G CFTR-RD nd p.Val1240Gly G1244R c.3730G>A uncertain: CF-PI and/or CF-PS nd p.Gly1244Arg G1244E c.3731G>A CF-PI,CF-PS CF-causing p.Gly1244Glu G1247R(G>C) c.3739G>C CF-PS nd p.Gly1247Arg W1282X c.3846G>A CF-PI CF-causing p.Trp1282* Q1291R c.3872A>G CF-PI,CF-PS,CFTR-RD nd p.Gln1291Arg 4016insT c.3884_3885insT CF-PI CF-causing p.Ser1297PhefsX5 4040delA c.3908delA CF-PI nd p.Asn1303ThrfsX25 N1303K c.3909C>G CF-PI CF-causing p.Asn1303Lys ex22-24del c.3964-3890_4443+3143del9454ins5 CF-PI nd ex22,23del c.3964-78_4242+577del1532 CF-PI CF-causing 4168delCTAAGCC c.4036_4042del CF-PI nd p.Leu1346MetfsX6 G1349D c.4046G>A CF-PI CF-causing p.Gly1349Asp H1375P c.4124A>C uncertain: CF-PI and/or CF-PS nd p.His1375Pro S1455X c.4364C>G CF-PS,CFTR-RD nd p.Ser1455* Q1476X c.4426C>T CFTR-RD nd p.Gln1476* nd,Not determined.According to the three rules described (see Materials and Methods),each mutated allele was classified according to its clinical outcome.It was impossible to univocally assign 16 of the 125 different mutated alleles to one or more macrocategories.A comparison with the CFTR2 project (11) (http://www.cftr2.org) is shown.The alleles are ordered according to their nucleotidic position. Login to comment

PMID: 25940043 [PubMed] Corvol H et al: "Translating the genetics of cystic fibrosis to personalized medicine."

No. Sentence Comment

53 A p.Trp1282X (W1282X) 1.49% c.3909C . Login to comment
138 In fact, patients with the p.Trp1282X (p.W1282X) were better responders than those carrying other class I mutations.53 In the last international phase III clinical trial, 238 patients older than 6 years were enrolled. 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

119 En effet, les patients porteurs de la mutation W1282X, en particulier, semblent mieux re &#b4;pondre au traitement que ceux porteurs d`autres mutations de classe I [32]. 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

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

PMID: 26115671 [PubMed] Molina SA et al: "Junctional abnormalities in human airway epithelial cells expressing F508del CFTR."

No. Sentence Comment

317 To confirm the observation that Cx43 mistrafficking in CuFi-5 cells was due to F508del CFTR expression, we examined Cx43 expression, localization, and gap junction-mediated dye transfer in IB3-1 cells, a different airway cell line that expresses one copy of F508del CFTR and one copy of a truncated CFTR, W1282X (Fig. 7). Login to comment
366 Cx43 gap junction function is rescued by 4-PBA treatment of heterozygous F508del/W1282X CFTR-expressing IB3-1 cells. 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

40 Most active compounds were further tested with a green fluorescent protein (GFP) based reporter and evaluated for the suppression of nonsense mutations in the CFTR gene in the human bronchial epithelial cell line IB3.1 (CFTR genotype W1282X/F508del). Login to comment
199 Since compounds 4a and 5b,i performed well in both Fluc and GFP reporters, we tested them for nonsense suppression in CF bronchial epithelial cell line IB3.1 derived from a CF patient (CFTR genotype W1282X/F508del). Login to comment
256 Treatment of IB3.1 cells with compounds 4a, 5b, and 5i induced the readthrough of the premature translation termination codon encoded by the hCFTR-W1282X nonsense mutation present in these cells, resulting in the partial restoration of the CFTR protein. Login to comment

PMID: 26160865 [PubMed] Oglesby IK et al: "miR-17 overexpression in cystic fibrosis airway epithelial cells decreases interleukin-8 production."

No. Sentence Comment

77 IB3 cells are a CF bronchial epithelial cell line (F508del/W1282X), S9s are their isogenic non-CF counterpart and both were obtained from Pamela Zeitlin (Johns Hopkins Children`s Centre, Baltimore, MD, USA) [30]. Login to comment

PMID: 26208274 [PubMed] Siryani I et al: "Distribution of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Mutations in a Cohort of Patients Residing in Palestine."

