ABCMdb

ABCC7 p.Arg117His

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II-III (maturation defect, gating defect) <a href="https://www.ncbi.nlm.nih.gov/pubmed/26823392">Veit et al.</a>
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Publications

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

No. Sentence Comment

363 R117H, a mutation associated with mild clinical disease, displayed altered single-channel properties and a reduction in open probability [45]. Login to comment

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

No. Sentence Comment

31 As might be expected, mutations in this class, such as R117H or P574H, are thought to confer a milder phenotype. Class V mutations reduce the level of normal CFTR protein by alterations in the promoter or by altering splicing. Login to comment
43 Perspective SERIES on cystic fibrosis James M. Wilson, Editor tion,R117H,occursinciswitheitherthe5Tor7Ttractvari- antinintron8.The5Talleleconfersapancreaticsufficient CF phenotype, whereas the 7T allele has been associated with male infertility caused by congenital bilateral absence ofthevasdeferens(CBAVD).Interestingly,womenwiththe R117H-7T allele tend to be asymptomatic. Login to comment
128 Class IV mutants such as R117H, G314E, R334W, and R347P are associated with normal PKA-dependent phosphorylation and ATP binding. Login to comment
131 R347P affects the rate of chloride flow, whereas R117H and P574H reduce the channel open time. Login to comment
133 Class IV mutations such as R117H, R334W, R347P, A455E, and P574H are associated with a pancreatic sufficient phenotype or late onset pancreatic insufficiency. Login to comment
141 A second murine model, the R117H mouse, expresses a mutant which is found in the cell surface in humans. 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

33 Later on, all samples, including the previous ones, were studied by using the CF(12)m polymerase chain reaction (PCR) kit (Zeneca Diagnostics, Abingdon, UK) allowing the detection of the mutations present in the INNO-LiPA CF kit (with the exception of the ∆I507 mutation) and the R117H, R1162X, R334W, 621ϩ1G→T and 3849ϩ10 kbC→T mutations. 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

24 Recently, the R117H mutation, a rare mutation in CF patients, was found to occur frequently in CBAVD patients (Gervais et al., 1993). Login to 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
75 The ∆F508 mutation was found in eight patients, R117H in six, A445E in three and 1717-1G→A and R553X both in one. Login to comment
76 Three partners were found to have a single CFTR gene mutation (R117H, R117H, ∆F508). Login to comment
80 Age History tests Laboratory Sweat ICM CFTR mutations T-stretch Remarks (years) Cl-/Naϩ test intron 8 1 36 NA NA 38/46 CF response (I) ∆F508/R117H 9/7 Non-Caucasian 2 27 Sinusitis/fat intol. Login to comment
81 Chymotr.Ͻ 23/22 CF response (I) ∆F508/R117H 9/7 CF in family 3 33 CARA/oily stools GgtϾ,Chymotr.Ͻ 23/36 CF response (I) ∆F508/- 9/7 4 31 Pelvic re kidney NA 10/22 CF response (I) -/- 7/7 5 32 Sinusitis/nasal Chymotr.Ͻ 50/52 CF low residual (II) A455E/- 9/5 Partner ∆dF508 polyps 6 38 NA NA 40/43 CF high residual (III) A445E/R117H 9/7 7 27 NA GgtϾ,Chymotr.Ͻ 28/44 CF high residual (III) R117H/R553X 7/7 Partner R117H 8 38 Nasal polyps NA 34/51 CF high residual (III) ∆F508/R117H 9/7 Pertussis 9 36 NA NA 58/70 CF high residual (III) ∆F508/- 9/5 10 31 NA GgtϾ 54/70 CF high residual (III) ∆F508/- 9/5 Partner R117H 11 32 Maldescended GgtϾ 16/34 CF high residual (III) -/- 9/7 Single kidney in family testis 12 35 NA NA 14/21 Inconclusive ∆F508/- 9/7 13 29 NA NA 43/70 Normal response (IV) A455E/R117H 9/7 14 38 NA NA 32/55 Normal response (IV) R117H/1717-1→G→A 7/7 15 29 NA GgtϾ 44/66 Normal response (IV) ∆F508/R117H 9/7 16 28 NA NA 42/48 Normal response (IV) R117H/- 7/7 17 36 NA NA 22/44 Normal response (IV) -/- 7/5 Non-Caucasian 18 34 NA NA 57/30 Normal response (IV) -/- 7/7 Non-Caucasian 19 39 NA NA 36/52 Normal response (IV) -/- 7/7 Non-Caucasian 20 31 NA NA 16/30 Normal response (IV) -/- 7/7 Non-Caucasian 21 34 NA NA 20/41 Normal response (IV) -/- 7/7 NA ϭ no abnormalities, GgT ϭ gamma glutamyl transpeptidase, Chymotr. Login to comment
90 Other mutations, like R117H, are associated with a milder form of CF where conductive chloride transport is defective, but not absent (Gervais et al., 1993). Login to comment
92 Mutations with a low frequency in classic CF, such as R117H, were found to occur regularly in CBAVD (Gervais et al., 1993). Login to comment

PMID: 10220462 [PubMed] Schreiber R et al: "The first-nucleotide binding domain of the cystic-fibrosis transmembrane conductance regulator is important for inhibition of the epithelial Na+ channel."

No. Sentence Comment

156 In fact, it has been shown that CFTR mutants producing only a little Cl-conductance such as R117H also inhibited in the range of 24% (19). Login to comment

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

No. Sentence Comment

60 Two CF newborns carrying mutation R117H and G551D or DF508 had lower IRT concentrations (1010 and 1070 mg LÀ1 ). Login to comment
72 In this study, CF newborns with one mutation in an exon encoding for either NBD1 or NBD2 (DF508, G542X, G551D, E585X, N1303K, etc.) and the other affecting one of the MSD (R117H, 574delA, I148T, G149R, L206W, etc.) had significantly lower IRT concentrations than CF neonates with both mutations located in NBD. Login to comment

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

No. Sentence Comment

74 The tenth, screened for raised IRT in the Rennes programme, was asymptomatic with a negative sweat test but showed two CFTR mutations ( F508/R117H). Login to comment
77 Other genotypes were F508/G542X (n=4), F508/N1303K (n=2), F508/I148T (n=2), F508/R117H, F508/R553X, F508/1717-1G->A, F508/ 1078delT, F508/2789+5G->A, F508/ E1308X (a novel CFTR mutation), R553X/ 394delTT, and N1303K/R553X. Login to comment
80 All also had a positive sweat test, except for the baby with a F508/R117H genotype (PAP = 6.8 ng/ml), who remains asymptomatic after 24 months. Login to comment
82 Because the 9T is always associated with the F508 allele, the R117H is associated with the 7T, which predicts absence of CF features. Login to comment
90 The two CF patients with PAP < 8.0 ng/ml had genotypes predicting a mild phenotype18 19 : F508/R117H (PAP = 6.8 ng/ml) and F508/ 2789 + 5 G->A (PAP = 4.9 ng/ml). Login to comment
108 The sixth was the asymptomatic baby (IRT = 1750 ng/ml, PAP = 6.8 ng/ml, F508/R117H) described above. Login to comment
121 We are concerned that we could miss those with pulmonary damage, albeit limited, but whether asymptomatic babies with a genotype predicting a mild pulmonary phenotype ( F508/R117H and 9T/7T, PAP = 6.8 ng/ml) should be screened is questionable. Login to comment
191 19 Fitzgerald D, Van Asperen P, Henry R, et al. Delayed diagnosis of cystic fibrosis in children with a rare genotype ( F508/R117H). 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

3 In 10 out of 14 patients with CAVD, CFTR mutations were found; nine patients had one ∆∆F508 mutation and one patient had two CFTR mutations (N1303K/R117H). Login to 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
64 Clinical status, semen characteristics and concentrations of follicle stimulating hormone (FSH) in azoospermic patients No. Plasma FSH Semen volume Semen pH Semen fructose Semen Semen carnitine CFTR genotype (mIU/ml) (ml) (µmoles) α-glucosidase (mIU) (nmoles) Patients with congenital absence of the vas deferens (CAVD) 1 4.5 0.7 6.5 0 3 20 ∆F508/N 9T/5T 2 6.9 0.5 6.8 - - - ∆F508/N 9T/7T 3 1.9 0.2 6.5 Ͻ1 - - ∆F508/N 9T/5T 4 0.7 0.5 6.8 0 3 20 ∆F508/N 9T/7T 5 6.0 0.3 6.8 - - - ∆F508/N 9T/5T 6 3.6 0.5 6.5 - 3 20 ∆F508/N 9T/5T 7 4.0 1.5 6.5 - - - ∆F508/N 9T/5T 8 5.9 1.2 6.5 0 4 20 ∆F508/N 9T/7T 9 3.8 - - - - - ∆F508/N 9T/5T 10 5.0 - - 0 - 24 N1303K/ 9T/7T R117H *11 2.0 0.8 7.1 0 2 - N/N 9T/7T 12 4.3 0.3 7.4 0 - 3.6 N/N 7T/7T 13 1.0 0.4 6.5 0 - - N/N 9T/5T 14 2.0 1.3 6.8 0 5 - N/N 9T/5T Patients without CAVD 15 7.4 1.8 8.3 29 1 126 N/N 7T/7T 16 - 2.2 8.5 33 20 154 N/N 7T/7T 17 - 4.4 8.3 35 12 352 N/N 7T/7T 18 3.6 8.5 8.1 187 82 680 N/N 7T/7T 19 3.1 2.5 8.5 25 - 100 N/N 7T/7T 20 3.4 0.4 6.5 Ͻ1 7 28 N/N 7T/5T 21 1.6 1.4 8.3 4.2 5 126 N/N 7T/9T 22 3.1 3.0 8.7 78 2 270 N/N 7T/7T 23 0.9 3.0 9.0 - - - N/N 7T/7T 24 4.4 10.0 7.9 190 - 300 N/N 7T/7T 25 1.3 2.2 8.1 40 - 44 N/N 7T/7T 26 2.9 2.6 8.3 26 8 286 N/N 7T/7T 27 1.7 2.1 8.3 44 - 84 N/N 7T/7T 28 - 9.0 8.1 180 27 540 N/N 7T/7T 29 - 1.5 8.3 23 - 120 N/N 7T/7T 30 4.1 0.3 7.1 - - - N/N 7T/7T 31 4.9 1.7 8.3 20 20 - N/N 7T/7T 32 7.2 1.0 7.9 Ͻ1 3 30 N/N 7T/7T 33 9.0 1.5 6.5 Ͻ1 2 - N/N 7T/5T 34 11.7 5.0 7.9 90 - 400 N/N 7T/7T 35 7.2 4.6 8.1 92 132 1518 N/N 7T/9T 36 4.4 2.5 8.1 30 11 1510 N/N 7T/7T 37 14 3.6 8.3 50 27 900 N/N 7T/7T 38 4.9 6.0 7.9 72 - 300 N/N 7T/7T 39 6.0 1.8 8.3 31 17 252 N/N 7T/7T 40 14.3 1.5 8.3 22 1 90 N/N 7T/9T 41 6.6 2.2 - 27 - 290 N/N 7T/7T 42 4.8 0.5 6.8 0 3 42 N/N 7T/7T 43 13.9 2.0 7.8 - - - N/N 7T/7T 44 3.9 3.9 8.3 47 11 - N/N 7T/7T 45 1.5 1.8 8.6 11 - - N/N 7T/7T 46 4.2 3.0 8.5 25 28 210 N/N 7T/7T 47 4.0 5.8 7.9 122 42 696 N/N 7T/9T 48 16.3 5.0 8.7 145 68 900 N/N 7T/7T 49 7.2 4.0 7.5 - - - N/N 7T/5T 50 8.0 4.3 8.1 34 200 1284 N/N 7T/7T 51 23.9 0.8 9.0 5.6 17 184 N/N 7T/7T 52 - 2.2 8.5 35 - 308 N/N 7T/9T 53 17.8 3.1 8.1 31 50 527 N/N 7T/7T Fructose, α glucosidase and carnitine are expressed per ejaculate. Login to comment
74 One patient was a compound heterozygote, R117H/N1303K. 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
99 Our results are in accordance with these data, since nine of the 14 patients (64.2%) with CAVD were heterozygous for one CFTR mutation (∆F508) and one patient with CBAVD (7.1%) was a compound heterozygote (R117H/N1303K) and was 7T/9T. Login to comment
101 R117H associated with a 5T variant is known to lead to a mild phenotype in CF patients. Login to comment
102 In CAVD without CF, R117H is probably associated with the 7T allele allowing correct splicing of exon 9 and translation into a CFTR protein which is partially functional (Kiesewetter et al., 1993). Login to comment
105 Detection of the R117H mutation by polymerase chain reaction (PCR). Login to comment
109 Lanes 2 and 7: heterozygote carrier for the R117H mutation. Login to comment

PMID: 10354464 [PubMed] Chabot H et al: "Downregulation of epithelial sodium channel (ENaC) by CFTR co-expressed in Xenopus oocytes is independent of Cl- conductance."

No. Sentence Comment

31 This hypothesis was based on the observation that the magnitude of Iamil downregulation was correlated with the ability of CFTR to conduct Cl- , was reduced for CFTR mutants that had diminished membrane Cl- permeability (G551D, ⌬F508, R117H) and was abolished by inhibition of CFTR Cl-conductance using diphenylamine-carboxylate (DPC; Mall et al., 1996; Briel et al., 1998). 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
39 The mutation most frequently identified was ⌬F508 (23 alleles), followed by R117H (9 alleles). Login to comment
45 (%) Men With 2 Mutations ⌬F508/IVS8-5T 7 (11) ⌬F508/IVS8-5T 1 (10) ⌬F508/IVS8-5T 1 (1.8) ⌬F508/R117H 6 (9) W1282X/IVS8-5T 1 (1.8) ⌬F508/L206W 1 (1.6) G544S/IVS8-5T 1 (1.8) ⌬F508/M952T 1 (1.6) V754M/-741T→G 1 (1.8) ⌬F508/P67L 1 (1.6) R75Q/R258G 1 (1.8) ⌬F508/S549R 1 (1.6) R334W/R334W 1 (1.6) R117H/R117H 1 (1.6) R117H/IVS8-5T 1 (1.6) R347P/IVS8-5T 1 (1.6) N1303K/IVS8-5T 1 (1.6) 1677delTA/IVS8-5T 1 (1.6) R117L/IVS8-5T 1 (1.6) D979A/IVS8-5T 1 (1.6) IVS8-5T/IVS8-5T 1 (1.6) Men With 1 Mutation IVS8-5T/N 10 (16) ⌬F508/N 1 (10) IVS8-5T/N 9 (16) ⌬F508/N 1 (2) ⌬F508/N 6 (9) IVS8-5T/N 1 (10) ⌬F508/N 1 (1.8) G542X/N 1 (2) W1282X/N 2 (3) R75Q/N 1 (1.8) IVS8-5T/N 5 (10) L206W/N 1 (1.6) W1282X/N 1 (1.8) 4016insT/N 1 (1.6) R117H/N 1 (1.8) 2423delG/N 1 (1.8) Men With No Mutations 18 (28) 7 (70) 37 (66) 42 (86) *N indicates that no CFTR mutations or variants were detected. Login to comment
58 (%) 31 Mutation panel† ⌬F508 23 (18) ⌬F508 2 (10) ⌬F508 2 (1.8) ⌬F508 1 (1) R117H 9 (7) W1282X 2 (1.8) G542X 1 (1) W1282X 2 (1.6) R117H 1 (0.9) R334W 2 (1.6) S549R 1 (0.8) R347P 1 (0.8) N1303K 1 (0.8) Extensive screen† ⌬F508 23 (18) ⌬F508 2 (10) ⌬F508 2 (1.8) ⌬F508 1Mutations included in R117H 9 (7) W1282X 2 (1.8) G542X 131 mutation panel W1282X 2 (1.6) R117H 1 (0.9) R334W 2 (1.6) S549R 1 (0.8) R347P 1 (0.8) N1303K 1 (0.8) L206W 2 (1.6)‡ R75Q 2 (1.8)‡Mutations not included in P67L 1 (0.8)‡ G544S 1 (0.9)‡31 mutation panel 1677delTA 1 (0.8)‡ 2423delG 1 (0.9)‡ R117L 1 (0.8)‡ V754M 1 (0.9)‡ 4016insT 1 (0.8)‡ -741T→G 1 (0.9)‡ D979A 1 (0.8)§ R258G 1 (0.9)§ M952T 1 (0.8)¶ IVS8-5T 25 (20)# 2 (10) 12 (11) 5 (5) Detectable mutations 72 (56)# 4 (20) 24 (21)# 7 (7) Detectable mutations missed by 31 mutation panel 33 (46) 2 (50) 19 (79) Detectable non-IVS8-5T mutations missed by 31 mutation panel 8 (17) 0 (0) 7 (58) *Percentages indicate allele frequency. Login to comment
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
85 These mild CFTR gene mutations are associated with pancreatic sufficiency and tend to be class 4 through 5 mutations: R117H, R334W, R347P, L206W,andP67L.Thethirdgroupcon- sists of mutations identified exclusively in some men with obstructive azoospermia; however, because these sequencealterationsareextremelyrare, it is only speculated that they contribute to this phenotype.7,10,12 These CFTR genesequencechangesincludeD979A, R258G, and M952T. Login to comment

PMID: 10388465 [PubMed] Friedman KJ et al: "Cystic fibrosis syndrome: a new paradigm for inherited disorders and implications for molecular diagnostics."

No. Sentence Comment

49 In the paper by Cohn et al. (19), a male patient with an aberrant genotype (⌬F508/R117H,7T,9T) had CBAVD and smooth P. aeruginosa in his sputum. Login to comment

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

No. Sentence Comment

13 Materials and methods CFTR screening included the most frequent CFTR mutations in the German population (R347P, ∆F508, G542X, S549I,N,R(A→C), G551D, R553X, N1303K, and 3849ϩ10kbC→T) (Do¨rk et al., 1994) as well as the mutation R117H and the analysis of the IVS8-T haplotype. Login to comment
14 Both, R117H and the splice variant IVS8-5T are frequently found in males affected by congenital bilateral or congenital unilateral absence of the vas deferens (CBAVD/CUAVD) (e.g. Casals et al., 1995; Chillon et al., 1995; Do¨rk et al., 1997). Login to comment
32 It is S.Jakubiczka et al. Table I. Frequency of CFTR mutations in 197 males affected by idiopathic infertility and 150 of their female partners Male patients IVS8T alleles n 5/5 5/7 5/9 7/7 7/9 9/9 Oligozoospermia 8 - - - 7 N/N 1 ∆F508/N - Asthenozoospermia 14 - - - 10 N/N 1 N/N - 3 ∆F508/N Oligoasthenozoospermia 125 - 11 N/N - 85 N/N 22 N/N 1 N/N 1 R117H/N 5∆F508/N OAT syndrome 23 - - - 14 N/N 6 N/N 1 N/N 1 R117H/N 1 ∆F508/N Azoospermia 27 - 1 N/N 1 ∆F508/N 22 N/N 3 N/N - Total no. Login to comment
33 male patients 197 0 12 N/N 138 N/N 32 N/N 2 N/N 1 ∆F508/N 2 R117H/N 10 ∆F508/N Total no. 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

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

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

No. Sentence Comment

51 Genomic DNA isolated from each subject was evaluated for the presence of any of twelve CFTR gene mutations (⌬F508, G551D, G542X, 621ϩ1G3T, ⌬I507, 1717-1 G3A, R117H, N1303K, W1282X, R560T, R553X, and 3849ϩ10kb C3T) by one of three standard assays (10, 11, 32). Login to comment

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

No. Sentence Comment

69 - Classe IV : anomalie de conduction transmembranaire du canal chlore (ex R117H). Login to comment

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

No. Sentence Comment

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

PMID: 10636451 [PubMed] Schaedel C et al: "Three common CFTR mutations should be included in a neonatal screening programme for cystic fibrosis in Sweden."

No. Sentence Comment

54 patients 1 S549I/S549I Lebanon I148T/unknown1 Turkey 1 711+3GA/ Italy G1244E R553X/G551D1 France 2 R553X/unknown Sweden, Germany 175insT/175insT Sweden2 R117H/unknown2 Sweden 3 Unknown/unknown Sweden, Syria, Turkey early intervention (1, 3). Login to comment
74 Two patients heterozygous for R117H were first diagnosed after an infertility investigation. 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

34 (ii) Satisfactory reports of percutaneous epididymal sperm 7T:9T 1 aspiration (PESA) (Shrivastav et al., 1994) led to the introduction of R117H only 7T:7T 1 PESA in 1996. Login to comment
77 There is an increased prevalence of genotype expected from the pre-implantation diagnostic pro- the R117H mutation within the CBAVD population. Login to comment
79 series, of the men with CBAVD (excluding the two with CF), At the request of the parents the CF genotypes of two six of the 25 (24%) of the CF chromosomes identified were children derived from fathers who were ∆F508 heterozygotes R117H. Login to comment
81 Both children are R117H in those patients with classic CF and is similar to the healthy, consistent with their heterozygous genotype. Login to comment
94 R117H occurs with twotion of CF gene mutations in both conditions. Login to comment
95 A review of variants 5T and 7T resulting in different phenotypes although420 published cases of CBAVD indicated 19% had two mutations, 47% carried a single mutation, and in 34% no no 5T variant of R117H was identified in this series. Login to comment
109 Her genotype (G551D/R117H) carrier of a severe CF gene mutation and the female tests comprised a severe CF mutation (G551D) combined with negative for the group of mutations screened. Login to comment
110 Therefore the R117H and the 7T allele identified on both chromosomes. Login to comment
112 No significant congenital could be made that the R117H was present on a chromosome anomalies have been identified. Login to comment
119 These couples both conceived; R117H compound heterozygotes that would be expected to however, one resulted in a miscarriage late in the first trimester, confer a mild phenotype to the child. Login to comment
121 without the ∆F508 mutation would confer a G551D or R117H Historically a few reports of fertile CF males have been heterozygote genotype. Login to comment
135 However the total number of live of either the R117H or R117C CF mutation, pregnancy did births reported remains small and continued study will be not occur despite the transfer of 25 embryos over nine cycles. Login to comment
137 ∆F508/R117H genotypes demonstrated a satisfactory embryo implantation rate. Login to comment

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

No. Sentence Comment

101 CF nasal epithelia alone or in combination with isoproterenol demonstrated a modest hyperpolarization in the CLASS IV CONDUCTION MUTATIONS AREnasal potential difference response to low chloride in ASSOCIATED WITH A MILD PHENOTYPEnormal volunteers, but not in CF patients homozygous Class IV mutants such as R117H, G314E, R334 W, andfor ⌬F508. Login to comment
106 R347P affects the rate of chloride flow, Chemical and pharmacologic mediators of protein whereas R117H and P574H reduce the channel open trafficking are needed in CF and other diseases caused time. Login to comment
118 A second murine model, Reprint requests to Pamela L. Zeitlin, M.D., The Johns Hopkins the R117H mouse, expresses a mutant which is found University, 600 N. Wolfe Street-Park 316, Baltimore, Maryland 21287- 2355, USA.on the cell surface in humans. 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

70 several publications followed to prove the occur- ground of the R117H mutation and phenotype. Login to comment
72 CBAVD is, mutation in association with IVS8-5T (see below), in contrast to seven CF patients and all CBAVDin most cases, a genital form of CF, which is either caused by compound heterozygosity for one typical males, where R117H was associated with IVS8-7T (Kiesewetter et al., 1993). Login to comment
75 Thereby, the mutational spectrum is distinct to typical CF, which is most frequently ported by our own study of 101 CBAVD and five CUAVD males: R117H was exclusively (24 inde-caused by typical (classes 1-3) CF mutations on both alleles (Table 2). Login to comment
76 pendent alleles) associated with IVS8-7T (Do¨rk et al., 1997).In Germany, DF508/R117H represents the most common CFTR genotype among CBAVD IVS8-5T itself may be the most common atypical CF mutation world-wide (Chillon et al., 1995;patients (Do¨rk et al., 1997; Table 2). Login to comment
77 Compound heterozygosity for R117H and DF508, or even Zielenski et al., 1995). Login to comment
78 The length of the polymorphic polypyrimidine tract (five, seven or ninehomozygosity for R117H, in CBAVD patients were also published by others (Bienvenu et al., thymidines) in intron 8 is important for exon 9 splicing efficacy. Login to comment
82 In contrast, exon 9 ispolypyrimidine tract in the splice acceptor site in intron 8 (IVS8-5T, 7T, 9T; Chu et al., 1993) of present (exon 9+) in 70-100% of CFTR mRNA transcripts from individuals with seven or ninethe CFTR gene in 38 CF patients bearing the genotype DF508/R117H and eight CBAVD males thymidines. Login to comment
83 World-wide, IVS8-5T is present on approximately 5% of CFTR alleles in the normalcarrying at least one R117H allele and identified a close association between chromosomal back- population (Chu et al., 1993 and Table 2) and on Table 1. Login to comment
84 CFTR mutations and male fertility Disorder Number of Proportion of Most frequent mutations (%) patients mutated alleles (%) Ethnic origin Reference CBAVD 17 20.6* DF508 (20.6) French Dumur et al. (1990b) CBAVD 25 38.0 DF508 (26.0) Northern European Anguiano et al. (1992) CBAVD 12 41.7 DF508 (20.8) French Culard et al. (1994) CBAVD 49 45.9 DF508 (32.6), R117H (6.1) Caucasians Oates & Amos (1994) CBAVD 47 21.3 DF508 (8.5), D1152H (3.2) Mostly Askenazim Augarten et al. (1994) CBAVD 30 41.7 DF508 (15.0), G542X (6.7), R117H (3.3) Spanish Casals et al. (1994) CBAVD 67 44.8 DF508 (20.9), R117H (4.5), W1282X (3.7) French Mercier et al. (1995) CBAVD 102 65.7+a DF508 (21.6), 5T (21.1), R347H (2.4) Caucasians Chillon et al. (1995) CBAVD 45 75.6+b DF508 (25.6), 5T (25.6), R117H (3.3), W1282X (3.3) French Costes et al. (1995) CBAVD 25 52.0+c 5T (26.0), DF508 (12.0), R117H (6.0) Caucasian Jarvi et al. (1995) CBAVD 70 68.6+d 5T (25.7), DF508 (19.3), W1282X (7.9) Mostly Caucasian Zielenski et al. (1995) CBAVD 101 79.2+e DF508 (26.2), R117H (11.4), 5T (12.9) Mostly German Do¨rk et al. (1997) CUAVD 10 5.0 DF508 (5.0) Spanish Casals et al. (1995) CUAVD 21 19.0 DF508 (9.5), R117H (4.8) Caucasian Mickle et al. (1995) BEDO 7 78.6 DF508 (28.5), 5T (21.4), R117H (14.3) Mostly German Meschede et al. (1997) IASV 16 3.1 I1139V (3.1) Mostly German Meschede et al. (1997) Azoospermia† 17 23.5+c 5T (14.7), R117H (5.9) DF508 (2.9) Caucasian Jarvi et al. (1995) Azoospermia 21 9.5 DF508 (2.4), G551D (2.4), R117H (2.4), G542X (2.4) Caucasian van der Ven et al. (1996) Spermatogenic failure 18 5.5+c G542X (2.8), 5T (2.8) Caucasian Jarvi et al. (1995) Spermatogenic failure 80 8.7 G542X (4.4), DF508 (3.1) Caucasian van der Ven et al. (1996) Spermatogenic failure 75 2.7+f DF508 (1.3), R117H (0.6), 5T (0.6) Dutch Tuerlings et al. (1998) *Testing only for DF508; +testing included the 5T allele; a-f, frequency of the 5T allele in the general population: a5.2%, n=498; b5.3%, n=131; c,dnot determined; e4.8%, n=186; f3.7%, n=212; †azoospermia with normal vas deferens and bilateral epididymal obstruction. Login to comment
95 Most patients are of German origin CFTR genotype (mutation class in brackets) Patients with typical CF (%) Patients with CBAVD (%) DF508 (2)/DF508 (2) 247 (59.4) 0 DF508 (2)/N1303K (2) 17 (4.1) 0 DF508 (2)/R347P (4) 13 (3.1) 0 DF508 (2)/R553X (1) 11 (2.6) 0 DF508 (2)/G542X (1) 11 (2.6) 0 DF508 (2)/G551D (3) 11 (2.6) 0 DF508 (2)/R1162X (1) 10 (2.4) 0 DF508 (2)/3849+10 KbC T (5) 9 (2.2) 0 DF508 (2)/2789+5G A (5) 9 (2.2) 0 DF508 (2)/3272-26 A G (5) 7 (1.7) 2 (2.6) DF508 (2)/1717-1G A (1) 6 (1.4) 0 DF508 (2)/CFTRdel21Kb (1) 5 (1.2) 0 DF508 (2)/R117H (4) 3 (0.7) 21 (26.9)* DF508 (2)/IVS8-5T (5) 2 (0.5) 9 (11.5)* DF508 (2)/other 33 (7.9) 20 (25.6) Other/other 22 (5.3) 26 (33.3) *Including one CUAVD patient each. Login to comment
116 men with BEDO were compound heterozygous Probably the largest molecular genetic study on for DF508 and R117H, two were heterozygous for the etiology of CUAVD was conducted by Mickle DF508, and two were heterozygous for R553X or et al. (1995) who investigated 21 CUAVD males, R347P, respectively. Login to comment
122 In this subgroup, eight out of nine patients In summary, CFTR mutations are the molecu- had one of the following mutations detected on lar cause for a variety of different forms of male one of their two CFTR alleles: DF508 (n=4), infertility due to obstructive azoospermia, ranging R117H (n=2), G551D (n=1) and N1303K (n=1) from CBAVD and CUAVD with contralateral (Mickle et al., 1995). Login to comment
125 In our own study of five CUAVD males, three had mu- CFTR mutations and spermatogenesis tations on both CFTR alleles (DF508/R117H, Although male infertility in typical or atypical DF508/IVS8-5T, V938G/V938G), one was het- (genital forms of ) CF is primarily due to obstruc- erozygous for DF508, and in only one patient was tion or absence of vas deferens, epididymis and/or no CFTR mutation detected after screening the ejaculatory duct, the question remains as to entire coding region and flanking sequences of the whether mutations in the CFTR gene may also CFTR gene (Do¨rk et al., 1997). Login to comment
134 Five of the patients with obstructive reduced sperm quality and two of 21 men (9.5%) with azoospermia carried one CFTR mutation.azoospermia were heterozygous for IVS8-5T, two were carriers of R117H, and one was heterozygous One azoospermic male was compound heterozygous for G551D and R117H. Login to comment
164 Germ cell maturation was not decreased in the presence target the male reproductive organs (e.g. R117H, IVS8-5T) and those that may leave the vasof one or two CFTR mutations in the absence of IVS8-5T. Login to comment
188 PGD is, mainly for ethical and legal reasons, not possible in all European countries (HandysideCFTR mutations R117H and IVS8-5T into the et al., 1992). Login to comment
217 R117H cystic fibrosis mutation in patients with congenital Chu CS, Trapnell BC, Curristin S, Cutting GR, Crystal RG absence of the vas deferens. Login to comment

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

No. Sentence Comment

76 Type of mutation Mutations that are predicted to prevent CFTR biosynthesis or produce grossly changed, unstable or nonfunctional proteins tend to have severe phenotypic consequences (type: nonsense, frameshift, splice, large in-frame deletion or insertion); effects of mutations that cause minor, local changes in the protein may range from mild to severe depending on other factors such as its molecular mechanism, amino acid change or location (type: missense, small in-frame deletion or insertion) B Molecular mechanism Immediate consequence of the mutation for CFTR biosynthesis, processing, trafficking to the membrane, stability and function (classes of mutations); the mechanisms of mutations are evaluated empirically on the molecular and cellular levels C Position in the gene (protein) Applies particularly to minor, local changes (missense); mutations in structurally or functionally critical regions of the protein tend to correlate with more severe phenotypes when compared with mutations in less important regions; amino acid substitutions in highly conserved regions of CFTR protein may also have more severe phenotypic consequences than mutations from unconserved regions D Net molecular effect The net amount of the functional CFTR present in the apical membrane of secretory epithelial cells, irrespective of type mutation or its mechanism; production of even a small amount of functional CFTR may be sufficient to prevent a severe disease (class IV and V mutations) E Intragenic modulators (complex alleles) In some cases, a second change in the same allele may modulate the phenotypic effect of the primary mutation; for example, the missense mutation R117H associated with the 5T variant in the T-tract of the acceptor splice site of intron 8 is typically associated with the pancreatic sufficient form of CF but only with infertility (males) or asymptomatic presentation (females) when on the 7T background F Impact of second mutation As a recessive disease, CF requires the presence of mutations in each allele; therefore, the type and molecular consequences of the second mutation in the genotype may be critical for the clinical outcome; for example, a severe allele is associated with PI only if the second mutation is severe; conversely, one mild mutation is sufficient to preserve pancreatic function, irrespective of the type of the second allele G Site of expression/organ pathophysiology/ secondary modulation A phenotypic impact of a mutation also depends on where the mutation is expressed and organ-specific pathophysiology; in some organs like the pancreas, a CFTR genotype closely correlates with the severity of its phenotype (PI vs. PS); in lungs, with complex pathophysiology, the primary effect of a particular genotype may be considerably modulated by secondary genetic factors and environment lated form and transported to the apical membrane. Login to comment
90 Several mutations (R117H, R334W, R347P) were shown to affect the properties of CFTR single-channel conductance [23]. Login to comment
165 Both studies showed that certain mild alleles (R117H; A455E; 3849+10kbC→T) from class IV or V tend to be associated with significantly lower Cl sweat levels than those for severe alleles ('F508; 621+1G→T; G542X; R553X, etc.). Login to comment
209 One of them, R117H, is a missense mutation present both in CF and CBAVD patients. Login to comment
211 Analysis of T-tract variants co-segregating with this mutation in groups of patients with CF and CBAVD revealed a tendency of the R117H allele to associate with the 5T variant in CF patients and the 7T variant in CBAVD patients. Login to comment
212 Thus, the R117H mutation on the 7T background affects almost exclusively the male reproductive tract and is not sufficient to produce other CF symptoms whereas the 5T allele enhances the phenotypic effect of the R117H mutation producing the pancreatic sufficient form of CF (table 1, E). Login to comment

PMID: 10798353 [PubMed] Dork T et al: "Characterization of a novel 21-kb deletion, CFTRdele2,3(21 kb), in the CFTR gene: a cystic fibrosis mutation of Slavic origin common in Central and East Europe."

No. Sentence Comment

110 We also noted that, in addition to those patients with classic CF listed in Table 1, two German adults were carriers of the genotypes R117H/CFTRdele2,3(21 kb) and IVS8-5T/CFTRdele2,3(21 kb); these patients had initially been diagnosed by urologists as having isolated congenital bilateral absence of vas deferens (Dörk et al. 1997). Login to comment

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

No. Sentence Comment

69 First, we tested these patients for 12 mutations selected for the following reasons: five are the most common mutations worldwide (∆F508, G542X, N1303K, G551D and R553X; CFGAC 1994); 362 Table 1 Frequency of the CFTR gene mutations in 97 (194 chromosomes) Mexican patients Mutation Number of Frequency affected alleles (%) ∆F508 79 40.72 G542X 12 6.18 ∆I507 5 2.57 S549N 5 2.57 N1303K 4 2.06 R75X 3 1.54 406-1G→A 3 1.54 I148T 3 1.54 2055del9→A 2 1.03 935delA 2 1.03 I506T 2 1.03 3199del6 2 1.03 2183AA→G 2 1.03 G551D 1 0.51 R553X 1 0.51 1924del7 1 0.51 G551S 1 0.51 1078delT 1 0.51 Y1092X 1 0.51 R117H 1 0.51 G85E 1 0.51 3849+10KbC→T 1 0.51 1716G→A 1 0.51 W1204X 1 0.51 W1098Ca 1 0.51 846delTa 1 0.51 P750La 1 0.51 V754M 1 0.51 R75Q 1 0.51 W1069X 1 0.51 L558S 1 0.51 4160insGGGGa 1 0.51 297-1G→Aa 1 0.51 H199Y 1 0.51 2869insG 0 0 R1162X 0 0 3120+1G→A 0 0 Total 34 145 74.58% aNovel mutations detected in this study Fig.1 Sequencing ladders showing the CFTR novel mutations. Login to comment

PMID: 10836331 [PubMed] Frossard PM et al: "Genotype-phenotype correlations in cystic fibrosis: clinical severity of mutation S549R(T-->G)."

No. Sentence Comment

57 [20] showed that a close association exists between chromosome background of the R117H mutation and clinical phenotype, which means that the genetic context in which a mutation occurs can play a significant role in determining the type of illness produced. Login to comment

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

No. Sentence Comment

57 In contrast, mutations L206W and R117H, Molecular analysis of the CFTR gene was performed in all 134 each causing a mild CF phenotype (Dean et al., 1990; patients. Login to comment
62 Recently, direct analysis of 31 CFTR mutations (PCR/OLA Cystic Fibrosis Assay; Perkin Elmer, Foster City) was 6(5T), ∆F508, G542X, L206W and R117H are the most performed in 30 of these infertile men. Login to comment
71 Six polymorphisms: 125G/C, 1525-61A/G, L206W 9 (6) 0 9 (5) 1898ϩ152T/A, 1716G/A, G576A and 875ϩ40A/G presented R117H 8 (5) 0 8 (5) frequencies of between 2.5% and 4.0%. Login to comment
95 CFTR genotypes in 24 patients with congenital unilateral absenceTable III. CFTR genotypes in 110 patients with congenital bilateral absence of the vas deferens of the vas deferens Mutations IVS8-6(T) n (%)Mutations IVS8-6(T) n (%) Two CFTR mutations 62 (56) Two CFTR mutations 5 (21) ∆F508/- 5T/9T 2 (8)∆F508/- 5T/9T 17 (15) G542X/- 5T/9T 6 (5) G542X/- 5T/9T 1 3732delA/- 5T/7T 1∆F508/L206W 9T/9T 6 (5) ∆F508/D1270NϩR74W 7T/9T 3 (3) L383S/- 5T/7T 1 One CFTR mutation 4 (17)∆F508/R117H 7T/7T 1 ∆F508/P1021S 7T/9T 1 ∆F508/-a 7T/9T 1 3732delA/-a 7T/7T 1∆F508/M952T 7T/9T 1 ∆F508/D110Y 7T/9T 1 Q890R/- 7T/7T 1 -/-a 5T/7T 1∆F508/S50P 5T/9T 1 ∆F508/2751ϩ3A→G 5T/9T 1 Negative CFTR mutations 15 (62) -/- 7T/7T 10 (42)G542X/R117H 7T/9T 1 G542X/2789ϩ5G→A 7T/9T 1 -/- 7T/9T 3 (12) -/- 9T/9T 2 (8)R117H/2789ϩ5G→A 7T/7T 1 R117H/712-1G→T 7T/9T 1 R117H/∆I507 7T/7T 1 aThree carrier patients with renal agenesis. Login to comment
102 However, the differences were not statistically R117H/- 7T/7T 2 (2) significant. Login to comment

PMID: 10875876 [PubMed] Viville S et al: "Histological and genetic analysis and risk assessment for chromosomal aberration after ICSI for patients presenting with CBAVD."

No. Sentence Comment

50 Slides were air-dried at room temperature, washed ∆F508/D443Y and R117H-7T/5T (see Table I) As expected once in PBS, dehydrated in an ethanol series (70, 90, 100%), air- the ∆F508 mutation was the most frequently found (64%). Login to comment
60 TMI score Johnsen score CF mutation screening Sweat test Karyotype Family history 1 1 12 NF ND ND No 2 1 12 ∆F508/NF ND Normal No 3 3 11 R117H-7T/5T ND Normal No 4 3 11 NF ND Normal Yes 5 1 11 ∆F508/NF ND Normal No 6 2 11 ∆F508/R347H ND ND Yes 7 4 10 ∆F508/5T ND ND No 8 3 10 ∆F508/NF Neg ND No 9 1 11 NF Pos ND No 10 2 11 ∆F508/R117C Pos ND Yes 11 2 11 ∆F508/D443Y Pos ND No TMI ϭ tubule/membrane/interstitium; CF ϭ cystic fibrosis; ND ϭ not determined; Neg ϭ negative; Pos ϭ positive; NF ϭ not found in 31 screened mutations, including ∆F508, R117H and the variant IVS5T. Login to comment

PMID: 10909845 [PubMed] Chen JM et al: "Molecular basis of hereditary pancreatitis."

No. Sentence Comment

20 To date, two missense mutations R122H (R117H)7 and N29I (N21I)15 in the cationic trypsinogen have been unambiguously associated with HP. Login to comment
21 R122H (R117H) R122H, which results from a G > A (CGC > CAC) single nucleotide change in exon 3 of the cationic trypsinogen gene, is the first and most frequent mutation identified as being associated with HP.7,16-26 Whilst no one doubts its disease-causing role in HP, some27 do argue that 'self-destruct` mechanism proposed for R122H7 has not yet been proven. 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
31 CFTR mutants that traffick successfully through the cell to the plasma membrane but are only partially activated through the cAMP signaling pathway (e.g. R117H) are called class IV conductance mutants and are associated with some degree of pancreatic sufficiency and milder phenotype. Login to comment
104 Interestingly, inorganic pyrophosphate stimulated G551S and R117H, a class IV mutation. Login to comment
115 R117H, R334W, and R347P are class IV mutants with reduced single-channel conductances [66]. Login to comment
118 Adenosine and its nucleotides have been shown to activate wild-type and R117H forms of CFTR in cell cultures through the A2B receptor that is present in human bronchial epithelium [67]. 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

28 To date, five mutations with varying effect on the developing of the disease have been identified (R117H, N21I, K23R, A16V, D22G (8-12). Login to 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
110 Neither the known mutations (R117H, N21I, K23R, A16V, D22G) nor any new mutations were present. Login to comment
117 Increased trypsin activity may either be achieved by reduced autolysis (R117H), acid stability (N21I), facilitated activation of trypsinogen to trypsin (D22G, K23R), or intracellular transport defects (A16V). Login to comment
143 This is supported by recent evidence that patients with chronic alcoholic pancreatitis do not carry the R117H and N21I mutations (23). 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: 10970190 [PubMed] Boyne J et al: "Many deltaF508 heterozygote neonates with transient hypertrypsinaemia have a second, mild CFTR mutation."

No. Sentence Comment

509 In addition, three transiently hypertrypsinaemic babies who would otherwise have qualified for the cohort had already been identified as compound heterozygotes for F508/R117H CF mutations through extended mutation analysis of their parents. Login to comment
522 R117H was the most common second mutation found, constituting 45% of the compound heterozygotes identified. Login to comment
526 Recent work has suggested that "polyvariant mutant CFTR genes" may, when combined, result in less functional or pathologically insuYcient CFTR.21 In the light of this, we determined the incidence of the intronic poly-T tract, IVS8-nT, which interacts with the R117H mutation. Login to comment
532 In general, the severity of lung disease is less predictable than the degree of pancreatic involvement.22 The R117H has been associated with a range of phenotypes and the intronic variant polyT tract (IVS8-nT) is known to aVect expression. Login to comment
533 The IVS8-5T variant is an ineYcient splice acceptor site and with R117H, in trans with F508, results in a pancreatic suYcient phenotype. Login to comment
534 The 7T variant and R117H combination in F508 heterozygotes is associated with congenital bilateral absence of the vas deferens and, in some cases, mild lung disease.19 23 Some females with this genotype are completely asymptomatic. Login to comment
538 These have been reported in patients with presenting phenotypes ranging from "cystic fibrosis" to oligospermia, but there have been too few cases Table 2 Compound heterozygotes detected Domain and mutation type Genotype Exon 1st IRT 2nd IRT Transmembrane, missense F508/P67L 3 129 34* F508/R117H 4 110 21* F508/R117H 4 84 34 F508/R117H 4 95 39 F508/R117H 4 104 40 F508/R117H 4 146 41 F508/R117H 4 104 48* F508/R117H 4 120 53 F508/R117H 4 111 54 F508/R117H 4 175 72* F508/R117L 4 129 70 F508/L967S 15 122 15 F508/F1052V 17b 189 29 F508/R1066H 17b 94 18 Transmembrane, nonsense F508/R75X 3 86 26 F508/R75X 3 171 27 F508/R851X 14a 112 76 Regulatory, missense F508/F693L 13 109 29 Alternate splice site F508/3849+10KB C→T i19 99 26* F508/3849+10KB C→T i19 112 36* None of these samples had the IVS8-5T variant sequence. 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: 10980944 [PubMed] Bornstein JD et al: "Cystic fibrosis in the pancreas: recent advances provide new insights."

No. Sentence Comment

64 The two genotypes found in these three patients (⌬F508/ R117H;9T/7T and ⌬F508/WT;9T/5T) are the most common CBAVD genotypes [21••,24], and each is known not to cause CF [25]. Login to comment
99 Genotypes of Seven ICP Patients with CFTR mutations Patient Gender Mutations Intron 8 Age at onset, y ICP # Days hospitalized ERCP class 1 Male ⌬F508/R117H 9T/7T 45 11 46 Moderate 2 Female ⌬F508/wt 9T/5T 32 7 52 Moderate 3 Female ⌬F508/wt 9T/5T 48 20 100+ Moderate 4 Female ⌬F508/wt 9T/7T 40 25 100+ Moderate 5 Female ⌬F508/wt 9T/7T 15 16 62 Mild 6 Female R117H/wm 7T/7T 32 6 60 Moderate 7 Male N1303K/wt 7T/9T 43 1 6 Moderate ERCP-endoscopic retrograde cholangiopancreatography; ICP-idiopathic chronic pancreatitis. 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: 11069835 [PubMed] Noone PG et al: "Lung disease associated with the IVS8 5T allele of the CFTR gene."