No. Sentence Comment

9 These mutations were c.1393-1G>A, F508del, W1282X, G85E, c.313delA, N1303K, deletion exons 17a-17b-18, deletion exons 17a-17b and Q1100P. Login to comment
34 Few studies from different countries reported the mutations present in the Palestinian patients they treated in those countries of which F508del, N1303K, W1282X, 3120+1Kbdel8.6Kb and G85E were the most common [9, 10]. Login to comment
46 Code Family Members Age (Years) District Result /Mutations Sweat Conductivity Equivalent NaCl (mmol/L) Pancreaticassessment Sputum Culture Results BMI 001 Pal-1 Daughter-1 5 Hebron c.1393-1G>A 125 PI P. aeruginosa 15.2 002 Pal-1 Daughter- 2 11 Hebron c.1393-1G>A 110 PI P. aeruginosa 16.1 027 Pal-1/ Cos Daughter-1 7 Hebron c.1393-1G>A 125 PI P. aeruginosa 14.0 005 Pal-2 Daughter-1 5 Hebron F508del 108 PI P. aeruginosa 14.3 011 Pal-3 Son-1 25 Bethlehem Deletion exons 17a-17b 137 PI P. aeruginosa 18.4 013 Pal-4 Son-1 16 Hebron W1282X 104 PI P. aeruginosa 18.6 014 Pal-4 Daughter-1 5 Hebron W1282X 119 PI P. aeruginosa 16.1 015 Pal-4 Daughter- 2 8 Hebron W1282X 92 PI P. aeruginosa 13.4 021 Pal-5 Son-1 14 Hebron c.1393-1G>A 135 PI NA 16.9 030 Pal-6 Daughter-1 2 Hebron Het (c.1393-1G>A) Het (W1282X) 103 PI P. aeruginosa 15.0 040 Pal-6/ Cos Son-1 11 Hebron c.1393-1G>A 108 PI P. aeruginosa 15.7 035 Pal-7 Son-1 6 Hebron F508del 130 PI Negative 14.0 036 Pa1-7 Daughter-1 10 Hebron F508del 132 PI Negative 15.7 038 Pal-8 Daughter-1 8 Hebron Het (F508del) Deletion Exons 17a-17b-18 110 PI P. aeruginosa 17.8 050 Pal-9 Daughter-1 14 Hebron N1303K 132 PI P. aeruginosa 12.6 058 Pal-10 Son-1 10 Hebron Het (F508del) Deletion Exons 17a-17b-18 111 PI P. aeruginosa 12.7 070 Pal-11 Daughter-1 4 Hebron W1282X 101 PI P. aeruginosa and MRSA 15.5 117 Pal-11/ Cos Daughter 0.5 Hebron W1282X 120 PI P. aeruginosa 13.3 072 Pa1-12 Daughter-1 5 Hebron G85E 102 PI P. aeruginosa 14.2 073 Pal-12 Daughter- 2 7 Hebron G85E 115 PI P. aeruginosa 15.3 074 Pal-12/ Cos Daughter-1 11 Hebron G85E 129 PI P. aeruginosa and MRSA 16.2 079 Pal-13 Son-1 4 Hebron 444DelA 116 PI MRSA 16.2 080 Pal-13 Son-2 7 Hebron 444DelA 101 PI Negative 15.2 081 Pal-13 Son-3 1 Hebron 444DelA 90 PI Negative 9.7 091 Pal-14 Son-1 7 Hebron c.1393-1G>A 117 PI Negative 15.2 093 Pal-15 Son-1 1 Hebron F508del 117 PI P. aeruginosa 15.2 099 Pal-16 Daughter-1 1 Hebron W1282X 124 PI P. aeruginosa 14.9 102 Pal-17 Son-1 30 Hebron Het (G85E)Het (Q1100P) 130 PI P. aeruginosa 20.1 (Continued) distantly related, rather than possessing a true founder mutation. Login to comment
76 The CFTR mutations detected were c.1393-1G>A, F508del, W1282X, G85E, c.313delA, N1303K, deletion exons 17a-17b-18, deletion exons 17a-17b and Q1100P. Login to comment
79 Interestingly, one Palestinian family (Table 1: Pal-6) had two different mutations in its family members, one family member was homozygous for the c.1393-1G>A mutation while his first cousin had a compound heterozygous mutations (c.1393-1G>A / W1282X). Login to comment
101 CFTR Mutations Exon/Intron # of Families Frequency (%) c.1393-1G>A / c.1393-1G>A Intron 9 6 28.58 F508del / F508delA Exon 10 4 19.05 W1282X / W1282X Exon 20 3 14.29 F508del / Deletion exons 17a-17b-18 Exon 10 / Exons 17a-18 2 9.52 G85E / G85E Exon 3 1 4.76 c.313delA / c.313delA Exon 4 1 4.76 Deletion exons 17a-17b-18 / Deletion exons 17a-17b-18 Exons 17a-18 1 4.76 N1303K / N1303K Exon 21 1 4.76 G85E / Q1100P Exon 3 / Exon 17b 1 4.76 Deletion exons 17a-17b / Deletion exons 17a-17b Exons 17a-17b 1 4.76 doi:10.1371/journal.pone.0133890.t002 mutation was detected in six families out of the twenty one involved in our study in both homozygous (28.6%), and heterozygous (4.8%) forms. Login to comment
105 In a cohort of 22 unrelated Lebanese patients with CF, F508del (34%) appeared to be the most common mutation followed by N1303K (27%), W1282X (7%), and S4X (7%). Login to comment
107 In Israel, W1282X has been reported as the most common mutation in patients from Arab ethnic background [10]. Login to comment
113 A different distribution of the CFTR mutations in a cohort of 144 unrelated Jewish patients from different ethnic origins was reported by Quint et al [22]; where the F508del (35.6%) appeared to be the most common mutation followed by the W1282X (31.3%) mutation [22]. 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: 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: 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: 26547591 [PubMed] Tsabari R et al: "CFTR potentiator therapy ameliorates impaired insulin secretion in CF patients with a gating mutation."