No. Sentence Comment

1 The 5T allele in intron 8 (IVS8) causes abnormal splicing in the CFTR gene, and is associated with lung disease when it occurs in cis with a missense mutation in the CFTR gene, R117H. Login to comment
13 Previously, the 5T and 7T alleles have been described as polymorphisms responsible for the variable expression of the mild CFTR gene mutation R117H. Login to comment
14 For example, an R117H- bearing allele in cis with a 7T allele may result in CBAVD, whereas when associated with the 5T allele, the phenotypic expression may be associated with mild CF lung disease and pancreatic sufficiency. Login to comment

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

No. Sentence Comment

5 After DNA isolation (2), we screened the samples for the 16 most common CFTR mutations: DF508, DI507 [heteroduplex analysis (3)] G542X, G551D, W1282X, N1303K, 3849+10kbCT, R553X, 621+1GT, R1162X, 1717-1GA, 2789+ 5GA, 3849+4AG, 1898+1GA, R117H [restriction fragment length polymorphism, (4-7)] and 3905insT [single-strand conformational polymorphism analysis (8)]. Login to comment
7 The presence of six different mutations was observed on 60 CF chromosomes: DF508, G542X, 1717-1GA, R117H, N1303K and R1162X (Table 1). Login to comment
17 The mutations N1303K, 1717-1GA and R117H were represented with the same frequency of 3.3%. 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

37 Molecular fate of CFTR protein Type of genetic defect and example Class-specific potential therapeutic approach Specific clinical examples I No synthesis Nonsense G542X Frameshift 394delTT Splice junction 1717-1G→A Aminoglycoside readthrough of premature termination site Gentamicin II Trafficking block AA deletion ∆F508 Missense N1303K Manipulation of intracellular folding environment (chemical or molecular chaperones) Phenylbutyrate, CPX III Block in regulation Missense G551D Stimulation of membrane localized mutant channel Genistein, MPB- compounds IV Altered conductance Missense R117H Augmentation of mutant channel conductance Milrinone, adenosine nucleotides V Reduced synthesis of normal protein Missense A455E Alternative splicing 3849+10kbC→T Maximal activation of decreased but functionally normal channels Stimulation of mRNA and protein synthesis ? Login to comment
106 These CFTR mutants including R117H, G314E, R334W, and R347P demonstrate a reduction in their chloride conductance or abnormal channel gating (see Fig. 2). Login to comment
108 R347P affects the rate of chloride flow, whereas R117H and P574H reduce the channel open time. Login to comment
114 In a murine R117H model, milrinone in combination with foskolin resulted in a favorable NPD measurement change [84]. Login to comment
116 Through this mechanism, adenosine indirectly activates wild-type as well as several surface-localized mutant CFTR channels including R117H, A455E, and G1349D. Login to comment

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

No. Sentence Comment

2 The genotype of these patients includes mutations in the CFTR gene, e.g. ∆∆F508, R117H and the T5 allele; all of which are commonly found in CAVD. Login to comment
6 Furthermore, high frequencies of the ∆∆F508 mutation (44.7%), the T5 allele (36.2%) and R117H mutation (19.1%) were observed. Login to comment
13 It is that infertility in adults with CF mutations is probably due toorganized in two membrane spanning domains, TMD1 and degeneration of the reproductive ducts.TMD2, each containing six transmembrane segments desig- The most common mutations found in isolated CAVDnated m1-m12, two nucleotide binding domains, NBD1 and phenotypes are ∆F508, R117H and the T5 allele (IVS8-T5)NBD2 (Riordan et al., 1989), and a cytoplasmic regulatory (Chillon et al., 1995; Jarvi et al., 1995). Login to comment
25 Furthermore, conditions for all the exons and DGGE was performed in a CBS the phenotypic expression of R117H has previously been Scientific apparatus (CA, USA), The DGGE conditions have been shown to be modulated by the polymorphic Tn locus. Login to comment
26 If an described elsewhere (Fanen et al., 1992; Bienvenu et al., 1995; R117H CFTR gene harbours a T5 allele, the mutant gene will Je´ze´quel et al., 1995). Login to comment
28 An R117H mutant CFTR gene that pattern of migration was further analysed by direct sequencing on an harbours a T7 allele can either result in CF or CAVD automatic ABI 373A DNA sequencer with the ABI prism dye (Kiesewetter et al., 1993). Login to comment
40 No sputum microbiology was R117H showed a high frequency (9/47 ϭ 19.1%). Login to comment
42 The eight chromosomes bearing the R117H mutation, five [R117H; results of sweat chloride analysis and additional clinical data on the (TG)10T7] haplotypes (62.5%) and three [R117H;(TG)11T7] patients are listed in Table I. Sweat chloride levels were determined haplotypes (37.5%) were found. Login to comment
43 In one case the [R117H; in 21 patients. Login to comment
45 R117H was always chloride of Ͼ70 mmol/l (Hall et al., 1990). Login to comment
50 total, ∆F508, T5 allele, R117H, R1070W and L375F representNone had undergone abdominal ultrasonography or excretory 83% of the mutation types in our cohort. Login to comment
54 The three men with CUAVD wereTotal genomic DNA was isolated from the patients` peripheral blood cells and analysed for mutations in the whole CFTR region and splice compound heterozygotes (G542X/R1070W, ∆F508/R117H, junctions. Login to comment
60 Tworegions (1, 2, 5, 6a, 6b, 7, 10, 11, 12, 14a, 14b, 15, 16, 17a, 17b, 18, 20, 22, 23, 24) were amplified with a GC-clamp primer and six exons mutations were found in 31.9% of patients, 31.9% had one Table I. Summary of the clinical and biological findings of a population of men with congenital bilateral absence of the vas deferens (CBAVD, n ϭ 37), congenital unilateral absence of the vas deferens (CUAVD, n ϭ 3) and obstructive azoospermia (Obs A, n ϭ 7) Patient Phenotype Surgical Age Weight Height Sweat test Other clinical CFTR exploration (years) (kg) (m) (Cl- mEq/l) manifestation genotype 1 CBAVD ϩ 40 63 1.72 72 ∆F508/T5 2 CBAVD ϩ 31 66 1.76 40 L1227S/3272-26A→G 3 CBAVD ϩ 29 ∆F508/T5 4 CBAVD 29 sinusitis -/- 5 CBAVD 32 50 1.60 ∆F508/T5 6 CBAVD 35 64 1.66 ∆F508/T5 7 CBAVD ϩ 28 ∆F508/R117H 8 CBAVD ϩ 34 69 1.80 24 ∆F508/R117H 9 CBAVD ϩ 35 65 1.70 R117H/T5 10 CBAVD ϩ 32 50 1.70 31 asthma ∆F508/T5 11 CBAVD ϩ 26 left hydrocele T5/- 12 CBAVD ϩ 23 left varicocele, G551D/T5 asthma, anosmia 13 CBAVD ϩ 29 ∆F508/T5 14 CBAVD ϩ 36 63 1.64 52 ∆F508/R117H 15 CBAVD ϩ 37 60 1.76 ∆F508/T5 16 CBAVD ϩ 34 70 1.65 24 ∆F508/A1067V 17 CBAVD 35 61 1.73 42 ∆F508/R117H 18 CBAVD 25 72 1.82 86 2183AA→G/T5 19 CBAVD 28 88 1.76 7 -/- 20 CBAVD ϩ 29 ∆F508/T5 21 CBAVD 31 48 epididymite -/- 22 CBAVD 28 ∆F508/T5 23 CBAVD ϩ 32 68 1.76 36 flatulence ∆F508/R1070W 24 CBAVD ϩ 31 64 1.76 39 R1162X/T5 25 CBAVD 30 17 asthma R117H/L375F 26 CBAVD ϩ 36 62 1.70 ∆F508/R1070W 27 CBAVD 30 6 -/- 28 CBAVD 35 85 1.70 R1070W/- 29 CBAVD 39 bronchectasis -/- 30 CBAVD ϩ 29 ∆F508/- 31 CBAVD 31 bronchectasis, -/- deafness 32 CBAVD ϩ 26 asthma, otitis -/- 33 CBAVD ϩ 28 allergy -/- 34 CBAVD 37 36 R117H/- 35 CBAVD 33 -/- 36 CBAVD ϩ 30 64 1.68 R117H/T5 37 CBAVD ϩ 37 71 1.78 31 pancreatitis, 621ϩ1G→T/I980K alcoholism 38 CUAVD 43 62 1.68 40 allergy G542X/R1070W 39 CUAVD ϩ 35 allergy ∆F508/R117H 40 CUAVD ϩ 34 hydrocele L375F/G551D 41 Obs A ϩ 32 26 T5/- 42 Obs A 23 60 sinusitis ∆F508/2789ϩ2insA 43 Obs A ϩ 25 80 sinusitis, chronic ∆F508/4428insGA 44 Obs A ϩ 30 bronchitis -/- anosmia 45 Obs A 29 50 -/- 46 Obs A 29 75 1.77 ∆F508/T5 47 Obs A ϩ 30 82 1.66 -/- mutation and the T5 allele, 10.7% had only one mutation and clinical palpation. Login to comment
71 This 25-year-old man (no. 43) with obstructive7 ∆F508/R117H (TG)10T9/(TG)10T7 8 ∆F508/R117H (TG)10T9/(TG)10T7 azoospermia who underwent surgical exploration had two 14 ∆F508/R117H (TG)10T9/(TG)10T7 hypoplastic vas deferens and bilateral aplasia of the epididymal 17 ∆F508/R117H (TG)10T9/(TG)10T7 cauda. Login to comment
72 In addition, he had an elevated sweat test (80 mEq/l)39 ∆F508/R117H (TG)10T9/(TG)11T7 23 ∆F508/R1070W (TG)10T9/(TG)10T7 and sinusitis. Login to comment
73 This mutation creates a stop codon 43 nucleotides 26 ∆F508/R1070W (TG)10T9/(TG)10T7 downstream leading to the deletion of 33 C-terminus amino 16 ∆F508/A1067V (TG)10T9/(TG)10T7 acids of the CFTR protein including the TRL-COOH domain.42 ∆F508/2789ϩ2insA (TG)10T9/(TG)10T7 43 ∆F508/4428insGA (TG)10T9/(TG)11T7 This highly conserved proteic site is a perfect match for the 25 R117H/L375F (TG)10T7/(TG)10T7 binding consensus domain of the Naϩ-Hϩ exchanger regulatory 38 G542X/R1070W (TG)10T9/(TG)11T7 factor (NHE-RF), a cytoplasmic phosphoprotein that may play40 L375F/G551D (TG)10T7/(TG)10T7 37 621ϩ1G→T/I980K (TG)10T9/(TG)10T9 an important regulatory role in CFTR function (Wang et al., 2 L1227S/3272-26A→G (TG)10T9/(TG)12T7 1998). Login to comment
77 The 4428insGA 22 ∆F508/- (TG)10T9/(TG)12T5 may, therefore, be considered as a mild allele responsible for9 R117H/- (TG)11T7/(TG)13T5 36 R117H/- (TG)11T7/(TG)12T5 elevated sweat test and obstructive azoospermia. Login to comment
78 12 G551D/- (TG)10T9/(TG)13T5 These three novel mutations have not been found in more 18 2183AA→G/- (TG)10T7/(TG)12T5 than 200 non-CF chromosomes and in a sample of 300 CF24 R1162X/- (TG)10T9/(TG)12T5 chromosomes from local classical CF patients, nor were theyOne mutation detected without T5 allele (3/47 ϭ 6.4%) reported by any other member of the CF Genetic Analysis30 ∆F508/- (TG)10T9/(TG)10T7 34 R117H/- (TG)12T7/(TG)10T7 Consortium. Login to comment
80 No mutation detected with one T5 allele (2/47 ϭ 4.3%) A rare missense mutation, L375F, first described elsewhere 41 -/- (TG)11T5/(TG)11T7 (Je´ze´quel et al., 1996) and located in exon 8 which codes for11 -/- (TG)11T5/(TG)11T7 a cytoplasmic region between the m6 transmembrane domainNo mutation detected (12/47 ϭ 25.5%) and NBD1, was found twice, once associated with G551D in4 -/- nd 44 -/- (TG)12T7/(TG)10T7 a CUAVD phenotype (no. 40) surgically explored and once 19 -/- (TG)11T7/(TG)11T7 with R117H in a CBAVD phenotype (no. 25) clinically45 -/- (TG)11T7/(TG)10T7 diagnosed in a 30-year-old man with a normal sweat test21 -/- (TG)11T7/(TG)11T7 27 -/- (TG)11T7/(TG)10T7 (17 mEq/l) and asthma. Login to comment

PMID: 11117575 [PubMed] Kimura S et al: "Polymorphism of cystic fibrosis gene in Japanese patients with chronic pancreatitis."

No. Sentence Comment

2 In this study, we investigated the association of mutations or polymorphisms of the CFTR gene with chronic pancreatitis in Japanese patients. Forty-seven patients with chronic pancreatitis (alcohol-related in 31, idiopathic in 14, and familial in 2) were examined for the ⌬F508 and R117H mutations and polymorphisms of intron 8. Login to comment
5 None of the patients had ⌬F508 or R117H mutations in the CFTR gene. Login to comment
13 These mutations include an arginine-to-histidine substitution at residue 117, and an asparagine-to-isoleucine substitution at residue 21 (1, 2). Login to comment
18 Among the CFTR mutations observed in patients with chronic pancreatitis, ⌬F508 is the most frequent and arginine-to-histidine substitution at residue 117 (R117H) is second most frequent in Caucasian populations. Login to comment
34 We extracted DNA from blood samples and tested for ⌬F508 and R117H mutations, which are commonly identified in Caucasian patients with chronic pancreatitis (4, 5). Login to comment
37 The allele-specific PCR was used to detect R117H mutation (8). Login to comment
61 The R117H mutation of exon 4 of the CFTR gene is a G-to-A substitution at nucleotide position 482. Login to comment
62 Two reactions were performed for each DNA sample, with specific primers for the wild-type and mutant R117H alleles. A 360-bp fragment of exon 3 of ␣1-antitrypsin was simultaneously amplified as an internal control. Login to comment
63 In 47 patients with chronic pancreatitis, we could not detect the mutant R117H bands in our samples (Figure 1B). Login to comment
73 Allele-specific polymerase chain reaction analysis of ⌬F508 (A) and R117H of the CFTR gene (B). Login to comment
75 Next two tracks are the products of the normal (lane N) and ⌬F508 or R117H mutant reactions (lane M) using a patient`s DNA sample. Login to comment
115 The pancreatic sufficiency phenotype occurs in patients who have one or two mild CFTR mutations such as R117H, whereas the pancreatic insufficiency phenotype occurs in patients with two severe alleles such as ⌬F508 (20). Login to comment
127 Other mutations included R117H in two patients and Q493X, R553X, R560T, and 621 ϩ 1(G-to-T) in one patient each. Login to comment
128 Cohn et al (5) studied 27 patients with chronic idiopathic pancreatitis and detected three different mutations in eight patients: ⌬F508 in five, R117H in two, and N1303K in one. Login to comment
130 The second mutation frequently detected in the patients with chronic pancreatitis is R117H. Login to comment

PMID: 11124965 [PubMed] Kogan I et al: "Perturbation of the pore of the cystic fibrosis transmembrane conductance regulator (CFTR) inhibits its atpase activity."

No. Sentence Comment

176 With regards to CFTR, there is indirect evidence supporting interaction between permeation and gating, in that certain mutations in the transmembrane segments of CFTR, namely S1118F in TM11 (33) and the disease-causing mutant R117H (50), exhibit altered channel open times. 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
58 Frequency of CFTR mutations in white CF chromosomes Mutation Number of chromosomes Frequency (%) DF508 291 76 3272-26AG 16 4 394delTT 14 3.6 G542X 5 1.3 R553X 4 1 1W1282X 4 14N1303K G551D 3 0.8 3120+1GA 2 0.5 R117H 1 0.3 Q493X 1 0.3 S549N 1 0.3 621+1GT 1 0.3 1717-1GA 1 0.3 2789+5GA 1 0.3 91Total 349/384 Table 2. Login to comment

PMID: 11168024 [PubMed] Scotet V et al: "Prevalence of CFTR mutations in hypertrypsinaemia detected through neonatal screening for cystic fibrosis."

No. Sentence Comment

101 This hypothesis is supported by the fact that some CF genotypes are associated with a normal sweat chloride level (DF508/R117H (7T), DF508/3849+10kb CT) (33-35). Login to comment

PMID: 11242048 [PubMed] Choi JY et al: "Aberrant CFTR-dependent HCO3- transport in mutations associated with cystic fibrosis."

No. Sentence Comment

18 Two of the mutations, I148T and R117H, are relatively common, and thus the clinical data are solid. Login to comment
23 To validate the ability of this procedure to accurately report Cl-channel activity, we determined the correlation between expression ef®ciency (green ¯uorescent protein (GFP) ¯uorescence), Cl- current and changes in [Cl- ]i in cells transfected with CFTR, CFTR(I148T) and CFTR(R117H). Login to comment
24 Figure 1a±h shows that similar results are reported by measurement of Cl- current and [Cl- ]i for CFTR and the mutants. Therefore, the Cl-transport capacity of all other CFTR letters to nature 94 NATURE | VOL 410 | 1 MARCH 2001 |www.nature.com NO3 - NO3 - NO3 - Forskolin 5 µM Forskolin 5 µM Forskolin 5 µM Cl-free Forskolin 5 µM Cl-free Cl-free Forskolin 5 µM Forskolin 5 µM 0.25 pHunits 250 s e WT f I148T g R117H i WT j I148T k R117H 10mMCl- 200 s 0 0.2 0.4 [Cl- ]change (mMs-1 ) n=6 n=4 n=3 WT R117H I148T 0 0.2 0.4 0.6 0.8 1.0 HCO3 -transport (∆pH+ min-1 ) n=8 n=4 n=3 I148T R117H WT l a WT b I148T c d h R117H 0 8 16 24 n=5 n=4n=3 WT I148T R117H Current (pApF-1 perGFP fluorescence) 120 s 100pA For 5 µMFor 5 µMFor 5 µM Figure 1 cAMP-stimulated Cl- and HCO3 transport by wild-type (WT) CFTR and the CFTR mutants I148T and R117H. Login to comment
32 (c) 2001 Macmillan Magazines Ltd mutants was evaluated from changes in [Cl- ]i. Figure 1e±l shows the experimental protocols used to measure the effect of the I148T and R117H mutations on Cl- and HCO3 transport. Login to comment
46 The results obtained with the R117H mutation are illustrated in Fig. 1. Login to comment
47 In sharp contrast with the results obtained with the mutants associated with CF with pancreatic insuf®ciency, and in agreement with previous reports25 , the R117H mutation reduced Cl- current and the MQAE response by about 70%. Login to comment
48 By contrast, the R117H mutation reduced the ability of CFTR to support HCO3 transport by only 37%. Login to comment
70 In this regard, although the R117H mutation markedly reduces Cl-channel activity and Cl-transport (Fig. 1), it is associated with a mild form of CF, probably because it supports substantial HCO3 transport (Fig. 1). Login to comment
186 letters to nature 96 NATURE |VOL 410 |1 MARCH 2001 |www.nature.com HCO3 -/Cl- transportratio 0 0.25 0.50 0.75 1.00 WT I148T G178R R297Q G551D H620Q G970R A1067T G1244E S1255P G1349D E193K G551S A800G H949Y R1070Q Pancreatic insufficient Pancreatic sufficientD648V N CI148T G178R E193K R297Q R117H A1067T R1070Q G1244E S1255P G1349D NBD2 RD H949Y G970R CL4CL3CL2CL1 NBD1 G551D G551S H620Q D648V A800G Figure 3 The HCO3:Cl-transport ratio of CFTR mutants associated with CF. Login to comment

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

No. Sentence Comment

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

PMID: 11276378 [PubMed] Rolston RK et al: "Genetic testing in acute and chronic pancreatitis."

No. Sentence Comment

42 In the older literature, this mutation was initially designated R117H, borrowing the amino acid numbering system based on the primary structure of chymotrypsinogen, another serine (Ser) protease, which uses 195Ser as the reference. Login to comment
45 Thus, R117H is now designated R122H [21]. Login to comment

PMID: 11278813 [PubMed] Hammerle MM et al: "Disease-associated mutations in the extracytoplasmic loops of cystic fibrosis transmembrane conductance regulator do not impede biosynthetic processing but impair chloride channel stability."

No. Sentence Comment

14 However, one relatively common missense mutation in EL1, R117H, was shown earlier to reduce chloride conductance (2). Login to comment
75 TABLE I Oligonucleotide primers used to generate mutations Mutation Primer S108F GGAAGAATCATAGCTTtCTATGACCCGGATAAC Y109C AGAATCATAGCTTCCTgTGACCCGGATAACAAG D110H ATCATAGCTTCCTATcACCCGGATAACAAGGAG P111A ATAGCTTCCTATGACgCGGATAACAAGGAGGAA P111L ATAGCTTCCTATGACCtGGATAACAAGGAGGAA E116K CCGGATAACAAGGAGaAACGCTCTATCGCGATT R117C GATAACAAGGAGGAAtGCTCTATCGCGATTTAT R117H GATAACAAGGAGGAACaCTCTATCGCGATTTAT R117L GATAACAAGGAGGAACtCTCTATCGCGATTTAT R117P GATAACAAGGAGGAACcCTCTATCGCGATTTAT E217G ATGGGGCTAATCTGGGgGTTGTTACAGGCGTCT T908N TATGCAGTGATTATCAaCAGCACCAGTTCGTAT P1013L GTCGCAGTTTTACAACtCTACATCTTTGTTGCA FIG. 2. Login to comment
119 C, squares, R117C; circles, R117H; triangles, R117L; diamonds, R117P. Login to comment
138 The R117H mutant was reported previously to exhibit a small reduction in both current amplitude and open time (2). Login to comment
149 Thus the more frequent R117H mutation seems to compromise open-channel structure less than the other three substitutions at this position. Login to comment
171 For example a nucleotide binding domain mutation, G551D, precludes virtually all TABLE II Relative charge transport capacity of mutants Mutants S108F Y109C D110H P111L P111A E116K R117H R117C R117L R117P E217G T908N P1013L Imutant/Iwt 100% 11 15 27 173 105 12 80 27 5 11 10 48 170 FIG. 5. Login to comment
176 Of missense mutations identified in codons for residues in extracytoplasmic loops, only R117H, which occurs relatively frequently in patients, has been studied in any detail (2). 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
52 In the panel, we also included the R117H which, although absent in our CF patients, has been reported in the literature with signi®cant frequency in CBAVD patients (Gervais et al., 1993; Patrizio et al., 1993; Schlegel et al., 1995). Login to comment
99 Interestingly, none of our CBAVD patients had the R117H mutation which has been found with a relatively high frequency in these patients (Gervais et al., 1993; Patrizio et al., 1993; Schlegel et al., 1995), This mutation is also extremely rare in patients with CF in Italy and in other European countries (Chillon et al., 1994; Estivill et al., 1997; Rendine et al., 1997). Login to comment

PMID: 11310970 [PubMed] Dworakowska B et al: "Ion channels-related diseases."

No. Sentence Comment

311 Milder forms of the disease result from such mutations as Arg117His, Glu193Lys, Arg334Trp and Arg347Pro which produce channels that are less likely to open or have reduced amplitude (Sheppard et al., 1993; Seibert et al., 1997). Login to comment

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

No. Sentence Comment

65 Non DF 508 alleles in the two groups were: 1237A group: G551D (3); N1303K (2); R117H (1); R560T (1); Unknown (3). Login to comment
66 1237G group: G551D (10); R117H (3); R560T (3); D1507 (2); E60X (2); N1303K (1); 1717-1 (1); 621H (1); G542X (1); POL 400 (1); R352Q (1); RT0F (1); 621+G4T (1); Unknown (15). Login to comment
70 For subjects heterozygous for DF508, the second allele was matched as closely as possible and included the following: G551D, N1303K, R117H and R560T. Login to comment
81 infective exacerbations over 2 years 4.7+0.7 2.8+0.6 0.03 over 4 yearsb 10.5+1.8 4.5+1.1 0.006 FEV1 % predicted 55.5+7.4 67.5+5.5 NS at reference visit 2 years post 53.1+8.5 68.4+5.5 (n=14) 0.09 (NS) reference visitb a Non DF 508 alleles in the two groups were: 1237A group: G551D (3); R117H (1); R560T (1); N1303K (2); Unknown (3); 1237G group: G551D (4); R117H (1); R560T (1); 621+G4T (1); Unknown (3). Login to comment

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

No. Sentence Comment

54 ⌬F508 was present in only 21 of the 50 patients and was in heterozygosis in all cases, carried together with L206W, 2789+5G>A, 3272-26A>G, R117H, 5T, R334W, or an unidentified mutation. Login to comment
64 Other genotypes present in our series ⌬F508/711+1G>T 2A 5T/5T 1B ⌬F508/5T 2B ⌬1507/- 1A ⌬F508/R117H 2B R1162X/1898+1G>A 1A ⌬F508/R1162X 1A 2183A/- 1A ⌬F508/N1303K 1A 1609-CA/1811+1.6kbA>G 1A ⌬F508/3272-26A>G 1B 1609-CA/R347P 1A ⌬F508/D836Y 1B Q890X/- 1A ⌬F508/1717-1G>A 1A R334W/- 1B G542X/W1282X 1A N1303K/2789+5G>A 1B G542X/2789+5G>A 1B 3659-C/- 1B G542X/P205S 1B G85E/- 1B G542X/D1270N 1B Negative 1A, 20B L206W/- 1B Unknown 2A creatic insufficiency was highly prevalent, affecting 33 patients (84.6%). Login to comment

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

125 It was unexpected that six of the next most common mutations after 3120 ϩ 1GϾA would be of Caucasian origin (R1158X, R117H, G551D, 1812-1GϾA, 1898 ϩ 1GϾA, and R1066C). Login to comment
128 By comparison, eight "African" mutations accounted for a similar percentage of the chromosomes analyzed (23%) in the study by Macek et al.6 In contrast, 11 of the 20 mutations detected in this study are considered to be "Caucasian" mutations and account for 10.5% of the chromosomes analyzed (R117H, 621 ϩ 1GϾT, R334W, Q493X, G551D, 1812-1GϾA, 1898 ϩ 1GϾA, R1066C, R1158X, R1162X, and 3905insT). 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

196 Reports indicate that some CF patients with uncommon alleles (i.e., conduction mutants such as R117H or R334W, or the uncommon A455E allele) may have abnormally elevated sweat [Cl- ] values diagnostic of CF but lower than those of the general CF population (9, 25-27). Login to comment

PMID: 11420207 [PubMed] Doull IJ et al: "Recent advances in cystic fibrosis."

No. Sentence Comment

27 The class IV mutation R117H occurs with either five or seven thymidine residues (5T or 7T), and disease severity is increased with the 5T variant. Login to comment
32 Azoospermia has long been recognised as a feature of cystic fibrosis, but mutational analysis of otherwise healthy infertile males with congenital bilateral absence of the vas deferens has demonstrated two CFTR mutations in up to 50% of subjects.8 Most subjects have either 5T splicing mutations or R117H, and although they are usually completely asymptomatic there is increasing evidence that they may still get respiratory complications. 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
43 The same genetic screening, with the exception of the R347P, R352Q, R117H mutations and of the poly(T) variant, was performed in the control population. Login to comment
44 All the mutations were analyzed by a Reverse Dot Blot Assay based on those described by Chehab et al (Chehab et al, 1992), with the exception of R117H, for which we used a restriction site generating PCR (Gasparini et al, 1992), and designed two primers: R117H-D [ACC CGG ATA ACA AGG AGG AGC] and R117H-R [GGC CTG TGC AAG GAA GTA TT] which create a CfoI restriction site when the mutation is absent. Login to comment
63 PATIENT A B C Sex (m/f) f f f Age (yrs) 27 60 53 Pancreatitis ICP IRAP IRAP CFTR mutations R1162X 2789+5G→A N1303K R117H R553X PolyT Splice Variant 7/7 7/9 7/9 Sweat Cl- (mEq/l) 108 42 91.75 Sweat Na+ (mEq/l) 106.5 42.8 84.25 NPD n.a. Basal and activated positive Basal negative, activated positive CF-compatible anamnestical and clinical features Chronic cough Lobectomy for bronchiectasis; hemoptysis and bronchial artery embolization Lobar atelectasis Sputum culture Staphylococcus aureus; Pseudomonas aeruginosa Staphylococcus aureus Staphylococcus aureus; Pseudomonas aeruginosa FVC (% predicted) 94 107 118 FEV1 (% predicted) 79 93 116 FEF25-75 (% predicted) 45 49 127 Chest X-ray Chrispin-Norman score 4 3 5 X-ray mucosal thickening of paranasal sinuses Maxillary bilateral Frontal bilateral Maxillary right Weight Z-score -0.86 0.08 -0.53 Height Z-score -0.28 -0.45 -0.12 Pancreatic evaluation § * Pancreatic sufficiency Pancreatic sufficiency n.a. : not available § : duodenal outputs of bicarbonate, lipase, amylase, trypsin and chymotrypsin assessed by pancreatic stimulation test * : normal fecal chymotrypsin and 72-hour steatorrhea The medical history disclosed in 20/53 (37.7%) cases one or more signs and symptoms frequently found in CF: diabetes in 9, sinusitis in 8, chronic cough in 7, malnutrition in 1, monolateral seminal vesicle agenesis in 1, lobectomy secondary to bronchiectasis in 1 and lobar atelectasis in 1 subject. Login to comment
81 She is a compound heterozygote, carrying N1303K and R117H. Login to comment
82 A close association between the latter mutation chromosomal background and its phenotype has been demonstrated (Kiesewetter et al, 1993): R117H, provided it is paired with CF-causing mutations, usually results in CF when in cis with the 5T allele, and in CBAVD when in cis with the 7T allele. Login to comment

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

No. Sentence Comment

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

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

No. Sentence Comment

65 Distribution of XK Haplotype on Chromosomes Bearing Uncommon Cystic Fibrosis (CF) Mutations A B C D S549N 4/4 DI507 3/3 N1303K 3/3 2055 del9!A 2/2 I148T 1/1 406-1G!A 1/1 R75X 1/1 I506T 1/1 935delA 1/1 2183AA!G 1/1 1924del7 1/1 G551S 1/1 1078delT 1/1 R117H 1/1 384910KbC!T 1/1 1716G!A 1/1 W1204X 1/1 W1098C 1/1 846delT 1/1 R75Q 1/1 W1069X 1/1 L558S 1/1 4160insGGGG 1/1 297-1G!A 1/1 Fig. Login to comment

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

No. Sentence Comment

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

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

No. Sentence Comment

3 ABSTRACT: Compound heterozygotes for a severe cystic fibrosis transmembrane conductance regulator (CFTR) mutation and the R117H or R117C mutation (R117H/ C) have clinical presentations that vary from classic cystic fibrosis (CF) to an incidental genetic finding. Login to comment
4 The aim of this study was to assess the influence of the intron-8 polythymidine sequence (IVS8) on the relationship between genotype and phenotype of individuals with R117H/C. Login to comment
5 All individuals with R117H/C known to CF clinics in Australia and New Zealand were retrospectively studied by collecting information on genotype, age, pancreatic status, sweat electrolytes, sputum microbiology and pulmonary function. Login to comment
6 Forty-one individuals (39 with R117H and two with R117C), 16 on an IVS8-5T background and 25 on an IVS8-7T background were identified. Login to comment
7 Twelve individuals presented clinically, four were siblings of known R117H/C compound heterozygotes and 25 were detected by newborn screening. Login to comment
8 Eleven of 14 of the IVS8-5T group (78%) with sweat chloride results available had sweat Clw60 mmol?L-1 compared to 5 (20%) of the R117H/7T group (Chi-squared~10.4, p~0.001). Login to comment
11 In conclusion, most individuals with R117H/C on a IVS8-5T background have an elevated sweat chloride and clinical cystic fibrosis, which in some cases is severe. Login to comment
12 Most individuals with R117H/C on an IVS8-7T background do not have clinical cystic fibrosis but should be followed for the development of clinical disease. Login to comment
15 Correspondence: R.J.H. Massie Dept of Respiratory Medicine Royal Children9s Hospital Melbourne 3052 Australia Fax: 61 393491289 Keywords: Cystic fibrosis genotype phenotype R117H Received: June 26 2000 Accepted after revision January 15 2001 The correlation between genotype and phenotype in cystic fibrosis (CF) is not always clear [1]. Login to comment
16 In general, individuals who are compound heterozygotes for a severe cystic fibrosis transmembrane conductance regulator (CFTR) mutation and R117H or R117C (R117H/C) have milder disease. Login to comment
18 R117H/C are class IV mutations associated with the production of a CFTR protein which has altered channel properties [3, 4]. Login to comment
19 Chloride transport through R117H/C CFTR is reduced and this is thought to explain the milder phenotype [3, 4]. Login to comment
20 The variable presentation amongst R117H/C compound heterozygotes may be explained, in part, by the efficiency of exon-9 splicing. Login to comment
25 The variable presentation of individuals with R117H/C makes it difficult to be certain of the clinical outcome. Login to comment
26 However, the widespread availability of CFTR gene mutation testing, in particular through newborn screening programmes and antenatal testing, has created the need to predict the prognosis of individuals who are compound heterozygotes for a severe CFTR mutation and R117H/C who may be asymptomatic at the time of testing. Login to comment
28 The criteria includes the presence of two disease producing CFTR mutations of which R117H/C are only considered disease producing mutations when in cis with IVS8-5T [8]. Login to comment
29 Despite this, there are reports of individuals with CF-like conditions who have R117H/C with the IVS8-7T allele [5, 9, 10] and there Eur Respir J 2001; 17: 1195-1200 Printed in UK - all rights reserved Copyright #ERS Journals Ltd 2001 European Respiratory Journal ISSN 0903-1936 is no definitive information as to strength of the relationship between R117H/C, the IVS8 polythymidine sequence and the clinical outcome. Login to comment
30 The aim of this study was to assess the relationship between genotype and phenotype of individuals known to have the R117H/C mutation and the influence of the IVS8 polythymidine sequence. Login to comment
32 Information was requested regarding all individuals, alive or deceased, who had been seen in their clinic and who were known to have the R117H or R117C mutation. Login to comment
33 R117H and R117C have been considered to be functionally equivalent [11] and have been combined in the analysis, referring to R117H and R117C collectively as R117H/C. Login to comment
35 Individuals were known to CF clinic directors and Clinical Genetics Services on the basis of either a clinical presentation (symptoms of CF or a sibling of a patient compound heterozygote for R117H/C) or identification through newborn screening. Login to comment
39 One Australian centre (South Australia) includes the mutations G551D, G452X, DI507, R553X and R117H as part of routine screening of infants with an elevated IRT [12]. Login to 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
45 R117H was detected by ARMS (Western Australia, New South Wales, Victoria, Tasmania, New Zealand) or ASO (South Australia) and R117C was detected using a restriction enzyme digest (Western Australia, New South Wales, Victoria, Tasmania), ASO (South Australia) or ARMS (New Zealand). Login to comment
54 Results Genotype Forty-one individuals with R117H/C (39 R117H and two R117C) being followed at one of the CF clinics in Australia and New Zealand were identified. Login to comment
56 Thirty-four of the 39 individuals were compound heterozygotes for R117H/C and DF508. Login to comment
57 Two of the individuals had a second severe mutation (G542X/R117H and G551D/R117H), four had an unknown second mutation and one patient was homozygous for R117H. Login to comment
58 Sixteen individuals had R117H on an IVS8-5T background and 25 on an IVS8-7T background. Login to comment
59 The phase of each chromosome was unknown, preventing identification of the direct association between R117H and the IVS8 polythymidine sequence. Login to comment
60 However, previous studies have indicated that where present, IVS8-9T occurs in cis with DF508 [5] and that R117H is the only mutation that occurs in cis with IVS8-5T [18]. Login to comment
62 Presentation Twenty-five of the 41 (61%) individuals were discovered through newborn screening, 12 (29%) because of respiratory symptoms and four (10%) were siblings of an R117H/C compound heterozygote (three had a younger sibling with a positive newborn screening test and one had a sibling presenting clinically). Login to comment
67 Both PI individuals had R117H/C on an IVS8-5T background. Login to comment
83 Discussion This study provides evidence that the variable presentation of individuals with the R117H/C mutation is associated with differences in the IVS8. Login to comment
84 Most individuals with R117H/C and the IVS8-5T allele fulfil clinical and sweat test criteria for the diagnosis of CF while most individuals with R117H/C and the IVS8-7T allele do not [8]. Login to comment
87 In general, individuals who are compound heterozygotes for a severe mutation and R117H/C on an IVS8-5T background have pancreatic sufficient CF which is mild compared to individuals with two severe mutations [2]. Login to comment
94 Symptoms of established suppurative lung disease were present in some of the older IVS8-7T individuals, raising the possibility that significant lung disease may develop in more of the IVS8-7T group with time. This study is similar to that of KIESEWETTER et al. [5] who studied 38 pancreatic sufficient CF individuals with the DF508/R117H genotype, of whom 31 had the IVS8-5T allele and seven the IVS8-7T allele. Login to comment
95 A further nine DF508/R117H individuals were studied, eight males had CAVD only and one female who was asymptomatic, and in each case the R117H was associated with the IVS8-7T allele. Login to comment
96 The difference between IVS8-5T and IVS8-7T distribution amongst symptomatic individuals with the DF508/R117H genotype was significant (Chi-squared~15.2, pv0.001). Login to comment
97 This study recognized the need for IVS8 polythymidine analysis to explain the variability amongst individuals with the R117H mutation. Login to comment
98 Other studies have found individuals with R117H on a IVS8-7T background to have pulmonary disease. Login to comment
99 DEAN et al. [9] reported a 56-yr-old female with R117H/IVS8-7T who had chronic bronchitis from the age of 10 yrs, complicated by allergic bronchopulmonary aspergillosis (ABPA). Login to comment
101 Similarly, one patient in a series of sweat test negative ABPA individuals had R117H a IVS8-7T background and could be considered to have a mild form of CF [10]. Login to comment
102 The variability of clinical presentation of individuals with the R117H/C mutations is largely, but not entirely explained by the IVS8 polythymidine sequence. Login to comment
106 The importance of understanding the role of the IVS8 polythymidine sequence amongst individuals with the R117H mutation was highlighted in a recent report by CHMIEL et al. [20]. Login to comment
107 In this report an infant was diagnosed with CF on the basis of the detection of DF508 and R117H in cord blood but without IVS8 polythymidine sequencing being performed until much later. Login to comment
109 The R117H was found to be on an IVS8-7T background and the diagnosis of CF was changed, but not without considerable emotional cost to the family. Login to comment
112 If R117H/C is detected then it is imperative that intron-8 polythymidine sequence analysis be performed to offer some guidance as to the likely phenotype. Login to comment
113 Most individuals with a severe cystic fibrosis mutation and R117H/C on the intron-8 polythymidine sequence-5T background will have an elevated sweat chlorine and clinical features of cystic fibrosis, which in some cases are severe and associated with an early death. Login to comment
114 Most individuals with R117H/C on the intron-8 polythymidine sequence-7T background do not have clinical features of cystic fibrosis although over half have elevated or borderline sweat chloride. Login to comment
115 Individuals with R117H/C on the intron-8 polythymidine sequence-7T background should be followed for the potential to develop clinical disease. Login to comment

PMID: 11504857 [PubMed] Chen JM et al: "A combined analysis of the cystic fibrosis transmembrane conductance regulator: implications for structure and disease models."

No. Sentence Comment

100 Moreover, all of the 11 most common missense mutations or single-amino-acid deletions (i.e., F508del, G551D, N1303K, R117H, R347P, I507del, G85E, R560T, A455E, R334W, and S549N) identified in classic and atypical CF patients worldwide (http://www.genet.sickkids.on.ca/cftr) occur in stringently conserved residues across the 15 CFTR sequences. Login to comment

PMID: 11547256 [PubMed] Lebecque P et al: "[Cystic fibrosis and normal sweat chloride values: a case-report]."

No. Sentence Comment

73 Dans des situations d`hétérozygotie composite, la présence de certaines d`entre elles a pu être associée de manière occasionnelle ou parfois plus consistante avec un taux de chlorure dans la sueur inférieur à 60 voire même (dans de très rares cas) 30 mmol/L. Dans ce singulier petit groupe, figurent notamment les mutations 3 849 + 10kb C→T, A455E, R117H, , R347H, G551S, D1152H. Login to comment

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

No. Sentence Comment

50 Blood samples were also collected from 10 members of five HP families, i.e., (i) seven patients with the R117H mutation of the cationic trypsinogen gene; (ii) one patient with the A16V mutation of the cationic trypsinogen gene; and (iii) a family with two affected brothers who tested negative for mutations of this gene. Login to comment
56 Using multiplex PCR, 15 genomic fragments were amplified which contain the following mutations: ⌬F508, ⌬I507, Q493X, V520F, 1717-1G3A, G542X, G551D, R553X, R560T, S549R, S549N, 3849 ϩ 10kbC3T, 3849 ϩ 4A3G, R1162X, 3659delC, W1282X, 3905insT, N1303K, G85E, 621 ϩ 1G3T, R117H, Y122X, 711 ϩ 1G3T; 1078delT, R347P, R347H, R334W, A455E, 1898 ϩ 1G3A, 2183AA3G, 2789 ϩ 5G3A. Login to comment

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

No. Sentence Comment

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

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

No. Sentence Comment

5 Results Severe pancreatic insufficiency was associated with the presence of two CFTR gene mutations (DF508, N1303K, CFTR dele 2,3 (21kb), G542X, 1717±1G-A, R533X, W1282X, 621GT, 2183AAG, R560T, 2184insA and DI507, G551D, 895T) and mild insufficiency with the presence of at least one mutation (R117H, 3171insC, A155P2, 138insL, 296 1 1G-A, E92GK, E217G, 2789 1 5G-A. Login to comment
51 Results Among 394 genotyped CF patients, the following mutations on alleles were found (n): DF508 (464), 3849 1 10kbC-T (30), CFTR dele2,3(21 kB) (21), N1303K (15), G542X (12), 1717±1G-A (9), R533X (6), W1282X (6), 621 1 G-T (3), R117H (2), 3171insC (2), A155P2 (2), 2183AAG (2), R334W (2), 895T (2), 296 1 1G-A (2), E92GK (2), 138insL (1), E217G (1), 2789 1 5G-A (1), R347P (1), R560T (1), 2184insA (1), I507 (1), G551D (1). Login to comment
58 156 mg g21 ) ± mildly affecting pancreatic function (R117H, 3171insC, A155P2, 296 1 1G-A, E92GK, 138insL, E217G, 2789 1 5G-A). 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: 11737931 [PubMed] Noone PG et al: "'CFTR-opathies': disease phenotypes associated with cystic fibrosis transmembrane regulator gene mutations."

No. Sentence Comment

30 Generally, one 'severe` allele is combined with one 'mild` allele, such that the 'mild` allele appears to dominate and cause the milder phenotype (e.g. ∆F508 in combination with R117H). Login to comment
41 For example, the mild CFTR mutation R117H is influenced by the polythymidine tract sequence, such that an R117H- bearing allele in cis with a 7T allele may result in CBAVD, whereas when R117H is associated with the 5T allele the phenotypic expression may be associated with atypical CF. Login to comment
42 R117H with a 9T allele may exhibit a normal phenotype. Login to comment

PMID: 11746017 [PubMed] White SM et al: "Cystic fibrosis: a further case of an asymptomatic compound heterozygote."

No. Sentence Comment

1 The R117H CFTR mutation, when found together with another CF mutation, has been associated with a variable phenotype ranging from classical CF to congenital bilateral absence of the vas deferens (CBAVD) [Gervais et al., 1993]. Login to comment
2 We report on a healthy 29-year-old woman who was found to be a R117H/deltaF508 compound heterozygote of the CF gene but who was completely asymptomatic. Login to comment
9 CF mutation analysis was undertaken as part of an evaluation for an egg donation program, and she was found to be a R117H/deltaF508 compound heterozygote of the CFTR gene. Login to comment
10 This is the second reported case of an asymptomatic person with the genotype R117H/deltaF508 [Lee et al., 1992; Chmiel et al., 1999]. Login to comment
11 Previous studies have shown that the length of the polythymidine tract in intron 8 of the CFTR gene is polymorphic and that particular lengths modulate the clinical effect of the R117H phenotype [Kiesewetter et al., 1993]. Login to comment
15 The R117H mutation is a missense mutation in exon 4, which is at the external end of the second transmembrane domain of the CFTR protein and affects a basic amino acid that appears to reduce the conduction properties of the CFTR Cl-channel. Login to comment
16 Since mRNAs lacking exon 9 generate CFTR proteins without chloride channel activity, it appears there may be a compounding effect between the shorter 5T tract and the R117H mutation. Login to comment
18 In addition to the in¯uence of partially penetrant mutations, modi®ers and variable ef®ciency of splicing in different tissues also play some role in predicting the deltaF508/R117H phenotype. Login to comment
20 The R117H mutation is found in the general population in cis with either a 5T, 7T, or, rarely, a 9T background. Login to comment
21 Kiesewetter et al. [1993] studied the polyT status of 38 pancreatic-suf®cient CF patients with the genotype R117H/deltaF508 and found 31 patients carried the 5T background with R117H and seven carried the 7T background. Login to comment
22 In eight patients with congenital bilateral absence of the vas deferens only, and in the single asymptomatic woman with R117H/ deltaF508, the 7T background was found with R117H in all cases. Login to comment
23 Chmiel et al. [1999] reported a case of a female infant with the R117H/deltaF508 genotype ascertained through screening of parents during pregnancy. Login to comment
24 The infant's genotype showed the 7T background was associated with the R117H mutation; no lung disease was present, the result of the sweat test was normal, and the child was thriving. Login to comment
26 The woman, an R117H/deltaF508 compound heterozygote, showed no pulmonary or pancreatic disease and had normal sweat electrolytes. Login to comment
27 In a further paper by the same group, Witt et al. [1996] reported the R117H mutation in this patient to be associated with the 7T background. Login to comment
28 Thus, the polyT tract length and sex are important factors in¯uencing the pathogenic effect of the R117H mutation. Login to comment
29 Rosenbluth and Goldenberger [1997] reported on a 70-year-old woman who was diagnosed with CF with a genotype R117H/deltaF508 and phenotype of chronic *Correspondence to: Dr. Login to comment
35 The incidence of the R117H mutation in population screening studies has been found to be higher than that predicted by studies based on patients clinically diagnosed with CF [Tsui, 1992]. Login to comment
36 In their study of over 5,000 pregnant women screened for CF mutations, Witt et al. [1996] found 16% carried the R117H mutation. Login to comment
37 This is consistent with R117H in cis with 7T not being a fully penetrant mutation. Login to comment
38 Analysis of the polythymidine tracts in our patient and in her parents showed that the R117H mutation was in cis with a 7T tract and the deltaF508 mutation in cis with a 9T tract. Login to comment
43 This case report demonstrates the need for poly-T studies in any patient found to have the R117H mutation, and caution in the genetic counseling of such families. 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
43 6) also carried a 14 CFTR gene mutation (R117H). Login to comment
61 Two patients carried two risk factors: 1 Klinefelter patient (47,XXY) also carried a R117H mutation in the CFTR gene; another man was found to have both an AZFc deletion of the Y chromosome and a ∆F508 CFTR gene mutation. Login to comment
72 Varicocele OAT 6.4 Deletion of the azoospermia factor (AZF) region: 1 AZFc Normal Normal OAT 2.8 2 AZFc Normal Hypogonadism OAT 7.3 CFTR:∆F508/- 3 AZFc Normal Normal OAT 1.0 4 AZFc Normal Varicocele OAT 6.0 5 AZFc Normal Hypogonadism Cryptozoospermia 8.0 6 AZFc Cryptorchidism Normal Azoospermia 6.1 7 AZFc Normal Normal Azoospermia 2.4 8 AZFc Normal Hypogonadism Azoospermia 14.8 Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations (T-Stretch): 1 R117H/- (7T/-) Sinusitis CBAVD Azoospermia 2.3 2 ∆F508/- (5T/9T) Normal CBAVD Azoospermia 4.6 3 ∆F508/R117H (7T/9T) Normal CBAVD Azoospermia 4.9 4 A445E/- (5T/9T) Ejaculatory failure Partial CBAVD Azoospermia 3.3 5 E60X/- (7T/7T) MAGI Normal OAT 2.5 6 R117H/- (7T/7T) Urethral valves Varicocele OAT 4.6 7 ∆F508/- (7T/9T) Normal Normal OAT 2.8 8 ∆F508/- (7T/9T) Cryptorchidism Normal OAT 16.0 9 ∆F508/- (7T/9T) Normal Hypogonadism OAT 7.3 AZFc deletion 10 R117H/- (7T/9T) Normal Hypogonadism Azoospermia 11.0 47,XXY karyotype 11 ∆F508/- (7T/9T) Normal Normal Azoospermia 3.2 12 ∆F508/- (9T/9T) Cryptorchidism Normal Azoospermia 10.0 13 ∆F508/- (7T/7T) Normal Normal Azoospermia 20.0 14 ∆F508/- (7T/7T) Normal Normal Azoospermia 3.2 CBAVD ϭ congenital bilateral absence of the vas deferens; MAGI ϭ male accessory gland infection; OAT ϭ oligo-astheno-teratozoospermia; AZF ϭ azoospermia factor (Yq11). Login to comment

PMID: 11773581 [PubMed] Raman V et al: "Increased prevalence of mutations in the cystic fibrosis transmembrane conductance regulator in children with chronic rhinosinusitis."