No. Sentence Comment

58 Further support for our observation is based on an additional case at another CF center where a 13.5 y girl with CF (W1282X/S549R) and BMI of 24.4 was diagnosed with CFRD based on blood glucose level of 206 mg/dl at 120 min during OGTT. Login to comment

PMID: 26567541 [PubMed] Bosch B et al: "Searching for a cure for cystic fibrosis. A 25-year quest in a nutshell."

No. Sentence Comment

48 Table 1 CF mutation classes and a potential approach for correcting the defect Mutation class CFTR defect result Mutation type Mutation example Potential therapy Mutation class Specific Aspecific I No full-length CFTR Premature stop codon, Large deletions, Out-of-frame deletions or insertions G524X, W1282X Read-through (e.g. ataluren) RNA correction Gene therapy II Processing defect Missense, amino acid deletion F508del, N1303K, 1507del Corrector III Regulation defect Missense G551D Potentiator (e.g. ivacaftor) IV Decreased conductance Missense R117H Potentiator V Reduced synthesis Missense, change in splicing efficiency 3849+10 kb C࢐G, A455E, 5 T Corrector (e.g. VX-809) Potentiator VI Altered channel stability Nonsense, frameshift 4326 delTC, 4279insA Potentiator Proteastasis inhibitor In class I mutation, no protein reaches the plasma membrane as transcription is halted prematurely in the case of premature stop codons or the protein is non-functional in the case of large deletions or out-of-frame deletions or insertions); in class II mutations, a block in protein folding and trafficking leads to protein degradation in the proteasome; class III mutations lead to a protein with defective channel regulation; in class IV, the CFTR channel has an altered conductance; in class V, the amount of CFTR channels synthetized present at the cell membrane is reduced; class VI mutations lead to a functional but less stable protein in the apical cell membrane. 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: 7533607 [PubMed] Snouwaert JN et al: "A murine model of cystic fibrosis."

No. Sentence Comment

101 monly caused by a mutation that creates a termination codon at residue 1282 in the CFTR coding sequence (W1282X). Login to comment
102 Similar to the S489X mutation in our CFTR(-1-) mice, the W1282X mutation is expected to result in a truncated CFTR protein. 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