No. Sentence Comment

15 Five patients had the ⌬F508, 1 had the R117H, and 1 had the I148T mutation. Login to comment
68 None of the patients had a family history of CF. Seven of the 58 patients were found to have CFTR mutations, including 5 with the ⌬F508 mutation, 1 with the R117H mutation, and 1 with the I148T mutation. Login to comment
85 The patient with the R117H mutation had the 5T polymorphism, which co-segregates as a single allele.17 None of the other patients with mutations was found to be positive for the 5T polymorphism, and none of the patients with the 5T allele had abnormal sweat-test results. 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

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
39 R117H is searched for only in male infertility, because of literature data in other populations (Dork et al., 1995; Mak et al., 1999; Casals et al., 2000) or in the Italian population (Garnerone et al., 1995; Pradal et al., 1998). Login to comment

PMID: 11788090 [PubMed] Strandvik B et al: "Spectrum of mutations in the CFTR gene of patients with classical and atypical forms of cystic fibrosis from southwestern Sweden: identification of 12 novel mutations."

No. Sentence Comment

27 MUTATIONS IDENTIFIED IN 258 CHROMOSOMES IN THE CF POPULATION ATTENDING THE SOUTH-WESTERN SWEDISH CF CENTRE Location in the Frequency of Mutation gene, exon Number of mutations mutation (%) Homozygotes Heterozygotes DF508 10 161 62.4 56 49 394delTT 3 13 5.0 3 7 R117C 4 7 2.7 7 3659delC 19 5 1.9 5 E60X 3 4 1.6 4 1112delT 7 4 1.6 1 2 R764X 13 4 1.6 1 2 621 1 1G ® T 4 3 1.2 3 G551D 11 2 0.8 2 I506L 10 2 0.8 2 N1088D (R75Q) 17b 2 0.8 2 Q1238X 19 2 0.8 2 R117H (IVS8-5T) 4 2 0.8 2 V603F (IVS8-5T) 13 2 0.8 2 1716G ® A 10 2 0.8 2 R75Q 3 2 0.8 2 R533X 11 1 0.4 1 2329A ® G Promoter 1 0.4 1 297-3 C ® A 2 1 0.4 1 Y161D 4 1 0.4 1 994del9 Exon/intron 6b 1 0.4 1 1154insTC 7 1 0.4 1 W361R 7 1 0.4 1 T338I 7 1 0.4 1 1249-5A ® G Intron 7 1 0.4 1 1717-2A ® G Intron 10 1 0.4 1 R560T 11 1 0.4 1 E1401X 23 1 0.4 1 3126del4 17a 1 0.4 1 S945L 15 1 0.4 1 R668C 13 1 0.4 1 2622 1 2del6 Intron 13 1 0.4 1 R1162Q Exon 19 1 0.4 1 3849 1 10kbC ® T Intron 19 1 0.4 1 R74W Exon 3 1 0.4 1 2363C ® T Promoter 1 0.4 1 IVS8-5Ta Intron 8 1 0.4 1 Unidentified 20 7.8 Total 258 100 61 116 The new mutations are displayed in bold. Login to comment
163 dR117C or R117H. Login to comment
182 The phenotypic effect of this mutation, like that of the more common R117H allele, may depend on the length of the T-tract variant in intron 8 (Massie et al., 1999). Login to comment

PMID: 11802242 [PubMed] Rosenstein BJ et al: "Cystic fibrosis diagnosis: new dilemmas for an old disorder."

No. Sentence Comment

17 It is of note that a CF diagnosis in the mother described by Crowley and Bush1 was con®rmed by ®nding two CFTR mutations, DF508 and R117H (9t/7t). Login to comment
18 However, according to the CFF consensus statement, R117H is considered a CF-causing mutation only in association with the 5t-splice site variant.8 Therefore, according to Cystic Fibrosis Center, Johns Hopkins Hospital, Baltimore, Maryland. Login to comment

PMID: 11802254 [PubMed] Crowley S et al: "Cystic fibrosis: keeping it in the family."

No. Sentence Comment

78 Some argue, however, that R117H/7T does not meet the criteria for a CF mutation.2 The North American Consensus Statement accepts that R117H/5T is CF disease-producing, but states that a diagnosis of CF in patients carrying R117H/ 7T requires the demonstration of a CFTR abnormality by sweat testing or nasal potential difference testing. Login to comment
79 Determination of the R117H haplotype (i.e., 5T or 7T) may therefore prove to be the most accurate risk estimate of whether an individual carries a mutant CF allele.14 It would be of interest to measure the TEPD responses to amiloride and low chloride/isoprenaline in both parents to obtain further evidence of CFTR dysfunction, but this was not available. Login to comment
86 Parents can be informed that possession of the R117H mutation is likely to be associated with mild pulmonary disease and pancreatic suf®ciency.10,15 While pancreatic insuf®ciency is likely in more than 99% of patients homozygous for DF508,16 it is not possible to make any prediction about the severity of their lung disease.15 Third, the diagnosis in the parents will have implications for life insurance, even though their prognosis is likely to be good. Login to comment

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

No. Sentence Comment

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

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

No. Sentence Comment

14 Other, i.e., toxic-metabolic, autoimmune, idiopathic, and obstructive causes were identified in chronic pancreatitis and have been extensively summarized in a recent review.4 The classical clinical feature of hereditary pancreatitis (HP; OMIM 167800) is characterized by the early onset of chronic pancreatitis in several members of one family without other etiological factors.5 A clear diagnosis or exclusion of HP is important, as these patients Received: July 27, 2001 / Accepted: September 28, 2001 Reprint requests to: J. Mössner trypsin numbering system as R117H and was later adapted to the trypsinogen nomenclature as R122H.15,16 As the mutation leads to a novel restriction site for Afl III, it was thought to be detected easily, and restriction digestion assays were used worldwide. Login to 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: 11840029 [PubMed] Witt H et al: "Genetics of chronic pancreatitis."

No. Sentence Comment

231 One patient was compound heterozygous for the ⌬F508 and the R117H mutation and 2 patients were heterozygous for the ⌬F508 mutation and the 5T allele. 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: 11897640 [PubMed] Lebecque P et al: "Mutations of the cystic fibrosis gene and intermediate sweat chloride levels in children."

No. Sentence Comment

75 Age at First Sweat Test (yr) Clin Sweat (mM) Nasal Potential (mV) Bacteriology (Throat Swab or Sputum Culture) GenotypePDmax ⌬Iso ϩ Cl-free 1 2.5 34 -15 -7* Staphylococcus aureus ⌬F508/D1152H 2 2.8 36 -21 -10 - ⌬F508/R117H, 7T 3 0.3 33 ND ND - ⌬F508/R117H, 7T 4 0.7 43 -51* -7* S. aureus S977F, 5T/2789 ϩ 5G→A 5 0.1 39 -16 -4* Haemophilus influenzae, S. aureus ⌬F508/R117C 6 0.1 37 -48* -9* H. influenzae, S. aureus ⌬F508/R117C 7 0.7 48 -15 -12 Pseudomonas aeruginosa, S. aureus R553X/R117H, 7T 8 6 34 -30 -10 H. influenzae 5T/5T 9 7 45 -24 -15 S. aureus ⌬F508/S1235R 10 9.5 45 -47* -11 P. aeruginosa ⌬F508/D1152H Definition of abbreviations: PDmax ϭ maximum basal nasal potential difference; ⌬Iso ϩ Cl-free ϭ cumulative change in PD after perfusion with chloride-free solution plus isoproterenol in the presence of amiloride. Login to comment
77 C→T (6-9), R347H (12), G551S (13), D1152H (14), R117H (15, 16), and R117C (17) mutations. Login to comment
91 Two of them are carrying a classic CFTR mutation on one gene and the R117H mutation on a 7T background on the other (Subjects 2 and 7). Login to comment
93 According to the consensus panel (18), this combination (R117H-7T) does not meet the criteria for a CF-causing mutation and a demonstration of CFTR abnormality by sweat testing or nasal PD testing is required to support a diagnosis of CF in such cases. 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

19 The genes R117H and R347P are examples of class IV mutations. 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

38 Only the known c.365G4A (CGC4CAC; R122H, originally termed R117H in the chymotrypsin numbering system5,24 ) mutation was found in a 42-year-old male subject (Table 1). Login to comment
72 Additionally, none of the genotyped F508del and R117H mutations were found in 14 Japanese patients with ICP,14 a not surprising result given that these alleles are extremely rare in the Japanese population. Login to comment

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

No. Sentence Comment

114 R117H R334W G314E R347P ∆F508 P574H PS Reduced chloride conductance Reduced levels of cell surface chloride transport Genistein Milrinone Phenylbutyrate UTP INS36217 Moli1901 Class V Mutations causing defects in CFTR channel expression levels. Login to comment
190 The somministration of adenosine and its nucleotides can activate wild type and R117H forms of CFTR in cell cultures binding to the A2B receptor, present in human bronchial epithelium [55]. Login to comment
448 55. Clancy JP, Ruiz FE,Sorscher EJ: Adenosine and its nucleotides activate wild-type and R117H CFTR through an A2B receptor-coupled pathway. Login to comment
450 •• This study indicates that adenosine and its nucleotides are capable of activating wild type CFTR-dependent halide permeability and also R117H mutant CFTR molecules. 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

5 Results Four (12.9%) ABPA patients were found to be carriers of a CF mutation (ÁF508 n 3, R117H n 1), one (4.3%) asthmatic SPT positive to Af without ABPA (ÁF508), and one (3.6%) asthmatic SPT negative to Af (R117H). Login to 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
77 Four (12.9%) ABPA patients had a CFTR mutation identi®ed (ÁF508 n 3, R117H n 1), which was not signi®cantly different to either group of asthmatics without ABPA; one (4.3%) asthmatic SPT positive to Af without ABPA (ÁF508) and one (3.6%) asthmatic SPT negative to Af (R117H) (P > 0.35). Login to comment
80 The R117H mutation can be associated with either the 5T or 7T variant of the polythymidine tract in intron 8 of the CF gene [33]. Login to comment
89 patient carrying R117H was homozygous for the 7T variant, indicating that R117H was associated with 7T in this patient. Login to comment
90 The status of the R117H mutation in the ABPA patient could not be established because the patient carried the 5T and 7T variants. Login to comment
117 Group comparison of CFTR mutations Asthma SPT-positive Af with ABPA Asthma SPT-positive Af without ABPA Asthma SPT-negative Af n 31 n 23 n 28 Presence of CFTR mutations n (%) 4 (12.9%)* 1 (4.3%) 1 (3.6%) (exact CI) (3.68, 29.8) (0.11, 21.9) (0.09, 18.3) Type of CFTR mutation ÁF508, n 3 R117H, n 1 ÁF508 R117H *No evidence of a difference in proportions in the three groups, P > 0.35. function as a disease modi®er, potentially increasing disease severity. Login to comment

PMID: 12001283 [PubMed] Schaedel C et al: "Predictors of deterioration of lung function in cystic fibrosis."

No. Sentence Comment

88 Furthermore, the inferred values for FEV1 and VC at age 5 years (the intercepts) were significantly lower TABLE 1- Allele Frequencies of 10 Most Common CFTR Mutations in Swedish CF Population Mutation Allele frequency (%) DF508 67.9 394delTT 7.1 3659delC 6.4 S945L 1.2 R117C 1.0 R117H 0.55 T338I 0.55 G551D 0.55 R553X 0.55 I506L 0.41 compared with those in the other CF patients (63.4% and 68.2% vs. 89% and 93.3%). Login to comment
121 TABLE 3CFTR Mutations Associated With Pancreatic Sufficiency in Swedish CF Population Y109C S549I/S549I Y109N S945L R117C N1088D À R75Q R117H G1244E L206W 711 þ 3A !G T338I 1249 À 5A !G A455E 2789 þ 5G ! Login to comment

PMID: 12006459 [PubMed] Venarske DL et al: "Sinobronchial allergic mycosis: the SAM syndrome."

No. Sentence Comment

115 Miller et al11 analyzed the CFTR gene in 11 patients with ABPM and found that 1 patient carried two CF mutations (⌬F508/R347H) and 5 patients carried one mutation (⌬F508, 4 patients; R117H, 1 patient). 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
117 It should be noted that the R117H mutation is only associated with classical CF when associated with the 5T variation. Login to comment
118 Therefore, identification of the R117H mutation should prompt investigation for the 5T variant as well, R117H (IVS8-5T), and this combination should be regarded as a single CF causing allele. Login to comment
220 c The mutation R117H is only associated with classical CF when associated with the 5T variation; therefore, identification of the R117H mutation should prompt investigation for the 5T variant as well, R117H(IVS8-5T). Login to comment

PMID: 12014388 [PubMed] Padoan R et al: "Negative sweat test in hypertrypsinaemic infants with cystic fibrosis carrying rare CFTR mutations."

No. Sentence Comment

8 Molecular analysis identified the following genotypes: F508del/A309D, F508del/3849+ 10kbCfiT, F508del/R117H (in two patients), R117H/ L997F, and F508del/R117L. Login to comment
14 Diagnostic delay has been reported for patients bearing specific CFTR gene mutations such as R117H, D1152H, 3849+10kbCfiT, A455E and 2789+5GfiA, which were associated with a non-pathological sweat chloride level [3, 6, 9,13]. Login to comment
34 Genetic analysis performed with PCR/OLA assay identified two other mutations (R117H in three patients and 3849+10kbCfiT in one). Login to comment
38 However, on a repeat sweat test, only two patients showed abnormal chloride values (patients 1 and 2), although the sweat chloride concentration found in patient 3 (R117H-7T/F508del) was higher than that found in previously performed sweat tests. Login to comment
40 Patients 1 and 2 presented lung disease and isolated severe nasal polyps respectively, whereas patients 3 and 5 (R117H-7T/F508del) suffered from recurrent upper respiratory infections, showing only bronchial thickening in the lower lobes on a chest X-ray film. Login to comment
42 Table 1 Diagnostic features of patients Patient number Sex First IRT (ng/ml) (cut-off) Second IRT (ng/ml) (cut-off) Sweat test chloride (mmol/l) Age at sweat test Age at re-evaluation Symptoms Repeat sweat test chloride (mmol/l) Genotype 1 M 47 (40) 39 (30) 43 4 months 3 years and 3 months Chronic respiratory 64 DF508/A309D 2 M 174 (55) 112 (40) <60 4 months 6 years and 6 months Severe nasal polyposis 68 DF508/3849+ 10kbCfiT 3 F 56 (55) 64 (40) 34 4 months 5 years and 4 months Recurrent upper airways infections 55 DF508/R117H-7T 4 F 84 (80) 102 (40) 55 4 months 4 years No symptoms Not determined R117H-5T/L997F 5 F 142 (80) 81 (40) 37 3 months 20 months Recurrent upper airways infections 47 DF508/R117H-7T 6 F 90 (80) 55 (40) 36 2 months 18 months No symptoms 49 DF508/R117L Discussion Our retrospective evaluation of patients diagnosed beyond 1 year of age at our centre over a ca. 6-year period shows that hypertrypsinaemic newborns carrying at least one ''mild`` CFTR mutation may have a chloride sweat test below 60 mmol/l and a delayed CF diagnosis. Login to comment
43 Rare mutations in the CFTR gene were identified in six patients showing increased b-IRT on newborn screening and a normal sweat test: R117H (three cases), R117L, A309D, L997F and the intronic alteration 3849+10kbCfiT. Login to comment
44 In the whole CF population followed at the Milan CF Centre (580 patients), R117L, A309D and L997F have never been identified before, whereas R117H and 3849+10kbCfiT account for only 0.51% and 0.68% of alleles, respectively. Login to comment
49 PolyT testing has been recommended to establish whether the R117H mutation is associated with CF, however in our patients the R117H-7T allele was associated with persistent neonatal hypertrypsinaemia, a sweat chloride in the upper borderline range, and recurrent respiratory symptoms in the first years of life. Login to comment
50 The diagnosis of CF was made in patient 3 after the birth of a sister with persistent neonatal hypertrypsinaemia, a sweat test above 30 mmol/l chloride and the same genotype (F508del/R117H-7T). 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

241 However, they based their comparison on an expected carrier rate in the general population which appears to be overestimated.1 The CFTR mutations identified in fetuses with echogenic bowel that have been reported so far are associated with pancreatic insufficiency (for example, ∆F508, G542X, G551D, Table 2 Ability of the ultrasound examination to detect cystic fibrosis Cystic fibrosis TotalYes No Utrasound examination Abnormal 14 128 142 Normal 112 346 300 346 412 Total 126 346 428 346 554 2183AA→G, ∆F311).9 13 27 43 To our knowledge, only one mutation associated with a mild phenotype (R117H)13 and one mild complex CFTR allele (D443Y-G576A-R668C)44 have been identified in two of the CF affected fetuses. Login to comment
246 Therefore, the spectrum of mutations identified in this fetal population is not representative of that identified in our CF population, in which we found a significant number of mild mutations or mutations for which the clinical consequences are not yet established (for example, G91R, R117H, R347L, R560K).34 35 These findings provide the foundation for further investigations towards understanding the pathogenesis of early bowel disease, but also why it results in manifestations in the bowel rather than in the lungs during the fetal period. 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
75 Sample 2 demonstrated simultaneous detection of three alleles; 5T, R117H, and 3659delC, consistent with the previously determined genotype. 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

51 T, R117H, Y122X, 711 þ 1G ! Login to comment
103 Heterozygous Cystic Fibrosis Cases With Abnormal Fetal Bowel at Ultrasound Examination Cases CFTR Gene mutations Ultrasound findings Outcome 22-27 DF508/X Hyperechogenic bowel Birth, thriving 28-29 DF508/X Hyperechogenic bowel Premature birth (32 wks), thriving 30 DF508/X Hyperechogenic bowel TOP cardiomegaly þ pulmonary hypoplasia 31 DF508/X Hyperechogenic bowel Lost to follow-up 32 DF508/X Hyperechogenic bowel þ short femur Died day 2 after birth, fetal distress 33 DF508/X Intestinal dilated loops Birth, thriving 34 DF508/X Hyperechogenic bowel þ fetal hydrops Birth, parvovirus-affected, thriving 35 DF508/X Intra-abdominal calcifications Birth, thriving 36 G542X/X Hyperechogenic bowel þ polyhydramnios Birth, thriving 37 R117H/X Hyperechogenic bowel Birth, thriving 38 A534E/X Hyperechogenic bowel Birth, thriving 39 D836Y/X Dilated loop (small bowel) þ polyhydramnios Birth, small bowel atresia, operated, not CF-affected In the present study, most CF cases with intestinal anomalies (15/20) were observed during the second trimester of pregnancy, because in France all pregnant women undergo ultrasound examinations at 11, 22, and 33 weeks. Login to comment

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

No. Sentence Comment

46 A series of mutations usually associated with pancreatic sufficiency have been identified and defined as ''mild`` with reference to pancreatic status [Kerem et al., 1989c]: G85E, G91R, R117H, E193K, P205S, R334W, T338I, R347H, R347L, R347P, R352Q, A455E, S492F, S549N, P574H, D579G, 711 þ 5 G > A, C866Y, F1052V, H1054D, R1066H, R1068H, H1085R, D1152H, S1159P, S1251N, F1286S, G1349D, 2789 þ 5 G > A, and 3849 þ 10kb C > T [Dean et al., 1990; Cutting et al., 1990a; Cremonesi et al., 1992; Highsmith et al., 1994]. Login to comment
59 Several findings suggest that the pulmonary phenotype is directly related to the CFTR genotype: 1) missense mutations (e.g., R117H and A455E) give rise to a milder pulmonary expression [Gan et al., 1995; De Braekeleer et al., 1997]; 2) CF patient homozygotes for DF508 and compound heterozygotes for DF508 and a nonsense mutation at the level of the nucleotide binding folder (NBF) encoding region of the CFTR gene are more susceptible to P. aeruginosa infections [Kubesch et al., 1993; Davidson et al., 1995]; and 3) CF patient homozygotes for DF508 invariably have a severe pulmonary phenotype [Johansen et al., 1991]. 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
286 In this group we found a greater number of R117H carriers than expected. Login to comment
312 These patients are then followed up at the CF centre, and receive a global approach to exclude or confirm CF diagnosis and correct genetic counselling.25 An unexpectedly high frequency of carriers for the R117H allele was found: we think that several people with this allele plus a second CFTR mutation leading to very mild disease or to a borderline or negative sweat test in the first months of life26 may still be undetected. 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
100 Two relatively frequent compound heterozygotes were F508/ R117H (3/33) and W1282X/5T (4/33). Login to comment
119 The compound heterozygote ∆F508/R117H, previously reported to occur commonly in CBAVD patients (Dork et al., 1997), was also a frequent genotype (3/33) in this study. Login to comment
120 It was noted that R117H occurred on two chromosomal backgrounds, one carrying a 5T allele in CF patients and the other carrying a 7T allele in CBAVD patients, when the other chromosome carries a severe mutation such as ∆F508 (Kiesewetter et al., 1993). Login to comment
123 Although it was not confirmed, our results indicate that ∆F508 and R117H were on chromosome backgrounds of 9T and 7T respectively, because at least one 9T allele was seen in each one of the 41 patients having a ∆F508 mutation, a 7T in each of the four patients with R117H mutation. Login to comment
125 The association of R117H in cis with a 5T allele results in CF when patients carry in trans ∆F508 or one of the severe mutations, and probably represents a general theme that a splicing mutation such as 5T, in cis with a mild mutation, can aggravate that mild mutation. 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

79 It is envisaged that the proposed screening programme will be based on a three-stage protocol.6 In Table 3 Genotypes of the UK CF Caucasian and ISC populations Percentage of Percentage of genotyped UK CF genotyped UK CF Caucasian population ISC population Genotype n=4753 (%) n=78 (%) DF508/DF508 57.5 24.7 DF508/Unknown 11.5 3.5 DF508/G551D 5.1 0.0 DF508/G542X 2.8 0.0 Unknown/Unknown 2.7 27.1 DF508/621+1G?T 2.0 1.2 DF508/R117H 2.0 0.0 DF508/1898+1G?A 1.0 0.0 DF508/1717-G?A 0.9 0.0 DF508/N1303K 0.8 0.0 DF508 DI507 0.8 0.0 DF508/R553X 0.6 0.0 DF508/R560T 0.6 0.0 DF508/Q493X 0.5 0.0 G551D/Unknown 0.4 0.0 Other/Other 2.8 15.3* DF508/Other 6.7 0.0 Y569D/Y569D 0.0 8.2 L218X/L218X 0.0 3.5 1161delC/1161delC 0.0 3.5 R709X/V456A 0.0 2.4 G542X/G542X 0.4 2.4 Other/Unknown 1.0 3.5 The shaded areas represent the commonest genotypes in the ISC population. Login to comment
85 Table 4 The commonest CFTR mutations in the UK Genotypes UK CF population Genotyped UK Caucasian CF Genotyped UK CF ISC (n=9866 chromosomes) population (n=9506 chromosomes) population (n=156 chromosomes) CFTR mutation gene frequency per 1000 genes gene frequency per 1000 genes gene frequency per 1000 genes DF508 741.0 752.0 294.9 G551D 33.7 34.3 12.8 G542X 18.5 18.4 25.6 R117H 12.5 12.7 0.0 621+1G?T 12.7 12.7 6.4 1717-1G?A 5.8 5.8 0.0 1898+1G?A 5.7 5.9 0.0 N1303K 5.6 5.4 0.0 DI507 4.8 5.0 0.0 R560T 4.2 4.3 0.0 R553X 3.3 3.4 0.0 1154insTC 3.2 3.3 0.0 Q493X 2.8 2.9 0.0 3659delC 2.8 2.9 0.0 E60X 2.4 2.4 0.0 W1282X 2.7 2.7 0.0 P67L 2.1 2.1 0.0 G85E 2.1 2.0 0.0 V520F 1.6 1.7 0.0 1078delT 1.3 1.4 0.0 Y569D 1.5 0.0 96.2 L218X 0.6 0.0 38.5 1161delC 0.7 0.1 38.5 R1162X 0.9 0.6 19.2 R709X 0.4 0.2 12.8 3849+10kbC?T 1.2 0.8 19.2 S549R* 0.6 0.0 0.0 *S549R mutations appear in the non-Caucasian but not the ISC subgroup. Login to comment
103 N1303K and G542X occur at a frequency of around 5% in Italy.11 In Germany, a study of 658 CF families revealed mutation frequencies of R553X (1.8%), N1303K (1.3%), G542X (1.1%), G551D (0.8%) and R347P (0.8%).12 The frequency of CFTR mutations recorded for just over 1000 patients for the Irish CF Database include G551D in 7%, R117H in 2% and DF508 in 72% of patients.13 In the white South African population, a paper based on 192 patients found that DF508 accounts for 76% of the mutations with 3272-26A?G (4%), 394delTT (3.6%) and G542X (1.3%) the other most common mutations.14 It is suggested that the 3272-26A?G and 394delTT mutations are more common due to a founder effect in white South Africans of European descent. Login to comment

PMID: 12394343 [PubMed] Rohlfs EM et al: "The I148T CFTR allele occurs on multiple haplotypes: a complex allele is associated with cystic fibrosis."

No. Sentence Comment

12 Most notable is the effect of the length of the intron 8 polythymidine tract (5, 7, or 9 thymidines) on exon 9 splicing and the phenotypic expression of the R117H mutation.7,8 Individuals with a severe CF mutation and R117H in cis with 5 thymidines (5T) may have moderate (pancreatic sufficient) CF, whereas those with R117H and 7 thymidines (7T) in cis may be asymptomatic and have CBAVD or later-onset lung disease such as bronchiectasis.8,9 Only a small number of all CFTR mutations result in a predict- ablediseasephenotype.Theclassificationisusuallybasedoncare- ful clinical description of patients with defined genotypes. Login to comment
90 This was first appreciated when the frequency of R117H in carriers was observed to be 16-fold higher than the frequency in CF patients.25 In the ethnically diverse US population reported here, the I148T allele is 100-fold more frequent in carriers than in CF patients. Login to comment
92 There are now several published reports of ⌬F508/R117H compound heterozygotes that are apparently healthy.22,25,26 The R117H mutation was first identified in 199027 and has been included in most routine CF genotyping programs, increasing the likelihood that these individuals would have been detected as large numbers of individuals were tested. Login to comment

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

No. Sentence Comment

60 Examples of such mutations include R117H, 3849 ϩ 10 kbCϾT, A455E, 2789 ϩ 5GϾA, G85E, and R334W. Login to comment
87 For example, R117H and I148T mutations may produce a more variable clinical phenotype, depending upon genetic modifiers, some of which may not be well defined. Login to comment
218 As described below, it is desirable to determine the 5/7/9T genotype only for diagnostic cases or carriers positive for the R117H mutation. 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
308 The 5/7/9T variant should be included for diagnostic panels to distinguish the genotypes of R117H associated with CF from those associated with CBAVD and as a potential pathogenic mutation for CBAVD. Login to comment
342 CF 3.5.2 Comments on phenotype issues with CBAVD, R117H and 5T, 7T background: ACMG has recommended that all R117H positive results require reflex testing for the 5T/7T/9T variant in the polythymidine tract at intron 8 in CFTR gene. Login to comment
343 Refer to model reports for carrier screening presented in the ACMG statement.1 For R117H/5T positive heterozygotes, testing of parents is recommended to determine the inheritance of the R117H and the 5T variant (i.e., cis vs. trans position). Login to comment
344 If the R117H and 5T variant are determined to be in cis, then the report should reflect that this mutation has been associated with a variable phenotype when R117H/5T (cis) or another CFTR mutation is present in patients with CF. Login to comment
345 If the R117H mutation and 5T are determined to be in trans, the report should indicate that the individual carries a relatively benign CF mutation that is not generally associated with the phenotype of typical CF patients but has been associated with CBAVD, leading to infertility in males and no known clinical features in females. Login to comment
348 For individuals who are R117H positive and 5T negative, the report should indicate that the R117H mutation is not expected to lead to a typical CF clinical phenotype. Login to comment
349 However, R117H has been associated with CBAVD. Login to comment

PMID: 12403872 [PubMed] Tate S et al: "Airways in cystic fibrosis are acidified: detection by exhaled breath condensate."

No. Sentence Comment

240 Choi et al11 showed that cultured cells expressing CFTR mutations known to be associated with pancreatic sufficiency (class 4-5 mutations such as R117H, A455E) displayed significantly greater bicarbonate conductance than mutations associated with pancreatic insufficiency (class 1-3 mutations, G452X, ∆F508, G551D). Login to comment

PMID: 12411484 [PubMed] Ko SB et al: "A molecular mechanism for aberrant CFTR-dependent HCO(3)(-) transport in cystic fibrosis."

No. Sentence Comment

6 The physiological signi®- cance of these ®ndings is demonstrated by interaction of CFTR and DRA in the mouse pancreas and an altered activation of DRA by the R117H and G551D mutants of CFTR. Login to comment
220 In (A) and (B), the cells were transfected with 0.5 mg of CFTR, in (C) with 0.5 mg of CFTR(R117H) and in (D) with 0.5 mg of CFTR(G551D). Login to comment
249 We focused on the R117H and the G551D mutants since these mutants are well characterized clinically and R117H is associated with a mild form and G551D with a severe form of CF (Wilschanski et al., 1995). Login to comment
252 Figure 8C and E shows that the R117H mutant activated DRA by only 2.5-fold (26% of that by the wild-type CFTR), whereas the G551D mutant was unable to activate DRA. Login to comment
283 A signi®cant ®nding was the modi®ed activation of DRA by the R117H and G551D mutants of CFTR. Login to comment
292 The R117H and G551D mutants were prepared as described (Choi et al., 2001). Login to comment

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

No. Sentence Comment

161 Other missense mutations show considerable phenotypic variation, such as CF-PI or CF-PS with R334W, CF-PS or congenital bilateral absence of the vas deferens (CVABD) with R117H (class IV). Login to comment

PMID: 12422349 [PubMed] Conway SP et al: "Cystic fibrosis presenting as acute pancreatitis and obstructive azoospermia in a young adult male with a novel mutation in the CFTR gene."

No. Sentence Comment

39 Their mutations (DF508/wild-type, 9T/5T in two, and DF508/R117H, 9T/7T in one) were those described most commonly in men whose only clinical manifestation of CF was obstructive azoospermia.7,8,10,11 Chillon et al., suggested that these mutations may produce CFTR protein with a normal structure but low levels of expression.10 CFTR function in these patients is about 10% of normal, compared to only 1% of normal in patients with classic CF. Login to comment

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

No. Sentence Comment

8 The only other CF-alleles that we found with these tests were the G542X allele (3 persons), the G551D allele (3 persons), the 3849+10kb C-T allele (2 persons) the R117H allele (2 persons) and the 621+1G-T allele (1 person). Login to comment
35 All probands (or their par- Table 1: Exons and introns that are amplified with the line probe assay, and the mutations they encompass Roche assay: Amplicon Mutations exon 4 R117H,621+1G → T exon 7 R334W, R347P exon 9 A455E, 5/7/9T polymorphism exon 10 ∆1507, ∆F508. Login to comment
36 F508C, I507V, I506V polymorphism exon 11 1717-1G → A, G542X, S549N, G551D, R553X, R560T exon 20 W1282X exon 21 N1303K intron 19 3849+10kb C → T Innogenetics assay: exon 3 394delTT, G85E, E60X exon/intron 4 621+1G-T, R117H exon 7 1078delT, R347P, R334W exon 13 2143delT, 2183AA-G, 2184delA exon 19 R1162X, 3659delC intron 5 711+5G-A intron8/exon 9 A455E,, 5T,7T,9T intron 14b 2789+5G-A intron 19 3849+10kb C-T Table 2: Genotypes of patients with mutations, final results Group 1) (patients with symptoms typical for/indicative of CF) No. Login to comment
38 IRT, normal sweat test f 0 7T/9T DF508/3849+10kb C-T x 2 CF, substantiation f 0 9T/9T 621+1G-T/621+1G-T 3 CF, substantiation f 1 9T/9T DF508/DF508 x 4 CF, substantiation f 5 9T/9T DF508/DF508 x x x 5 CF, substantiation f 7 9T/9T DF508/G542X x x 6 CF, substantiation, rec. diarrhoe, pancreas insufficiency, pos. sweat test f 8 9T/9T DF508/DF508 x 7 CF, substantiation f 12 9T/9T DF508/DF508 x 8 CF, substantiation f 13 9T/9T DF508/DF508 x 9 f 13 7T/9T DF508/WT 10 CF, substantiation f 16 9T/9T DF508/G542X 11 indicative linkage analysis f 22 7T/9T DF508/WT x 12 f 24 7T/9T DF508/WT x 13 bronchiectasis, bronchopulmonal infections since infancy f 28 7T/9T DF508/3849+10kbC-T x 14 pos. sweat test f 28 9T/9T DF508/WT x 15 typical clinic, pos. sweat test f 31 7T/9T DF508/WT x x 16 f 32 7T/7T 3849+10kb C-T/WT 17 pulmonal course typical of CF f 32 7T/9T DF508/WT x x x 18 f 34 7T/7T G551D/WT x x 19 f 41 7T/7T DF508/WT 20 CF, substantiation f 56 7T/9T DF508/3849+10kb C-T x 21 22 CF, substantiation m 0 9T/9T DF508/DF508 x 23 m 1 7T/9T DF508/WT x 24 impaired lung function, intestinal complications m 3 7T/9T DF508/WT x x 25 CF, substantiation m 5 9T/9T DF508/DF508 26 m 12 7T/7T G551D/WT x x 27 CF, substantiation m 17 9T/9T DF508/DF508 28 m 18 7T/7T R117H/WT&1466delAATT/1466delAATT 1466delAATT x 29 pos sweat test m 20 7T/9T DF508/WT 30 CF, substantiation m 25 9T/9T DF508/DF508 31 . Login to comment
40 infect., azoospermia, pancreatitis m 31 9T/9T DF508/WT 35 CF, substantiation m 33 9T/9T DF508/DF508 x 36 m 33 7T/9T DF508/WT 37 m 33 7T/9T DF508/WT 38 m 38 7T/9T R117H/G542X Group 2a) (Patients from IVF clinics) No. Login to comment
95 Among 114 children < 18 yrs in group 1), we found 9 patients to be homozygote for ∆F508, two compound heterozygote for ∆F508/G542X, one compound heterozygote for ∆F508/3849+10kbC-T, five heterozygote for ∆F508, one G551D/WT, one R117H/WT, one homozygote for 621+1G-T, and one girl with 5T/7T alleles in intron 8 (total of 18% with mutations). Login to comment
96 Twenty-two percent of the adults in group 1) had CFTR mutations, namely two ∆F508/∆F508, thirteen ∆F508/ WT, one compound for R117H/WT and 1466delAATT (frameshift mutation in exon 9), one R117H/G542X, one G551D/WT, one 3849+10kb C-T/WT, one compound heterozygote for ∆F508/1248+1 A → G (splice mutation in intron 7), and two individuals with ∆F508/3849+10kb C-T. Login to comment
116 In comparison to CF mutation-frequencies in some European countries, the CF alleles we found (>2%) with our tests show the following distribution in our cohort: ∆F508: 83% (Romania:27%, Switzerland: 43%, Denmark: 87,2% [19]); G542X: 4,4% (France: 3,1%, Italy: 4,8%, Spain: 7,7%); G551D: 4,4% (UK: 3,1%, Czechia: 4,0%, Ireland: 6,9%), 3849+10kbC-T: 2,9% (Germany: 1,2%, Poland: 2,6%, Latvia: 12,5%), R117H: 2,9% (Greece: 1,2%, Ireland: 2,0%, Norway: 3,0%) Because we participate in the European Quality assessment trial for Cystic Fibrosis, we could evaluate the quality of the Roche Amplicor CF test in this regard as well. Login to comment

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

No. Sentence Comment

95 recently published data on some case histories where no high frequency of severe mutations (such as ⌬F508 and R117H) was found in patients with chronic pancreatitis (19, 20). Login to comment

PMID: 12499931 [PubMed] Hayakawa T et al: "2nd international symposium: Frontiers in pancreatic research-from basics to clinic and exocrine glands, Japan-Korea."

No. Sentence Comment

191 Notably, the mutant CFTR(R117H), associated with a mild form of CF, showed reduced activation of DRA/CLD, whereas the mutant CFTR(G551D), associated with a severe form of CF, was unable to activate Cl- /HCO3 - exchange by DRA/CLD. Login to comment

PMID: 12509709 [PubMed] Watson MS et al: "Cystic fibrosis carrier screening: issues in implementation."

No. Sentence Comment

37 The R117H mutation and its association with the 5T polymorphism was appreciated at the time the carrier screening mutation panel was developed and was discussed in some detail. Login to comment
39 The 7T variant can also be found in CBAVD when paired with the R117H mutation. Login to comment
40 Similarly, the 5T mutation, when paired in a trans configuration with R117H, has been found in men with CBAVD. Login to comment
41 When R117H is paired with 5T in a cis configuration and another CF mutation is present, it is associated with a variable CF phenotype. Login to comment
44 Furthermore, 5T homozygosity or ⌬F508/5T has been reported in rare cases of adult-onset CF-like pulmonary disease, though on a background of TG12-M470 V that complicates its interpetation.9 However, because the goal of the screening program was to identify individuals at risk for classical CF, not CBAVD, it was recommended that 5T status only be reflexly tested or reported in a parent demonstrated to have the R117H mutation. Login to comment

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

No. Sentence Comment

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

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

No. Sentence Comment

17 Eight common mutations were screened using polymerase chain reaction-restriction enzyme analysis (PCR-REA): R117H, 1717±1G > A, DI507, DF508, G542X, G551D, R553X and R560T. Login to comment
26 PCR-REA An in-house PCR-REA procedure was used to screen for the eight common mutations (R117H, 1717±1G > A, DI507, DF508, G542X, G551D, R553X and R560T). Login to comment
65 Frequency of common CF mutations Mutation Numberof chromosomes Frequency (%) R117H 25 2.70 1717^1G >A 20 2.16 DI507 4 0.43 DF508 658 70.97 G542X 4 0.43 G551D 70 7.55 R553X 2 0.22 R560T 4 0.43 Total 788 85 Frequencypercentages areadjustedtorepresent 85%. Login to comment
67 Frequency of rarer CF mutations and polymorphisms Mutation Numberof chromosomes Frequency (%) Polymorphism Frequency (%) E60X 1 0.24 IVS6a-8 25.0 P67L 1 0.24 (TG)m 37.5 G85E 1 0.24 IVS8-Tn 23.8 6211G >T 1 0.24 M470V 41.3 IVS8^5T 5 1.21 V520F 2 0.48 18981G >A 2 0.48 R117H 1 ^ DF508 17 ^ Total 80 15 Frequencypercentages areadjustedtorepresent 85%. Login to comment
72 The R117H mutation (2.7%) was found at a higher frequency than the UK (15) (0.46%) and similar to that of Ireland (11) (2.0%) and Northern Ireland (13) (4.1%). Login to comment
89 For example, the R117H mutation is found in pancreatic-sufficient CF patients as well as in CBAVD patients and the difference in phenotypic expression has been explained by the polymorphic Tn locus in front of exon9 (21). Login to comment

PMID: 12631449 [PubMed] Grendell JH et al: "Genetic factors in pancreatitis."

No. Sentence Comment

41 Additionally, many patients with hereditary pancreatitis who carry the R117H mutation in the cationic trypsinogen gene demonstrate a natural history of disease, beginning with recurrent attacks of acute pancreatitis and leading to chronic pancreatitis, and, in some individuals, to pancreatic cancer [2]. Login to comment

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

No. Sentence Comment

332 One patient was compound heterozygous for the ∆F508 and the R117H mutation and two patients were heterozygous for the ∆F508 mutation and the 5T allele. Login to comment
423 Also, the presence of other genetic alterations within the same allele can significantly influence the phenotypic effect as in the case of the R117H mutation.51 CFTR mutations can be divided into five or six general classes that reflect their known or predicted molecular dysfunction85-87 (fig 3). Login to comment
427 Class IV mutations such R117H and R347P affect the chloride conductive function and are associated with decreased but residual CFTR function. Login to 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
490 For instance, the R117H mutation in exon 4 of the CFTR gene may be located in cis (on the same chromosome) with 5T. Login to comment
491 The R117H mutation on the 5T background shows a cumulative effect and is associated with pulmonary disease in CF, whereas R117H combined with the more common 7T allele is typically observed in CBAVD without lung disease.51 Disseminated bronchiectasis Poller and coworkers described an increased frequency for the F508del mutation in patients with disseminated bronchiectasis.144 Subsequent studies confirmed the association between CFTR variants and disseminated bronchiectasis.145-149 Pignatti and coworkers found a CFTR mutation or rare variant in 37.5%145 and the 5T allele in 31% of bronchiectasis patients.146 Several CFTR variants were also detected in French patients with idiopathic bronchiectasis, however, the 5T allele was not detected in any patient.147 Other studies described a CFTR mutation in 5 of 16 patients (22%) respectively in 5 of 19 patients (26%).148 149 Asthma Conflicting data exist about the influence of CFTR mutations on the risk of asthma. Login to comment

PMID: 12658399 [PubMed] Hayakawa T et al: "Clinical evidence of pathogenesis in chronic pancreatitis."

No. Sentence Comment

39 Hereditary pancreatitis Clinical background Hereditary pancreatitis is a rare condition characterized by acute and chronic pancreatitis in an autosomal dominant fashion at a penetrance of 80%.14,15 A genetic defect was first identified by Whitcomb et al.,16 who described the R117H mutation (R122H in the trypsin nomenclature) in the cationic trypsinogen gene. 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

19 R117H and A455E also are considered to be `mild' mutations: they are associated with better lung function.18 Moss and King11 reported that DF508 homozygosity was found more frequently in the patients undergoing sinus surgery (58%) than in a control population (48%). Login to 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

PMID: 12714375 [PubMed] Cobb BR et al: "Adenosine receptors and phosphodiesterase inhibitors stimulate Cl- secretion in Calu-3 cells."

No. Sentence Comment

14 29, pp. 410-418, 2003 Originally Published in Press as DOI: 10.1165/rcmb.2002-0247OC on April 24, 2003 Internet address: www.atsjournals.org inhibitors could theoretically potentiate low level activity of mutant CFTR molecules that spontaneously localize to the cell surface (e.g., R117H CFTR, G551D CFTR) or can be localized to the cell surface at low levels by corrective molecules (e.g., butyrate compounds for rescue of ⌬F508 CFTR, aminogylcosides to suppress premature stop mutations) (12-15). Login to comment

PMID: 12746094 [PubMed] Kujat A et al: "Genetic counseling in assisted reproduction: a case of cystic fibrosis identified after two successful intracytoplasmic sperm-injection pregnancies."

No. Sentence Comment

19 Molecular studies of the ABCC7 gene (cystic fibrosis CFTR-gene) carried out 2 years ago with the InnoLipa reverse hybridization test detected only one mutated allele carrying the R117H mutation. Login to comment
24 To find out whether both mutations were located on the same allele we investigated both parents of the patient and found the R117H mutation in the DNA of the patient`s father and the CFTR dele2,3 (21 kb) mutation in his mother`s DNA. Login to comment
37 The mutation R117H found in the patient`s DNA occurs in 0.8% of mutant alleles in CF patients. Login to comment
38 Three different phenotypes were observed to be associated with the genotype R117H: typical CF, males with CBAVD, and asymptomatic females [6]. Login to comment
39 The mutation R117H has been previously found in 24 German CBAVD patients [2] in the majority of these cases in the combination with DF508. Login to comment
42 In further studies a strong correlation between R117H and the chromosomal background has been considered. Login to comment
43 The R117H mutation and the polyT tract length of 7T has been found, together in a significant higher proportion than other variants, such as 5T in males with CBAVD [4]. Login to comment

PMID: 12770858 [PubMed] Bush A et al: "Mutations of CFTR gene and intermediate sweat chloride levels."

No. Sentence Comment

219 nasal potential studies and a ⌬508/R117H (7T) CFTR genotype. Login to comment

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

No. Sentence Comment

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

PMID: 12799389 [PubMed] Vastag B et al: "Cystic fibrosis gene testing a challenge: experts say widespread use is creating unnecessary risks."

No. Sentence Comment

37 However, one of the mutations, called R117H, presents a risk for cystic fibrosis only if carried in conjunction with another genetic variant, called 5T. Login to comment
38 Parents should be tested for 5T only if positive for R117H. Login to comment
39 And even after testing positive for both, a parent can be con- sideredacarrieronlywhenathirdround of testing shows that the R117H and 5T variations lie on the same allele. Login to comment
41 Therefore, to ensure that tests for cystic fibrosis-related mutations "focus on CF and not create unnecessary anxiety concerning the fertility of the fetus," ACOG and ACMG guidelines recommend that a so-called reflex test for the 5T genetic variant be considered only when a first round of testing has revealed the presence of the R117H mutation. Login to comment
42 In the cases outlined by Quest, the laboratory reported a positive 5T test in instances where the parents were negative for R117H and thus should not have been tested for 5T at all. Login to comment

PMID: 12802335 [PubMed] Reddy MM et al: "Control of dynamic CFTR selectivity by glutamate and ATP in epithelial cells."

No. Sentence Comment

156 In contrast, duct cells from heterozygous patients with R117H/DF508 mutant CFTR also lost most of the Cl2 conductance, yet retained significant HCO3 2 conductance. Login to comment
219 CFTR-g Cl is decreased in R117H/DF508 ducts by ,85% and in DF508/DF508 ducts by ,100%. Login to comment
221 Results are for n ¼ 10 ducts from eight normal subjects, n ¼ 9 ducts from two R117H/DF508 cystic fibrosis patients and n ¼ 8 ducts from three DF508/DF508 cystic fibrosis patients. Login to comment
223 0.01. b, Effect of R117H and DF508 CFTR mutations on glutamate/ATP-activated CFTR-g HCO3 . Login to comment
225 The ducts from R117H/DF508 cystic fibrosis patients retained ,50% of CFTR-g HCO3 compared with normal controls. Login to comment
227 Results are for n ¼ 10 ducts from eight normal subjects, n ¼ 9 ducts from two R117H/DF508 cystic fibrosis patients, and n ¼ 8 ducts from three homozygous DF508 cystic fibrosis subjects. Login to comment
247 In contrast, the R117H mutant CFTR, in which Arg 117 has been changed to His, is processed to the membrane and retains partial Cl2 conductance24,25 . Login to comment
249 As shown in Fig. 4, DF508/DF508 ducts showed no detectable gCl response to glutamate, whereas the R117H/DF508 heterozygous ducts showed a significantly decreased (compared with the wild type), but clearly present, Cl2 conductance. Login to comment
250 Equally compelling evidence is that only R117H/DF508 duct cells (but not DF508/ DF508 cystic fibrosis ducts) retained a significant CFTR-gHCO3 . Login to comment
251 Thus, in the R117H/DF508 ducts we observed a decrease of nearly 85% in CFTR-gCl, whereas the same ducts retained about 50% of CFTR-gHCO3 (Fig. 4) compared with the wild type. Login to comment
252 (Because the R117H mutation significantly decreases the gCl and open probability of the CFTR25 , the fact that at least 50% of normal gHCO3 seems to be present in the heterozygous ducts suggests that this mutation exhibits a gHCO3 that is equal to or even larger than normal. Login to comment
256 The phenotypes of such mutations are broadly classified as 'mild`, in which patients fare better and retain pancreatic digestive function (for example R117H/DF508), and as 'severe`, in which patients fare worse and lack pancreatic function (for example DF508/DF508). Login to comment
258 A role for CFTR in HCO3 2 transport is still not well defined27-29 , but the glutamate/ATP-activated CFTR-gHCO3 might reflect a crucial role in cystic fibrosis pathology and indicates a molecular basis for the observation that mild mutations such as R117H spare enough CFTR-gHCO3 to preserve pancreatic function in cystic fibrosis patients whereas severe mutations like DF508 do not, either because of poor conductance or poor expression in the plasma membrane23,24,26 (Fig. 4). Login to comment
259 In heterologous systems, Cl2 /HCO3 2 exchange was reported to be dependent on the CFTR mutation, and R117H retained substantial ability to support the anion exchange func- tion29,30 . 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

7 In Brittany, the most common abnormalities were: c.1078delT (3.6%), c.4041C>G (N1303K: 1.4%), c.2670G>A (W846X2: 1.0%) and c.1717-1G>A (1.0%), whereas in the cohort of Dublin, the main mutations were: c.482G>A (R117H: 3.0%), c.1811G>C (R560T: 2.4%) and c.621+1G>T (1.7%). Login to comment
8 Finally, in the Cork area, only the c.482G>A mutation (R117H) reached a frequency of 1%. Login to comment
44 Firstly, the National Centre for Medical Genetics, Dublin performed an analysis of the most common CFTR mutations, using the ARMS test (Ferrie et al., 1992), which enables the detection of the following mutations: F508del, R117H, I507del, G542X, G551D, R560T, N1303K, R352Q, 1717-1G>A and 621+1G>T. Login to comment
50 Dublin Centre 1262 CF alleles 35 mutations F508del 76.5% G551D 6.5% R117H 3.0% R560T 2.4% 621+1G>T 1.7% Cork Area 278 CF alleles 10 mutations F508del 81.3% G551D 9.7% R117H 1.4% Brittany 778 CF alleles 62 mutations F508del 74.8% G551D 3.7% 1078delT 3.6% N1303K 1.4% W846X2 1.0% 1717-1G>A 1.0% Statistical analysis We determined the spectrum of the CFTR mutations identified in the three cohorts of patients and compared their respective frequencies by a Chi square test. 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
73 In the cohort from Dublin, the three mutations presenting a frequency greater or equal to 1% were different: R117H (3.0%), R560T (2.4%) and 621+1G>T (1.7%). Login to comment
74 In the cohort from Cork, only one mutation other than F508del and G551D reached a frequency of 1%: R117H (1.4%). 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
83 The other most frequent genotypes were: F508del/G551D (9.5%), F508del/R117H (3.5%) and F508del/R560T (2.7%). Login to comment
84 Finally, in the Cork area, about 70.0% of patients were homozygous for the main mutation, 13.7% were F508del/G551D and 2.9% were F508del/R117H. Login to comment
98 Number Frequency Number Frequency 1652_1655del 3 bp F508del 966 76.5% 226 81.3% 1192 77.4% 1784G>A G551D 82 6.5% 27 9.7% 109 7.1% 482G>A R117H 38 3.0% 4 1.4% 42 2.7% 1811G>C R560T 30 2.4% 2 0.7% 32 2.1% 621+1G>T 21 1.7% 21 1.4% 1648_1653delATC I507del 10 0.8% 1 0.4% 11 0.7% 1717-1G>A 9 0.7% 9 0.6% 1756G>T G542X 8 0.6% 8 0.5% 1187G>A R352Q 3 0.2% 2 0.7% 5 0.3% 1461ins4 5 0.4% 5 0.3% 4041C>G N1303K 5 0.4% 5 0.3% 310G>T E60X 4 0.3% 4 0.3% 1690G>T V520F 4 0.3% 4 0.3% 3007delG 4 0.3% 4 0.3% 3272-26A>G 2 0.2% 2 0.7% 4 0.3% 386G>A G85E 3 0.2% 3 0.2% 3849+10kbC>T 3 0.2% 3 0.2% Unidentified Unidentified 41 3.2% 11 4.0% 52 3.4% Total Total 1262 100.0% 278 100.0% 1540 100.0% Dublin cohort Cork cohort Ireland Amino acid change Nucleotide change We noted similar high frequencies of the F508del and G551D mutations in the three cohorts studied. Login to comment

PMID: 12820707 [PubMed] Hicks K et al: "Cystic fibrosis: S158N (605G --> A) is a rare genetic variant found in coupling with deltaF508."

No. Sentence Comment

27 This was especially true because, although the patient was asymptomatic, mutations in exon 4 can be associated with mild CF (e.g., R117H in cis with IVS8-5T) or can even be asymptomatic (e.g., R117H in cis with IVS8-7T or 9T) when seen as a compound heterozygote with DF508 (Kieswetter et al., 1993). Login to comment
47 The example of R117H and IVS8-polyT has already been discussed. Login to comment

PMID: 12835696 [PubMed] Wine JJ et al: "Rules of conduct for the cystic fibrosis anion channel."

No. Sentence Comment

22 Preferential sparing of bicarbonate transport by this same mutant form of CFTR (called R117H) was reported previously, but was interpreted as being caused by CFTR control of anion exchangers2 that were subsequently shown to be electrogenic members of the SLC26 family3. 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

143 For example, R117H was noted to be present in PS patients and therefore an assumption was made that this was a mild mutation.9 From these studies it was determined that most individuals with PI have two severe CFTR mutations while those with the PS phenotype have one or two mild mutations. 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

PMID: 12879148 [PubMed] Curlee KV et al: "Membrane transplantation to correct integral membrane protein defects."

No. Sentence Comment

201 Clancy JP, Ruiz FE, Sorscher EJ (1999) Adenosine and its nucleotides activate wild-type and R117H CFTR through an A2B receptor-coupled pathway. 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

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

No. Sentence Comment

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

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

No. Sentence Comment

42 Between 70% and 75% of males with CBAVD carry mutations in each CFTR gene-the most common being deltaF508/R117H (without the 5T thymidine run in intron 8).12 A proportion of these patients who are homozygous for CFTR mutations also have sweat chlorides in the intermediate or abnormal range. Login to comment
108 Modifying genes co-inherited within the CFTR gene The mutation R117H is associated with CBAVD but does not cause lung disease-indeed it is commonly found in otherwise healthy males attending infertility clinics. Login to comment
147 pancreatic sufficiency has been linked to certain mutations such as R117H and A445E although insufficiency may emerge with time . Login to comment
176 She was found to have a disease-associated mutation in each CFTR gene (N1303K and R117H associated with the 7T variant in intron 8). Login to comment

PMID: 12919133 [PubMed] Cruger DG et al: "Genetic analysis of males from intracytoplasmic sperm injection couples."

No. Sentence Comment

36 CFTR mutation analysis. DNA analysis of the CFTR gene included PCR-based analysis for four different mutations: the two most common (90%) CFTR mutations in the Danish population - DF508 and 394delTT (4) - and the R117H and IVS8T-5T mutations associated with infertility and congenital bilateral absence of the vas deferens (CBAVD) (5, 6). Login to comment
42 Results of genetic analysis of males from 392 ICSI couples and 100 controls Extreme oligospermia Severe oligospermia Oligospermia Normal sperm count Sperm count Azoospermia < 1 Â 106 1-5 Â 106 > 20 Â 106 5-20 Â 106 Unknown Controls Number 77 47 92 77 90 9 100 Y-microdeletions 5a 1 0 0 0 0 0 CFTR mutations DF508/R117H 2 0 0 0 0 0 0 394delTT/R117H 1 0 0 0 0 0 0 DF508/- 2 2 1 0 0 0 4 394delTT/- 0 0 0 0 0 0 0 R117H/- 2 0 0 1 1 0 3 IVS8T-5T/- 2 1 4 1 3 0 4 Karyotypes 47,XXY 5 1 0 0 0 0 - 46,X,del(Y) 2 0 0 0 0 0 - 46,XX ish rec(X)(Y190þ) 1 0 0 0 0 0 - 46,X,?i(Y) ish idic(Y)(q11) 1 0 0 0 0 0 - Translocations 0 0 3b 1c 0 0 - Others 0 0 0 1d 1e 0 - a Including the four non-Klinfelter men with Y-chromosome aberrations. Login to comment
59 In the group of men with normal semen analysis, 4.4% were heterozygous (one R117H and three IVS8T-5T). Login to comment
60 In the control group of 100 men, 4% carried the DF508 mutation, 3% the R117H mutation and 4% the IVS8T-5T mutation. Login to comment
105 The most common mutations are DF508, R117H and IVS8T-5T (24, 25). Login to comment
112 The IVS8T-5T mutation is probably only involved in CBAVD, whereas the R117H mutation can be involved in cystic fibrosis, especially if the 5T variant is present (26). Login to comment
114 However, this seems unlikely as the search for DF508, 394delTT, R117H and IVS8T-5T mutations should identify >90% of CFTR mutations. Login to comment

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

No. Sentence Comment

33 Mutation screening of the CFTR gene The 31 most frequent mutations (F508del, I507del, G551D, G542X, N1303K, 1717-1G4A, W1282X, R553X, R347P, R347H, R334W, 3849+10kb C4T, R117H, 621+1G4T, A455E, S549N, R560T, S549R, V520F, Q493X, 3849+ 4A4G, 1078delT, R1162X, 3659delC, 3905insT, Y122X, 2183delAA4G, 2789+5G4A, 1898+1G4A, 711+1G4T, and G85E) were examined with the polymerase chain reaction (PCR) followed by an oligonucleotide ligation assay (OLA, Applied Biosystems, Foster City, CA, USA) and finally a sequence-coded separation. Login to comment

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

No. Sentence Comment

73 Class IV mutations include cases where the CFTR gene encodes a protein that is correctly trafficked to the cell membrane and responds to stimuli but generates a reduced Cl- current (for example R117H). Login to comment
155 Mutations R117H, R334W and R347P are usually associated with less severely impaired pancreatic function (reviewed by Tsui, 1992). Login to comment
188 The R117H mutation is usually responsible for mild CF disease due to production of a partially functional protein that is localised to the apical cell membranes. Login to comment
189 However, this mutation appears to be modulated by the presence of the T7 allele in intron 8 of the CFTR gene, with a CF phenotype only occurring if R117H is present with the T5 allele (Kiesewetter et al. 1993). Login to comment
190 In eight individuals with CBAVD and one asymptomatic individual (R117H/ F508) the R117H allele was found in association with the T7 allele. Login to comment
192 Therefore, R117H/T7 individuals would produce normal levels of partially functional CFTR resulting in a mild CF phenotype. Login to comment
193 This is in contrast to R117H/T5 individuals where the amount of full-length CFTR mRNA is reduced, resulting in a more severe phenotype due to a decreased amount of R117H CFTR protein at the cell membrane. 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

50 Among the 10 worldwide disease-causing mutations, only one case of R117H was found in a control subject. Login to comment
74 CFTR genetic variants analyzed in this study Variations found by TDGS Most common worldwide disease-causing mutations Reported disease-associated microsatellite À8G/C (50 UTR)a R117H (exon 4) T5-7,9 (IVS 8) (16) I125T (exon 4)b 621 þ 1G > T (intron 4) E217G (exon 6a)b F508del (exon 10) 1059C > T (exon 7, A309)a 1717-1G > A (intron 10) M470V (exon 10)b G542X (exon 11) I556V (exon 11)b G551D (exon 11) 2694T/G (exon 14a, T854)b R553X (exon 11) Q1352H (exon 22)b R1162X (exon 19) R1453W (exon 24)b W1282X (exon 20) N1303K (exon 21) Mutation names and nucleotide numbers are presented according to the Cystic Fibrosis Genetic Analysis Consortium (CFGAC; www.genet.sickkids.on.ca/). Login to comment
107 Frequency of CFTR gene variants in the Korean population Variation Genotype Group (number) Healthy control (n ¼ 117) Bronchiectasis (n ¼ 47) Pancreatitis (n ¼ 28) Diallelic -8G/C þ/þ 105 44 22 þ/Àa 12 3 6 R117H þ/þ 116 47 28 þ/À 1 0 0 I125T þ/þ 116 46 27 þ/À 1 1 1 E217G þ/þ 114 43 27 þ/À 3 4b 1 1059C > T þ/þ 117 47 27 (A309) þ/À 0 0 1 M470V þ/þ 23 3 6 þ/À 52 28 14 À/À 42 16 8 I556V þ/þ 111 45 28 þ/À 6 2 0 2694T/G þ/þ 41 16 8 (T854) þ/À 51 27 14 À/À 25 4 6 Q1352H þ/þ 116 43 24 þ/À 1 4* 4** R1453W þ/þ 115 46 28 þ/À 2 1 0 Microsatellite T5-7,9 5/7 4 6* 2 (IVS 8) 6/7 0 1 0 7/7 110 39*c 26 7/9 3 1 0 Differences between control and disease groups were analyzed by a chi-square test. When an expected cell value was less than 5, Fisher`s exact test was used. Login to comment
114 Haplotype assembly Allele ID -8G/C R117H I125T E217G 1059C/T T5-7,9 M470V I556V 2694T/G Q1352H R1453W Group a M470V-2694T/G background Control, n (%) Bronchiectasis, n (%) Pancreatitis, n (%) 1 G R I E C WTb V I T Q R 121 (51.7) 47 (50.0) 24 (42.9) 2-1 2 G R I E C WT M I G Q R 78 (33.3) 25 (26.6) 18 (32.1) 1-2 3 C R I E C WT M I G Q R 11 (4.7) 3 (3.2) 5 (8.9) 1-2 4 G R I E C WT V I T H R 1 (0.4) 4 (4.3)* 4 (7.1)** 2-1 5 G R I E C 5 V I T Q R 2 (0.9) 5 (5.4)* 1 (1.8) 2-1 6 G R I G C WT M I G Q R 3 (1.3) 4 (4.3)c 1 (1.8) 1-2 7 G R I E C WT V V T Q R 5 (2.1) 2 (2.2) 0 (0.0) 2-1 8 G R I E C WT V I G Q R 4 (1.7) 1 (1.0) 0 (0.0) 2-2 9 G R I E C 5 M I G Q R 2 (0.9) 1 (1.0) 1 (1.8) 1-2 10 G R I E C WT M I G Q W 2 (0.9) 1 (1.0) 0 (0.0) 1-2 11 G R T E C WT V I T Q R 1 (0.4) 1 (1.0) 1 (1.8) 2-1 12 G R I E C WT M I T Q R 2 (0.9) 0 (0.0) 0 (0.0) 1-1 13 C R I E C WT V I G Q R 1 (0.4) 0 (0.0) 0 (0.0) 2-2 14 G H I E C WT V V T Q R 1 (0.4) 0 (0.0) 0 (0.0) 2-1 15 C R I E T WT M I G Q R 0 (0.0) 0 (0.0) 1 (1.8) 1-2 Total 234 (100.0) 94 (100.0) 56 (100.0) Haplotypes were assembled using a software based on the Bayesian algorithm (Haplotyper) (7). Login to comment
152 Among the 10 common worldwide disease-causing mutations, only one case of R117H was found Figure 2. Login to comment

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

No. Sentence Comment

8 R117H, D1152H, L206W, 3272-26A>G, S1235R, G149R, R1070W, S945L, and the poly-T tract variation commonly called IVS8-5T were also observed. Login to comment
18 Other mutations that might be associated with intermediate (40-60 mmol/L) or normal sweat chloride values have been reported: R117H [Kerem et al., 1997; Massie et al., 2000], G551S [Strong et al., 1991], A455E [Gan et al., 1995], L206W [Desgeoges et al., 1995], D1152H [Feldmann et al., 1995; Lebecque et al., 2001]. Login to 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
52 Other common mutations observed in our study such as 3849+10kbC>T, R117H, D1152H, L206W were found at a low prevalence in typical CF patients (0.4 % to 0.2 %). Login to comment
82 Other common mutations observed in our study were R117H, IVS8(5T), D1152H, and L206W. Login to comment
83 Usually, in patients with typical CF, R117H alleles also bear the 5T-splice variant [Kiesewetter et al., 1993; Friedman et al., 1997]. Login to comment
84 In our study, none of the patients carried the R117H-5T allele. Login to comment
85 Massie et al. [2000] and Padoan et al. [2002] have reported patients with R117H and an elevated IRT with a normal sweat test. Login to comment
88 Recently, Lebecque et al. [2002] reported on two patients with sinopulmonary disease and R117H-7T in trans of a severe mutation. Login to comment
89 It is possible that not only the 5T-splice variant, but also other genetic variations may modulate the phenotype of the R117H mutant. Login to comment

PMID: 14500307 [PubMed] Curnow L et al: "Genetic counselling after carrier detection by newborn screening when one parent carries DeltaF508 and the other R117H."

No. Sentence Comment

140 One of the mutations in the extended mutation analysis is R117H, which is considered to be a mild CF mutation associated with a broad phenotype, ranging from no clinical disease, to CF with suppurative lung disease.3 Subjects who are compound heterozygotes for ∆F508/R117H may have raised (Cl >40 mmol/l) or normal (Cl <40 mmol/l) sweat electrolytes. Login to comment
141 In the course of routine carrier testing following NBS, we have identified four couples in which one partner carried the ∆F508 mutation, and the other R117H. Login to comment
142 The findings from the carrier testing raised the question of how to counsel these families regarding the carrier infant who could be a compound heterozygote (∆F508/R117H) with a normal sweat test and their risk of subsequent children being affected with CF. Login to comment
144 The aim of this paper is to present the details of NBS and carrier testing offered to these four families and to discuss the implications for genetic counselling when both parents of ∆F508 carrier babies are found to be carriers, one with ∆F508 and the other with R117H. Login to comment
145 We believe that this information is extremely important for centres that are already screening or considering the introduction of CF newborn screening so that appropriate genetic counselling is offered and an approach to the discovery of well infants who are compound heterozygotes with ∆F508/R117H is developed. Login to comment
149 His father was found to be the ∆F508 carrier and his mother carried R117H. Login to comment
151 After genetic counselling (LC and JM) the parents elected to test the infant for R117H and he was found to be a compound heterozygote for ∆F508/R117H (9T/7T). Login to comment
152 The parents also elected to test their other two children aged 6 and 4 who were well, and one was also a ∆F508/R117H (9T/ 7T) compound heteroygote and the other a carrier of R117H (7T/7T). Login to comment
156 DISCUSSION In the course of newborn screening for CF we have identified four infants who were ∆F508 heterozygotes with normal sweat electrolytes and whose parents were both identified as carriers, one with ∆F508, and one with R117H. Login to comment
158 In each case, the infants were found to be compound heterozygotes for ∆F508/R117H. Login to comment
206 R117H a class IV cystic fibrosis transmembrane conductance regulator (CFTR) gene mutation, which is known to produce a CFTR protein with reduced chloride transport.4 5 The intron 8 polythymidine sequence in the gene influences the severity of the CF phenotype when R117H is found in conjunction with a severe CF mutation.6 The thymidines are found in sequences of 5(5T), 7 (7T), or 9 (9T) repeats with the fewer number of thymidines associated with less efficient mRNA splicing at the splice acceptor site with greater skipping of exon 9 in the CFTR protein. Login to comment
207 As a result, there is lower than normal level of full length CFTR mRNA and a decrease in mature, functional CFTR protein.7 R117H on a 5T background is acknowledged as a disease producing CFTR mutation and in combination with a severe mutation (for example, ∆F508) generally results in pancreatic sufficient CF.8 There is less known about R117H on a 7T background. Login to comment
208 In one series, subjects were asymptomatic or had absent vas deferens only.9 A more recent series of patients known to CF clinics through clinical presentation or NBS included a small number of adults with adult onset CF disease.3 It is possible, however, that compound heterozygotes with R117H on a 7T background remain asymptomatic and are never tested. Login to comment
209 The range of possible phenotypes associated with the R117H mutation highlights the importance of obtaining the intron 8 polythymidine sequence prior to predicting the severity of the phenotype in an R117H compound heterozygote.10 The difficulty lies in the certainty of the information provided to parents and patients; in particular those with R117H on a 7T background. Login to comment
211 It was explained that the infant detected by newborn screening may be a carrier of ∆F508 only or could be a compound heterozygote with ∆F508/R117H, but that it was not possible to determine which outcome was likely from the results of the sweat test alone. Login to comment
218 With this information, the families all made the choice to test their infants for R117H. Login to comment
221 The next decision was whether to test the healthy siblings of the carrier infant to clarify their genotypes as it was possible that they too may be compound heterozygotes with ∆F508/R117H. Login to comment
227 The result of the R117H testing revealed that all four infants were compound heterozygotes for ∆F508/R117H on a 7T background as were a number of their healthy siblings. Login to comment
231 In one series of 57 ∆F508 infants detected by NBS, five were Table 1 Details of four infants identified by newborn screening as ∆F508 carriers with both parents identified as cystic fibrosis carriers, one parent with ∆F508 and the other with R117H Newborn screening results Sweat test Parents` genotype Infant`s genotype Siblings Infant 1 IRT 99th centile Cl 28 mmol/l Mother: R117H/- ∆F508/R117H (7T/7T) F, 10 y, asymptomatic, ∆F508/R117H (7T/9T) ∆F508/- Na 21 mmol/l Father: ∆F508/- M, 12 y, asymptomatic, R117H Infant 2 IRT 99th centile Cl 18 mmol/l Mother: R117H/- ∆F508/R117H (9T/7T) M, 5 y, asymptomatic, R117H ∆F508/- Na 17 mmol/l Father: ∆F508/- Infant 3 IRT 99th centile Cl 33 mmol/l Mother: R117H/- ∆F508/R117H (9T/7T) F, 6 y, asymptomatic, ∆F508/R117H (9T/7T) ∆F508/- Na 27 mmol/l Father: ∆F508/- M, 4 y, asymptomatic, R117H (7T) Infant 4 IRT 99th centile Cl 29 mmol/l Mother: R117H/- ∆F508/R117H (9T/7T) Nil ∆F508/- Na 29 mmol/l Father: ∆F508/- Genetic counselling after carrier detection by newborn screening www.archdischild.com found to be compound heterozygotes with R117H(7T) and 10 with 5T.15 The frequency of R117H has been reported as 1% of CFTR mutations in CF patients who have been genotyped, but may be higher in the community.16 Witt et al found 0.6% of pregnant women to be R117H carriers, but this paper did not include intron 8 polythymidine sequences.17 The final issue for the four couples was to determine the frequency of follow up of healthy compound heterozygote children with ∆F508/R117H(7T). Login to comment
235 Given the uncertain nature of the outcome of asymptomatic infants detected with R117H, it could be questioned as to the value of including it in a CFTR mutation panel. Login to comment
236 The current technology used for the extended CFTR mutation analysis uses multiplex testing for a number of severe exon 4 mutations, and R117H is also detected. Login to comment
238 In the future, gene sequencing may solve this problem; however, it can be argued that finding R117H on a 5T background is worthwhile as it is a disease producing mutation. Login to comment
239 We have developed an approach to the counselling of couples who have an infant detected by newborn screening as a ∆F508 heterozygote with a normal sweat test but who are both CFTR mutation carriers, one ∆F508 and the other R117H. Login to comment
240 It will take many years to know whether the asymptomatic compound heterozygotes with R117H on a 7T background develop features of CF to justify their early detection. Login to comment

PMID: 14534402 [PubMed] Boyle MP et al: "Nonclassic cystic fibrosis and CFTR-related diseases."

No. Sentence Comment

66 The polythymidine tract is also of particular importance in determining the clinical effect of the CF mutation R117H. Login to comment
67 When paired in trans with another CF mutation, the R117H / 5T alleles will usually cause a classic CF phenotype, R117H / 7T will cause CBAVD alone, and R117H / 9T will not cause any disease [37]. Login to comment

PMID: 14551163 [PubMed] Gilljam M et al: "Airway inflammation and infection in congenital bilateral absence of the vas deferens."

No. Sentence Comment

57 DEMOGRAPHIC DATA FOR MEN WITH CONGENITAL BILATERAL ABSENCE OF THE VAS DEFERENS Sweat Chlorides Nasal PD FEV1 Patient Age (yr) Genotype (mmol/l) (mean/⌬, mV) (%pred)‡ 1 41 ⌬F508/R117H, 7T 50 -34/13 106 2† 31 R117H, 7T/R117H, 7T 31, 40 -31/5 107 3† 36 G551D/R117H, 7T 66, 64 -29/8 118 4† 44 ⌬F508/R117H, 7T 54, 67 -23/6 109 5† 35 ⌬F508/4016insT 74, 88 -46/9 110 6 41 ⌬F508/unidentified, 5T 23, 24 -32/7 118 7 37 ⌬F508/M952T 41, 44 -20/20 122 8† 45 ⌬F508/P67L 47, 59 -36/6 78 Definition of abbreviations: mean/⌬ ϭ mean basal potential difference/change in response to perfusion with a chloride-free solution plus isoproterenol; PD ϭ potential difference. Login to comment
156 The R117H mutation should not be considered a CF-causing mutation unless combined with the 5T variant or evidence of CFTR malfunction demonstrated by sweat test or nasal PD measurements (28). Login to comment
157 In our study population, three of the four men with infertility who carried the R117H mutation in association with the 7T mutation had independent clinical or laboratory evidence of CFTR malfunction with elevated sweat chlorides and/or abnormal nasal PD. Login to comment
158 In addition to the T-tract length, it is possible that environmental factors or modifier genes play a role in determining whether patients with R117H mutations presenting with CBAVD eventually will develop multiorgan disease (10). Login to comment
159 Nontypical CF disease sometimes develops late in life as described in an elderly woman with the ⌬F508/R117H mutation (unknown T-tract) (55). Login to comment

PMID: 14562574 [PubMed] Morinville V et al: "Genetic disorders of the pancreas."

No. Sentence Comment

30 The close monitoring of the families affected with this condition played an important role in the identification of their genetic anomaly; the S family, described by McElroy and Christiansen in 1972 [34], was to play a pivotal role in helping Whitcomb et al 25 years later to uncover the Table 1 Recent genetic information on pancreatitis in children Gene Chromosome Mutations References Cationic trypsinogen (protease, serine1; PRSSI) 7q35 R122H; N29I A16V; others [4,11-19] Pancreatic trypsin inhibitor (PSTI) (SPINK1-serine protease inhibitor, Kazal Type 1) 5 N34S [20-22] CFTR-cystic fibrosis transmembrane regulator 7 DF508; R117H; Q493X R560T; R553X; 5Tallele; 621 + 1(G!T) and others [23-27] Parathyroid cell receptor (CaR) 3 (3q21-24) N178D; R220Q; P221S; R648X; others [28-30] Lipoprotein lipase (LPL) 8 (8p22) N291S, S447X; G715A [31,32] Apolipoprotein C-II (apoC-II) 19 (19q13.2) Val 18, Gln 2 and others [31] chromosomal [11], then the genetic abnormality [1], while in France Le Bodic et al [12] identified a very similar anomaly in a family described in 1963 by Cornet et al [35]. Login to comment
52 Pfutzer and Whitcomb [17] also found CFTR R117H mutation in one family affected with A16V mutation, leading them to raise the question as to whether this latter mutation might represent a modifier gene requiring another mutation, rather than an independent risk factor, for development of pancreatitis. Login to comment
77 Mutations, including delta F508, R117H, Q493X, 621 + 1 (G!T), R560T, R553X, were found at 2.5 times the frequency expected in the general population studied (600 controls included). Login to comment
80 Ten of twenty-seven (37%) had at least one abnormal CFTR allele (deltaF508, R117H, N1303K, and the 5T allele), none with criteria diagnostic of cystic fibrosis. Login to comment
84 Mutations of CFTR include: deltaF508, R117H, D1152H, P574H, 3120 G > A, 621 + 1 G > T, G1069R, N1303K. Login to comment

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

No. Sentence Comment

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

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

No. Sentence Comment

59 Patients no 1 and no 8 bear a CBAVD and the R117H mutation which is very often responsible for this CFTR pathology. Login to comment
60 Patient no 2 is a compound heterozygote for R117H and N1303K: her phenotype is that of a moderate cystic fibrosis as shown by respiratory signs and an abnormal nasal potential difference in the context of a borderline sweat test. Login to comment
80 Patient CFTR no PolyT genotype Sex genotype Age (years) Sweat chloride (mmol/L) Anamnestic features known to be associated with atypical CF Reference 1 F508del/R117H 9T/7T M 45 29 CBAVD [4] 2 N1303K/R117H 9T/7T F n.a. 37 bronchiectasis, sinusitis, positive NPD [5] 3 R1162X/2789+5G>A 7T/7T F n.a. 108 chronic cough [5] 4 I336K/R75Q 7T/7T F 26 26 nasal polyposis [7] 5 F508del/L997F 9T/7T M 17 24 none [11] 6 3849+10kbC>T/3878delG 7T/7T M 14 n.a. none [11] 7 S1235R/L997F 5T/7T M 27 25 none [11] 8 F508del/R117H n.a. M 45 29 CBAVD, smooth P. aeruginosa [12] 9 F508del/I1027T n.a. F 32 59 none [12] 10 F508del/D1152H n.a. M 8 62 none [12] 11 F508del/D1152H n.a. F 15 32 none [12] 12 F508del/P574H n.a. F 26 81 sinus surgery, S. aureus, S. maltophilia [12] 13 F508del/3120G>A n.a. F 40 n.a. n.a. [12] 14 F508del/G1069R n.a. M 16 n.a. n.a. [12] 15 G542X/S1235R 7T/7T M 35 15 none [this study] n.a.: not available. Login to comment

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

No. Sentence Comment

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

63 R117H, R334W and R347P are examples of mutations that appear to yield a milder clinical phenotype even when in combination with a more severe allele. 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
91 When 5T is in cis with R117H, there is further reduction in CFTR function. Login to comment

PMID: 14696845 [PubMed] Gronowitz E et al: "Association between serum oncofetal antigens CA 19-9 and CA 125 and clinical status in patients with cystic fibrosis."

No. Sentence Comment

45 The remaining 23 patients had at least one mild (I506L, R117C, S945L, T338I, W301R, 3849 10KBC → T, 1249-5 → G, R117H, R75Q), moderate (G551D, R560T, V603F) or unknown mutation. Login to comment

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

No. Sentence Comment

50 Meanwhile, there are polymorphisms in the gene that may be harmless by themselves but influence the expression of a mutation on the same or opposite allele (e.g., R117H and 5T). Login to comment
64 The major recommendations for population-based CF carrier screening are: • Testing should be pan-ethnic/racial and universal, though perhaps offered more aggressively to the highest risk groups (Caucasians and Ashkenazi Jews) • Testing should be in the prenatal setting, though preconception screening should be encouraged whenever possible • Whether testing sequentially or simultaneously, both members of the couple must be provided with their test results • The minimal core test panel which must be offered consists of 25 mutations and several associated polymorphisms • The intronic poly-T tract polymorphism is to be assessed only as a reflex test after an individual tests positive for the R117H mutation • Extended mutation panels beyond the core 25 are not encouraged for general population screening • Couples with positive screening results or unusual variants should be considered for referral to a genetics center for further counseling [13] While these recommendations may appear straightforward, when put into practice on a large scale (much larger and including more mutations than the pilot studies), a number of complex challenges inevitably arise. Login to comment
161 Also considered in these models are the complex reporting situations with certain CFTR mutations, particularly R117H and 5T, and the reader is referred to these resources for a more detailed discussion. Login to comment
200 One is the R117H mutation, which can be a CF mutation in the presence of a 5T allele on the same chromosome (cis) or a CBAVD-associated mutation when in cis with a 7T allele. Login to comment
201 Comparison of R117H frequency in the general population versus the CF population indicates that it occurs around 20-times more frequently in the general population than predicted, which suggests that it occurs in two different forms. Login to comment
204 Thus, the ACMG recommended that the R117H mutation be included in the screening panel (since it does cause CF) and when identified, that reflex testing for the 5T allele be performed as a routine laboratory procedure to enable more informative genetic counseling. Login to comment
230 The committee to review the panel of mutations has reconvened and is currently deliberating the merits of inclusion or exclusion of the R117H, 5T, I148T and 3199del6 mutations/variants. Login to comment
305 In order to bring the laboratories up to speed on reporting for this larger and more complex panel, the ACMG recommendations included an appendix containing several model test report forms representing the major positive and negative outcomes, along with various combinations of the R117H mutation and 5T/7T polymorphisms [13]. Login to comment
308 It is suggested that the following test result situations (among others) should prompt consideration for referral of the couple to a specialized genetics center for more lengthy and target counseling: positive-positive couples, positive-negative couples with residual anxiety, individuals with a family history of CF, individuals testing positive for R117H and the 5T/7T polymorphism, and infertile males who are found to carry a CFTR mutation or variant. Login to comment
358 The first changes are likely to be minor, perhaps involving the I148T or R117H mutations. Login to comment

PMID: 14718229 [PubMed] Pradal U et al: "Cystic fibrosis patients, infertile men, and their noses."

No. Sentence Comment

85 For most patients with congenital bilateral absence of the vas deferens, including those in the study by Gilljam and coworkers (2), the detection of mutations, such as R117H, which may be associated with a broad phenotype, does not help in characterizing the disease. Login to comment
86 It should be noted that asymptomatic newborn babies that are compound heterozygotes for ⌬F508 (the main severe mutation in CF patients) and R117H are followed on a regular basis in CF clinics to monitor their clinical status properly (9). Login to comment
125 Genetic counselling after carrier detection by newborn screening when one parent carries ⌬F508 and the other R117H. Login to comment

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

No. Sentence Comment

7 In contrast, patients with at least one copy of type IV and V mutations, for example R117H or A455E, usually have sufficient preservation of their exocrine pancreatic function to prevent malabsorption and are classified as pancreatic sufficient. Login to comment
23 Contributed by Kevin J Gaskin Department of Gastroenterology and James Fairfax Institute of Pediatric Nutrition,The Children`s Hospital,Westmead, NSW 2145, Australia Table 1 Classification of cystic fibrosis transmembrane conductance regulator (CFTR) mutations Type Description Example I CFTR mRNA or protein not formed G542X II CFTR trafficking defect, and protein fails to locate in cell membrane DF508 III Regulation defect. CFTR inserts into cell membrane but no response to cAMP G551D IV Channel defect. CFTR inserts into cell membrane but function is reduced R117H V Synthesis defect. CFTR inserts into membrane and functions normally, but the amount of CFTR synthesized is reduced from normal Login to comment

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

No. Sentence Comment

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

PMID: 14747162 [PubMed] Wu CC et al: "Cystic fibrosis transmembrane conductance regulator gene screening and clinical correlation in Taiwanese males with congenital bilateral absence of the vas deferens."

No. Sentence Comment

5 No mutations of DF508 or R117H were identi®ed in any of the samples analysed. Login to comment
30 DNA analysis We isolated genomic DNA from peripheral blood lymphocytes and ampli®ed it with a PCR-based assay to evaluate the DF508 and R117H mutations. Login to comment
42 Screening by an INNO-LiPA CFTR17+Tn kit For further con®rmation, we used a commercial kit (INNO-LiPA CFTR17+Tn; Innogenetics, Ghent, Belgium) that allowed the detection of 17 mutations (including 394delTT, G85E, E60X, 621+1G®T, R117H, 711+5G®A, 1078delT, R347P, R334W, A455E, 2143delT, 2183AA®G, 2184delA, 2789+5G®A, R1162X, 3659delC and 3849+10kbC®T) associated with IVS8-Tn polymorphisms (5T/7T/9T) in the CFTR gene to analyse our 27 patients and 46 normal, fertile control males. Login to comment
47 The clinical variables of 27 patients Patient no./age (years) Genetic results Ultrasonographic status Semen analyses ART DF508 R117H IVS8-Tn Kidney Seminal vesicles Volume (ml) pH Fructose 1/26 Neg Neg 5T/7T N BHy MESA 2/32 Neg Neg 5T/7T N RA+LHy MESA 3/38 Neg Neg 5T/7T N RHy+LA MESA 4/31 Neg Neg 5T/7T <1 Neg MESA 5/35 Neg Neg 7T/7T N N 1.5 MESA 6/32 Neg Neg 5T/7T MESA 7/33 Neg Neg 5T/5T RHy+LA MESA 8/28 Neg Neg 5T/7T BA 1±2 6 Neg MESA 9/31 Neg Neg 5T/7T 2±3 MESA 10/33 Neg Neg 5T/5T N BHy <1 11/33 Neg Neg 7T/7T N BHy 12/29 Neg Neg 5T/7T N BA 13/31 Neg Neg 5T/7T 0.6 MESA 14/43 Neg Neg 5T/7T N BHy 0.3 6 15/44 Neg Neg 5T/7T N N MESA 16/35 Neg Neg 5T/7T N BA 1.5 6.5 Neg TESE 17/33 Neg Neg 7T/7T N BHy 18/33 Neg Neg 7T/7T N BHy TESE 19/28 Neg Neg 7T/7T BHy 0.8 7.5 MESA 20/27 Neg Neg 5T/5T N BA 1 6.5 Neg MESA 21/33 Neg Neg 5T/7T N BHy <1 6 Neg MESA 22/43 Neg Neg 5T/7T N BHy 4 5 23/28 Neg Neg 5T/5T N RA+LHy 1 6 Neg 24/39 Neg Neg 7T/7T 25/25 Neg Neg 7T/7T 26/31 Neg Neg 7T/7T N 4 6.5 Neg 27/38 Neg Neg 5T/5T Neg, negative; N, normal; B, bilateral; R, right; L, left; Hy, hypoplasia; A, aplasia; ART, assisted reproductive technology. Login to comment
50 We did not identify any mutations of DF508 or R117H in any of the samples analysed (Table I). Login to comment
63 Another CF mutation, R117H, was found to occur at a high frequency in CBAVD patients (Gervais et al., 1993). Login to comment
64 Molecular analysis of these two most-frequent CFTR mutations involved in CBAVD was performed in our 27 cases, and none of them was found to carry a single allele mutation of either DF508 or R117H. Login to comment
65 The extremely low frequency of DF508 and R117H mutations in CBAVD patients reported here might be correlated to the rarity of CF occurrence in Taiwan. Login to comment
77 In the present study, we found a low frequency of major CFTR mutations (DF508 and R117H) in Taiwanese CBAVD patients. Login to comment
81 Series review of DF508, R117H and IVS8-poly T frequencies in patients with CBAVD Series No. Login to comment
82 of cases DF508 (%) R117H (%) IVS8-Tn (%) Reference 5T 7T 9T Caucasian series German population 106 26.9 11.3 12.7 39.6 31.6 Dork et al. (1997) Spanish population 102 21.1 47.5 31.4 Chillon et al. (1995) French population 25.6 3.3 25.6 Costes et al. (1995) Canada population 25 12.0 6.0 26.0 Jarvi et al. (1995) Egyptian population 20 2.5 0 43.7 46.9 9.4 Lissens et al. (1999) Taiwanese population 27 0 0 44.4 55.6 0 This study C.C.Wu et al. atAcquisitionServicesonAugust8,2011humrep.oxfordjournals.orgDownloadedfrom may provide further evidence to explore the racial differences in this genetic disorder. Login to comment

PMID: 14965334 [PubMed] Vogt PH et al: "Molecular genetics of human male infertility: from genes to new therapeutic perspectives."

No. Sentence Comment

284 Compound heterozygotes of CBAVD patients with a 5T allele in one gene copy and a Arg117-to-His117 (R117H) mutation in exon 4 of the second gene copy have a severe CF phenotype, whereas the 7T allele would only result in CBAVD [117]. 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
85 Cauc. Het. * DF508/R117H Mutation/mutation Yesd 7 CBAVD Asian-Indian Het. Negative Het. V456A Mutationc No 8 CBAVD Asian Negative * Het. Q1352H Mutation Nod 9 CBAVD Asian Negative * Negative No mutation detected Yes 10 CBAVDb N.E. Cauc./ Asian/Ashkenazi Negative * I556V/2752±26A®G Mutation/mutation Nod 11 CBAVD Hispanic Homozygous * Het. W1098C Mutation Nod 12 CBAVD Asian Negative Negative Het. 3499+25C®G Variant of unknown signi®cance No 13 CUAVD Hispanic Negative * Negative No mutation detected Yes 14 CBAVDb N.E. Cauc. Negative * Negative No mutation detected Yes 15 Idiopathic obstruction Asian-Indian Negative * Het. I807M Mutationc Nod 16 Idiopathic obstruction N.E. Cauc. Het. * Het. DF508 Mutation Yesd *Analysis not done. Login to comment
121 Mutations and variants of unknown signi®cance detected in 16 patients with CAVD Detection method 31 common mutation panel and poly T analysis Sequence method and poly T analysis Mutations 5T 7 7 DF508 2 2 R117H 1 1 P750L ± 1 V201M ± 1 Q1352H ± 1 I556V ± 1 2752±26A®G ± 1 W1098C ± 1 I807M ± 1 V456A ± 1 V520I ± 1 Variants of unknown signi®cance 1717±4A®G ± 1 3601±3C®A ± 1 3499+25C®G ± 1 Total 10 22 the vas deferens is particularly susceptible to the decreased levels of CFTR protein product. Login to comment
124 However, 5T in cis with certain mutations (i.e. R117H) may exert a more deleterious effect that contributes to disease phenotype. Login to comment
125 For example, one patient in this series (DF508/R117H and one 5T allele) lost a brother to cystic ®brosis and reported that he has a personal history of a chronic cough, which could represent a mild CF phenotype. Login to comment

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

No. Sentence Comment

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

PMID: 15039139 [PubMed] Hentchel-Franks K et al: "Activation of airway cl- secretion in human subjects by adenosine."

No. Sentence Comment

186 The nature of this effect is unknown, but previous studies from our laboratory have shown that Ado stimulation of A2B ARs can activate surface localized mutant CFTR molecules, including ⌬F508 CFTR after growth at permissive temperatures, G551D CFTR, and R117H CFTR (15, 32). Login to comment

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

No. Sentence Comment

4 The five mutations [and the percentages of Irish (3) and worldwide (2) cases] are F508del (77.4%, 66.0%), G551D (7.1%, 1.6%), R117H (2.7%, 0.3%), 621ϩ1 GϾT (1.4%, 0.7%), and G542X (0.5%, 2.4%). Login to comment
20 The first reaction detects the G551D, R117H, and F508del mutations (87.2% frequency in Ireland, 67.9% worldwide). Login to comment
26 R117H and 621ϩ1 GϾT ARMS products are detectable by the CF4ARMS-A (5Ј- CCTTTTGTAGGAAGTCACCAAAGCAGTAC-F-3Ј) and CF4ARMS-P (5Ј-LCRed640-GCCTCTCTTACTGGGAA- GAATCA-P-3Ј) hybridization probes (F indicates a fluorescein, and P indicates phosphate). Login to comment
53 Melting curve profile of a R117H/G551D compound heterozygote. Login to comment
54 The F2 channel (top plot) detects both the wild-type and mutant F508del and R117H ARMS products with their respective peaks seen at ϳ51 and 62 °C. Login to comment

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

No. Sentence Comment

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

PMID: 15070876 [PubMed] Dayangac D et al: "Mutations of the CFTR gene in Turkish patients with congenital bilateral absence of the vas deferens."

No. Sentence Comment

113 Our results implicate D1152H as a common missense mutation in Turkey which appears to be speci®cally associated with CBAVD, perhaps comparable to the role of the R117H missense substitution in Central Europe (Gervais et al., 1993; DoÈrk et al., 1997). Login to comment

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

No. Sentence Comment

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

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

No. Sentence Comment

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

PMID: 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

78 DNA Amplification and colorimetric detection on linear array strips with Analyte Specific Reagents for a 16-mutation assay (gift from Roche Molecular Systems, Alameda, CA) and a 27-mutation assay (Linear Array CF-31; Roche Molecular Biochemicals, Indianapolis, IN) were used.20 For both panels, the DNA assay assessed only CFTR mutations; detection of polymorphisms was incorporated as a reflex test for confirmation of putative ⌬F508 homozygotes (assay for F508C, I506V, and I507V) or for genotype elucidation on detection of 2 mutations including R117H (assay for IVS8polyT 5/7/9T). Login to comment
79 The 16-mutation panel included ⌬F508, R117H, G551D, G542X, W1282X, N1303K, R334W, 621 ϩ 1GϾT, R553X, ⌬I507, 1717-1GϾA, R347P, R560T, 3849 ϩ 10kbCϾT, A455E, and S549N. Login to comment
122 False-Negative Results One of the 2 infants who were not detected by the Ͼ95th daily percentile screen had an IRT value at the 93.9th percentile and meconium ileus (positive sweat test; G542X/unknown); the other infant missed by the screen had an IRT value at the 84th percentile and presented at 2 months with failure to thrive and upper respiratory tract infection (positive sweat test; ⌬F508/R117H). Login to comment
133 † An additional 2 infants have been shown to have 2 CFTR DNA variants when mother`s prenatal DNA testing on a subsequent pregnancy prompted infant genotyping; neither infant meets CFF criteria for diagnosis (one is ⌬F508/S1235R, has sweat-test-negative results, and is well; the other is ⌬F508/R117H 7T/7T, has sweat-test-borderline results, and is well). Login to comment
150 112 CF-Affected MA Infants Who Were Screened: Details of CF Newborn Screening Results and Diagnostic Follow-up Sweat Test Result (mEq Cl-/L) CF-Screen Positive CF-Screen Negative Total 2 Mutations 1 Mutation 0 Mutations Positive (Ն60) 62 19 3 2 86 Borderline (Ն30 and Ͻ60) Within expectations for specific CF genotype* 5 3 8¶ Monozygotic twin sweat test positive† 1 1 Negative (Ͻ30) Within expectations for specific CF genotype‡ 4 1 5 Incomplete (not done or QNS) 2 CFTR mutations identified and clinical symptoms§ 6 1 7 2 CFTR mutations identified without clinical symptoms࿣ 5 5 Total 82 25 3 2 112 * ⌬F508/R117H;7T (3), ⌬F508/3849 ϩ 10kb (2), ⌬F508/L206W (1), G551D/R117C (1), and G85E/R117C (1). Login to comment
154 ‡ ⌬F508/D1152H, ⌬F508/R117H (2), G85E/R117H, and G551D/R117H. 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

138 In patients carrying mutations such as R117H, A455E, R334W and 3849z10 kb CwT, which are reported to correlate with a milder phenotype, 40-87% have PS [21, 27]. 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
130 In a study of more than 500 CF patients, five mutations (R117H, R334W, R347P, A455E, and P574H) were found exclusively in pancreatic sufficient patients (8). 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

15 Mice bearing different mutations in the murine homolog to CFTR (Cftr) (R117H, S489X, Y122X, and ⌬F508, all backcrossed to the C57BL/6J background) were compared with respect to growth and in their ability to respond to lung infection elicited with Pseudomonas aeruginosa-laden agarose beads. Login to comment
39 On the other hand, if it is the lack of CFTR in the apical membrane that is the primary driver of the inflammatory response, cystic fibrosis mice bearing the R117H allele should have signifi- Address for reprint requests and other correspondence: A. Login to comment
49 In these experiments we tested cystic fibrosis mice bearing the ⌬F508, R117H, Y122X, or S489X genotypes, all backcrossed to the common C57BL/6J genetic background, using the mucoid P. aeruginosa agarose bead model to compare their inflammatory responses. Login to comment
56 Nomenclature rules available on the Jackson Laboratory website were followed; B6.129S6-Cftrtm2Uth mice bear the R117H mutation, and B6.129S6-Cftrtm3Uth mice bear the Y122X mutation. Login to comment
61 Cystic fibrosis mice bearing the severe mutations S489X, Y122X, and ⌬F508 were fed the liquid elemental diet Peptamen (Nestle Clinical Nutrition, Deerfield, IL) after weaning, whereas cystic fibrosis mice bearing the mild mutation R117H were fed a standard rodent chow until 1 wk before the start of the experiment at which point they were fed Peptamen until the termination of the experiment. Login to comment
125 The weight of cystic fibrosis mice bearing the mild R117H Cftr mutation did not differ significantly from wild-type controls at 7 days of age (P Ͼ 0.05) and weighed significantly more than mice bearing the severe mutations at 7 and 14 days of age (P Ͻ 0.05); however, they weighed significantly less than wild-type controls thereafter (P Ͻ 0.05) and were not significantly different from cystic fibrosis mice bearing the severe Cftr mutations at 21 days of life (P Ͼ 0.05). Login to comment
133 Absolute body weight of cystic fibrosis mice before weaning Cftr Genotype Sample Size Age, days 7 14 21 S489X/S489X 14 3.0Ϯ0.6 5.8Ϯ0.9 7.0Ϯ1.1 Y122X/Y122X 4 3.6Ϯ1.7 6.1Ϯ2.3 7.2Ϯ2.5 ⌬F508/⌬F508 10 3.1Ϯ0.9 5.6Ϯ1.2 6.7Ϯ0.8 R117H/R117H 15 4.7Ϯ0.7* 7.1Ϯ0.9* 7.9Ϯ1.8 Data are represented as means Ϯ SD. Login to comment
146 Similarly, comparisons between mice bearing the S489X mutation and those bearing the ⌬F508 mutation were made by combining data from experiments 68, 75, 90, and 94, and by combining data from experiments 64 and 94, comparisons were made between mice bearing the S489X mutation and those bearing the R117H mutation. Login to comment
149 There were no significant differences in starting weight between cystic fibrosis mice bearing the S489X mutation and those bearing any other Cftr mutation (Fig. 3A). Login to comment
152 After differences between the experiments are taken into consideration (Fig. 3B), weight loss in cystic fibrosis mice bearing the S489X mutation is significantly greater than those bearing the Y122X mutation on days 1, 2, and 3 (P Ͻ 0.05) and significantly less than those bearing the R117H mutation on days 1 and 2 (P Ͻ 0.05). Login to comment
162 L947ROLE regard to TNF-␣ and IL-1beta concentrations in the epithelial lining fluid, although there were no significant differences in cytokine levels between cystic fibrosis mice bearing the S489X mutation and those bearing the ⌬F508 or R117H mutations. Login to comment
165 Cystic fibrosis mice bearing the R117H mutation had significantly lower relative neutrophil numbers and greater absolute alveolar macrophage numbers (Table 5) compared with those bearing the S489X mutation in direct comparisons when stratifying for experiment. Login to comment
167 In a comparison of S489X vs. Y122X, ⌬F508, and R117H genotypes, the available sample sizes provide 80% power to detect Fig. 2. Login to comment
171 The difference in nasal PD from the start of the response to 1 min later was determined, and representative tracings are shown to the end of the tracing period from wild type (A), S489X (B), Y122X (C), ⌬F508 (D), and R117H (E) mice. Login to comment
173 Nasal potential differences in wild-type mice and mice bearing mutations in Cftr Cftr Mutation Sample Size Amiloride, mV Chloride-free, Amiloride, Forskolin, mV None 3 -2.1Ϯ1.5 14.4Ϯ1.2 S489X 7 -13.2Ϯ5.1* -2.6Ϯ2.2* Y122X 3 -10.9Ϯ3.7 -0.8Ϯ1.3* ⌬F508 6 -7.6Ϯ3.5 -1.8Ϯ0.8* R117H 3 -8.5Ϯ0.1 0.1Ϯ0.8* Data are means Ϯ SD. Login to comment
176 Starting sample sizes in each experiment Experiment Mouse Strain by Cftr Mutation S489X Y122X ⌬F508 R117H 64 9 (1) 0 0 9 (1) 68 8 4 5 0 72 8 (1)* 8 0 0 75 7 (1) 0 11 (1) [2]* 0 80 9* 10 0 0 90† 10 0 10 0 94† 9 7* 9 (1) 9 (1)* Total 60 (3) 29 35 (2) [2] 18 (2) The number of mice that died due to surgical complications or pulmonary obstruction is noted in parentheses and brackets, respectively. Login to comment
196 Inflammatory mediators in epithelial lining fluid Parameter Comparison 1 Comparison 2 Comparison 3 Y122X S489X ⌬F508 S489X R117H S489X TNF-␣ 7.8* (5.1/13.1) 10.3 (6.0/14.3) 8.0 (6.7/12.2) 9.5 (7.2/12.4) 14.7 (5.9/23.5) 13.6 (9.1/22.3) IL-1beta 14.5* (5.6/19.3) 16.0 (7.5/25.7) 14.4 (10.0/20.2) 16.0 (8.2/20.2) 12.2 (3.0/32.6) 18.2 (8.1/24.3) IL-6 12.3 (5.9/28.4) 14.6 (7.9/33.1) 11.9 (7.8 (22.8) 13.4 (8.0/19.2) 16.6 (7.3/24.7) 20.8 (9.0/62.4) MIP-2 55.8 (12.1/86.3) 66.9 (34.8/107.3) 90.8 (58.8/129.7) 102.2 (48.0/140.8) 55.6 (21.2/202.5) 96.0 (37.6/131.5) KC 4.1 (3.3/5.5) 5.9 (3.5/7.8) 5.4 (4.1/9.4) 6.3 (4.8/8.6) 12.8 (5.0/15.8) 7.4 (4.6/10.7) LTB4 1.2 (0.2/3.3) 2.3 (1.3/7.8) 5.9 (3.6/10.5) 7.1 (2.3/10.5) 2.1 (1.2/16.7) 2.3 (1.3/7.8) PGE2 4.4 (2.3/6.0) 8.0 (4.4/12.2) 11.4 (7.3/16.6) 12.9 (7.6/22.0) 9.2 (5.9/13.5) 8.0 (4.4/12.2) Data are pooled from available data, are represented as the median (25th/75th percentiles), and are expressed as ng/ml epithelial lining fluid (ELF). Login to comment
207 Correcting the Cftr defect in the gut of cystic fibrosis mice bearing the S489X mutation, by transgenic provision of human CFTR driven by the fatty acid binding protein promoter, results in a much more robust cystic fibrosis mouse that grows normally and does not have intestinal obstruction on a diet of normal mouse chow. Login to comment
210 In this model of lung infection and inflammation, four different genotypes of cystic fibrosis mice were tested: two knockout mice, Y122X and S489X; mice homozygous for the major processing mutation in cystic fibrosis, ⌬F508; and mice homozygous for a channel mutant, R117H, which reaches the plasma membrane but does not function normally. Login to comment
211 None of the cystic fibrosis mice studied here grows as well as their wild-type littermates, although the cystic fibrosis mice bearing the R117H mutation maintain weight better at week 1 of life. Login to comment
214 Here we show that cystic fibrosis mice bearing the Cftr mutations S489X, ⌬F508, Y122X, and R117H on the congenic C57BL/6J background also display the cystic fibrosis electrophysiological phenotype. Login to comment
225 The R117H allele, unlike those of the other genotypes studied here, is expected to reach the plasma membrane. Login to comment
226 Although the R117H animals have weight comparable to wild-type littermates at 1 wk of age, as early as 2 wk of age Table 5. Login to comment
227 Cell numbers in BAL fluid Parameter Comparison 1 Comparison 2 Comparison 3 Y122X S489X ⌬F508 S489X R117H S489X %AM 5.3 (2.8/41.1) 6.0 (4.3/11.9) 5.8 (3.3/8.7) 4.3 (2.4/5.9) 12.7 (5.8/25.0) 4.7 (4.3/7.4) %PMN 94.3 (58.9/96.9) 94.0 (87.3/95.6) 94.2 (91.3/96.7) 95.3 (94.1/97.6) 87.3* (75.0/94.2) 95.0 (92.6/95.3) %Lymph 0.0 (0.0/0.7) 0.0 (0.0/1.3) 0.0 (0.0/0.0) 0.0 (0.0/0.0) 0.0 (0.0/0.0) 0.0 (0.0/0.0) AM/ml 36 (12/66) 34 (15/72) 47 (23/88) 60 (12/126) 104* (32/168) 78 (56/102) PMN/ml 787 (14/1,449) 801 (422/1,528) 850 (396/1,310) 1,378 (423/1,714) 857 (415/1,549) 1,520 (1,125/1,716) Data are pooled from available data and are represented as the median (25th/75th percentiles). Login to comment
13 Mice bearing different mutations in the murine homolog to CFTR (Cftr) (R117H, S489X, Y122X, and ⌬F508, all backcrossed to the C57BL/6J background) were compared with respect to growth and in their ability to respond to lung infection elicited with Pseudomonas aeruginosa-laden agarose beads. Login to comment
37 On the other hand, if it is the lack of CFTR in the apical membrane that is the primary driver of the inflammatory response, cystic fibrosis mice bearing the R117H allele should have signifi- Address for reprint requests and other correspondence: A. Login to comment
46 In these experiments we tested cystic fibrosis mice bearing the ⌬F508, R117H, Y122X, or S489X genotypes, all backcrossed to the common C57BL/6J genetic background, using the mucoid P. aeruginosa agarose bead model to compare their inflammatory responses. Login to comment
53 Nomenclature rules available on the Jackson Laboratory website were followed; B6.129S6-Cftrtm2Uth mice bear the R117H mutation, and B6.129S6-Cftrtm3Uth mice bear the Y122X mutation. Login to comment
58 Cystic fibrosis mice bearing the severe mutations S489X, Y122X, and ⌬F508 were fed the liquid elemental diet Peptamen (Nestle Clinical Nutrition, Deerfield, IL) after weaning, whereas cystic fibrosis mice bearing the mild mutation R117H were fed a standard rodent chow until 1 wk before the start of the experiment at which point they were fed Peptamen until the termination of the experiment. Login to comment
122 The weight of cystic fibrosis mice bearing the mild R117H Cftr mutation did not differ significantly from wild-type controls at 7 days of age (P Ͼ 0.05) and weighed significantly more than mice bearing the severe mutations at 7 and 14 days of age (P Ͻ 0.05); however, they weighed significantly less than wild-type controls thereafter (P Ͻ 0.05) and were not significantly different from cystic fibrosis mice bearing the severe Cftr mutations at 21 days of life (P Ͼ 0.05). Login to comment
130 Absolute body weight of cystic fibrosis mice before weaning Cftr Genotype Sample Size Age, days 7 14 21 S489X/S489X 14 3.0Ϯ0.6 5.8Ϯ0.9 7.0Ϯ1.1 Y122X/Y122X 4 3.6Ϯ1.7 6.1Ϯ2.3 7.2Ϯ2.5 ⌬F508/⌬F508 10 3.1Ϯ0.9 5.6Ϯ1.2 6.7Ϯ0.8 R117H/R117H 15 4.7Ϯ0.7* 7.1Ϯ0.9* 7.9Ϯ1.8 Data are represented as means Ϯ SD. Login to comment
143 Similarly, comparisons between mice bearing the S489X mutation and those bearing the ⌬F508 mutation were made by combining data from experiments 68, 75, 90, and 94, and by combining data from experiments 64 and 94, comparisons were made between mice bearing the S489X mutation and those bearing the R117H mutation. Login to comment
159 L947ROLE regard to TNF-␣ and IL-1beta concentrations in the epithelial lining fluid, although there were no significant differences in cytokine levels between cystic fibrosis mice bearing the S489X mutation and those bearing the ⌬F508 or R117H mutations. Login to comment
164 In a comparison of S489X vs. Y122X, ⌬F508, and R117H genotypes, the available sample sizes provide 80% power to detect Fig. 2. Login to comment
168 The difference in nasal PD from the start of the response to 1 min later was determined, and representative tracings are shown to the end of the tracing period from wild type (A), S489X (B), Y122X (C), ⌬F508 (D), and R117H (E) mice. Login to comment
170 Nasal potential differences in wild-type mice and mice bearing mutations in Cftr Cftr Mutation Sample Size Amiloride, mV Chloride-free, Amiloride, Forskolin, mV None 3 -2.1Ϯ1.5 14.4Ϯ1.2 S489X 7 -13.2Ϯ5.1* -2.6Ϯ2.2* Y122X 3 -10.9Ϯ3.7 -0.8Ϯ1.3* ⌬F508 6 -7.6Ϯ3.5 -1.8Ϯ0.8* R117H 3 -8.5Ϯ0.1 0.1Ϯ0.8* Data are means Ϯ SD. Login to comment
193 Inflammatory mediators in epithelial lining fluid Parameter Comparison 1 Comparison 2 Comparison 3 Y122X S489X ⌬F508 S489X R117H S489X TNF-␣ 7.8* (5.1/13.1) 10.3 (6.0/14.3) 8.0 (6.7/12.2) 9.5 (7.2/12.4) 14.7 (5.9/23.5) 13.6 (9.1/22.3) IL-1beta 14.5* (5.6/19.3) 16.0 (7.5/25.7) 14.4 (10.0/20.2) 16.0 (8.2/20.2) 12.2 (3.0/32.6) 18.2 (8.1/24.3) IL-6 12.3 (5.9/28.4) 14.6 (7.9/33.1) 11.9 (7.8 (22.8) 13.4 (8.0/19.2) 16.6 (7.3/24.7) 20.8 (9.0/62.4) MIP-2 55.8 (12.1/86.3) 66.9 (34.8/107.3) 90.8 (58.8/129.7) 102.2 (48.0/140.8) 55.6 (21.2/202.5) 96.0 (37.6/131.5) KC 4.1 (3.3/5.5) 5.9 (3.5/7.8) 5.4 (4.1/9.4) 6.3 (4.8/8.6) 12.8 (5.0/15.8) 7.4 (4.6/10.7) LTB4 1.2 (0.2/3.3) 2.3 (1.3/7.8) 5.9 (3.6/10.5) 7.1 (2.3/10.5) 2.1 (1.2/16.7) 2.3 (1.3/7.8) PGE2 4.4 (2.3/6.0) 8.0 (4.4/12.2) 11.4 (7.3/16.6) 12.9 (7.6/22.0) 9.2 (5.9/13.5) 8.0 (4.4/12.2) Data are pooled from available data, are represented as the median (25th/75th percentiles), and are expressed as ng/ml epithelial lining fluid (ELF). Login to comment
208 None of the cystic fibrosis mice studied here grows as well as their wild-type littermates, although the cystic fibrosis mice bearing the R117H mutation maintain weight better at week 1 of life. Login to comment
222 The R117H allele, unlike those of the other genotypes studied here, is expected to reach the plasma membrane. Login to comment
223 Although the R117H animals have weight comparable to wild-type littermates at 1 wk of age, as early as 2 wk of age Table 5. Login to comment
224 Cell numbers in BAL fluid Parameter Comparison 1 Comparison 2 Comparison 3 Y122X S489X ⌬F508 S489X R117H S489X %AM 5.3 (2.8/41.1) 6.0 (4.3/11.9) 5.8 (3.3/8.7) 4.3 (2.4/5.9) 12.7 (5.8/25.0) 4.7 (4.3/7.4) %PMN 94.3 (58.9/96.9) 94.0 (87.3/95.6) 94.2 (91.3/96.7) 95.3 (94.1/97.6) 87.3* (75.0/94.2) 95.0 (92.6/95.3) %Lymph 0.0 (0.0/0.7) 0.0 (0.0/1.3) 0.0 (0.0/0.0) 0.0 (0.0/0.0) 0.0 (0.0/0.0) 0.0 (0.0/0.0) AM/ml 36 (12/66) 34 (15/72) 47 (23/88) 60 (12/126) 104* (32/168) 78 (56/102) PMN/ml 787 (14/1,449) 801 (422/1,528) 850 (396/1,310) 1,378 (423/1,714) 857 (415/1,549) 1,520 (1,125/1,716) Data are pooled from available data and are represented as the median (25th/75th percentiles). Login to comment

PMID: 15274098 [PubMed] Davis PB et al: "Relation of sweat chloride concentration to severity of lung disease in cystic fibrosis."

No. Sentence Comment

26 T (12); A455E (1); D1270N; G85E (3); R117H (4); R334W (1); R347H (1); T347P (6); 2859 þ 5 G ! Login to comment

PMID: 15286085 [PubMed] Wright AM et al: "Novel regulation of cystic fibrosis transmembrane conductance regulator (CFTR) channel gating by external chloride."

No. Sentence Comment

227 The disease-causing mutation R117H is known to reduce the open state probability of CFTR by ϳ30% (37). Login to comment

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

No. Sentence Comment

59 In the French population high frequencies of the ΔF508 mutation (44.7%), the T5 allele (36.2%) and R117H mutation (19.1%) were observed [13]. Login to comment

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

No. Sentence Comment

32 The most common CFTR mutations in CAVD are the F508del, R117H and the 5T allele (Chillo´n et al., 1995; De Braekeleer and Fere´c, 1996). Login to comment
92 The frequency of the other mutations was: four of 62 (6.5%) for R334W, two of 62 (3.2%) for R117H, P205S and G576A, and one of 62 (1.6%) for D614G, V562I, R668C, 2789-5G ! Login to comment
104 Of the 22 NOAZ patients with conserved spermatogenesis and normal renal development, there were seven (31.8%) Table I. CFTR mutations and IVS8-5T variants found in 77 Portuguese azoospermic patients Syndromes Mutations n CFTR mutations IVS8 poly(T) variants Two mutations One mutation CBAVD F508del/R117H 1 1 - 7/9 F508del/D614G 1 1 - 7/9 R334W/R334W 1 1 - 7/7 R334W/V562I 1 1 - 5/7 R117H/P205S 1 1 - 7/7 2789 þ 5G ! Login to comment
125 Contrary to all other countries, the second most frequent mutation found in Portugal was R334W (6.5%), whereas no differences from other countries were found regarding the third most frequent mutations, R117H, P205S and G576A (3.2%), with the exception of Germany regarding R117H (11%) (Dork et al., 1997). Login to comment

PMID: 15343184 [PubMed] Borowitz D et al: "Use of fecal elastase-1 to classify pancreatic status in patients with cystic fibrosis."

No. Sentence Comment

116 FE-1 values in subjects with CFTR mutations associated with pancreatic sufficiency11 N Mean (mg/g stool) Median (mg/g stool) Range (mg/g stool) Subjects with at least one PS allele* FE-1 >200 mg/g stool 16 584 582.9 349-773 FE-1 <200 mg/g stool 5 64.4 74.8 0-125 Subjects with at least one PS variable alleley FE-1>200 mg/g stool 29 496.2 493.6 224-798 FE-1 <200 mg/g stool 13 76.1 65.9 0-187 *Pancreatic sufficient dominant CF alleles G551S R117H R347H P574H R334W R352Q T3381 yVariable pancreatic sufficient CF mutations G85E 3849 + 10 kb C fi T R347P 2789 + 5G fi A A455E In summary, FE-1 is an accurate, easily obtained screening test to classify patients with CF as PI or PS. Login to comment

PMID: 15354327 [PubMed] Palomaki GE et al: "Prenatal screening for cystic fibrosis: an early report card."

No. Sentence Comment

9 The ACMG Standards and Guidelines included recommendations that testing for the 5T/7T/9T polymorphism be performed reflexively only when the R117H mutation was identified. Login to comment
10 It was well known that only when the R117H mutation is found with the 5T variant on the same chromosome is that mutation usually associated with classic cystic fibrosis. Login to comment

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

No. Sentence Comment

12 The ACMG also recommended that a reflex test for the IVS-8 5T variant be performed in the presence of the mild CF mutation R117H.2 As with the introduction of any large scale screening program, the initial 18 months of population-based CF carrier screening revealed the imperfections of such a program. Login to comment
37 In addition, patients with R117H are divided into those with and those without the 5T variant because only those individuals with R117H and 5T in the same allele are at risk for having children with classic CF. Login to comment
42 Using the data from Table 1, which omits I148T cases, excludes carriers of the mild mutation R117H without 5T, and also excludes half of the patients with R117H and 5T (because only half would be predicted to have the 5T in cis), there are 10,139 carriers of classic CF. Login to 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
48 b R117H without 5T is not considered a classic CF mutation (see text). Login to comment
49 c Only half of these patients were used for calculations due to the prediction that 50% of the 5T alleles will be in trans to the R117H (see text). Login to comment
62 These are all postnatal samples and no efforts to determine the phase of 5T and R117H were made. Login to comment
64 One sample obtained from a CF center had the genotype delta F508/R117H without 5T. Login to comment
66 There was also a male patient homozygous for R117H without 5T who was azoospermic and infertile but had bilateral presence of vas deferens. Login to comment
68 Two of these patients have isolated pancreatitis without significant pulmonary disease and have the genotype delta F508/R117H (with an IVS-8 genotype of 9T/5T) and delta F508/2849ϩ10kb C3T respectively. Login to comment
71 It is possible that the 2789ϩ5GϾA mutation is a mild CF mutation, causing sinusitis comparable to R117H causing CBAVD. Login to comment
74 Excluding patients with I148T and R117H without 5T, in our series of 335,204 patients, only 4 patients were discovered to have 2 CF mutations who did not previously have the diagnosis of CF, yielding a "false positive" rate of 0.0012% for 2 CF mutations. Login to comment
81 One mother was a compound heterozygote for delta F508 and R117H (without 5T), the father was heterozygous for I148T, and the fetal genotype was delta F508/I148T. Login to comment
84 of patients ⌬F508 ⌬F508 116 ⌬F508 Classic CF mutationa 55 ⌬F508 R117H 38 R117H R117H 4 R117H Classic CF mutation 6 Classic CF mutation Classic CF mutation 20 a All ACMG panel mutations except R117H (without 5T) and ⌬F508. Login to comment
85 R117H in cis to 5T is considered a classic CF mutation. Login to comment
86 Table 3 Patients with 2 CF mutations and unexpected phenotypes Genotype Gender Age Symptoms ⌬F508/R117H Female 22 years no respiratory symptoms (5T/9T) 3 episodes of pancreatitis ⌬F508/3849 ϩ 10kb CϾT Female Adult chronic pancreatitis 2789ϩ5 GϾA/2789ϩ5 GϾAa Female 29 years chronic sinusitis ⌬F508/2789ϩ5 GϾA Female 40 years recurrent sinusitits requiring surgery a Both parents confirmed to be carriers of 2789ϩ5 GϾA. I148T and the other for delta F508 had potentially affected genotypes and no pregnancy losses occurred. Login to comment
104 Clinical significance of 5T The ACMG statement recommends that the 5T allele be analyzed as a reflex in the presence of the R117H, a usually mild CF mutation. Login to comment
105 The presence of a 5T allele causes aberrant splicing and reduces the amount of functional CFTR mRNA from the gene containing it.16-18 The ACMG recommendation is based on 2 factors: an effort to screen only for patients at risk for offspring with classic CF and the fact the R117H mutation, when on a chromosome that does not contain a 5T allele, usually does not cause classic CF in combination with a classic CF mutation. Login to comment
106 Compound heterozygous males for R117H and a classical CF mutation are often infertile due to congenital bilateral absence of the vas deferens (CBAVD). Login to comment
108 However, when an allele contains R117H and a 5T, this allele can cause classic CF when inherited with a classic CF mutation. Login to comment
118 homozygous wild type Both parents CF carriers 90 17 45 28 Echogenic bowel 100 1 5 94 Abnormal sonogram (not echogenic bowel) 5 0 1 4 Family history of CF (Parents not tested) 20 0 3 17 Population screening (Prenatal performed for other indications) 88 0 4 84 One parent carrier 57 0 31a 26 One parent carrier other parent 5T 33 0 19 14 One or both parents 5T 32 0 0 0 Miscellaneous 3 0 1 2 Indication unavailable 17 0 1 16 a 1 patient was compound heterozygous for R117H/delta F 508 and negative for 5T. Login to comment

PMID: 15354332 [PubMed] Monaghan KG et al: "Preconception and prenatal cystic fibrosis carrier screening of African Americans reveals unanticipated frequencies for specific mutations."

No. Sentence Comment

36 Reflex testing for the 3199del6 and intron 8 polyT locus was performed for carriers of the I148T and R117H mutations, respectively. Login to comment
41 The next most common mutations detected were G622D (19%), R117H/7T (12%), which was increased compared to previous estimates of this mutant allele frequency (P Ͻ 0.001), and G551D (6%). Login to comment
50 ⌬F508 was the most common CF mutation identified followed by G622D, R117H/7T, and G551D. Login to comment
51 R117H has been previously reported at an increased frequency among individuals undergoing carrier screening compared to those with a diagnosis of cystic fibrosis.8 An unexpected result was the lack of 3120ϩ1G3A carriers, although 4 were expected given that this mutation accounts for Ϸ12% of the CF muta- Table 1 Summary of carrier screening results using various methods employed between December 2001 and September 2003 OLA v2.0, heteroduplex analysis (exons 4 and 13) and RFLP analysis (3120ϩ1G3A) OLA v3.0 INNO-LiPA Total screened 818 1274 97 No. of carriers identified 16 14 3 Observed carrier frequency 1/51 1/81 Mutations identified ⌬F508 (6), G622D (3), R117H/7T (3), I148T (3199del6 negative), Q98R, 1898ϩ1G3A, and G551Da ⌬F508 (14), R117H/7T, R553X, and G551D a In addition, 2 persons were positive for F693L (TTG) and 1 was positive for P140S (C3T at 550); both are variants of unknown clinical significance. Login to comment
80 However, laboratories, which receive a large proportion of specimens from individuals with a lower Table 2 Summary of ACOG/ACMG CF mutations identified among 2189 African Americans (4378 chromosomes) undergoing carrier screening Mutation Carriers identified Mutation frequency (%) (this study) Published mutation frequency (%)6,7 ⌬F508 20/33 61 29a -48 R117H/7T 4/33 12 1 G551D 2/33 6 1 I148T (3199del6 negative) 1/33 3 0 1898ϩ1G3A 1/33 3 1 R553X 1/33 3 0.5 3120ϩ1G3A 0 0 12-14 a The lower frequency of ⌬F508 reported by Heim et al. was most likely due to ascertainment bias. 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

61 Furthermore, individuals with R117H and 5T are at risk of having offspring with CF if their partner is also a CF carrier and should be counseled accordingly. Login to comment
63 Because the frequency of R117H-5T is appreciable, the Working Group recommends retaining R117H, whereas emphasizing the need to perform a screening test for 5T only as a reflex when R117H is present. Login to comment
65 Warner et al.12 suggest that it is inappropriate to screen for mutations such as R117H for which a definitive prediction of clinical outcome can not be provided. Login to 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
71 Because the CF mutation testing platforms included the reflex tests this led to the reporting of the 5T allele in the absence of R117H by some laboratories. 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

7 The mutation distribution seen in both the carrier screening populations reflected an increased frequency of mutations with variable expression such as D1152H, R117H, and L206W. Login to 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
63 The most prevalent mutations were as follows: ⌬F508, D1152H, R117H, G542X, L206W, I148T (3199del6 status unknown), ⌬I507, R1066C, R553X, 3849ϩ10kbCϾT, and R334W representing 83.72% of the total identified. Login to comment
71 In the carrier screening group, 4 mutations, D1152H, R117H, ⌬I507, and L206W, had frequencies of 3.8% 1 CFTR mutation distribution among Hispanic CF patients and carrier screening referrals CFTR Mutation Identified CF Patients Carrier Screening Referrals # of CF Chromosomes % Detection # of Carrier Screen Referrals % of Positive Carriers ⌬F508a 118 37.11c 136 47.39 G542Xa 11 3.46 12 4.18 R334Wa 11 3.46 6 2.09 3120 ϩ 1G Ͼ Aa 7 2.20 5 1.74 3876delAb 7 2.20 4 1.39 W1089Xb 7 2.20 R1066Cb 6 1.89 9 3.14 3849 ϩ 10kbC Ͼ Ta 3 0.94 6 2.09 R1162Xa 2 0.63 5 1.74 G85Ea 2 0.63 3 1.05 S549Nb 2 0.63 2 0.70 711 ϩ 1G Ͼ Ta 2 0.63 1 0.35 2789 ϩ 5G Ͼ Aa 2 0.63 1 0.35 1949del84b 2 0.63 1 0.35 R117Ha 1 0.31 14 4.88 ⌬I507a 1 0.31 11 3.83 R553Xa 1 0.31 7 2.44 ⌬F311b 1 0.31 1 0.35 1078delTa 1 0.31 1 0.35 621 ϩ 1G Ͼ Ta 1 0.31 1 0.35 3659delCa 1 0.31 1 0.35 Q890Xb 1 0.31 1 0.35 G551Da 1 0.31 1812 - 1G Ͼ Ab 1 0.31 I148T ϩ 3199del6a 1 0.31 A559Tb 1 0.31 1717 - 1G Ͼ Aa 1 0.31 3905insTb 1 0.31 3821delTb 1 0.31 G178Rb 1 0.31 D1152Hb 18 6.27 L206Wb 11 3.83 I148T (3199del6 status unknown)a 10 3.48 N1303Ka 4 1.39 W1282Xa 4 1.39 R117Cb 4 1.39 R352Qb 2 0.70 712 - 1G Ͼ Tb 2 0.70 Y1092Xb 1 0.35 444delAb 1 0.35 S549Rb 1 0.35 1609delCAb 1 0.35 Negative for mutations analyzed 120 37.74 15046 Total 318 62.20d 15333 100.00 a Mutation included in the ACMG/ACOG Recommended Core Mutation Panel for general population CF carrier screening.4,5 b Mutation not included in the ACMG/ACOG Recommended Core Mutation Panel for general population CF carrier screening. Login to comment
88 The most frequent mutations were ⌬F508 (52.1%), 3120ϩ1GϾA (9.6%), A559T (6.38%), and R117H (5.32%). Login to comment
91 These include mutations known to be associated with variable phenotypic expression such as R117H,21,22 D1152H,23-25 and 3849ϩ10kbCϾT.27,28 Assuming Ϸ74% detection for the mutations analyzed and an observed carrier frequency of 1/95, an adjustment to 100% detection would result in a carrier frequency of 1/76, which is not significantly different than the expected 1/613 based on the disease incidence (P ϭ 0.1779). Login to comment
112 In both the Hispanic and African American populations, mutations associated with a variable clinical phenotype such as R117H, D1152H, and L206W were more common in the carrier screening population than the affected population. Login to comment

PMID: 15371904 [PubMed] Rohlfs EM et al: "Analysis of 3208 cystic fibrosis prenatal diagnoses: impact of carrier screening guidelines on distribution of indications for CFTR mutation and IVS-8 poly(T) analyses."

No. Sentence Comment

6 However, more than 40% of these cases could be attributed to parental R117H mutations. Login to comment
12 They also recommend that laboratories offering CF screening include a minimum of 25 specific mutations in their panel, with additional mutations included if warranted by the local demographics.10,11 Included in the ACMG/ACOG 25 mutation panel is R117H, a mutation known to have variable phenotypic expression. Login to comment
13 When R117H is identified during carrier screening, the guidelines recommend additional testing to determine the length of the intron 8 polythymidine tract (poly(T)). Login to comment
14 When R117H is found in cis with 5 thymidines (5T), and trans to a severe CF mutation, individuals may have moderate (i.e., pancreatic sufficient) CF. Login to comment
15 When R117H is identified in cis with 7 thymidines (7T) and in trans to a CF mutation individuals may be asymptomatic, have congenital absence of the vas deferens (CAVD), or later onset lung disease (i.e., a milder phenotype).12,13 In addition to being identified on the same chromosome as R117H, the 5T allele occurs alone in approximately 10% of the general population.12 When the 5T allele is included in CF From the 1 Genzyme Corporation, Genzyme Genetics, Molecular Diagnostic Laboratory, Westborough, Massachusetts; 2 Genzyme Genetics, Philadelphia, Pennsylvania. Login to comment
62 A significant number of these tests could be attributed to parental R117H mutations. Login to comment
63 More than 50% of those cases with a family history of CF or a CF carrier that were tested for poly(T), were at risk for inheriting an R117H mutation. Login to comment
64 The two prenatal screening cases that were also tested for poly(T), were done so after identification of R117H in the fetus. Login to comment
75 with R117H carrier parent (%) Unrelated to 5T status 3116 (97.1) 47 (1.6) 20 (42.6) Abnormal fetal ultrasound 1232 (38.4) 10 (0.8) 2 (20.0) Family history of CF or CF carrier 1176 (36.7) 35 (3.0) 18 (51.4) Prenatal screening 708 (22.0) 2 (0.3) 0 Related to 5T status 92 (2.9) 92 (100) 7 (7.6) Fetus at risk for 5T and CF mutation in trans 48 (1.5) 48 (100) 7 (14.6) One or both parents positive for only 5T 44 (1.4) 44 (100) 0 All indications 3208 139 (4.3) 27 (19.4) DISCUSSION Our purpose was to determine the frequency of specific indications for prenatal CFTR and poly(T) testing and to determine if the ACMG/ACOG CF screening statement influenced the frequency of these requests. Login to comment
93 As a result, the ACMG/ACOG guidelines specifically state that screening for 5T alleles should only be performed when the R117H mutation is identified. Login to comment
98 When those cases related to an R117H mutation are excluded (i.e., parental or fetal R117H), the percentage drops further to 0.8%. Login to comment
99 Providing poly(T) information in the context of an R117H mutation is recommended by the ACMG/ACOG carrier screening guidelines and is necessary and appropriate for the genetic counseling process. Login to comment
104 In summary, we find that the frequency of prenatal referral indications shifted after publication of the CF carrier screening guidelines and that poly(T) testing is not routinely ordered on prenatal specimens unless one of the parents has been previously identified with a 5T allele or carried an R117H mutation. 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."

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

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

No. Sentence Comment

54 Among the over 2,300 AJ screenees tested, one screenee was identified who carried R117H, one carried G551D and two carried I148T. Login to comment
62 The additional mutations that were detected were R117H (n ϭ 7), I148T (6), A455E (2), R334W (2), G551D (1), and R553X (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
94 When MSSM and DY testing laboratories introduced expanded screening panels, several other CF mutations were found among AJ screenees; these were R117H, G551D, I148T, and 1898ϩ1GϾA. Login to comment
95 Of interest, R117H and G551D represented 0.8 and 2.5% of alleles in the non-Hispanic Caucasian CF patients, respectively,8 but were rare in the AJ population (each seen only once in over 2,300 screenees). Login to comment

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

No. Sentence Comment

45 Due to ACOG/ACMG recommendations that polyT analysis only be performed as a reflex test for R117H-positive individuals, the polyT status of most of the patients included in this report was not determined. 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."

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28 In compliance with ACMG recommendations, this assay provides reflex testing on R117H positive samples for the 5T, 7T, and 9T polymorphic alleles at the intron 8 polythymidine tract.6 Robotic automation was applied at the pre-PCR (Multiprobe II HT, Perkin Elmer and Biomek FX, Beckman) and post-PCR processes (Multimek, Beckman). Login to comment
77 This assay also demonstrated heterozygosity for the G542X mutation, and reflex testing for the 5T variant at CFTR intron 8 showed a genotype of 7T/9T in this patient (data not Table 3 Description of the 16 multiplex assays designed to analyze 51 CFTR mutations Multiplex Mutations Exon 1 1078delT, G314E, R352Q, G330X 7 2 R347H, R347P, R334W, 1717-1A 7, 11 3 R553X, S549N, R1162X 11, 19 4 A559T, R560T, G551D 11 5 G542X, S549R, 621ϩ1T, Y122X 4, 11 6 W1282X, 3876delA, 3905insT, D1152H 18, 20 7 3849ϩ4G, 3659delC, 1898ϩ1A 12, 19 8 405ϩ1A, 405ϩ3C, 3120A, 3120ϩ1A 3, 16 9 394delTT, E60X, G85E 3 10 A455E, ⌬F508a 9, 10 11 G480C, Q493X, V520F 10 12 711ϩ1T, G178R, 3199del6 5, 17a 13 2143delT, 2184delA, K710X, F316L 7, 13 14 I148T, R117H, R117C 4 15 N1303K, 2789ϩ5A, 3849ϩ10kbT 14b, intron19, 21 16 ⌬I507a 10 17 5Tb intron 8 a F508C and I507V, I506V, I506M variants are tested for concurrently with the ⌬F508 and ⌬I507 assays respectively. Login to comment
78 b 5T reflex testing is performed for R117H- and R117C-positive individuals. 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

7 Key Words: cystic fibrosis, carrier screening, BeadChip technology Cystic fibrosis (CF) results from mutations in the CF transmembrane conductance regulator (CFTR) and is a common autosomal recessive disorder, particularly in individuals of Caucasian and Ashkenazi Jewish (AJ) ancestry.1,2 CF also affects individuals from other ethnic groups, including Hispanics, African Americans, and Asians with carrier frequencies ranging from 1in46to1in90.1 Morethan1000mutationshavebeendescribed in the CFTR gene and although many of them are private mutations, there are a number of mutations that are distributed worldwide and still others that are common to specific ethnic groups.3 In2001,theAmericanCollegesofMedicalGenetics(ACMG)and Obstetrics and Gynecologists (ACOG) established guidelines for prenatal carrier testing for CF that included a panel of 25 panethnic mutations with allele frequencies Ն 0.1% among CF patients inNorthAmerica.1,4 Inaddition,theyrecommendedthatcarriers of R117H be subsequently tested for the 5/7/9T polymorphic alleles in intron 8 and that individuals positive for delF508 and delI507 have reflex testing for interference from the benign variants F508C, I506V, and I507V.1 The ACMG/ACOG recommendations precipitated a dramatic increase in the number of CF tests performed in genetic testing laboratories. Login to 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
48 Reflex testing for the 5T/7T/9T variants of the intron 8 polypyrimidine tract was performed for all R117H-positive samples. 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
111 This reflex test is used for screenees who test positive for the R117H mutation or are referred for male factor infertility and is performed by ASOH in our laboratory. 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
162 j Proficiency sample ϩs: delF508/G551D, R117H/delF508, R553X, delF508/delF508, 621ϩ1GϾT/delF508, delI507, delF508/3659delC, delF508/G551D k Control samples were not included in calculation of failure rates. Login to comment

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

No. Sentence Comment

12 In a subsequent study, the R117H mutation was found at a higher frequency compared with the control population (Gervais et al., 1993). Login to comment
13 Here four of 18 (22%) CBAVD patients carried the R117H mutation, while only 0.016% random individuals are expected to be heterozygous for this mutation. Login to comment
82 The R117H mutation can either result in CF or CBAVD (Kiesewetter et al., 1993). Login to comment
83 Indeed, R117H is either associated with a T5 or T7 allele. Login to comment
84 In CBAVD patients with the R117H mutation, always the mildest R117H-T7 haplotype is found. Login to comment
85 In CF patients, the more severe R117H-T5 haplotype is mostly found, but it should be noted that the R117-T7 haplotype is also found in CF patients. Login to comment
88 The opposite is true for other mutations, such as the class IV mutation R117H. Login to comment

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

No. Sentence Comment

74 At least one of the two CF mutations is 'mild` (e.g., IVS8-5T or Arg117His). Login to comment

PMID: 15479696 [PubMed] Whitcomb DC et al: "Value of genetic testing in the management of pancreatitis."

No. Sentence Comment

62 Most cases of hereditary pancreatitis are associated with mutations in the cationic trypsinogen gene (PRSS1).17 18 Although nearly 20 pancreatitis associated mutations in the PRSS1 gene have been described, the R122H and N29I mutations (also numbered as R117H and N21I using the chymotrypsinogen amino acid numbering system) represent the vast majority of cases. Login to comment

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

No. Sentence Comment

219 RESULTS Patients Four of the 79 CF patients included in the study had a normal sweat test; three were compound heterozygous for the F508D mutation and the R117H, D1152H and R347H mutations, respectively, and one patient was compound heterozygous for the G542X and 3849+10 kb (C)R (T) mutations. Login to comment
240 Tracings are shown for two CF patients with pancreatic insufficiency (top panels) and FEV1 ,50% pred (left panel) or FEV1 .50% pred (right panel), both of whom were homozygous for the F508D mutation and belonged to the ''severe`` genotype group; and two CF patients with pancreatic sufficiency (bottom panels) and FEV1 ,50% pred (left panel) or FEV1 .50% pred (right panel), both of whom were compound heterozygous for the F508D mutation and the R117H and G85E mutations, respectively, and belonged to the ''mild`` genotype group. Login to comment

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

No. Sentence Comment

136 The subjects were divided into three groups according to the results of a previous screening: (i) 43 CF patients who fulfilled the diagnostic criteria of CF15 and who carried a CF mutation, and seven parents of deceased CF patients, a CF mutation having already been identified in the other parent (50 unidentified CF alleles); (ii) 12 CF patients with no identified CF mutation (24 unidentified CF alleles); and (iii) 16 patients apparently homozygous for a CFTR mutation and who had CF (F508del 2n = 6-, 2104insA22109del10, S945L, 3120+1GRA, N1303K) or a CFTR related disease, that is, isolated CBAVD (D110H, R117H, L997F, R74W-D1270N) or DB (R334W, R668C- G576A-D443Y) (0-16 unidentified CF alleles). Login to comment
184 One further rearrangement was identified in the third group of 16 patients, in a CBAVD patient who was apparently R117H homozygous. Login to comment
193 The complete deletion was identified in a patient having CBAVD, and who apparently carried two R117H-7T copies (R117H in cis with the IVS8-7T variant). Login to comment
194 Posterior analysis of his parents confirmed the compound heterozygosity for R117H and the deletion. Login to comment
251 In the particular case of patient no. 10, we considered that a R117H-7T homozygous genotype could not explain the CBAVD phenotype and suspected rather the presence of a severe CF anomaly in trans of R117H. 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

72 Twelve alleles were found to have common CFm-v mutations, including 5T in 10 patients and R117H in two patients. Login to comment
78 The European data Table 1 Abnormal CFTR and PSTI genotypes detected in two studies of idiopathic chronic pancreatitis* CFTR genotype category N Genotypes detected in individual subjects US study (Noone et al [47]) CFsev / CFm-v compound heterozygotes 8 DF508 / R117H-7T**; DF508 / 5T; DF508 / 5T; DF508 / D1152H; DF508 / D1152H; DF508 / P574H; DF508 / 3120G>A; 621þ1G>T/G1069R CFm-v / CFm-v compound heterozygotes 1 5T / 5T** CFsev / - (CF carriers) 1 N1303K / - CFm-v / - 7 R117H-7T / -; 5T / -**; 5T / -; 5T / -; 5T / -; 5T / -; 5T / - Normal (- / -) CFTR genotype 22 1 was homozygous for the N34S PSTI mutation; 5 were N34S carriers European study (Audrezet et al [50]) CFsev / CFm-v compound heterozygotes 4 DF508/R352Q; DF508/P5L; DF508/Q1476X; W1282X/5T*** CFm-v / CFm-v compound heterozygotes 2 V562I/5T; E217G/A1136T CFsev / - (CF carriers)**** 3 DF508 / -; DF508 / -; G542X / - CFm-v / - 9 L967S/-**; IVS18-20T>C/-**; c.4575þ2G>A/-; IVS3-6T>C; 5T/-; 5T/-; 5T/-; 5T/-; 5T/- Normal (- / -) CFTR genotype 17 1 was homozygous for the N34S PSTI mutation; 1 was a N34S carrier * CFTR mutations were classified as causing either severe (CFsev ) or mild-variable loss-of-function (CFm-v ) [18,47]; all detected CFsev mutations are CF-causing mutations according to current consensus criteria [79]. Login to comment

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

No. Sentence Comment

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

No. Sentence Comment

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
25 R117H mutation was detected in a 3.5-year-old female suffering from pulmonary infections with no reported data concerning pancreatic insufficiency. Login to comment
24 R117H mutation was detected in a 3.5-year-old female suffering from pulmonary infections with no reported data concerning pancreatic insufficiency. Login to comment

PMID: 15562283 [PubMed] Viel M et al: "Novel length variant of the polypyrimidine tract within the splice acceptor site in intron 8 of the CFTR gene: consequences for genetic testing using standard assays."

No. Sentence Comment

57 19 Shrimpton AE: R117H and IVS8-5T cystic fibrosis mutation detection by restriction enzyme digestion. 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: 15618592 [PubMed] Divac A et al: "CFTR mutations and polymorphisms in adults with disseminated bronchiectasis: a controversial issue."

No. Sentence Comment

169 3 Shrimpton AE. R117H and IVS8-5T cystic fibrosis mutation detection by restriction enzyme digestion. 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

13 A total of 282 infertile male patients were screened for the most common CF mutations (DF508, R117H, IVS8-5T). Login to comment
15 We identified 23 patients carrying mutations in the CF gene (DF508: 10 patients; R117H: six patients; IVS8-5T: 11 patients). Login to comment
16 Two patients were compound heterozygote for DF508/R117H, two others for DF508/IVS8-5T. Login to comment
20 In Germany, DF508/R117H represents the most common CFTR phenotype among CBAVD (Do¨rk et al., 1997). Login to comment
48 The three most frequent CFTR mutations (DF508, R117H, IVS8-5T) causing CBAVD in the German population were analysed. Login to comment
53 R117H was identified by mismatch primers used by Rave-Harel et al. (1995) (117-CFTR-F: 5' -ACC CGG ATA ACA AGG AGG AG-3' ; 117-CFTR-R: 5' -TTG TAC CAG CTC ACT ACC TA-3' ) followed by digestion with the restriction endonuclease HaeII. Login to comment
76 Four patients carried compound heterozygote mutations (two patients: DF508/R117H; two patients: DF508/ IVS8-5T). Login to comment
77 Nine DF508 (1.9% of the analysed chromosomes), six R117H (1.3% of the analysed chromosomes) and 10 IVS8-5T (2.1% of the analysed chromosomes) were identified. Login to comment
80 One of these was a compound heterozygote (sweat chloride: 46 mmol/l: DF508/R117H), while the other three patients (sweat chloride: 50 mmol/l: DF508/WT; 60 mmol/l: R117H/WT; and 54 mmol/l: IVS8-5T/WT) were heterozygous with regard to CFTR mutations. Login to comment
82 Twenty-seven of the 78 azoospermic Table1ClinicaldataandhistoryofpatientswithidentifiedCFTRmutationslistedaccordingtomutationandspermcount Patient no.Age BMI (kgm)2 )MedicalhistoryReproductivehistory CFTR mutation (n=23) Spermcount (millionml)1 ) Ejaculate volume (ml) Ejaculate pH Total testicular volume(ml) Sweat chloride (mmol/l) FSH (Ul)1 ) LH (Ul)1 ) Testosterone (nmol/l) 14125.2NormalNormalDF508/R117H00.16.531.4n.a.5.13.015.6 23127.3Normals.p.Cryptorchismand orchidopexia,1972 DF508/R117H00.56.824.94610.03.014.7 33330.4Normals.p.Ligationofvaricocele; CBAVDknown DF508/IVS8-5T00.66.525.2n.a.3.53.26.9 43525.8Onedaughter(spontaneous conception)CFTR screeningnegative s.p.Orchitis,1965;s.p. epididymitis,1993;sincethen knownazoospermia DF508/WT03.88.315.0247.50.57.0 53427.0RecurrentURTinfectionss.p.Cryptorchismand unilateralseminoma,1975 DF508/WT07.17.917.12313.04.011.5 63827.7RecurrentURTinfectionss.p.Urethritisand pyelonephritis,1972 DF508/WT00.7n.a.18.9503.53.08.2 73929.4Recurrentpancreatitiss.p.Hernia,1968and1975R117H/WT01.38.737.8604.23.79.9 84621.7NormalNormalR117H/WT00.36.516.63615.07.410.4 93837.0Normals.p.Cryptorchismand orchidopexia,1965 IVS8-5T/WT03.4n.a.15.4n.a.11.24.812.2 104325.8RecurrentURTinfections inadolescence s.p.Cryptorchism,1965; s.p.epididymitis,2000 IVS8-5T/WT2(total)5.58.117.6n.a.8.61.719.2 113326.0NormalNormalDF508/IVS8-5T3.36.5n.a.12.6n.a.8.33.518.4 123921.9Normals.p.Ligationofvaricocele,1996DF508/WT16.66.67.922.1n.a.7.34.527.8 135127.1Spontaneousconception in1993 s.p.Mumpsorchitis,1986DF508/WT0.10.89.017.8n.a.2.57.819.2 144027.9NormalNormalDF508/WT1.52.37.99.3n.a.1.80.84.3 153523.4s.p.Steroidabuses.p.Ligationofvaricocele,1993; s.p.STD,1997 R117H/WT0.45.58.319.120/389.25.017.4 163224.3Normals.p.Cryptorchismand orchidopexia,1973and1977 R117H/WT0.72.1n.a.14.82010.81.715.2 173127.7Normals.p.Cryptorchismand orchidopexia,1974 IVS8-5T/WT2.53.37.916.51813.24.3288 183627.4Normals.p.Hernia,1992IVS8-5T/WT13.42.68.124.9355.43.713.9 193227.1Normals.p.Bilateralorchidopexia,1979IVS8-5T/WT1.60.89.026.9548.92.714.3 203824.2Normals.p.Hernia,1980;s.p.ligation ofvaricocele,1990 IVS8-5T/WT3.34.07.921.5n.a.5.43.418.7 214120.8NormalNormalIVS8-5T/WT2.81.6n.a.16.2n.a.5.83.613.2 223328.5NormalNormalIVS8-5T/WT624.68.117.8n.a.6.61.67.6 233123.0Knownmaternal Robertsontranslocation s.p.Mumpsorchitis,1980IVS8-5T/WT0.93.28.020.2n.a.10.43.920.2 BMI,bodymassindex;CBAVD,congenitalbilateralabsenceofthevasdeferens;CFTR,cysticfibrosistransmembraneconductanceregulator;FSH,follicule-stimulatinghormone;LH,luteinizinghormone;n.a., notavailable;s.p.,statuspost;STD,sexuallytransmitteddisease;URT,upperrespiratorytractinfection;WT,wildtype.Normalvalues:spermcount:>20millionml)1 ;ejaculatevolume:‡2ml;ejaculatepH: ‡7.2and£8.0;totaltesticularvolume:‡15ml;sweatchlorideconcentration:normal:<30mmol/l,borderline:30-60mmol/l,pathological:>60mmo/l;FSH:<15Ul)1 ;LH:2.0-10.0Ul)1 ;testosterone:12.030.0nmol/l.Patients22and23arenotincludedinfurtheranalysis(chrom.aberration/normalspermcount). Login to comment

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

No. Sentence Comment

49 T, R553X, N1303K, and R117H; New Zealand, DF508, G551D, and G542X. Login to comment
61 In most instances, the mutations are class I, II, or III mutations causing a severely reduced CFTR product or function, and are associated with severe disease.14 Only one state includes the class IV mutation, R117H, that has a range of phenotypes depending on other chromosomal factors (the intron 8 polythymidine tract length).7,15,16 The problem with including this mutation is that infants who are compound heterozygotes with a severe mutation and R117H (e.g., DF508/R117H) may not have CF, but be labeled as such.17 The intron 8 polythymidine sequence, 5T, also has a variable phenotype,18 and is unhelpful to use in a screening program. Login to comment

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

No. Sentence Comment

234 The 5T allele as a genetic modifier of a CF mutation A possible role for the 5T variant in disease was first suspected by the observation of variable phenoiypes when ii is associated on a single ChTR gene (/;i vis) with a missense mutation (R117H) whieh gives rise lo a partially funetional CFTR protein (Sheppard et at.. 1993). Login to comment
237 Analysis of Tn alieles co-segregating with RI 17H in groups of patients with CF and CBAVD revealed a tendency ofthe R117H allele to be asstxiated wilh the 5T variiint in CF patients, whereas il was associated with the 7T variant in CBAVD patients (Kiesewetter et at.. 1993). Login to comment
239 R117H-7T would cause CBAVD. Login to comment

PMID: 15744829 [PubMed] Schrijver I et al: "Novel contributions to the Asian CFTR mutation spectrum: Genotype and phenotype in Thai patients with cystic fibrosis."

No. Sentence Comment

19 It was described in combination with the p. R117H mutation in a pancreatic sufficient patient from Southern France with mild CF manifestations, which included mild respiratory symptoms and congenital bilateral absence of the vas deferens (CBAVD). 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

75 Twelve alleles were found to have common CFm-v mutations, including 5T in 10 patients and R117H in two patients. Login to 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: 15758625 [PubMed] Turcios NL et al: "Cystic fibrosis: an overview."

No. Sentence Comment

55 Pancreatic Sufficient CF Mutations Dominant Pancreatic-Sufficient Variable Pancreatic-Sufficient G551S G85E P574H R347P R117H 3849 + 10kb C ! Login to comment

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

No. Sentence Comment

43 Twelve alleles were found to have common CFm-v mutations, including 5T in 10 and R117H in 2. Login to 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: 15775704 [PubMed] Lamprecht G et al: "Relapsing pancreatitis due to a novel compound heterozygosity in the CFTR gene involving the second most common mutation in central and eastern Europe [CFTRdele2,3(21 kb)]."

No. Sentence Comment

7 Here we describe a case of relapsing pancreatitis in a female patient due to compound heterozygosity Key Words Idiopathic pancreatitis ؒ CFTR compound heterozygosity ؒ CFTRdele2,3(21 kb) ؒ R117H ؒ Cationic pancreatic trypsinogen ؒ PRSS1 ؒ Pancreatic secretory trypsinogen inhibitor ؒ SPINK1 Abstract A 43-year-old otherwise healthy female patient presented with mild pancreatitis. Login to comment
9 Genotyping of the patient demonstrated CFTR compound heterozygosity CFTRdele2,3(21 kb) and R117H and wild type alleles of the poly-T-tract in intron 8 (7T/7T). Login to comment
13 Copyright (c) 2005 S. Karger AG, Basel and IAP Published online: March 16, 2005 Georg Lamprecht 1st Medical Department, University of Tübingen Otfried-Müller-Strasse 10, DE-72076 Tübingen (Germany) Tel. +49 7071 2983187, Fax +49 7071 295221 E-Mail hans-georg.lamprecht@uni-tuebingen.de (c) 2005 S. Karger AG, Basel and IAP 1424-3903/05/0051-0092$22.00/0 Accessible online at: www.karger.com/pan Fax +41 61 306 12 34 E-Mail karger@karger.ch www.karger.com 93 for CFTR mutations (CFTRdele2,3(21 kb) and R117H), which has not been implicated with pancreatic disease previously. Login to comment
32 Analysis of the CFTR gene (addressing 18 CFTR mutations which comprise 84% of all CFTR mutations in the German population) showed compound heterozygosity for the mutations CFTRdele2,3(21 kb) and R117H. Login to comment
66 Because the patient was supposed to be a carrier of a severe CFTR mutation, genotyping for CFTR mutations was performed and revealed the deletion of a 21-kb fragment spanning exons 2 and 3 and part of the adjacent introns [CFTRdele2,3(21 kb)] as well as the point mutation R117H. Login to comment
73 Depending on the splicing efficiency of exon 9, which is determined by the length of the poly-T-tract in intron 8, the R117H mutation can result in mildly or severely reduced function of the transcribed CFTR protein [12]. Login to comment
74 Because the splicing efficiency of exon 9 appeared normal (wild-type IVS8-7T alleles), the R117H mutation in this patient has to be judged as 'mild`. Login to comment
82 The R117H mutation also has a fairly high allele frequency of 0.3% in northern Europe. Login to comment

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

No. Sentence Comment

274 p.P99L, p.R117H, p.R334W, and p.R347D/H/P form ClÀ channels with altered permeation properties but are processed normally and are therefore indexed as class IV mutants [Sheppard et al., 1993, 1996; Tabcharani et al., 1993]. Login to comment

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

No. Sentence Comment

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

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

No. Sentence Comment

55 CFTR Mutations and Associated Phenotype Classic Nonclassic Cystic Fibrosis Cystic Fibrosis Variant Normal 621 + 1G→T R117H G85E* 7T 711 + 1G→T R334W 5T† 9T 1078delT R347P M470V‡ F508C I507 A455E I507V F508 2789 + 5G → A I506V 1717 - 1G→A 3849 + 10kbC→T G542X G551D R553X R560T R1162X 3659delC W1282X N1303K * Classic cystic fibrosis and nonclassic cystic fibrosis. Login to comment
96 McGill and colleagues found common mutations G551D and R117H in one copy of CFTR in 2 (10.5%) of 19 PSC patients, a frequency not significantly different from that of carriers of CF mutations in the general population (21). Login to comment
106 of Classic CF Nonclassic CFTR Mutations Reference PSC Patients Mutations CF Mutations IVS8-5T of Unknown Effect McGill (1996) (21) 19 1 (G551D) 1 (R117H) NA NA Girodon (2002)(19) 29 0 3 (L997F, S1235R, D1270N) 2 1 (N782K) Sheth (2003)* (18) 19 0 3 (2752-26A→G, 3849 + 10kbC→T, I1139V) 1 3 (S686Y, I1366F, R75Q) Gallegos-Orozco (2004) 59 1 ( F508) 0 2 NA Total, no. 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

133 In addition, mutations such as R117H and I148T have been found at unexpectedly high frequencies in healthy populations, suggesting that they are not completely penetrant (Rohlfs et al., 2002; Strom et al., 2002; Witt et al., 1996). Login to comment
134 Further evidence for a variable phenotypic effect of these and other mutations is found by the observation of the same genotype ( F508/R117H) in individuals with and without disease. Login to comment
156 Mutations described as "mild", for example, R117H, R334W, R347P, and A455E (Kristidis et al., 1992; The CF genotype-phenotype consortium, 1993), are more likely to be associated with pancreatic sufficiency regardless of the class of the second mutation. Login to comment
169 Complex CFTR genotypes-where more than one CFTR mutation or variant is present in the same copy of the gene (in cis) and the presence or absence of that variant affects phenotype- characterize two common CFTR mutations, I148T and R117H. Login to comment
181 The R117H mutation is also a complex allele, occurring on different intron 8 polythymidine ("polyT") backgrounds: 5T or 7T (Kiesewetter et al., 1993). Login to comment
184 The R117H mutation has been reported to occur on the same chromosome as the 5T or 7T intron 8 variants. Login to comment
185 Individuals with a disease-causing CF mutation on one chromosome (such as F508) and an R117H mutation on the other have been reported with a variety of clinical presentations: no symptoms (Massie et al., 2001), congenital absence of the vas deferens in males (Dork et al., 1997), chronic pancreatitis (Noone et al., 2001), and nonclassic and pancreatic sufficient CF (Kiesewetter et al., 1993; Massie et al., 2001). Login to comment
187 However, individuals with F508 (or another CF mutation) on one chromosome, and R117H/5T in cis on the other chromosome, would be expected to have cystic fibrosis (likely pancreatic sufficient), whereas an individual with a CF mutation on one chromosome and R117H in cis with 7T or 9T on the opposite chromosome (Massie et al., 2001; Chu et al., 1993) is more likely to be asymptomatic or have milder symptoms, e.g. CBAVD in males. Login to comment
189 Current carrier testing recommendations therefore include performing polyT variant analysis reflexively for individuals identified as R117H positive. Login to comment
190 POLY T The poly T tract in intron 8 poses counseling challenges, regardless of the presence of R117H. Login to comment
204 Testing for the 5T allele may help to identify the etiology of CBAVD or nonclassic CF symptoms (Kere et al., 1997; Richards et al., 2002), in addition to its use in reflex testing for R117H. 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: 15857421 [PubMed] Derichs N et al: "Homozygosity for L997F in a child with normal clinical and chloride secretory phenotype provides evidence that this cystic fibrosis transmembrane conductance regulator mutation does not cause cystic fibrosis."

No. Sentence Comment

28 We currently do not see evidence for the possibility of L997F being a 'mild` CFTR gene mutation (like R117H or 5T), resulting in CF disease only when found in compound heterozygosity with a 'severe` 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
170 The systems also differed in requirements for reflex testing for F508del homozygosity and R117H. Login to comment
172 In the case of R117H, the OLA and eMAP assays require a separate reflex test, whereas the INNO-LiPA, CF Gold, and Tag-IT systems do not. Login to comment

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

No. Sentence Comment

65 For example, substitution of histidine for arginine at codon 117 (R117H) is a class 4 allele that is associated with variable length of a polythymidine tract at the intron 8 splice acceptor. Login to comment
66 When the R117H allele contains five thymidines at the intron 8 splice acceptor (the ''5T`` form of the acceptor site), it is associated with pancreatic-sufficient CF, whereas when it contains seven thymidines (7T), it is associated with much milder ''atypical`` CF lung disease or only CAVD [18-20]. Login to comment
70 That the allele frequencies of R117H (7T) and wild type (5T) in the non-CF population approach or exceed the frequencies of these alleles in CF patients [24, 25] reflects the low rate of genetic penetrance of these alleles with respect to CF lung disease and indicates that some pedigrees with atypical forms of CFTR deficiency can exhibit non-Mendelian inheritance patterns. Login to comment
71 Modifier genes as modulators of CF lung phenotype Some DF508 homozygous individuals develop severe obstructive lung disease during the first and second decades of life despite maximal medical therapy, while others with the same genotype have little or no obstructive lung disease despite minimal therapy during Table 2 Examples of disease-associated CFTR alleles CFTR allele Allele class Usual clinical status (when compounded with a severe CFTR allelea ) Allele frequency in Caucasiansb General populationc CF CAVD G542X (9T) 1 Pancreatic-insufficient CF 0.001 0.023 0.003 DF508 (9T) 2 Pancreatic-insufficient CF 0.012-0.016 0.694 0.20 G551D (7T) 3 Pancreatic-insufficient CF 0.001 0.022 0.01 R117H (5T) 4 Pancreatic-sufficient CF 0.0001 0.004 ND R117H (7T) 4 CAVD or carrier 0.002-0.003 0.003 0.04 A455E (9T) 5 Pancreatic-sufficient CF ND 0.001 ND 3849+10kbC fi T 5 Pancreatic-sufficient CF ND 0.007 ND WT (5T) 5 CAVD or carrier 0.042 d 0.19 Other allelese 1-5 Variable 0.002-0.006 0.247 0.55 WT (7T or 9T) Wild-type Carrier 0.935 e e a Severe CFTR allele is defined as a class 1, 2, or 3 allele. Login to comment

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

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

No. Sentence Comment

58 C-D565G II DF508 D1507 S549R S549I S549N S549R S945D S945L H1054D G1061R L1065P R1066C R1066M L1077P H1085R N1303K G85E III G551D S492F V520F R553G R560T R560S Y569D IV R117H, R117C, R117P, R117L D1152H, L88S, G91R, E92K, Q98R, P205S, L206W, L227R, F311L, G314E, R334W, R334Q, I336K, T338I, L346P, R347C, R347H, R347L, R347P, L927P, R1070W, R1070Q V 3849 þ 10 kb C ! Login to comment
198 R117H, R334W, and R347P are class IV mutants with reduced single-channel conductance.65 Increases in the overall cell surface content of these mutants might overcome the relative reduction in conductance. Alternatively, restoring native chloride pore characteristics pharmacologically might be effective. Login to comment
199 Adenosine and its nucleotides were shown to activate wild-type and R117H forms of CFTR in cell cultures through the A2B receptor that is present in human bronchial epithelium.66 Activators of CFTR at the plasma membrane may function by elevating cytosolic cAMP (promoting CFTR phosphorylation), by inhibiting phosphatase activity (blocking CFTR dephosphorylation), and/or by interacting directly with CFTR.67,68 Modulation of CFTR protein-protein interactions, such as with PDZ-binding proteins69,70 and syntaxins,71 may also affect CFTR function. Login to comment

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

No. Sentence Comment

75 There are a number of less common missense mutations of CFTR, such as R117H, that have normal intracellular localization and reduced chloride transport function [54]. Login to comment
89 Mutations associated with milder clinical phenotypes and pancreatic sufficiency, such as R117H, maintain some ability to regulate Clÿ and HCO3 ÿ transport [63]. 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: 15970608 [PubMed] Mei-Zahav M et al: "The prevalence and clinical characteristics of cystic fibrosis in South Asian Canadian immigrants."

No. Sentence Comment

237 Two were homozygous for rare mutations (1868A.G and D1152H) and four were heterozygous for DF508 (R117H/7T(2), R117H/5T, 5T). Login to comment
238 The patients with R117H/7T, 5T, and homozygous D1152H all had nasal potential difference testing which confirmed CF. Login to 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: 15987793 [PubMed] Weiss FU et al: "Complete cystic fibrosis transmembrane conductance regulator gene sequencing in patients with idiopathic chronic pancreatitis and controls."

No. Sentence Comment

233 CFTR mutations in idiopathic pancreatitis www.gutjnl.com Three of the four compound heterozygous ICP patients carried one severe DF508 mutation (genotypes: DF508/ R117H, DF508/A1087P, DF508/D1152H) and one carried two mild mutations (S1235R/R668C). Login to comment
256 The reason why numbers for compound heterozygous ICP patients in these studies are diverse (4/67 = 6% in our study) may be due to differences Table 1 CFTR and SPINK1 sequence variations identified in 30 of the 67 ICP patients PatientSex CFTR mutation T allele TG repeats PSTI mutation 1 M DF508/R117H 7/7 9/10 -/- 2 W DF508/A1087P 7/9 10/11 -/- 3 M DF508/D1152H 7/9 10/10 -/- 4 M S1235R/R668C 7/7 11/12 -/- 5 M 2184insA/- 7/7 10/12 -/- 6 M R31C/- 7/7 10/11 -/- 7 M R75Q/- 7/7 11/11 -/- 8 M R347P/- 7/7 11/12 -/- 9 M S1235R/- 7/7 11/12 -/- 10 W S1235R/- 7/7 11/12 -/- 11 M G576A/- 7/7 10/10 -/- 12 W M348V/- 7/9 10/10 -/- 13 M V754M/- 7/7 10/11 -/- 14 M -/- 5/7 11/12 -/- 15 W -/- 5/7 11/12 -/- 16 M -/- 5/7 11/12 -/- 17 W -/- 5/9 11/12 -/- 18 M -/- 5/7 11/12 -/- 19 M -/- 5/7 10/10 -/- 20 W -/- 5/7 10/10 -/- 21 W -/- 5/7 11/12 N34S/- 22 W -/- 7/7 10/11 N34S/- 23 M -/- 7/9 10/11 N34S/- 24 M -/- 7/7 11/11 N34S/- 25 M -/- 7/7 11/11 N34S/- 26 W -/- 7/7 11/11 N34S/- 27 M -/- 7/7 11/11 N34S/- 28 W -/- 7/7 10/11 N34S/- 29 W -/- 7/7 11/11 P55S/- 30 W -/- 7/7 11/11 IVS3+2TC/- Table 2 CFTR sequence variations identified in 11 of 60 healthy controls Control group Number DF508/- 3 R117H/- 2 I148T/- 1 L997F/- 1 5T/12TG 1 5T/11TG 3 in patient recruitment, the catchment populations, or the stringency with which cystic fibrosis patients were excluded. Login to comment

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

No. Sentence Comment

185 Although there are a few rare mutations such as A455E and R117H which are clearly linked to a better pulmonary outcome,12 13 the effect on the lungs of F508del and most other mutations cannot be separated and attempts to link mutations in CFTR to severity of lung disease have been unsuccessful.14 Furthermore, genes other than CFTR and environmental factors such as access to specialised centres and treatment strategies may be more important factors in modifying the development, progression, and severity of pulmonary disease. Login to 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
251 The mild pulmonary phenotype seen in patients with genotype I-II/III-V is consistent with previous reports where a few rare mutations such as A455E, R117H, 3849+10kbCRT, 2789+5GRT, and P67L (all class IV or V mutations) are clearly linked to a better pulmonary outcome.13 14 26-28 The findings observed in this study support the hypothesis that differences in CF pulmonary phenotype could be related to the effect of the genotype on CFTR protein production and function. Nevertheless, it is important to recognise that specific mutations may have characteristics of more than one 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 20 30 40 50 60 Follow up (years) Events Lung transplant Dead I-II/I-II 9 6 I-II/III-V 1 0 Genotype I-II/III, IV or V I-II/I-II p<0.001 (Log-rank test for trend) Figure 3 Kaplan-Meier survival curves by genotype. Login to comment
264 They found that patients who were homozygous for F508del have significantly higher overall mortality and higher crude mortality adjusted for sex and age than those who were homozygous for mutation class IV and V or heterozygous for F508del with R117H, 3849+10kbCRT and 2789+5GRT. Login to comment

PMID: 16020494 [PubMed] Millson A et al: "Direct molecular haplotyping of the IVS-8 poly(TG) and polyT repeat tracts in the cystic fibrosis gene by melting curve analysis of hybridization probes."

No. Sentence Comment

17 When the 5T allele is found in conjunction with the mutation R117H, it has the potential to compound the already affected CFTR transcript. Login to comment
18 If the R117H mutation and the 5T allele are found on the same chromosome (in cis), the result is a phenotypically more severe CF chromosome (6). Login to comment
51 We used allele-specific amplification targeting the R117H locus combined with long-range PCR (12) to amplify two 17.7-kb amplicons from an R117H/⌬F508 compound heterozygote. Login to comment
73 One ⌬F508/R117H compound heterozygous sample with 9T/5T repeats was haplotyped with long-range allele-specific PCR (12) and the TG-T haplotyping probes. Login to comment
74 Haplotype analysis showed ⌬F508-TG10-9T on one chromosome and R117H-TG12-5T on the other (Fig. 3). Login to comment
88 R117H/polyT/poly(TG) haplotyping. Login to comment
90 Two were allele-specific, for either the wild type or mutant R117H, and the third amplified both alleles. Login to comment
91 Addition of the TG-T haplotyping probes shows the mutant R117H allele, carrying the TG12-5T, and the wild-type R117H allele, containing the ⌬F508 mutation, in cis with the TG10-9T. Login to comment
105 The haplotyping result for the R117H/⌬F508 compound heterozygote was surprising in view of the current theory regarding the effect of the TG influence on CFTR transcripts. Login to comment
107 Although the genotype/phenotype correlation is not well established, the chromosome containing R117H-TG12-5T can lead to classic CF because of the combined effects of the 3 variants. Login to comment
110 Other CFTR polymorphisms, such as M470V, have been shown to exert influence on the production of the CFTR protein and might help explain the penetrance of the R117H- TG12-5T chromosome (7). 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

86 In another study, Irving et al. [15] detected three carriers of CFTR mutations (two DF508 and one R117H) screening a group of 55 adults with severe nasal polyps, who had no other clinical features that might allow for the diagnosis of cystic fibrosis. Login to comment
101 The existence of other CFTR alterations (for example novel in-frame mutation 591del18 or mutation R117H), not analyzed herein, may also be combined with a normal CFTR allele on the other chromosome. Login to comment

PMID: 16088537 [PubMed] Luisetti M et al: "Genetics of idiopathic disseminated bronchiectasis."

No. Sentence Comment

67 Eleven ABPA subjects, all but one with Bx, either central or disseminated, and with a normal sweat test, were analyzed for CFTR gene mutations.24 Six ABPA subjects carried at least one CF mutation (p < 0.003 vs the general population), one patient carried two CF mutations (⌬F508/R347H), and five were heterozygous for one CF mutation (four ⌬F508 and one R117H). 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
58 The missense mutations R117H, R334W, and R347P were shown to form a chloride channel with a normal phosphorylation and ATP-dependent regulation, but with reduced single-channel currents.20 Alleles in this class are typically associated with a milder clinical phenotype. Login to comment
67 SSCP analysis is one of the most popular methods for the detection of sequence variants in polymerase chain reaction (PCR) amplified DNA fragments.29 The princi- Table 3 Cystic Fibrosis Mutations Detected by Commercial Kits INNO-LiPA Mutations CF2 ⌬F508, ⌬I507, G542X, 1717-1G→A, G551D, R553X, W1282X, N1303K CFTR12 ⌬F508, ⌬I507, G542X, 1717-1G→A, G551D, R553X, W1282X, N1303K, S1251N, R560T, 3905insT, Q552X CFTR17+Tn 394delTT, G85E, 621+1G→T, R117H, 1078delT, R347P, R334W, E60X, 2183AA→G, 2184delA, 711+5G→A, 2789+5G→A, R1162X, 3659delC, 3849+10kbC→T, 2143delT, A455E, (5T/7T/9T) Elucigene CF4 ⌬F508, G542X, G551D, 621+1G→T CF12 ⌬F508, G542X, G551D, N1303K, W1282X, 1717-1G→A, R553X, 621+1G→T, R117H, R1162X, 3849+10kbC→T, R334W CF20 1717-1G→A, G542X, W1282X, N1303K, ⌬F508, 3849+10kbC→T, 621+1G→T, R553X, G551D, R117H, R1162X, R334W, A455E, 2183AA→G, 3659delC, 1078delT, ⌬I507, R345P, S1251N, E60X CF Poly-T 5T/7T/9T OLA CF OLA assay ⌬F508, F508C, ⌬I507, Q493X, V520F, 1717-1G→A, G542X, G551D, R553X, R560T, S549R, S549N, 3849+10kbC→T, 3849+4A→G, R1162X, 3659delC, W1282X, 3905insT, N1303K, G85E, 621+1G→T, R117H, Y122X, 711+1G→T, 1078delT, R347P, R347H, R334W, A455E, 1898+1G→A, 2183AA→G, 2789+5G→A b Figure 2 Mutation screening of exon 19 of the cystic fibrosis transmembrane conductance regulator (CFTR) gene using polymerase chain reaction (PCR) followed by single-strand conformation polymorphism/heteroduplex (SSCP/HD) analysis on a silver-stained polyacrylamide gel. Login to comment

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

No. Sentence Comment

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

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

No. Sentence Comment

136 Finally, patients bearing CFTR mutations associated with pancreatic sufficiency such as R117H have very low rates of meconium ileus (119). 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
79 Concerning instead the mutations found in the male group, besides ∆F508 the following have been found: 2789+5 g/a, 711+5 g/a, D1152H, G85E, N1303K, Q552X, R1158X, R117H, R334Q, R334W and R553X. 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
108 The three corresponding patients are therefore not included in the body of data analysed in Table I. CFTR mutation IVS8T M470V TG W356X* 5-7 G-G Not determined D443Y* 5-7 A-G 10/12 R1162X 7-7 A-G 10/11 None 7-7 A-G 10/12 ∆F508/R117H 7-9 A-A Not determined ∆F508 5-9 A-G Not determined None 5-7 A-A 11/10 R1162X/2789+5ga 7-7 A-A Not determined 3667insTCAA* 5-7 A-A 11/10 ∆F508 5-9 A-A 13/10 Table IV. Login to comment

PMID: 16142007 [PubMed] Maire F et al: "[Genetic testing for acute or chronic pancreatitis]."

No. Sentence Comment

19 La mutation sur le codon 122, appelée R122H (R117H dans l`ancienne classification), responsable d`une substitution d`une arginine (R) par une histidine (H) est la plus fréquente [7]. Login to comment

PMID: 16179637 [PubMed] Plant BJ et al: "Cystic fibrosis, disease severity, and a macrophage migration inhibitory factor polymorphism."

No. Sentence Comment

77 Inclusion of heterozygosity for the CFTR mutation R117H in the regression model confirmed previous reports of pancreas-sparing with this mutation (OR, 0.04; 95% CI, 0.01-0.24), but the protective effects of the MIF5-CATT genotypes remained after adjusting for R117H heterozygosity. Login to comment
85 After DF508, the commonest variant alleles were G551D (18 alleles) and R117H (10 alleles). Login to comment
112 Although pancreatic sufficiency is seen in patients with the R117H mutation (13, 32, 33), it should be noted that, in this study, there was a total of 10 R117H alleles of which five were in the 5-CATT repeat group and five in the non-5-CATT group. Login to comment
113 Inclusion of this CFTR mutation in the regression model confirmed previous reports of pancreas-sparing with this mutation, but the protective effects of the MIF5-CATT genotypes remained after adjusting for R117H heterozygosity. Login to comment

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

No. Sentence Comment

38 Among the 48 babies screened as having CF, 43 presented with symptoms compatible with CF or abnormal sweat test results ($60 mEq/L), but 5 were classified as having a borderline form of CF because they exhibited no symptoms, had normal sweat test results (<60 mEq/L), and mild mutations [R117H, TG12-T5(IVS8), S1251N, L997F, R347H], and they did not evolve toward CF status (appearance of clinical symptoms or elevation of sweat test) after more than 1 year of follow-up. Login to comment

PMID: 16187186 [PubMed] Lee KH et al: "Mutation analysis of SPINK1 and CFTR gene in Korean patients with alcoholic chronic pancreatitis."

No. Sentence Comment

27 Pancreatic duct obstruction induced by a defective chloride channel, as a result of mutations in the CFTR gene, such as F508del, R117H, and N1303K, is the cause of pancreatic insufficiency in patients with cystic fibrosis. Login to comment
29 However, cystic fibrosis is extremely rare in Asia, and F508del or R117H has not been reported in Japanese patients with chronic pancreatitis (24). Login to comment
95 F508del is the most frequent and R117H is the second most frequent mutation in Caucasian population (31). Login to comment
96 However, cystic fibrosis is a rare disease in East Asia and common mutations in Caucasian populations such as F508del and R117H are rare in Korean and Japanese populations (24, 25). Login to comment

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

No. Sentence Comment

31 ❚Table 1❚ Mutations Analyzed in the Study Position From 5' Exon (or Intron) Genotype* No. of Samples Nucleotide Change SNP Class† End/Amplicon Size (bp) 3 394delTT 1 Del‡ - 132/234 4 R117H 1 G→A 1 83/270 Y122X 1 T→A 4 99/270 I148T 2 T→C 1 176/270 Intron 4 621+1 2 G→T 2 233/270 7 R334W 1 C→T 1 208/345 R347P 1 G→C 3 248/345 9 A455E 2 C→A 2 155/263 10 I507del 1 Del‡ - 171/292 F508del 3 Del‡ - 174/292 F508del/F508del 1 Del - 174/292 F508C 1 T→G 2 175/292 11 G542X 1 G→T 2 90/175 G542X/G542X 1 G→T 2 90/175 G551D 1 G→A 1 118/175 R553X 2 C→T 1 123/175 R560T 1 G→C 3 145/175 13 2184delA 1 Del‡ - 356/458 17b M1101K 1 T→A 4 196/292 21 N1303K 1 C→G 3 175/250 bp, base pairs; SNP, single nucleotide polymorphism. Login to comment
55 Mutations altering a wild-type G::C bp (R117H and 621+1) showed greater differences than those that altered a wild-type T::A bp (I148T). Login to comment
58 However, the R117H trace was similar to the control sample, resulting in the single false-negative result for dHPLC in our study (Figure 1D). Login to comment
72 Such double peaks usually are interpreted as Temperature (°C) Fluorescence 79 80 81 82 83 84 85 86 100 - 90 - 80 - 70 - 60 - 50 - 40 - 30 - 20 - 10 - 0 - R117H het C::A T::G WT G::C Temperature (°C) Fluorescence 79 80 81 82 83 84 85 86 100 - 90 - 80 - 70 - 60 - 50 - 40 - 30 - 20 - 10 - 0 - 621+1 het C::T A::G WT G::C Temperature (°C) Fluorescence 79 80 81 82 83 84 85 86 100 - 90 - 80 - 70 - 60 - 50 - 40 - 30 - 20 - 10 - 0 - I148T het C::A T::G WT T::A Time (min) Absorbance(mV) 0 1 2 3 20 - 19 - 18 - 17 - 16 - 15 - 14 - 13 - 12 - 11 - 10 - 9 - 8 - 7 - 6 - 5 - 4 - 3 - 2 - 1 - 0 - 621+1 het I148T het R117H het WT A B C D ❚Figure 1❚ High-resolution melting and denaturing high-performance liquid chromatography (dHPLC) analysis of exon 4 of the cystic fibrosis transmembrane conductance regulator gene. Login to comment
73 Melting data were normalized and temperature shifted as previously described.19 A, Heterozygous (het) R117H and the wild-type (WT) control sample. B, Heterozygous I148T and the WT control sample. C, Intronic heterozygous 621+1 G/T and the WT control sample. D,The dHPLC profile of heterozygous mutations in exon 4. Login to comment
97 In our hands, all heterozygous mutations were detected except R117H (exon 4), resulting in a heterozygote detection sensitivity of 95%. Login to comment
104 336 DOI: 10.1309/BF3MLJN8J527MWQY (c) American Society for Clinical Pathology Chou et al / CFTR GENE SCANNING BY MELTING R117H with an overall heterozygote detection sensitivity of 90% when a single, predicted column temperature was used for each exon. Login to comment

PMID: 16193325 [PubMed] Bishop MD et al: "The cystic fibrosis transmembrane conductance regulator gene and ion channel function in patients with idiopathic pancreatitis."

No. Sentence Comment

80 Of the 50 random blood donors, none carried two mutations and 11 (22%) had mutations, with an allelic frequency of 11%, as follows: R117H in one blood donor, 1716A fi G in two, R75Q in two, and S1235R in one. Login to comment
90 If screening were limited to 27 mutations recommended for diagnostic testing by the American College of Genetics or the American College of Obstetrics and Gynecology (Gilbert 2001), only one mutation in the control group (R117H) and two mutations in patients with pancreatitis (F508del and R117H) would have been detected. 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
31 When R117H was detected, reflex testing for the polythymidine tract in intron 8 (5T, 7T, and 9T) was performed. Login to comment
64 Two alleles, with 1 being an R117H: 5 cases of DF508/R117H(7T/9T), 1 case of G542X/ R117H(7T/9T), 1 case of R117H/R117H(5T/7T), and 1 case of I148T/R117H(7T/9T). Login to comment

PMID: 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
103 Modification of the mutation panel to exclude pancreatic sufficient mutations not associated with classic CF (eg, R117H) so that elevated IRT level and at least 1 severe mutation became the screening gate that would allow infants to proceed to sweat testing is another potential solution. Login to comment

PMID: 16202790 [PubMed] Sontag MK et al: "Two-tiered immunoreactive trypsinogen-based newborn screening for cystic fibrosis in Colorado: screening efficacy and diagnostic outcomes."

No. Sentence Comment

86 The pancreatic sufficient mutations identified were 18981 5G>T, 278915G>A, A455E, G551S, G85E, I336K, P67L, R117C, R117H, R334W, R347P. Login to comment
129 Initial and repeat sweat chloride values and CFTR mutations in infants with borderline sweat test results Sweat Cl2 (mmol/L) Infant <6 months >6 months Genotype A 55 65 DF508/A455E B 50 - DF508/R117H C 45 77 DF508/R117C (7T/9T) D 33 26 DF508/- E 43 76 R117H/F575Y (7T,7T) F 43 25 312011G-A/- Figure 4. Login to comment

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

No. Sentence Comment

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

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

No. Sentence Comment

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

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

No. Sentence Comment

51 The 29 Mutations and Tn Polymorphism That Can Be Detected by INNO-LiPA Assays Mutation Exon/Intron (i) E60X, G85E, 394delTT 3 621 + 1 G ., R117H (i) 4, 4 711 + 5 G . Login to comment

PMID: 16263954 [PubMed] Cottin V et al: "Late CF caused by homozygous IVS8-5T CFTR polymorphism."

No. Sentence Comment

158 When in trans with a known CFTR mutation, the IVS8-5T allele may be responsible for congenital bilateral absence of the vas deferens or recurrent pancreatitis.4 It may modulate the variable expression of ''mild`` CFTR mutations such as when present in cis of the R117H mutation, thus causing a CF phenotype. 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

13 The most common mutation was ΔF508 with a frequency of 43% (6/14), followed by R117H with 29% (4/14). Login to comment
27 In CBAVD patients, ΔF508 is the most common CFTR gene mutation and the second common mutation is a missense change, R117H (Gervais et al. 1993; Casals et al. 1995; Mercier et al. 1995). Login to comment
34 ΔF508 and G542X are known as severe alleles and R117H as a mild allele. Login to comment
35 Homozygosity of a mild allele or compound heterozygosity of mutant alleles, such as R117H/D1152H (mild/mild) or R117H/ΔF508 (mild/severe), could cause a mild form of CF (Dean et al. 1990; Kerem et al. 1990; Pignatti 1994) or male infertility without other clinical signs (Gervais et al. 1993; Oates and Amos 1993). Login to comment
58 Second common mutation R117H allele frequency was found in 4/14 CF alleles (29%). Login to comment
60 The genotypes of two compound heterozygotes were ΔF508/R117H and ΔF508/M952I. Login to comment
62 The genotypes of 3 patients with R117H mutation were one homozygote R117H/R117H and two compound heterozygotes, R117H/621+1 G- > T and R117H/ΔF508. Login to comment
73 The patient is a compound heterozygote with a mild missense mutation R117H. Login to comment
74 R117H Mutation. A G to A transition at nucleotide position 482 in the coding region of exon 4. Login to comment
76 This mutation was found in 4 of 44 alleles in 3 patients; one case is homozygote and other two are compound heterozygotes of R117H/621+1 G- > T and R117H/ ΔF508. Login to comment
84 Exon 10 Exon 4 Exon 11 Exon 15 Exon 18 Genotype 1440 ΔF508 mut. het R117H Missense mutation, het. Login to comment
85 ΔF508 / R117H 1474 R117H Missense mutation, hom. Login to comment
86 R117H / R117H 1628 R117H Missense mut., het. Login to comment
88 R117H / 621 + 1 G- > T 1635 D1152H Missense mutation, het. Login to comment
109 The genotypes R117H/R117H (homozygosity of mild/mild), ΔF508/M952I and ΔF508/ R117H (compound heterozygosity of severe/ mild), R117H/621+1 G- > T (compound heterozygosity of mild/mild) (Table 1) are known to cause male infertility with CBAVD but without CF clinical signs (Gervais et al. 1993; Oates and Amos 1993). Login to comment
110 The compound heterozygous status ΔF508/R117H is a genotype that occurs commonly in CBAVD patients (Wang et al. 2002). Login to comment

PMID: 16281647 [PubMed] Southern KW et al: "Establishing a diagnosis of cystic fibrosis."

No. Sentence Comment

47 Given that R117H is one of the more common CFTR mutations and is often associated with a severe phenotype, it will continue to be included in most newborn screening programmes that employ DNA analysis. Login to comment

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

No. Sentence Comment

59 Case 1 In a 34-year-old male subject affected by obstructive azoospermia resulting from CBAVD diagnosed by scrotal exploration and impalpable vasa clinically observed, no signal could be obtained at either the wild-type or the mutated site with the allele-specific probes R117H, Y122X and 621 ϩ 1G Ͼ T (Fig. 1). Login to comment
64 Because the nucleotide substitution occurs 22 bp upstream to the R117H mutation site, it can be postulated that this change does not allow the annealing of the PCR forward primer. 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

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: 16443646 [PubMed] Van Goor F et al: "Rescue of DeltaF508-CFTR trafficking and gating in human cystic fibrosis airway primary cultures by small molecules."

No. Sentence Comment

387 Genotype/phenotype correlations of Cl-channel function with disease severity show that mutations resulting in a only modest recovery toward wild-type levels (e.g., 5-30%) increase in CFTR expression or activity (e.g., A455E, 2,789 ϩ 5G3A, 5T, R334W, R347P, and R117H) and are typically associated with pancreatic sufficiency, a slower rate of pulmonary function decline, and a better severity index than that shown in patients with severe disease genotypes (5, 6, 10, 36, 49). Login to comment

PMID: 16460283 [PubMed] Tarran R et al: "Regulation of normal and cystic fibrosis airway surface liquid volume by phasic shear stress."

No. Sentence Comment

430 Adenosine and its nucleotides activate wild-type and R117H CFTR through an A2B receptor-coupled pathway. Login to comment

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

No. Sentence Comment

50 With a class IV mutation (e.g. R117H, R334W, R234P) CFTR processing to the apical membrane and regulation by cAMP and PKA are not altered. Login to comment

PMID: 16481891 [PubMed] Hantash FM et al: "A large deletion in the CFTR gene in CBAVD."

No. Sentence Comment

56 Recently, Niel et al. described the complete deletion of one copy of the CFTR gene and the presence of R117H(-7T) on the other chromosome in a 37-year-old man with CBAVD.19 This situation is predicted to result in reduced CFTR channel function due to the R117H allele,8 and indeed this patient did not have pancreatic insufficiency or lung disease.19 A second CBAVD patient in that study harbored ⌬F508 and a deletion of exons 17-17b; however, this individual displays classic CF symptoms. Login to comment

PMID: 16481896 [PubMed] Kobler D et al: "Identification of an 11T allele in the polypyrimidine tract of intron 8 of the CFTR gene."

No. Sentence Comment

10 It modulates in cis the phenotypic consequences of the R117H mutation; R117H/5T is associated with CF, and R117H/7T is associated with congenital bilateral absence of the vas deferens.10,11 To meet the accuracy and throughput demands now required by CF testing laboratories, diagnostic companies have developed various products, including ELUCIGENE CF- Poly-T (Tepnel Diagnostics, Abingdon, Oxon, UK), INNO-LiPA CFTR (Innogenetics, Gent, Belgium), and the Tag-It™ Cystic Fibrosis Kit (Tm Bioscience, Toronto, Ontario, Canada). Login to comment

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

No. Sentence Comment

79 As hypothesized, the contribution of the enhancer polymorphism to the prediction of percent predicted FEV1 TABLE 2-Frequency of CFTR Alleles in Dublin and Belfast CF Populations Allele1 Frequency Dublin Belfast Full study population Disease category2 DF508 76.1% 54.3% 68.3% Nonmild G551D 6.1% 3.9% 5.3% Nonmild R117H 2.7% 4.8% 3.4% Mild 621 þ 1 G ! 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

115 CFTR is also regulated by phosphorylation of the regulatory domain but there appear to be fewer mutations in this domain than in other parts.59 Class IV: Defective Conduction Many missense mutations have been identified in the membrane spanning domains, where the CFTR gene encodes a protein that is correctly trafficked to the cell membrane and responds to stimuli but generates a reduced chloride current.59 Some examples include mutations in which arginine is replaced by histidine at residue at 117 (R117H), tryptophan at 334 (R334W), or proline at 347 (R347P). Login to comment
117 In addition, at least for R117H, the amount of time that the channel is open is also reduced.75 R117H is a particularly interesting mutation as the affected CFTR function is also determined by the M470V polymorphism and the amount of protein produced.69,76 The clinical effects vary from pancreatic insufficient CF through to no clinical disease depending on the combination of these factors.77 Class V: Reduced Abundance Mutations in this group include missense, e.g. A455E (substitution of glutamic acid for alanine) and aberrant exon splicing, e.g. 3849 10kbC→T and the intron 8 polythymidine and TG repeat sequences that regulate exon 9 splicing.67,78 These mutations produce a reduced amount of CFTR transcript and low levels of functional protein that is translocated to the cell membrane. Login to comment
157 Warren and colleagues described a patient in whom NBS and mutation analysis suggested a diagnosis of cystic fibrosis, however the clinical course and sweat test results were not consistent with the diagnosis.68 Direct sequencing of the patient`s genomic DNA showed compound heterozygosity for ΔF508 and ΔF508C, a polymorphism not associated with clinical disease.Areport from Chmiel and colleagues presented a case where an asymptomatic female infant (3 weeks of age) was given the diagnosis of CF solely based on DNA analysis from cord blood which was positive for both the ΔF508 and R117H mutations.88 Despite any other presentations and a normal sweat chloride, she received pancreatic enzyme supplements. Login to comment
244 Highsmith and colleagues (1994) studied 23 patients with pulmonary disease characteristic of CF but with a normal sweat test and identified a point mutation in intron 19 of the CFTR gene, termed 3849+10kb C-T.15 This mutation produces an alternative splicing site and decreased amounts of CFTR mRNA can be detected.16 Thus, according to the classification of the CFTR mutations, this mutation falls into Class V.16,67 Other mutations associated with normal or borderline sweat electrolytes are R117H, D1152H, A455E, G551S and 2789+5G - A.9,24,78 An interesting phenotype, presenting with elevated sweat chloride concentration in the absence of other CF symptoms, has been described in a patient with a nonsense mutation, S1455X.105 This mutation truncates 26 amino acids from the C-terminus of the protein product. Login to comment
367 Genetic counselling after carrier detection by newborn screening when one parent carries DeltaF508 and the other R117H. Login to comment
446 Nat Genet 1993;5:274-8. 77. Massie RJ, Poplawski N, Wilcken B, Goldblatt J, Byrnes C, Robertson C. Intron-8 polythymidine sequence in Australasian individuals with CF mutations R117H and R117C. 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

63 Mild CFTR mutations (Class IV and V) ϭ R117H, R334W, G85E, R347P, 3849ϩ10KbC→T, 2789ϩ5G→A, A455E. Login to comment

PMID: 16714368 [PubMed] Radpour R et al: "Molecular analysis of the IVS8-T splice variant 5T and M470V exon 10 missense polymorphism in Iranian males with congenital bilateral absence of the vas deferens."

No. Sentence Comment

90 Mutation geno types IVS8-PolyT M470V n (%) Two mutations detected F508del/R117H 9T/9T M/M 1 (0.94) F508del/621+1G>T 7T/7T V/V 1 (0.94) 1540A/G/1540A/G 7T/7T M/M 2 (1.89) R347H/R117H 9T/7T M/V 1 (0.94) G551D/IVS8-5T 7T/5T M/V 2 (1.89) F508del/IVS8-5T 7T/5T M/V 8 (7.55) 9T/5T M/M 6 (5.67) 1717-1G>A/IVS8-5T 7T/5T M/V 4 (3.77) R117H/IVS8-5T 7T/5T M/V 2 (1.89) 621+1G>T/IVS8-5T 7T/5T M/V 3 (2.83) 9T/5T M/M 2 (1.89) 1540A/G/IVS8-5T 7T/5T M/V 2 (1.89) R553X/IVS8-5T 7T/5T M/V 1 (0.94) IVS8-5T/IVS8-5T 5T/5T V/V 3 (2.83) 5T/5T M/M 8 (7.55) One mutation detected G85E/- 7T/7T V/V 2 (1.89) G551D/- 9T/7T V/V 1 (0.94) 621+1G>T/- 7T/7T M/M 2 (1.89) 9T/7T M/V 1 (0.94) R334W/- 7T/7T M/V 1 (0.94) F508del/- 7T/7T M/V 7 (6.60) 9T/7T M/M 3 (2.83) 9T/9T M/V 2 (1.89) IVS8-5T/- 5T/7T M/M 3 (2.83) 5T/9T M/V 2 (1.89) 1717-1G>A/- 7T/7T M/V 3 (2.83) 9T/7T M/V 2 (1.89) R117H/- 7T/7T M/M 2 (1.89) 9T/7T M/V 1 (0.94) 2789+5G>A/- 7T/7T M/M 1 (0.94) 3120+1G>A/- 9T/7T M/V 2 (1.89) R560T/- 9T/7T M/V 1 (0.94) N1303K/- 9T/7T V/V 1 (0.94) 1651A/G/- 7T/7T M/V 1 (0.94) R553X/- 9T/7T M/V 1 (0.94) No mutation detected -/- 7T/7T M/M 12 (11.32) -/- 9T/9T M/M 3 (2.83) -/- 9T/7T M/V 6 (5.66) Table IV. Login to comment
93 1 - - 0/2 (allele) 2 R117H/? Login to comment

PMID: 16778407 [PubMed] Koh WJ et al: "Report of a Korean patient with cystic fibrosis, carrying Q98R and Q220X mutations in the CFTR gene."

No. Sentence Comment

59 Furthermore, only two mutations (R117H and delF508) are found among 25 mutations in the screening panel for Caucasian CF patients recommended by the American College of Medical Genetics (11). Login to comment

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

No. Sentence Comment

195 Class 4 (e.g. R117H) and class 5 (e.g. 3849+10kbCRT and IVS8-5T) are associated with altered chloride conductance of CFTR or reduced expression and with mild phenotypes. Login to comment

PMID: 16840743 [PubMed] Wilschanski M et al: "Mutations in the cystic fibrosis transmembrane regulator gene and in vivo transepithelial potentials."

No. Sentence Comment

54 CFTR GENE MUTATIONS IN THE PATIENT GROUPS Control Subjects (n ϭ 31) Heterozygotes (n ϭ 21) CBAVD-1 (n ϭ 18) CBAVD-2 (n ϭ 36) CF-PS (n ϭ 24) CF-PI (n ϭ 26) G542X*/R75Q ⌬F508*/- (n ϭ 16) ⌬F508* (n ϭ 6) ⌬F508*/2789ϩ5G→A* ⌬F508*/R117H [5T]* (n ϭ 4) ⌬F508*/⌬F508* (n ϭ 11) ⌬F508* ⌬F508*/5T W1282X*/5T (n ϭ 8) R334W*/R334W* ⌬F508*/A455E* (n ϭ 2) ⌬F508*/G542X* (n ϭ 2) G542X* W1282X*/- (n ϭ 2) D1152H† ⌬F508*/R117H [7T] (n ϭ 10) ⌬F508*/3849ϩ10kbC→T* (n ϭ 2) ⌬F508*/G551D* (n ϭ 2) R117H[7T] G85E† /R75Q L206W† ⌬F508*/R117C [7T] G551D*/3849ϩ10kbC→T* ⌬F508*/621ϩ1G→T* (n ϭ 2) S431G R75Q/- A198P G551D*/R117H [7T] ⌬F508*/3272-26A→G† (n ϭ 2) ⌬F508*/2789ϩ5 G→A* 5T ⌬F508*/5T (n ϭ 8) ⌬F508*/P574H† (n ϭ 2) ⌬F508*/W1282X* G542X*/5T ⌬F508*/I1234V† ⌬F508*/G85E* W1282X*/5T ⌬F508*/P67L† ⌬F508*/L1077P† (n ϭ 2) ⌬F508*/P67L† ⌬F508*/R347H† G551D*/G480C† ⌬F508*/L206W† ⌬F508*/5T ⌬F508*/- (n ϭ 2) ⌬F508*/M952T† ⌬F508*/875ϩ1G→C† -/- ⌬F508*/S549R† G551D*/R75Q A455E*/L206W† ⌬F508*/- (n ϭ 2) 621ϩG→T*/R117C [7T] A455E*/- R117H [7T]/5T ⌬I507*/- R117L[7T]/5T -/- R117H/R117H [7T/7T] D979A/5T 5T/-741T→G 4016insT† /D110H Definition of abbreviations: CBAVD ϭ congenital bilateral absence of the vas deferens; CF-PI ϭ pancreatic-insufficient cystic fibrosis; CF-PS ϭ pancreatic-sufficient cystic fibrosis. Login to comment
74 * Results not available for six men (CBAVD-1 [n ϭ 3], CBAVD-2 [n ϭ 3]), because the DNA was denatured. patients with CBAVD carrying the R117H allele cosegregated with the 7T variant, whereas the R117H allele was associated with the 5T variant in all four CF-PS patients. Login to comment
160 For example, the 7T variant, which allows more efficient splicing than 5T, was associated with the mild missense R117H mutation in all men with CBAVD, whereas R117H was associated with the less-efficient 5T splice variant in all the CF-PS patients (41). Login to comment

PMID: 16865559 [PubMed] Tluczek A et al: "Newborn screening for cystic fibrosis: parents' preferences regarding counseling at the time of infants' sweat test."

No. Sentence Comment

62 Abnormal CF screen results, for which sweat testing would be recommended, are categorized into 3 types: (a) the presence of two CF gene mutations indicates a CF diagnosis (with the exception of R117H-7T compound heterozygotes); (b) the presence of one CF gene mutation indicates that the infant is at least a carrier and possibly has CF; and (c) an extremely high IRT level without mutations plus the presence of a family history of CF and/or symptoms of CF indicates possible CF diagnosis. Login to comment

PMID: 16973827 [PubMed] Radpour R et al: "Two novel missense and one novel nonsense CFTR mutations in Iranian males with congenital bilateral absence of the vas deferens."

No. Sentence Comment

21 The most common mutations found in isolated CBAVD phenotypes are F508del, R117H and the T5 allele (IVS8-T5) (Chillon et al., 1995; Jarvi et al., 1995). Login to comment

PMID: 16998246 [PubMed] Kandula L et al: "Acute pancreatitis in association with Campylobacter jejuni-associated diarrhea in a 15-year-old with CFTR mutations: is there a link?"

No. Sentence Comment

50 She was found to have a compound heterozygote R117H/delF508 CFTR genotype. Login to comment

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

No. Sentence Comment

54 Patients With More Than 1 CFTR Mutation CFTR Mutation 1 CFTR Mutation 2 CFTR Mutation 3 No. of Patients deltaF508 5T 3 deltaF508 D1152H 1 deltaF508 deltaF508 1 deltaF508 F575Y 1 deltaF508 K598E 1 deltaF508 T164S 1 deltaF508 R74W D1270N 1 deltaF508 Q1476X 1 deltaF508 L997F 1 R553X D1152H 1 R553X G1069R 1 2789+5 G9A 2183 AA9G 1 3849+10kb C9T L1260P 1 711+3 A to G I1139V 1 1341+1 G9A G194R 5T 1 621+25 A9G 3500-19 C9T 1 R74W V855I 1 G542X R117H 1 G551D F311L 1 G576A R668C 2 K710X L997F 1 L997F L320V 1 G1069R 5T 1 1818+18 G9A 5T 1 F1074L 5T 1 F834L 5T 1 R74Q R297Q 1 R74Q R297Q 5T 1 R785Q 5T 1 R117H 5T 3 deltaF508 I1027T 1 Total patients 36 MutationsinboldfacewouldnothavebeendetectedbytheAmericanCollegeofObstetrics and Gynecology (ACOG)/American College of Medical Genetics (ACMG) mutation panel. Login to comment
71 Patients With 1 CFTR Mutation CFTR Mutation 1 No. of Patients 1717-1 G9A 1 2789+5 G9A 1 3849+10kb C9T 2 3849+45 G9A 1 621+3 A9G 2 A1364V 1 A349V 1 A455E 1 D1152H 1 D1445N 1 deltaF508 16 E217G 1 F1286C 1 F316L 1 G542X 1 G551D 1 I148T 1 I807M 1 L206W 1 L967S 2 L997F 2 P55S 1 Q179K 1 Q220X 1 R117H 3 R1453W 1 R297Q 1 R31C 1 R668C 2 S1235R 1 S573C 1 S945L 1 V562A 1 V754M 2 Y1092X 1 Total patients 58 MutationsinboldfacewouldnothavebeendetectedbytheACOG/ACMGmutationpanel. Login to comment
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: 17015492 [PubMed] Scotet V et al: "Immunoreactive trypsin/DNA newborn screening for cystic fibrosis: should the R117H variant be included in CFTR mutation panels?"

No. Sentence Comment

5 A monthly ARTICLE Immunoreactive Trypsin/DNA Newborn Screening for Cystic Fibrosis: Should the R117H Variant Be Included in CFTR Mutation Panels? Login to comment
10 The panels of mutations used in most cystic fibrosis newborn screening programs enable the detection of a relatively frequent CFTR variant (R117H) whose implication in cystic fibrosis remains unclear. Login to comment
13 The aim of this study was to describe the clinical outcome of the children found to be compound heterozygous for R117H by screening in Brittany (western France), where cystic fibrosis newborn screening was set up in 1989, and to assess whether this CFTR variant should be included in the newborn screening mutation panels. METHODS. Login to comment
16 Since our screening protocol has enabled detection of R117H (ie, in 1995), 360 466 newborns have been screened for cystic fibrosis in Brittany, of whom 124 had elevated immunoreactive trypsin and 2 mutations in the CFTR gene. Login to comment
17 Nine of these children (7.3%) were compound heterozygous for R117H, which in all cases was linked to the 7T࿝11TG haplotype [IVS8-nT variant/m(TG) repeat]. Login to comment
18 Their genotypes were F508del/R117H (n ϭ 7), I507del/R117H (n ϭ 1), or G551D/ R117H (n ϭ 1). Login to comment
19 At the time of this writing, the mean age of these 9 children was 7.0 years (the oldest being Ͼ10 years of age), and none of them had yet developed www.pediatrics.org/cgi/doi/10.1542/ peds.2005-3161 doi:10.1542/peds.2005-3161 Key Words cystic fibrosis, newborn screening, R117H, genetic counseling, Brittany Abbreviations CF-cystic fibrosis CFNS-cystic fibrosis newborn screening IRT-immunoreactive trypsin CFTR-cystic fibrosis transmembrane conductance regulator nT-n thymidines FEV1-forced expiratory volume in 1 second FVC-forced vital capacity Accepted for publication May 24, 2006 Address correspondence to Claude Fe´rec, MD, PhD, Inserm U613 Ge´ne´tique Mole´culaire et Ge´ne´tique E´pide´miologique, Laboratoire de Ge´ne´tique Mole´culaire, EFS-Bretagne, 46 Rue Fe´lix Le Dantec, BP 62026, 29220 Brest Cedex 2, France. Login to comment
22 Moreover, we observed that, in Brittany, all the patients carrying the R117H variant have been identified exclusively through cystic fibrosis newborn screening. Login to comment
24 In view of the high frequency of R117H-7T identified by cystic fibrosis newborn screening, the uncertain outcome of the asymptomatic children, and physicians` difficulty in managing these situations, we propose the withdrawal of the R117H variant from the panels of CFTR mutations used in cystic fibrosis newborn screening, given the expanding implementation of cystic fibrosis newborn screening. Login to comment
28 In France, the molecular part of the screening protocol relies on the use of a kit of 30 mutations (Elucigene CF30; Tepnel Diagnostics Ltd, Abingdon, Oxfordshire, United Kingdom), and the first results of this program have revealed the high frequency of one variant (R117H), which now seems to be the most frequent after the main F508del mutation. Login to comment
29 The first 2-year experience of the French CFNS program shows that this variant has been found in 7.2% of the newborns screened positive with 2 CFTR mutated alleles (18 of 249 newborns, including 16 compound heterozygotes for R117H and 2 homozygotes for this variant).4 Similar findings have been reported elsewhere. Login to comment
30 For example, CFNS in Massachusetts found that 8.0% of the CF-affected newborns carried R117H as 1 of their 2 abnormal CFTR alleles (9 of 112).5 The situation is quite different, however, in the CFNS program of Wisconsin, where this frequency reaches 26.7% (8 of 30 newborns detected from March 2002 to June 2003).6 Because these 8 infants had normal or borderline sweat-test values, they were not included in the calculation of CF incidence in the state. Login to comment
31 The R117H variant, which is located in exon 4 of the CFTR gene, belongs to the class IV mutations, which are known to produce a CFTR protein that affect ion conductance.7 The implication of this variant in CF remains ambiguous. Login to comment
32 The phenotype of subjects who are compound heterozygous for a severe CFTR mutation and R117H can range from a classical form of CF to congenital bilateral absence of vas deferens or even to no clinical disease, especially in women. Login to comment
33 This large phenotypic heterogeneity may be explained in part by the efficiency of exon-9 splicing, which is influenced by a polythymidine sequence of intron 8 of the CFTR gene (IVS8-nT), which can include a succession of 5 (5T), 7 (7T), or 9 thymidines (9T).8 The length of this tract influences the efficiency of mRNA splicing, with a decrease in mature functional CFTR protein observed for the shorter alleles.9-11 This is why a given F508del/R117H genotype can be associated with a mild form of CF characterized by pancreatic sufficiency and moderate lung disease (when it is found in cis with the 5T allele), with male infertility only, or even with absence of any clinical signs (when it is found in cis with the 7T allele).8,12-15 The efficiency of mRNA splicing is also modulated by the length of a polymorphic TG locus [m(TG)], which is located just upstream of the polythymidine sequence. Login to comment
34 The number of TG repeats ranges from 9 to 13, and a decrease in mature functional CFTR protein is observed for the longer alleles.16 According to the North American Cystic Fibrosis Foundation Consensus Panel,17 only the R117H-5T haplotype is considered to be a disease-causing mutation, but this is still a matter of debate in the clinical community. Login to comment
35 The other form (R117H-7T) is detected most frequently in the screening protocols (frequency ranges from 70% to 100% in white populations).6,18-20 Whereas R117H-5T acts as a deleterious mutation, the situation is less clear for R117H-7T. Login to comment
36 Most subjects who are compound heterozygous for R117H on a 7T background have normal or borderline sweat test results, and it is probable that the majority of them will not progress toward CF symptomatology. Login to comment
38 Because the outcome of children found to be compound heterozygous for R117H-7T remains difficult to predict at this time, it is hard to offer satisfactory genetic counseling to the families concerned.23 There are questions of how to counsel the parents: Which information should be given to the parents of a compound heterozygous child with normal sweat test results? Login to comment
43 The aim of this article was to review the data of the 16 years of experience of CFNS in Brittany in order to present the clinical outcome of the children screened positive with an R117H-7T and a second severe CFTR mutation. Login to comment
44 To date, our screening protocol has identified 9 children as compound heterozygous for R117H, which in all cases was linked to the IVS8-7T variant. Login to comment
45 These data lead us to reconsider our position and to wonder whether R117H should be included in mutation panels. METHODS Newborn Screening for CF in Brittany A pilot program of newborn screening for CF was implemented in Brittany in 1989.1 Since then, 2 protocols have successively been used: first an IRT/IRT protocol and then, from 1992, an IRT/DNA analysis protocol. Login to comment
48 This extended molecular analysis had enabled the detection of the R117H variant since 1995. Login to comment
49 Since the implementation of the CFNS program in the whole of France in 2002, the initial analysis of 3 exons of the CFTR gene has been replaced by the use of a kit of 30 mutations (Elucigene CF30), which directly enables identification of the R117H variant. Login to comment
52 Study Population Our study population was the cohort of children screened for CF in Brittany since 1995, when the CFNS protocol first enabled detection of the R117H variant. Login to comment
54 Among them, 124 were screened positive (ie, with an elevated IRT level and 2 mutations in the CFTR gene), of whom 9 were found to be compound heterozygous for R117H. Login to comment
56 Assessment of Clinical Status The clinical status at the last follow-up visit of the 9 children who are compound heterozygous for R117H and of the 9 control children was documented by the referring physicians. Login to comment
59 Statistical Analysis We assessed the frequency of the R117H variant in the cohort of newborns who screened positive for CF in Brittany since 1995. Login to comment
61 Finally, we compared the frequency of R117H in the cohort of newborns screened positive for CF with that observed in a cohort of CF patients born in Brittany before the CFNS protocol enabled the detection of the R117H (1960-1994 period). Login to comment
64 RESULTS Pilot newborn screening for CF was implemented in Brittany in 1989 and has enabled the detection of the R117H variant since 1995. Login to comment
66 Nine of these children (7.3%) were compound heterozygous for R117H, which was only associated with the 7T࿝11TG haplotype. Login to comment
67 Their genotypes were F508del/R117H (n ϭ 7), I507del/R117H (n ϭ 1), or G551D/R117H (n ϭ 1). Login to comment
70 At the time of this writing, the mean age of these children was 7.0 years (range: 4.0-10.9 years), and none of TABLE1ClinicalOutcomeofthe9ChildrenScreenedatBirthinBrittanyWhoAreCompoundHeterozygousforR117H-7T(1995-2004) CaseCase1Case2Case3Case4Case5Case6Case7Case8Case9 GenderFMMFMMMFF Yearofbirth199519951997199719992001200220022002 Currentage,y10.910.48.98.86.84.84.24.24.0 Ageatthelastvisit,y10.21.37.6-5.73.21.83.03.0 GenotypeG551D/R117HF508del/R117HF508del/R117HF508del/R117HI507del/R117HF508del/R117HF508del/R117HF508del/R117HF508del/R117H IVS8-nT/m(TG)7T_11TG7T_11TG7T_11TG7T_11TG7T_11TG7T_11TG7T_11TG7T_11TG7T_11TG IRT900␮g/L1840␮g/L1675␮g/L1700␮g/L1175␮g/L1190␮g/L90ng/mL157ng/mL60ng/mL Sweattest,mEq/L453156-4035291835 MeconiumileusNoNoNoNoNoNoNoNoNo PancreaticstatusPSPSPS-PSPSPSPSPS Anthropometry Height,cm(zscore)141.0(1.0)97.5(-0.3)125.0(0.4)-108.0(-0.9)102.0(1.9)-100.8(2.5)92.0(-0.2) Weight,kg(zscore)35.0(1.4)13.0(-2.1)22.2(-0.5)-16.7(-1.2)16.5(2.0)11.3(-0.6)17.0(2.5)13.8(0.1) BMI,kg/m217.613.714.2-14.315.9-16.716.3 Pulmonaryfunction FEV1,L(%)NotperformedNotperformed1.91(132.4)-(116.1)NotperformedNotperformedNotperformedNotperformed FVC,L(%)NotperformedNotperformed2.20(128.6)-(123.7)NotperformedNotperformedNotperformedNotperformed IntravenousantibioticcuresNoNoYes-NoNoNoNoNo Ifyes,n(during)2(10d)- HospitalizationsNoneNoneNone-NoneNoneNoneNoneNone ComplicationsNoneNoneNone-NoneNoneNoneNoneNone ConclusionVerygoodnutritional andpulmonary status Perfectclinical exam Verygood growth Lostatfollow-upGoodgrowth, good clinical evolution Satisfactory evolution Satisfactory evolution Verygoodnutritional status,verygood development Goodclinical state PSindicatespancreaticsufficiency;-,datanotavailable. Login to comment
78 Despite the small sample size, this comparison highlighted the fact that the genotypes including R117H were associated with lower IRT levels (1413.3 [SD: 374.9] vs 2038.3 [SD: 443.4] ␮g/L; P ϭ .030), lower sweat chloride concentrations (36.1 [SD: 11.3] vs 96.2 [SD: 19.9] mEq/L; P Ͻ .001), less frequent hospitalizations (0 of 8 vs 6 of 9; P ϭ .009) and seemed to have better pulmonary function, evidenced by higher spirometric data (FEV1: P ϭ .051; FVC: P ϭ .053). Login to comment
79 P aeruginosa was found in the cultures of more than half of the control children (5 of 9), whereas it was found only once in 1 child who was compound heterozygous for R117H (the colonization by this CF pathogen was detected at the age of 3 in this child and was never found thereafter). Login to comment
81 It is interesting to note that, in our area, all the patients carrying the R117H variant have been identified exclusively through the CFNS program (ie, the 9 mentioned above who all carried the IVS8-7T allele). Login to comment
83 TABLE 3 Comparison of the Clinical Characteristics of the 9 R117H Compound Heterozygous Children to Those of the Control Group Cases Controls P Current age, y 7.0 (2.8) 7.1 (3.2) NS Age at the last visit, y 4.5 (3.1) 6.9 (3.2) NS IRT, ␮g/L 1413.3 (374.9) 2038.3 (443.4) .030 IRT, ng/mL 102.3 (49.7) 182.0 (29.7) NS Sweat test (mEq/L) 36.1 (11.3) 96.2 (19.9) Ͻ.001 Meconium ileus, n/N 0/8 0/9 - Pancreatic status (PI), n/N 0/8 9/9 Ͻ.001 Anthropometry Height, z score ϩ0.6 (1.2) -0.1 (1.7) NS Weight, z score ϩ0.2 (1.6) -0.2 (1.7) NS BMI, kg/m2 15.5 (1.5) 15.8 (2.1) NS Pulmonary function FEV1, % 124.3 (11.3) 77.2 (5.8) .051 FVC, % 126.2 (3.5) 86.2 (5.9) .053 IV antibiotic cures, n/N 1/8 3/9 NS Hospitalizations, n/N 0/8 6/9 .009 Complications, n/N 0/8 2/9 NS NS indicates not significant. Login to comment
84 patients with CF born in Brittany over a 40-year period (1960-1999).2 By observing these data, we noted that the R117H variant was never observed in the cohort of the 394 patients with CF born before the CFNS protocol enabled the detection of R117H (ie, in 1995) (Fisher`s exact test: P Ͻ .0001). Login to comment
85 Moreover, to date, no diagnosis of CF has been made in the CF centers of Brittany in patients aged Ն45 years (ie, born before 1960, the first year of our retrospective study) and who carry a genotype including R117H. Login to comment
86 DISCUSSION Since our CFNS protocol has enabled the detection of the R117H variant (ie, in 1995), 9 children compound heterozygous for R117H have been detected, which represents 7.3% of the CF children screened in Brittany over this period. Login to comment
87 R117H was only associated with the 7T form of the IVS8-nT variant and the 11TG sequence of the m(TG) repeat, which does not correspond to the lengths classically observed in the most expressive forms (12 or 13 TG).16 We show here that none of these children have yet developed any signs of CF, the oldest being Ͼ10 years of age. Login to comment
89 Moreover, no patient bearing a genotype including R117H-7T has yet been diagnosed in adulthood in our area. Login to comment
90 However, manifestations of CF lung disease have been reported in some patients bearing R117H on a 7T background in 1 of their 2 CFTR mutated alleles.18,21,22 In 2001, Massie et al18 reported data on a cohort of 38 patients compound heterozygous for R117H who were diagnosed through CFNS or on the basis of clinical signs. Login to comment
91 Close to 60% of these subjects carried R117H on a 7T background (n ϭ 22). Login to comment
96 A recent article reported late diagnosis of CF in 2 elderly men carrying an R117H-7T haplotype heterozygous with either an N1303K or F508del mutation.21 The first patient, aged 61 years, presented with "a 7-month history of progressive weight loss, dyspnea, cough and fever"; his FEV1 and FVC were 60% and 65% of the predicted values, respectively. Login to comment
100 Another article reported the delayed diagnosis of CF in a 63-year-old woman who carried an F508del/R117H genotype (the IVS8-nT sequence was not known). Login to comment
101 This woman presented with cough and dyspnea on exertion and was asymptomatic until that time.22 In 2000, Boyne et al20 reported that 3 children screened at birth in the Trent region (United Kingdom) and who were F508del/R117H-7T compound heterozygous already had symptoms of lung disease. Login to comment
103 Finally, in a recent abstract, Parad et al24 reported that in the CFNS program in Massachusetts and New York, 19 children compound heterozygous for R117H were detected (18 were associated with the 7T variant) and that 3 of them had respiratory symptoms consistent with early CF. Login to comment
105 In these different reports, it would be important from a genetic point of view to know whether the entire CFTR gene has been analyzed in all these symptomatic patients to ensure the absence of another mutation in cis with the R117H-7T. Login to comment
107 One can note that description in the literature of compound heterozygous CF patients bearing an R117H-7T haplotype who have progressed toward pulmonary signs of CF remains uncommon and contrast with the high frequency of this haplotype in CFNS programs. Login to comment
109 The high frequency of the R117H-7T haplotype identified by CFNS programs and the uncertain outcome of these asymptomatic children raise the question of whether this variant should be included in a CFTR mutation panel used for newborn screening. Login to comment
112 However, does the possible development of such signs in adulthood (perhaps not before the age of 60 years as has e SCOTET et al been reported21,22) justify the formal diagnosis of classical CF at birth, with its consequences in terms of anxiety, possible discrimination for employment or insurance, and so forth?25 In view of these data, we propose the withdrawal of the R117H variant from the panels of CFTR mutations used in newborn screening in light of the expanding implementation of CFNS worldwide. Login to comment
113 The R117H-5T haplotype is more obviously considered to be a disease-causing mutation17; therefore, it is not the overall frequency of the R117H variant that should be considered when deciding whether to include it in panels of mutations, but only the frequency of the R117H-5T haplotype. 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

124 The most phenotypically severe CFTR mutation, ⌬F508, was present in 12% of subjects in this study, compared to the general frequency of 3% in the white population in the United States.39,40 The R75Q mutation frequency was 14% in this study, compared to the general frequency of 1% in Northern Europeans.41 The intron 8 5T polymorphism was present in 17% of subjects in this study, compared to 5 to 10% in the general population.42,43 CFTR mutations identified in this study, including ⌬F508, R75Q, R117H, S1235R, D1152, L183I, and IVS8 5T, have been associated with mild symptoms of CF41,44-46 or with atypical manifestations of CF, such as isolated bronchiectasis14-17,19,20,22,23,25-27 and CBAVD.42,43,47 This study also reports three novel CFTR mutations, each in a separate patient with normal sweat chloride level: A394V, C1344S, and F650L. 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: 17314234 [PubMed] Radpour R et al: "Molecular study of (TG)m(T)n polymorphisms in Iranian males with congenital bilateral absence of the vas deferens."

No. Sentence Comment

77 CFTR gene mutations in 112 CBAVD patients and 7 CBAVD patients* Samples Mutation genotype3 (TG)m(T)n n (%) CBAVD Two mutations detected (5 /112 5 4.46%) F508del / R117H (TG)10 9T / (TG)10 9T 1 (0.89) F508del / 621+1G.T (TG)11 7T / (TG)11 7T 1 (0.89) 1540A/G / 1540A/G (TG)11 7T / (TG)11 7T 2 (1.79) R347H / R117H (TG)10 9T / (TG)11 7T 1 (0.89) One mutation detected with one 5T allele (32 / 112 5 28.57%) G551D / - (TG)10 7T/ (TG)13 5T 2 (1.79) F508del / - (TG)12 7T/ (TG)13 5T 8 (7.14) (TG)11 9T/ (TG)13 5T 6 (5.36) 1717-1G.A / - (TG)11 7T/ (TG)12 5T 4 (3.57) R117H / - (TG)12 7T/ (TG)13 5T 2 (1.79) 621+1G.T / - (TG)11 7T/ (TG)13 5T 3 (2.68) 2 (1.79) 1540A/G / - (TG)11 7T/ (TG)13 5T 2 (1.79) R553X / - (TG)12 7T/ (TG)13 5T 1 (0.89) Y122H / -4 (TG)11 7T / (TG)13 5T 1 (0.89) T338A / -4 (TG)10 7T / (TG)13 5T 1 (0.89) No mutation detected with two 5T alleles (11 / 112 5 9.82%) - / - (TG)12 5T / (TG)13 5T 3 (2.68) - / - (TG)13 5T / (TG)13 5T 8 (7.14) One mutation detected without 5T allele (35 / 112 5 31.25%) G85E / - (TG)11 7T / (TG)11 7T 2 (1.79) G551D / - (TG)10 9T / (TG)12 7T1 1 (0.89) 621+1G.T / - (TG)11 7T / (TG)11 7T 2 (1.79) (TG)10 9T / (TG)11 7T 1 (0.89) R334W / - (TG)12 7T / (TG)10 7T 1 (0.89) F508del / - (TG)11 7T / (TG)11 7T 7 (6.25) (TG)11 9T / (TG)12 7T 3 (2.68) (TG)10 9T / (TG)10 9T 2 (1.79) 1717-1G.A / - (TG)11 7T / (TG)12 7T 3 (2.68) (TG)10 9T / (TG)11 7T 2 (1.79) R117H/- (TG)12 7T / (TG)12 7T 2 (1.79) (TG)10 9T / (TG)11 7T 1 (0.89) 2789+5G.A / - (TG)10 7T / (TG)11 7T 1 (0.89) 3120+1G.A / - (TG)10 9T / (TG)11 7T 2 (1.79) R560T / - (TG)10 9T / (TG)11 7T 1 (0.89) N1303K / - (TG)10 9T / (TG)11 7T 1 (0.89) 1651A/G / - (TG)11 7T / (TG)12 7T 1 (0.89) R553X / - (TG)10 9T / (TG)10 7T 1 (0.89) K536X / -4 (TG)10 9T / (TG)10 9T 1 (0.89) No mutation detected with one 5T alleles (7 / 112 5 6.25%) - / - (TG)13 5T / (TG)12 7T 3 (2.68) - / - (TG)13 5T / (TG)10 9T 4 (3.57) No mutation detected (22 / 112 5 19.64%) - / - (TG)11 7T / (TG)11 7T 12 (10.71) - / - (TG)11 7T / (TG)12 7T 1 (1.79) - / - (TG)10 9T / (TG)10 9T 3 (2.68) - / - (TG)10 9T / (TG)11 7T 6 (5.36) CUAVD One mutation detected without 5T allele (2 / 7 5 28.57%) R334W / - (TG)10 9T / (TG)11 7T 1 (14.29) R117H / - (TG)11 7T / (TG)11 7T 1 (14.29) No mutation detected with one 5T alleles (3 / 7 5 42.86%) - / - (TG)11 9T / (TG)13 5T 2 (28.57) - / - (TG)10 7T / (TG)13 5T 1 (14.29) No mutation detected (2 / 7 5 28.57%) - / - (TG)10 9T / (TG)12 7T 2 (28.57) * CBAVD indicates congenital bilateral absence of the vas deferens; CUAVD, congenital unilateral absence of the vas deferens. Login to comment
88 As stated earlier, R117H is considered a mild mutation unless it is found in cis with the 5T variant. 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

15 The most frequent are the main CF-associated defect, F508del (21-40% of alleles in CBAVD patients, depending on studies), and two mild defects, the T(5) variant of the polypyrimidin tract of the intron 8 (IVS8) acceptor splice site (19-37%) and R117H (3-14%). Login to 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
63 Patient #3 had already been referred to in Niel et al. (2004): he was apparently homozygous for R117H with IVS8(T)7 in cis and was found to carry a complete deletion of the CFTR gene, inherited from his mother. Login to comment
67 Rearrangements, found in 6.9% of 58 unknown alleles (57 alleles from the first two groups of patients and one allele from the patient who was apparently homozygous for R117H), thus accounted for 0.9% of CBAVD alleles and 1% of the identified alleles. Login to comment
93 1 Two CFTR mutations 15 0-15 0 [R117H] þ [(TG)13(T)5] 1 [R117H] þ [(TG)12(T)5] 1 [R117H] þ [(TG)11(T)5] 1 [R117H] þ [M952I] 1 [D1152H] þ [(TG)12(T)5] 2 [D1152H] þ [Y1032C] 1 [(TG)11(T)5;V562I] þ [L997F] 1 [(TG)11(T)5;V562I] þ [S977F] 1 [E1473X] þ [(TG)13(T)5] 1 [V232D] þ [(TG)12(T)5] 1 [R334W] þ [(TG)12(T)5] 1 [G622D] þ [(TG)12(T)5] 1 [3272-26A . Login to comment
95 C)] þ [I556V] 1 Apparent homozygosity 3 0-3 1 [R117H] þ [R117H] 1 1 [D110H] þ [D110H] 1 [R74W;D1270 N] þ [R74W;D1270 N] 1 Total 61 57-75 4 F508del, 2221dupA, as well as variants at the IVS8(TG)m(T)n polymorphic site. Login to comment
113 Phenotype and genotype data of patients carrying CFTR rearrangements Patient Current age (years) Origin Allele 1 Allele2 Reference Simple name Extent 1 45 Syria (TG)12(T)5 CFTRdele17a_18 8.6 kb deletion Lerer et al. (1999) 2 33 France/Southern Italy V938G CFTRdele22_23 1.5 kb deletion Audre´zet et al. (2004) 3 47 France R117H CFTRdele1_24 3 Mb deletion This study and Niel et al. (2004) 4 34 Morocco (TG)12(T)5 CFTRdup11_13 Unknown (4.9-35.2 kb duplication) This study Figure 1. Login to comment
124 A complete CFTR gene deletion was found in one patient who had previously been referred to in Niel et al. (2004) and who was apparently homozygous for R117H. Login to comment
146 CBAVD genotypes were varied, the most frequent combined F508del either with the IVS8(T)5 variant (28.0% of 222) or with R117H (6.3%). Login to comment
152 Moreover, genotypes combining two mild alleles were found, such as [R117H] þ [(TG)13(T)5], [(TG)11(T)5;V562I] þ [L997F] or homozygosity for [R74W;D1270N]. Login to comment

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

No. Sentence Comment

154 Risks with R117H When the typically milder R117H mutation is found in the same allele as the 5T polythymidine tract upstream of the intron-8 splice site that reduces splicing efficiency, the two nucleotide modifications together usually result in a more severe CFTR allele. Login to comment
155 Thus, the ACMG Cystic Fibrosis Committee recommended that all patients testing positive for the R117H mutation found in the 23-mutation panel have a reflex test for the 5T allele. Login to comment
157 However, a subsequent report found that even when R117H is found in trans (i.e., on a separate allele) from the 5T sequence, half of the compound heterozygotes with R117H mutations have elevated sweat tests and a proportion of these develop clinical disease (Massie et al. 2001). Login to comment
159 When the phase of the R117H and 5T sequences in one carrier parent is unknown and the other parent is unavailable for testing for CF carrier status, testing the fetus will not only reveal which CFTR allelic sequences the fetus carries but also determine the most likely phase of the R117H and 5T sequences in the known carrier parent. Login to comment
160 Given both tests are accurate, when the fetus inherits the R117H allele without the 5T allele, the likelihood that these two alleles are not linked exceeds 99%. Login to comment
161 Alternatively, when the fetus inherits a 5T allele without the R117H allele, the likelihood the R117H and the 5T allele are not linked is 95% because the unavailable parent has a 10% likelihood of carrying a 5T allele, and there is a 50% likelihood of transmitting an existing allele to each offspring. Login to comment
162 For the same reason, if the fetus inherits the R117H and 5T alleles, the likelihood that these were inherited on the same parental allele is 95%. Login to comment
178 If the untested U.S. Caucasian partner is negative for the 23-mutation test panel, the likelihood of having a fetus with CF is about 1 in 280, while the risk of having a child that is a carrier of a CF allele is equal to the reliability of the test for two CYSTIC FIBROSIS SCREENING 23 TABLE 5. AFTER-TEST RISKS: ASYMPTOMATIC WITH NEGATIVE FAMILY HISTORY AND PATIENT TESTING POSITIVE FOR BOTH THE R117H AND 5T SEQUENCES WHICH MAY BE ON ONE OR TWO CHROMOSOMES Carrier Carrier Fetal risk when the testing risk of untested partner shares positive with untested the same ethnicity Ethnic origin R117H and 5T partner as known carrier Northern 1/1 1/29 1/58 (1.7%) or European (100%) 3.4% 1/116 (0.9%) Caucasiana,b European 1/1 1/29 1/58 (1.7%) or Caucasian (100%) 3.4% 1/116 (0.9%) origin unspecified Ashkenazi 1/1 1/29 1/58 (1.7%) or Jewish (100%) 3.4% 1/116 (0.9%) Southern 1/1 1/29 1/58 (1.7%) or European (100%) 3.4% 1/116 (0.9%) Caucasiana Hispanic American 1/1 1/46 1/92 (1/1%) or (100%) 2.2% 1/184 (0.5%) African 1/1 1/65 1/130 (0.8%) or American (100%) 1.5% 1/260 (0.4%) Asian 1/1 1/90 1/180 (0.6%) or Americanc (100%) 1.1% 1/360 (0.3%) aNorthern Europe includes the Alps; southern Europe is south of the Alps. Login to comment
186 Genotypes R117H/R117H, 5T/5T, and R117H/⌬F508 have all been reported to result in CBAVD. Login to comment
187 The R117H/⌬F508 genotype has also been found in CF patients with milder lung disease. Login to comment

PMID: 17394391 [PubMed] Lebo RV et al: "Variable penetrance and expressivity of the splice altering 5T sequence in the cystic fibrosis gene."

No. Sentence Comment

23 Extensive experience screening mutations that had not been characterized thoroughly in patients with CF-like symptoms has resulted in adding a 5T reflex test for the R117H mutation and deleting two mutations from the original ACMG-recommended panel of 25 mutations (Grody et al. 2001; Watson et al. 2004). Login to comment
34 This is in contrast to finding the 5T sequence on the same allele (in cis) with the R117H mutation so that the effect of both nucleotide modifications becomes more severe. Login to comment
35 Thus, the ACMG Cystic Fibrosis Committee recommended that all patients testing positive for the R117H mutation found in the 25-mutation panel have a reflex test for the 5T allele. Login to comment
85 (Note: These calculations are unrelated to the 5T allele found with an R117H mutation.) Login to comment
126 At the same time, unlike other reports of mutations in cis like the R117H and 5T sequences (cf. Login to comment

PMID: 17400678 [PubMed] Keen C et al: "Airway nitric oxide in patients with cystic fibrosis is associated with pancreatic function, Pseudomonas infection, and polyunsaturated fatty acids."

No. Sentence Comment

30 Patients in group 3 were heterozygous for mutations dF508 and V603F, R560T, or 621 ϩ 1G-T; group 4 patients were heterozygous for mutations dF508, 3659del C, or 394delTT and a mutation linked to a "mild" phenotype (eg, N1088D, R117C, R117H, R75Q, R658X, S945L, 1154insTC, or T338I). Login to comment

PMID: 17400751 [PubMed] Ramu Y et al: "Inhibition of CFTR Cl- channel function caused by enzymatic hydrolysis of sphingomyelin."

No. Sentence Comment

93 In contrast, the product of CFTR-R117H (29), another relatively common mutant, folds properly, is well transported to the cytoplasmic membrane in affected patients but is only partially functional. Login to comment
94 SMases C and D inhibited currents through both ⌬F508 and R117H mutant CFTR channels (Fig. 6). Login to comment
137 Inhibition of disease-causing CFTR mutants by bacterial SMases C and D. Normalized I-V relations of ⌬F508 (A and C) or R117H (B and D) mutants before and after exposure to BaSMase C (A and B) or CpSMase D (C and D). Login to comment
178 The ⌬F508 and R117H mutant CFTR cDNAs were obtained through PCR-based mutagenesis and confirmed by DNA sequencing. Login to comment

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

No. Sentence Comment

14 The most common CFTR mutations found in CAVD are T5 allele, deltaF508, and R117H, with the combination between the T5 allele and a severe CF mutation in the other allele being the main cause of CAVD.9 The polymorphic polythymidine locus (Tn) is located within the 3= splice acceptor site of intron 8 (IVS8 poly[T]n). Login to comment
93 DeltaF508 was the second most common mutation, representing 21 (23.3%) of total alleles, followed by R334W (6, Table 1 CFTR gene mutations and polymorphisms in patients with congenital absence of the vas deferens Mutation Location Nucleotide alteration Effect Method 1 CFTRdele2,3 Exons 2-3 Deletion of exons 2 and 3 Frameshift QFM-PCR 2 R117H Exon 4 G¡A at 482 AA substitution 31 mutation panel 3 P205S Exon 6a C¡T at 745 AA substitution DGGE/dHPLC 4 L206W Exon 6a T¡G at 749 AA substitution DGGE/dHPLC 5 R258G Exon 6b A¡G at 904 AA substitution DGGE/dHPLC 6 R334W Exon 7 C¡T at 1132 AA substitution 31 mutation panel 7 T5 allele Intron 8 Deletion of 2T at 1342-12 to -6 Aberrant splicing DGGE/DNA sequencing 8 P439S Exon 9 C¡T at 1447 AA substitution DGGE/dHPLC 9 D443Ya Exon 9 G¡T at 1459 AA substitution DGGE/dHPLC 10 I507del Exon 10 Deletion of 3 bp at 1648-1653 AA deletion 31 mutation panel 11 DeltaF508 Exon 10 Deletion of 3 bp at 1652-1655 AA deletion 31 mutation panel 12 G542X Exon 11 G¡T at 1756 Truncation 31 mutation panel 13 V562I Exon 12 G¡A at 1816 AA substitution DGGE/dHPLC 14 G576Aa Exon 12 G¡C at 1859 Aberrant splicing DGGE/dHPLC 15 D614G Exon 13 A¡G at 1973 AA substitution DGGE/dHPLC 16 R688Ca Exon 13 C¡T at 2134 AA substitution DGGE/dHPLC 17 V754M Exon 13 G¡A at 2392 AA substitution DGGE/dHPLC 18 E831X Exon 14a G¡T at 2623 Truncation DGGE/dHPLC 19 3272-26AϾG Intron 17a A¡G at 3272-26 Aberrant splicing DGGE/dHPLC 20 2789ϩ5G¡A Intron 14b G¡A at 2789ϩ5 Aberrant splicing 31 mutation panel 21 V1108L Exon 17b G¡C at 3454 AA substitution DGGE/dHPLC 22 L1227S Exon 19 T¡C at 3812 AA substitution DGGE/dHPLC 23 S1235R Exon 19 T¡G at 3837 AA substitution DGGE/dHPLC 24 P1290S Exon 20 C¡T at 4000 AA substitution DGGE/dHPLC 25 N1303K Exon 21 C¡G at 4041 AA substitution 31 mutation panel 26 E1401K Exon 23 G¡A at 4333 AA substitution DGGE/dHPLC Polymorphisms 1 TG repeats Intron 8 9-13 copies at 1342-12 to -35 Sequence variation DGGE/DNA sequencing 2 M470V Exon 10 A or G at 1540 Sequence variation DNA sequencing 3 125G/C Exon 1 G¡C at 125 Sequence variation DGGE/dHPLC 4 1001ϩ11T/C Intron 6b C¡4T at 1001ϩ11 Sequence variation DGGE/dHPLC 5 1716G/A Exon 10 G¡A at 1716 Sequence variation DGGE/dHPLC 6 1899-136T/G Intron 12 T¡G at 1899-136 Sequence variation DGGE/dHPLC 7 T854T Exon 14a T¡G at 2694 Sequence variation DGGE/dHPLC 8 3601-65C/A Intron 18 C¡A at 3601-65 Sequence variation DGGE/dHPLC 9 4521G/A Exon 24 G¡A at 4521 Sequence variation DGGE/dHPLC QFM-PCR, semiquantitative fluorescent multiplex polymerase chain reaction; bp, base pair; DGGE, denaturing gradient gel electrophoresis; dHPLC, denaturing high-performance liquid chromatography. Login to comment
97 The allelic frequency of the other mutations was 4.4% for R117H, G576A, and R668C, 3.3% for S1235R and 3272-26A¡G, and 2.2% for P205S, L206W, D443Y, G542X, D614G, and N1301K, whereas the remaining 12 mutations were present in single patients (Table 3). Login to comment
101 The missense M470V polymorphism was evaluated in all 45 pa- tientswithCAVD(Table2).TheallelicfrequencyoftheM470variant Table 2 CFTR genotypes identified in patients with congenital absence of the vas deferens CFTR mutation genotypes [(TG)mTn] genotype M470V Patients N % DeltaF508 (TG)10T9 (TG)12T5 M V 11 24.4 DeltaF508 (TG)10T9 (TG)11T5 M M 1 2.2 DeltaF508 R117H (TG)10T9 (TG)10T7 M M 2 4.4 G542X (TG)10T9 (TG)12T5 M V 2a 4.4 DeltaF508 R334W (TG)10T9 (TG)11T7 M V 1 2.2 DeltaF508 D443Y-G576A-R668C (TG)10T9 (TG)10T7 M M 1 2.2 DeltaF508 D614G (TG)10T9 (TG)11T7 M V 1 2.2 DeltaF508 E831X (TG)10T9 (TG)11T7 M V 1 2.2 DeltaF508 L1227S (TG)10T9 (TG)11T7 M M 1 2.2 DeltaF508 E1401K (TG)10T9 (TG)11T7 M V 1 2.2 I507del D614G (TG)11T7 (TG)10T7 M V 1 2.2 N1303K L206W (TG)10T9 (TG)9T9 M M 1 2.2 R117H P205S (TG)11T7 (TG)10T7 M V 1 2.2 R117H R334W (TG)10T7 (TG)11T7 M V 1 2.2 R334W P439S (TG)11T7 (TG)11T7 M V 1 2.2 R334W R334Wb (TG)11T7 (TG)11T7 V V 1 2.2 R334W V562I (TG)11T7 (TG)11T5 V M 1 2.2 D443Y-G576A-R668C 3272-26A¡G (TG)10T7 (TG)10T7 M M 1 2.2 G576A-R668C V754Mb (TG)10T7 (TG)11T7 M M 1 2.2 S1235R S1235Rb (TG)13T5 (TG)13T5 M M 1 2.2 2789ϩ5G¡A S1235Rb (TG)10T7 (TG)13T5 M M 1 2.2 3272-26A¡G P1290S (TG)11T7 (TG)10T7 M V 1 2.2 P205S (TG)11T7 (TG)12T5 V V 1 2.2 G576A-R668C b (TG)10T7 (TG)11T5 M M 1 2.2 V1108L b (TG)11T7 (TG)11T5 V M 1 2.2 N1303K (TG)10T9 (TG)12T5 M V 1 2.2 3272-26A¡G b (TG)10T7 (TG)12T5 M V 1 2.2 CFTRdele2,3 b (TG)11T7 (TG)13T5 V M 1 2.2 b (TG)11T5 (TG)12T5 M V 1 2.2 b (TG)13T5 (TG)12T5 M V 1 2.2 DeltaF508 - (TG)10T9 (TG)11T7 M V 1a 2.2 L206W -b (TG)9T9 (TG)11T7 M V 1 2.2 R258G -b (TG)11T7 (TG)11T7 V V 1 2.2 a CUAVD. Login to comment
110 Large Table 3 Allelic frequencies of CFTR mutations in patients with congenital absence of the vas deferens CBAVD CUAVD Total Patients 42 3 45 Alleles 84 6 90 Mutations N % N % N % 1 T5 allele 26a 31 2 33.3 28 31.1 2 DeltaF508 20 23.8 1 16.7 21 23.3 3 R334W 6a 7.1 0 0 6 6.7 4 R117H 4 4.8 0 0 4 4.4 5 G576A 4b 4.8 0 0 4 4.4 6 R688C 4b 4.8 0 0 4 4.4 7 S1235R 3a 3.6 0 0 3 3.3 8 3272-26A¡G 3 3.6 0 0 3 3.3 9 P205S 2 2.4 0 0 2 2.2 10 L206W 2 2.4 0 0 2 2.2 11 D443Y 2b 2.4 0 0 2 2.2 13 D614G 2 2.4 0 0 2 2.2 14 N1303K 2 2.4 0 0 2 2.2 12 G542X 0 0 2 33.3 2 2.2 15 R258G 1 1.2 0 0 1 1.1 16 P439S 1 1.2 0 0 1 1.1 17 I507del 1 1.2 0 0 1 1.1 18 V562I 1 1.2 0 0 1 1.1 19 V754M 1 1.2 0 0 1 1.1 20 E831X 1 1.2 0 0 1 1.1 21 2789ϩ5G¡A 1 1.2 0 0 1 1.1 22 V1108L 1 1.2 0 0 1 1.1 23 L1227S 1 1.2 0 0 1 1.1 24 P1290S 1 1.2 0 0 1 1.1 25 E1401K 1 1.2 0 0 1 1.1 26 CFTRdele2,3 1 1.2 0 0 1 1.1 CBAVD, congenital bilateral absence of the vas deferens; CUAVD, congenital unilateral absence of the vas deferens. Login to comment
142 In fact, they occur in highly conserved regions of the CFTR protein, which share 100% amino acid sequence homology between species48 and affect the NBD1, NBD2, and transmembrane regions of the protein, which are known to regulate chloride conductance and permeability.49-51 P439S was previously reported in a child with CF with pancreatic insufficiency and mild lung disease, in association with the P439S/R688C genotype.52 The E1401K mutation occurs at a position in which other mutations, E1401X and E1401A, have been described in patients with CF with pancreatic insufficiency.8 Some difficulties in defining CF or CAVD-causing mutations were observed with some missense mutations.6,27 G576A and R668C have been found independently, in pairs, or combined with the D443Y mutation on the same chromosome in patients withaCF-relatedsyndrome.Inaccordancewithpreviousstudies, we expected that G576A and R668C were located in cis in two patients and combined with D443Y in the same chromosome in two patients.6,9,12 Although initially described as polymorphisms,27 they were later considered mild mutations associated with the CBAVD phenotype when combined in trans with the severedeltaF508mutation.53 However,ourpresentresultssuggest they might also cause the CAVD phenotype when associated with other mild CFTR mutations, because three of four patients carry- ingthesecomplexallelesharboredamildorverymildmutationin the other chromosome (D443Y-G576A-R668C/3272-26A¡G, Table 5 Comparative analysis of CFTR mutation allelic frequencies (%) in patients with congenital absence of the vas deferens Countries Patients T5 allele DeltaF508 R334W R117H References Argentina 36 NA 20.8 NA 5.6 43 Austria 22 NA 13.6 NA 9.1 44 Italy 12 8.3 29.2 NA 4.2 39 The Netherlands 21 9.5 19.0 NA 21.4 38 Germany 106 12.3 26.4 0.5 11.3 30 Greece 14 14.3 14.3 NA NA 32 France 800 16.3 21.8 NA 4.4 6 United States 92 17.9 21.2 NA 2.2 41 Canada 74 18.2 16.9 1.4 6.1 5 Turkey 51 19.6 2.9 NA NA 35 Brazil 17 20.6 11.7 NA 2.9 34 Spain 134 20.9 16.0 0.4 3.0 33 Iran 113 25.7 12.4 0.9 3.5 37 Egypt 16 43.7 6.2 NA NA 40 Taiwan 27 44.4 NA NA NA 42 Portugal 45 31.1 23.3 6.7 4.4 13, 36, PS NA, not available; PS, present study. 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: 17489851 [PubMed] Tzetis M et al: "Contribution of the CFTR gene, the pancreatic secretory trypsin inhibitor gene (SPINK1) and the cationic trypsinogen gene (PRSS1) to the etiology of recurrent pancreatitis."

No. Sentence Comment

85 Mutation CFTRdel2,3 (21 kb) considered a severe mutation and found once in our patient cohort, has been previously reported in an otherwise healthy 43-year-old woman, who presented with mild relapsing pancreatitis and had R117H in trans (28). Login to comment

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

No. Sentence Comment

60 Classes of CFTR mutations, with molecular and phenotypic consequences Class Molecular consequence Example Phenotypic consequence I nonsense or frameshift mutations that result in no significant protein product G542X typical CF phenotype II protein product does not negotiate intracellular trafficking pathways phe508del R1066C A561E typical CF phenotype III protein product transported to the cell membrane but no significant ion transport function G551D typical CF phenotype IV protein product transported to cell membrane and functions at a low level R117H R334W associated with pancreatic sufficiency V reduced mRNA expression, protein product normal 5T variant of intron poly T region. Login to comment
136 Additionally 5T can occur in trans with R117H (a mild class IV mutation). Login to comment

PMID: 17557942 [PubMed] Quinton PM et al: "Cystic fibrosis: lessons from the sweat gland."

No. Sentence Comment

292 Neither the basis nor the role of these phenomenon are understood, but when glutamate or precursors and ATP were applied to CF ducts from patients of different genotypes, those ducts from patients with a "mild" phenotype (pancreatic sufficient: ⌬F508/R117H) exhibited a significantly larger (almost normal) HCO3 - conductance, whereas ducts from patients with a "severe" phenotype (pancreatic insufficient: ⌬F508/⌬F508) remained impermeable to HCO3 - (132). Login to comment

PMID: 17580535 [PubMed] Dinic J et al: "Analysis of Y chromosome microdeletions and CFTR gene mutations as genetic markers of infertility in Serbian men."

No. Sentence Comment

141 Shrimpton AE. R117H and IVS8-5T cystic fibrosis mutation detection by restriction enzyme digestion. 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

43 Five of the 31 mutations included in the basic genetic panel were found to occur in more than 1 of the 64 alleles examined (Table 1 and Fig. 1): F508del in 15 alleles (23.4%), N1303K in four alleles (6.3%), 2789 1 5G-.A in two alleles (3.1%), R117H in two alleles (3.1%), and R347P in two alleles (3.1%). Login to comment
48 CFTR genotypes, IRT2 and sweat test values of the 32 newborns analyzed Newborn CFTR genotype IRT2 Sweat test (mmol/l [Cl2 ]) at enrolment True heterozygous subjects 1 N1303K/1 Negative 18 2 2183AAtoG/1 Negative 11 3 G85E/1 Positive 19 4 F508del/1 Negative 21 5 F508del/1 Negative 20 6 R117H/1 Negative 6 7 1717-1GtoA/1 Positive 7 8 W1282X/1 Negative 14 9 278915GtoA/1 Negative 23 10 N1303K/1 Negative 19 11 F508del/1 Negative 14 12 G542X/1 Negative 39 % of positivity ¼ 16.7% Average Æ SD ¼ 18 Æ 9 Compound heterozygous subjects 13 F508del/D806G Positive 24 14 F508del/D836Y Negative 12 15 R347P/R1162L Negative 18 16 F508del/P5L (TG)11T5 Negative 16 17 F508del/L997F Positive 32 18 R347P/D1152H Positive 42 19 F508del/P5L Negative 42 20 278915GtoA/71113AtoG Positive 33 21 F508del/P5L Positive 39 22 F508del (TG)12T7/(TG)12T5 Negative 23 23 N1303K/S1235R (TG)12T7 Negative 30 24 F508del/L997F Positive 34 25 F508del/(TG)12T5 Negative 34 26 R117H/(TG)12T7 Positive 22 27 F508del/P1013L Positive 8 28 F508del/L997F Negative 28 29 N1303K/(TG)12T5 Positive 13 30 F508del/L997F Positive 50 31 R1162X/P5L Negative 31 32 L997F/S549R(AtoC) Positive 38 % of positivity ¼ 55.0% Average Æ SD ¼ 29 Æ 12 CFTR, cystic fibrosis transmembrane conductance regulator. Login to comment
75 Discussion The majority of the mutations found (F508del, R347P, D1152H, 2789 1 5G-.A, 711 1 3A-.G, N1303K, R117H, R1162X, S549R(A-.C), 2183AA-.G, G85E, 1717-1G-.A, G542X, and W1282X) have an established pathogenic role (26-44). Login to comment

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

No. Sentence Comment

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: 17632692 [PubMed] Roussey M et al: "Neonatal screening of cystic fibrosis: diagnostic problems with CFTR mild mutations."

No. Sentence Comment

7 The most frequent mild mutation is R117H ISV8j7T (50%). Login to comment

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

No. Sentence Comment

177 The activity was CFTR mutation-specific and, for example, mutations such as R117H (the pancreas is spared in compound CF heterozygotes such as R117H/ΔF508)appeared to retain the ability to support exchange even though Cl-conductance was depressed while mutations such as H620Q did not support exchange, but retained a disputed[240] Cl-conductance. 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

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

No. Sentence Comment

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

PMID: 17943404 [PubMed] Zoller H et al: "CFTR gene mutations in pancreatitis: Frequency and clinical manifestations in an Austrian patient cohort."

No. Sentence Comment

67 Out of the 29 genetic variants analysed, four distinct genetic variants were detected in pancreatitis patients (∆F508, R1162X, R117H and one intronic variant: 5T allele of the polythymidine tract in intron 8). Login to comment
75 The mutations detected are listed in www.elucigene.com/pdfs/cfcf029_isgb002.pdf Mutation Number of pancreatitis patients with mutations (n) Frequency of mutation in pancreatitis cohort (%) Frequency of mutation in carrier group (%) Frequency in 76 healthy controls Frequency of mutation in Tyrolean CF patients [22] (%) Intron 8 Poly T (5T) homozygous 1 0.8 6.7 0 0 Intron 8 Poly T (5T) heterozygous 8 6.0 53.3 3,6 0 ∆F508 heterozygous 3 2.3 20.0 - 74.6 R1162X heterozygous 2 1.5 13.3 - 8.7 R117H heterozygous 1 0.8 6.7 - 0 39 patients with calcifications, 13 had mutations in the CFTR gene (33.3%), which is significantly more than the proportion of pancreatitis patients without CT evidence for parenchymal calcification but mutations in the CFTR gene (3/68, 4.4%, χ2 = 16.2, p < 0.01). 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: 18394117 [PubMed] Lee TW et al: "Respiratory exacerbations in childhood associated with compound heterozygosity Phe508del/Arg117His-7T of the cystic fibrosis transmembrane regulator gene."

No. Sentence Comment

2 DOI:10.1111/j.1651-2227.2008.00716.x Abstract Debate continues regarding the clinical implications for compound heterozygotes identified with Phe508del and Arg117His-7T mutations of the cystic fibrosis transmembrane regulator (CFTR) gene. Login to comment
4 Conclusion: The compound heterozygote cystic fibrosis (CF) mutation Phe508del with Arg117His-7T should not necessarily be considered benign in childhood. Login to comment
11 Consequently, for many mutations such as Arg117His-7T it remains unclear whether they should be screened for, how intensive monitoring and treatment should be and what information about prognosis should be given. Login to comment
12 Scotet et al. have recently suggested that Arg117His should be removed from the newborn screening mutation panel, as in their experience compound heterozygotes with Arg117His-7T remain asymptomatic in childhood (5). Login to comment
13 We present a case with significant respiratory complications in early childhood, in whom Arg117His-7T was identified (compound heterozygote with Phe508del). Login to comment
25 Mutation screen for 32 common CFTR gene mutations identified her as a compound heterozygote for Phe508del and Arg117His mutations on a background of a polythymidine tract of 9T/7T at intron 8. Login to comment
36 DISCUSSION It has been suggested that Arg117His with a 7T allele should not be considered as a true CF mutation in the presence of a 670 C 2008 The Author(s)/Journal Compilation C 2008 Foundation Acta Pdiatrica/Acta Pædiatrica 2008 97, pp. 663-672 Lee et al. Respiratory exacerbations with R117H-T CF mutation Figure 1 Chest X-ray demonstrating significant respiratory exacerbation with right middle lobe and lower lobe collapse and consolidation, with additional patchy consolidation bilaterally. Login to comment
39 Arg117His is an exon 4 missense mutation, which results in a full length of normally processed protein, but with reduced function at the cell membrane. Login to comment
43 Arg117His on a 5T background is associated with moderate-to-severe pancreatic-sufficient CF, however, Arg117His-7T can be associated with normal sweat electrolytes and some groups have suggested that it should not therefore be considered a CF causing mutation (6-8). Login to comment
48 Scotet et al. (2006), describing compound heterozygotes with Arg117His-7T identified through the newborn screening programme in Brittany, France, reported that none of the nine children had developed any signs of CF by a mean age of 7 years, and argued that Arg117His should be removed from the newborn screening mutation panel (5). Login to comment
51 Lording et al. (2006) describe a series of children who are compound heterozygous for Arg117His with the 7T allele and conclude that most children with this genotype have bacterial isolates from routine airway cultures that require antibiotic therapy three to four times a year (12). Login to comment
52 Similarly, Massie et al. (2001) have described three children, compound heterozygote Arg117His with 7T, who had borderline sweat tests and recurrent cough (13). Login to comment
53 O`Sullivan et al. (2006) described four cases of Phe508del with Arg117His-7T identified through newborn screening in Massachusetts USA (14). Login to comment
55 Although variation in genes other than the CFTR gene can cause CF-like symptoms (15), our paper provides additional evidence that significant respiratory exacerbations can be associated with Arg117His-7T in childhood. Login to comment
56 CONCLUSION Mild CF mutations such as Arg117His-7T are associated with less rapidly progressive lung disease but are not necessarily benign. Login to comment

PMID: 18428009 [PubMed] Umlawska W et al: "Growth and nutritional status in children and adolescents with cystic fibrosis."

No. Sentence Comment

72 (2) Thirty-nine per cent had a Á508/Mt genotype, where Mt represents a mutation other than Á508, such as R334W or R117H. Login to comment

PMID: 18449561 [PubMed] Zhou JJ et al: "Identification of positive charges situated at the outer mouth of the CFTR chloride channel pore."

No. Sentence Comment

144 Slightly reduced unitary conductance has previously been reported in the cystic fibrosis-associated mutant R117H [9, 20]; we suggest that this effect results from partial removal of this important positive charge and its electrostatic attractive effects on external Cl- ions. Login to comment

PMID: 18458238 [PubMed] Griesenbach U et al: "Validation of nasal potential difference measurements in gut-corrected CF knockout mice."

No. Sentence Comment

200 Most importantly, patients with ''mild`` CF mutations such as R117H who have some residual CFTR function (19) generally have less severe lung disease. 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

59 These samples, derived from CF patients, CF mutation carriers, and noncarriers, represented the mutations: 1717-1G4A (c.1585-1G4A), 3272-26A4G (c.3140-26A4G), F508del (c.1521_1523delCTT, p.Phe508del), and R117H (c.350G4A, p.Arg117His). Login to comment
72 The MMQCI-CF-P1 control distributed to EQA participants contained six homozygous mutations and one polymorphism: R553X (c.1657C4T, p.Arg553X), I507del (c.1519_1521delATC, p.Ile507del), R117 H (c.350G4A, p.Arg117His), 394delTT (c.262_263delTT, p.Leu88fs), 2183AA4G (c.2051_2052delAAinsG, p.Lys684fs), R347 H (c.1040G4A, p.Arg347His), and 5 T (c.1210-12T[5]). Login to comment
153 These very faint signals for wild-type R553X (c.1657C4T, p.Arg553X), wild-type R117H (c.350G4A, p.Arg117His), mutant G542X (c.1624G4T, p.Gly542X), and mutant A455E (c.1364C4A, p.Ala455Glu) signal were often not visible to the assessors on the copies of the raw data. Login to comment
191 For example, reporting the weak bands for wild-type R553X (c.1657C4T, p.Arg553X) and R117 H (c.350G4A, p.Arg117His), mutant G542X (c.1624G4T, p.Gly542X) and A455E (c.1364C4A, p.Ala455Glu) seen by some of the laboratories using the INNO-LiPA assay could be explained in this respect. Login to comment
84 Further, although reflex 5 T (c.1210-12T[5]) testing is required clinically when R117 H (c.350G4A, p.Arg117His) is detected in carriers [Grody et al., 2001b], not all laboratories performed or reported a reflex test for the polymorphic tract in intron 8 (polyT), again probably due to the synthetic nature of the sample. Login to comment
151 Similarly, one laboratory reported a weak signal for wild-type R117 H (c.350G4A, p.Arg117His) and normal signal for mutant R117 H (c.350G4A, p.Arg117His) instead of mutant R117 H (c.350G4A, p.Arg117His) homozygote. Login to comment

PMID: 18493878 [PubMed] Paranjape SM et al: "Atypical cystic fibrosis and CFTR-related diseases."

No. Sentence Comment

40 For example, the mild mutation R117H/7T can result in CBAVD and R117H/5T in nonclassic CF, whereas R117H/9T exhibits a normal phenotype. Login to comment
64 Determination of the transepithelial nasal potential difference has been beneficial in establishing a CF Table 1 Mutations, sites, and molecular consequences associated with either an atypical presentation of CF respiratory disease or pancreatic sufficiency or late-onset pancreatic insufficiency (http:// www.genet.sickkids.on.ca) Mutation Site Consequence Atypical presentation M1210I Exon 19 Met to Ile at 1210 S1455X Exon 24 Ser to Stop at 1455 1811+18G→A Intron 11 mRNA splicing defect L346P Exon 7 Leu to Pro at 346 Y161D Exon 4 Tyr to Asp at 161 R31C Exon 2 Arg to Cys at 31 I752S Exon 13 Ile to Ser at 752 2811G/T Exon 15 Sequence variation Pancreatic sufficiency or late-onset pancreatic insufficiency R600G Exon 13 Arg to Gly at 600 D1152H Exon 18 Asp to His at 1152 Y89C Exon 3 Tyr to Cys at 89 R117H Exon 4 Arg to His at 117 D110E Exon 4 Asp to Glu at 110 296 + 3insT Intron 2 mRNA splicing defect E217G Exon 6a Glu to Gly at 217 V392G Exon 8 Val to Gly at 392 N1088D Exon 17b Asn to Asp at 1088 S737F Exon 13 Missense 1716+1G→A Intron 10 mRNA splicing defect R334W Exon 7 Arg to Trp at 334 R347P Exon 7 Arg to Pro at 347 A455E Exon 9 Ala to Glu at 455 P574H Exon 12 Pro to His at 574 3850-3T→G Intron 19 mRNA splicing defect diagnosis in many atypical cases. Login to comment

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

No. Sentence Comment

107 For example the R117H mutation results in decreased chloride conductance [24], and when associated with a 5T polymorphism in intron 8, it leads to CF lung disease [18]. Login to comment
108 However, patients with an R117H/7T haplotype have been reported to also have clinical features of CF lung disease [25, 26]. Login to comment
114 Figure reproduced from Ref. [6], with permission Table 7 Classes of CFTR gene mutations associated with CF disease Mutation class Mechanism of action Examples I Absence of protein synthesis because of a stop codon in the gene G542X II Improper folding and processing ΔF508 III Reduced response to regulatory molecules G551D IV Reduce ion conductance R117H V Decreased protein production due to splice defects or promoter mutations 3,849+10 kb C→T VI Decreased protein stability Q1412X 104 measurement of transepithelial ion flow in the nasal mucosa [28-30]. Login to comment

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

No. Sentence Comment

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

PMID: 18597042 [PubMed] Mornon JP et al: "Atomic model of human cystic fibrosis transmembrane conductance regulator: membrane-spanning domains and coupling interfaces."

No. Sentence Comment

209 The arginine R117 residue in ECL1 has been found to influence the channel properties and, accordingly, the well-known R117H mutation, which is generally associated with mild clinical disease, leads to reduced single-channel properties and open probability [63]. Login to comment

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

No. Sentence Comment

35 the IVS8-5T variant and R117H (Claustres. 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
148 It may be difficult to distinguish these individuals from those with disease in single organs (eg, congenital absence of the vas deferens, idiopathic pancreatitis, various sinopulmonary disorders), who carry a higher frequency of CFTR gene mutations than the general population.16,57,58 An example of the complexity of mutation analysis is found in the evolving picture of individuals who are compound heterozygotes for a CF-causing mutation and the R117H mutation in the CFTR gene. Login to comment
149 The likelihood of CF in this group is driven by the length of a polythymidine tract in intron 8 of the R117H allele. Login to comment
150 The presence of a 5T tract in the R117H background is usually associated with CF, whereas R117H(7T) is more often associated with isolated male infertility or pancreatitis.59 But individuals from both groups may display sweat chloride values in the normal, intermediate, or diagnostic range,60 and some individuals with R117H(7T) can present with CF lung disease. Login to comment

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

No. Sentence Comment

144 A (T)5 variant can either be associated with (TG)11, (TG)12, (TG)13, and rarely (TG)15 repeats.74 When (T)5 is found in diagnostic testing, for example, for CBAVD or atypical presentation, determination of Table 4 Classification of CFTR mutations with regard to their potential for causing disease Mutation group Examples CF-causing F508del Mainly nonsense, frameshift, splicing (invariant dinucleotide): G542X, R553X, W1282X, 2183AA4G, 3659delC, 1717-1G4A, 3120+1G4A Missense that severely affects CFTR synthesis or function: G551D, N1303K, R347P 2789+5G4A, 3849+10kbC4T, 3272-26A4G, L206Wa , D1152Ha , (TG)13(T)5a CFTR-related disorders associated L206Wa , D1152Ha , (TG)13(T)5a [R117H;(T)7], (TG)12(T)5, L997F, V562I, [R668C;G576A;D443Y], [R74W;D1270N] (TG)11(T)5b , S1235Rb No clinical consequences 875+40A4G, M470V (1540A4G), I506V (1648A4G), F508C (1655T4G), 1716G4A, 2694T4G, 4002A4G, 2752-15G4C (TG)11(T)5b , S1235Rb Unproven or uncertain clinical relevance Mainly missense mutations G622D, R170H, V938G, I125T Putative splice mutations: 406-6T4C, 2752-26A4G, 3601-17T4C Only a fraction of mutations and patients have been characterized in detail and, with the exception of frequent mutations, only small numbers of patients have been available for the study of most mutations. Login to comment
151 I148T should not be routinely screened for and is currently being removed from the panels of commercial assays.25 R117H Can be found in cis with IVS8 (T)5 or (T)7. Login to comment
152 [R117H;(T)5] is considered a mild CF-causing complex allele, whereas [R117H;(T)7] is considered more as a CFTR-RD mutation. Login to comment
153 In neonatal screening programmes, the high frequency of R117H in newborns with elevated immunoreactive trypsinaemia78 has raised the question of its penetrance and its clinical significance for genetic counselling. Login to comment
154 So far, children who are compound heterozygous for [R117H;(T)7] and a severe CF-causing mutation have shown no clinical signs of CF.78 Given these observations, identification of R117H in trans with F508del in neonates should be completed by IVS8 poly(T) testing. Login to comment
155 If R117H is in cis with (T)7, genetic counselling should be reassuring. 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
64 R117H, R553X, N1303K & G551D were identified by ARMS on a total of five chromosomes. Login to comment
96 Table 2 Genotypes of CF subjects (n=50) Genotype Number of subjects Delta F508/Delta F508 5 Delta F508/3849+10kb C-T 1 Delta F508/S549N 2 Delta F508/S158N 1 Delta F508/Y1381H 1 Delta F508/1525-1 G-A 2 V520F/R117H 1 I530L/I530L 1 876-6del4/876-6del4 1 1792ins A/1792insA 1 3986-3987delC/3986-3987delC 1 Delta F508/U 10 1161 delC/U 2 L69H/U 1 R117H/U 1 Q493L/U 1 Y517C/U 1 S549N/U 3 G551D/U 1 E1329Q/U 1 N1303K/U 1 Y1381H/U 1 L218X/U 1 R553X/U 1 1525-1G-A/U 3 3120+1G-A/U 2 3849+10kb C-T/U 2 U/U 1 U-unidentified Table 3 Outcome prediction scores of novel substitution mutations identified in Indian CF patients Wild type Mutant Position Output Reliablity Prediction L H 69 0.5210 0 Pathological S N 158 0.3304 3 Neutral Q L 493 0.7784 5 Pathological I L 530 0.0591 8 Neutral E Q 1329 0.1018 7 Neutral Molecular Modelling and Bioinformatics (MMB) program (http://mmb.pcb.ub.es/PMut/) was used for pathological predictions of novel sequence variants. Login to comment
113 We first identified five of the mutations by ARMS (Delta F508, R117H, R553X, N1303K & G551D) and one by restriction digestion (3849+10kbC-T) and later identified by SSCP eight known (Y517C, V520F, S549N, Y1381H, 1525-1G-A, 3120+1G-A, 1161delC and L218X) and eight previously unreported mutations (L69H, S158N, Q493L, I530L, E1329Q, 876-6del4, 1792insA and 3986-3987delC). 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

39 R117H, N1303K, and R553X mutations were analyzed by single ARMS PCR, and 621 ? Login to comment

PMID: 18846238 [PubMed] Chen J et al: "Dysfunction of Nrf-2 in CF epithelia leads to excess intracellular H2O2 and inflammatory cytokine production."

No. Sentence Comment

86 To test whether differences in the redox proteins observed in CF cells extended to an in vivo model of CF, we examined protein expression, by 2-D gel analysis, in the excised nasal epithelia (NE) and whole lungs of R117H mutant mice compared with normal littermates. Login to comment
358 The B6.129S6-Cftrtm2Mrc mice are R117H murine Cftr mutants that have been back-crossed into the C57BL6j background [46]. 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: 18953522 [PubMed] Tuttelmann F et al: "[Genetics of male infertility]."

No. Sentence Comment

73 Diese Befunde begründen die nachfol- gende genetische Diagnostik, die bei CBAVD-Patienten in >70% der Fälle zwei mutierte CFTR-Allele und in ca. 10% der Fälle ein mutiertes Allel ergibt [10], wobei sich das Mutationsspektrum teilweise von demjenigen bei CF-Patienten unterscheidet. Die häufigsten Mutationen bei CBAVD sind ΔF508, das 5T-Allel und R117H. Login to comment

PMID: 19033671 [PubMed] Coakley RD et al: "17beta-Estradiol inhibits Ca2+-dependent homeostasis of airway surface liquid volume in human cystic fibrosis airway epithelia."

No. Sentence Comment

282 Five patients were homozygous for ΔF508, 2 patients carried 1 copy of ΔF508 with an unidentified mutation on the other allele, 1 patient carried 1 copy of ΔF508 and 1 copy of R117H, 1 patient carried 1 copy of ΔF508 and 1 copy of 2789+5G→A, and 1 patient carried 1 copy of 1717-1G→A and 1 copy of N1303K. 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
98 For example, compound heterozygotes with ⌬F508/A455E have better pulmonary function than individuals who are homozygous for ⌬F508.10 In individuals with one or two R117H mutations, the severity of lung disease depends on the presence of a variation in the poly T tract of intron 8.44,45 Individuals with the 5T variant in cis configuration with the R117H mutation plus a second CFTR disease-causing mutation usually develop the lung disease of CF; but those individuals with the 7T variant in cis configuration with the R117H mutation plus a second CFTR disease-causing mutation have a highly variable phenotype, which can range from no symptoms to mild lung disease (Table 4).44,46 Because the A455E and R117H mutations are associated with pancreatic sufficiency, the less severe lung disease seen in individuals with these mutations could be the consequence of better nutritional status. Login to comment
99 CAVD usually results from the combination of one severe CFTR mutation on one chromosome with either a mild CFTR mutation or the 5T allele (even in the absence of R117H) on the other chromosome (Table 5). Login to comment
104 The mechanism of partial penetrance of the 5T allele for CAVD is due to variation in the length of the adjacent TG tract (estimated at 60% in one study).50,51 Thus, interpretation of the disease implications of the 5T variant requires assessment of the number of TG repeats adjacent to the polythymidine tract.51 DIAGNOSIS AND TESTING Clinical phenotype Phenotypic features of CF include but are not limited to the following: ● Chronic suppurative sinopulmonary disease, with chronic coughandsputumproduction,chronicwheezeandairtrap- ping, obstructive lung disease on lung function tests, persistent colonization with pathogens commonly found in individuals with CF, chronic chest radiograph abnormalities, chronic pansinusitis, and/or digital clubbing Table 5 Proportion of CFTR genotypes detected in men with CAVD, based on pooled data4,47,57,116 Allele 1 Allele 2 Proportion (%)a 5T 5T 2 Other than 5T Other than 5T 26 5T Other than 5T 26 5T Wild type 8 Other than 5T Wild type 17 Wild type Wild type 22 a Percentages total to Ͼ100% because of rounding Table 4 CFTR genotype-phenotype correlations41,44,50,51,57,114-116 Allele 1 Allele 2 Range of phenotypes Classica Classic Classic ϾϾ nonclassic Milda Classic or mild Nonclassic Ͼ classic R117H/5T Classic or mild Nonclassic Ͼ classic R117H/7T Classic or mild Asymptomatic female or CAVD Ͼ nonclassic 5T/TG13 or TG12 Classic or mild CAVD or nonclassic CF ϾϾ asymptomatic carrier 5T/TG11 Classic or mild Asymptomatic Ͼ CAVD 7T or 9T Classic or mild Asymptomatic 7T or 9T 7T or 9T Asymptomatic a Classic refers to Class I, II, and III mutations (e.g., ⌬F508); mild refers to Class IV and V mutations (e.g., A455E) exclusive of R117H and 5T alleles (see Table 1). Login to comment
152 The 5T variant decreases the efficiency of intron 8 splicing.72 If an individual with R117H also has the 5T allele, family studies are recommended to determine if the 5T allele is in cis configuration or trans configuration with the R117H allele. Login to comment
156 b Detection is based on re-sequencing of all coding sequences, splice donor and acceptance sites, the promotor region and two intronic sequences.73 with a shorter poly T tract (5T) has the strongest adverse effect on proper intron 8 splicing.50,51 5T/TG tract analysis should not be included in a routine carrier screen, but is appropriate as a reflex test when an R117H mutation is detected. 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
73 In the CAVD patients with normal renal development, the initial screening identified one extra, R117H mutation in three chromosomes. Login to comment
75 Other identified mutations R117H, 3120 þ 1 . Login to comment
105 A compound heterozygous, R117H/F87I, genotype was identified in a CBAVD subject with normal sweat chloride and no CF-like symptoms. Login to comment
107 of alleles T5 Reduction of oligo T tract to 5T at 1342-6 Aberrant splicing Intron 8 25 F508del Deletion of 3 bp (CTT or TTT) between 1652 and 1655 Deletion of phenylalanine at 508 Exon 10 11 L69Ha T to A at 338 Leucine to histidine at 69 Exon 3 1 F87Ia T to A at 391 Phenylalanine to isoleucine Exon 3 1 R117H G to A at 482 Arginine to histidine at 117 Exon 4 3 G126Sa G to A at 508 Glycine to serine at 126 Exon 4 1 F157Ca T to G at 602 Phenylalanine to cystine at 157 Exon 4 1 E543Aa A to C at 1760 Glutamate to alanine at 543 Exon 11 1 Y852Fa A to T at 2687 Tyrosine to phenylalanine at 852 Exon 14a 1 3120 þ 1 G-A G to A 3120 þ 1 Aberrant splicing Intron 16 1 P1021S C to T at 3193 Proline to serine at 1021 Exon 17a 1 D1270Ea T to A at 3942 Aspartate to glutamate at 1270 Exon 20 1 Total chromosomes: 100; known mutations: 48%; unknown mutations: 52%. Login to comment
145 of patients (%) Two mutations detected 22% IVS8-T5/IVS8-T5 5 (10) (TG)12T5/(TG)12T5 2/2 2/2 1/1 1/1, 1/2 2 (4) (TG)12T5/(TG)13T5 1/1 2/1 2/1 (1), 2/2 (1) 1/1 (1), 1/2 (1) 2 (4) (TG)11T5/(TG12)T5 1/2 1/1 2/2 2/2 1 (2) IVS8-T5/F508del (TG)13T5/(TG10)T9 2/2 1/1 1/1 1/1 1 (2) IVS8-T5/R117H (TG)12T5/(TG)12T7 1/1 2/2 2/2 1/1 1 (2) IVS8-T5/Y852F (TG)12T5/(TG)12T7 1/1 1/2 2/1' 1/2 1 (2) IVS8-T5/D1270E (TG)12T5/(TG)12T9 1/1 1/1 2/2 2/2 1 (2) F508del/G126S (TG)10T7/(TG)11T7 2/2 1/1 1/1 1/1 1 (2) R117H/F87I (TG)12T7/(TG)12T7 1/1 2/1 2/2 1/2 1 (2) One mutation detected 52% F508del/? Login to comment
149 (TG)12T7/(TG)12T7 1/1 2 1 2 1 (2) R117H/? Login to comment

PMID: 19298730 [PubMed] Radpour R et al: "Novel cause of hereditary obstructive azoospermia: a T2 allele in the CFTR gene."

No. Sentence Comment

9 This patient carried a [TG11 T9 ; R117H; p.Met470Val] haplotype on the other chromosome. Login to comment
10 Since the TG13 T2 allele was a compound heterozygote with R117H mutation, it was difficult to judge the severity of this allele. Login to comment
56 Whole gene screening for base substitutions and exon rearrangements identified the R117H mutation and M470V polymorphism. Login to comment
57 The T2 allele was found to be associated with haplotype [TG13 T2 ; p.Met470], while haplotype [TG11 T9 ; p.Val470; R117H] was present on the other allele (Table 1). Login to comment
64 Trans-abdominal ultrasonography in patient with R117H and IVS8-2T mutations. Login to comment
68 Mutation type IVS8-(TG)m Tn M470V R117H TG11 T9 /TG13 T2 M/V Mutation genotypes were designated following the recommended nomenclature (Beaudet and Tsui, 1993). Login to comment
94 Since the TG13 T2 allele was a compound heterozygote with R117H, it was difficult to judge the severity of thisallele and its role in the CBAVD phenotype.To better understand the complex regulation of exon 9 splicing, the levels of correctly spliced CFTR transcripts in cultured CFTR-expressing epididymal cells and vas deferens cells were analysed. These data emphasize the role of the T2 allele in CBAVD, and identify the T2 allele as a severe CBAVD disease-causing mutation. Login to comment

PMID: 19318346 [PubMed] Goubau C et al: "Phenotypic characterisation of patients with intermediate sweat chloride values: towards validation of the European diagnostic algorithm for cystic fibrosis."

No. Sentence Comment

113 CF-PI, sweat chloride concentration .60 mmol/l and pancreatic insufficiency; CF-PS, sweat chloride concentration .60 mmol/l and pancreatic sufficiency; CFTR dysfunction, sweat chloride concentration 30-60 mmol/l and two mutations identified and/or abnormal nasal potential difference (NPD); CF unlikely, patients with an intermediate sweat chloride concentration but no detection of two CFTR mutations and/or normal NPD; FEV1, forced expiratory volume in 1 s. restricted to patients with both NPD parameters abnormal and only accepting mutation R117H or 5T when associated with TG13 or TG12 (n = 45), the study conclusions that patients with CFTR dysfunction differ from patients with ''CF unlikely`` remain steadfast (see online supplement). Login to comment

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

No. Sentence Comment

62 We had initially focused on CF mutations potentially prevalent in our local, ethnically mixed, but mainly German population: F508del, I507del, 1677delTA, R347P, G542X, G551D, R553X, N1303K, 1717-1GϾA, 3849ϩ10kb CϾT, CFTRdele2,3 (21 kb), R117H, 1342-6 (T)n (5T/7T/9T) (reported by our laboratory only if a R117H allele was present, unless genetic analysis served to investigate a case of CBAVD or atypical mild CF), and the (TG)n region starting at base position 1342-12 of IVS 8 (exclusively tested in the case of a 5T allele) (Fig. 1, boldface text), with an expected sensitivity of 85% among German patients. Login to comment
88 A PSQ-adapted long-range PCR [modification of method of Pont-Kingdon et al. (25)] for haplotyping of 5T and R117H will complement the panel if an R117H-5T (CF haplotype) control becomes available. Login to comment
100 Diagnostic evaluation of the PSQ-based first-level testing of a predominantly German CF population.a Panethnic population Clinical diagnosis All patients Sweat test-confirmed CF Suspected atypical CF Carrier screening Chromosomes, n 310 184 96 30 PSQ screen 168 (54.2%) 158 (85.9%) 5 (5.2%) 5 (33.3%) Conventional sequencing 25 (8.1%) 25 (13.6%) 0 (0%) 0 (0%) Total detected alleles 193 (62.3%) 183 (99.5%) 5 (5.2%) 5 (33.3%) German ethnicity Other ethnicities Clinical diagnosis Sweat test-confirmed CF Sweat test-confirmed CF Chromosomes, n 146 38 PSQ screen F508del 106 (72.6%) 14 (36.8%) I507del 1 (0.7%) 1 (2.6%) 1677delTA 0 (0%) 2 (5.3%) G551D 6 (4.1%) 0 (0%) R553X 2 (1.4%) 0 (0%) Q552X 1 (0.7%) 0 (0%) G542X 2 (1.4%) 1 (2.6%) S549N 0 (0%) 2 (5.3%) W1282X 1 (0.7%) 3 (7.9%) R117H 1 (0.7%) 0 (0%) 1342-12 (TG)11-5T 0 (0%) 0 (0%) R347P 2 (1.4%) 1 (2.6%) 3849ϩ10kb CϾT 2 (1.4%) 0 (0%) N1303K 3 (2.1%) 3 (7.9%) 1717-1 GϾA 1 (0.7%) 0 (0%) CFTRdele2,3 (21 kb) 2 (1.4%) 1 (2.6%) Sum 130 (89.0%) 28 (73.7%) Conventional sequencing 16 (11.0%) 9 (23.7%) Total detected alleles 146 (100%) 37 (97.4%) a Data are presented as the number of chromosomes (percent). Login to comment
130 With respect to haplotyping of R117H-5T, we suggest an assay based on a long-range PCR described by Pont-Kingdon et al. (25) that we have adapted to PSQ but have not yet been able to validate because of a lack of positive-control samples. Login to comment

PMID: 19453252 [PubMed] Chen JM et al: "Chronic pancreatitis: genetics and pathogenesis."

No. Sentence Comment

52 The Old Chymotrypsinogen Numbering System Versus the New Standard Numbering System Although the first two HP-causing missense mutations in the PRSS1 gene, R117H (139) and N21I (46), were originally named under the old chymotrypsinogen numbering system, all those subsequently found have been numbered in accordance with the new standard numbering system in which the initiator methionine is counted as +1. Login to comment
53 R117H and N21I were renamed R122H and N29I in 2000. Login to comment

PMID: 19648474 [PubMed] Griesenbach U et al: "Limitations of the murine nose in the development of nonviral airway gene transfer."

No. Sentence Comment

277 Most importantly, patients with ''mild`` CF mutations, such as R117H who have some residual CFTR function (35), generally have less severe lung disease. Login to comment

PMID: 19700644 [PubMed] Nichols DP et al: "The triterpenoid CDDO limits inflammation in preclinical models of cystic fibrosis lung disease."

No. Sentence Comment

10 In our experiments, mice carrying the R117H Cftr mutation have significantly reduced airway inflammatory responses to both LPS and flagellin when treated with CDDO before inflammatory challenge. Login to comment
42 In this paper, we test the hypothesis that the synthetic triterpenoid, 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO) can effectively suppress the inflammatory response in preclinical models of CF airway inflammation using human airway epithelial cells lacking CFTR and mice carrying the Cftr mutation R117H. Login to comment
119 Thirty-two mice with the R117H CFTR mutation (B6.129S6-Cftrtm2Mrc ) and 18 wild-type (WT) mice on the C57BL/6 genetic background were bred and housed in our Animal Research Core facility under specific pathogen-free conditions. Login to comment
120 R117H mice were selected as this is a human CF mutation and may avoid additional NF-␬B activation caused by protein misfolding and the buildup of dysfunctional proteins in the endoplasmic reticulum (ER) that can occur with other mutations (e.g., ⌬F508) (45). Login to comment
122 Electrophysiological phenotype (i.e., nasal potential difference) and inflammatory responses in the lung to P. aeruginosa are very similar in R117H mice and multiple other CF transgenic mice, including mice bearing the ⌬F508 or S489X mutation (40). Login to comment
254 In addition to characterizing the effect of CDDO in CF models, a primary aim of this research was to test the biological relevance of this synthetic triterpenoid in an in vivo CF model using mice carrying the R117H Cftr mutation. Login to comment

PMID: 19717257 [PubMed] Maire F et al: "[From the chronic pancreatitis to chronic pancreatites]."

No. Sentence Comment

30 Une mutation faux sens, appelée initialement R117H (dite R122H dans la nomenclature internationale) était présente chez la quasi-totalité des patients et absente chez les sujets sains. Login to comment

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

No. Sentence Comment

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

PMID: 19734299 [PubMed] Comer DM et al: "Clinical phenotype of cystic fibrosis patients with the G551D mutation."

No. Sentence Comment

10 Conclusions: Mutations on different chromosomes are not independent of each other for the overall impact on the amount of functional CFTR. This study suggests that patients with the G551D mutation and a second severe mutation have a milder clinical phenotype than F508del homozygous patients, but the phenotype is not as mild as patients with the R117H mutation. Login to comment
24 To address this, we compared the clinical phenotype of patients with a G551D mutation, a Class 3 mutation, with patients homozygous for F508del and those with the missense mutation R117H (Arginine to histidine mutation of residue 117), a Class 2 and 4 mutation, respectively. Login to comment
25 Including the R117H mutation, a missense mutation in exon 4 and the most common mutation in its class, allowed a comparison across three groups to be established. Login to comment
26 Compound heterozygotes for the G551D and R117H were studied as a separate group. Login to comment
30 Group 1 included F508del homozygote patients, Group 2 with the G551D on either chromosome (and without the R117H mutation), Group 3 with the R117H mutation on either chromosome (and without the G551D mutation) and Group 4 compound heterozygotes for the R117H and G551D mutation. Login to comment
36 Results Group 1 (F508del homozygote patients) included 61 patients, Group 2 (patients heterozygous for G551D) 13 patients, Group 3 (patients heterozygous for R117H) 23 patients and Group 4 (compound R117H/G551D patients) 4 patients. Login to comment
39 Two patients in Group 2 (G551D/621+1G!T, G551D/3659delC) and 1 in Group 3 (R117H/ E60X) were heterozygous with a CFTR mutation other than F508del. Login to comment
54 Discussion Comparing F508del homozygous CF patients to those heterozygous for G551D and R117H, we have shown that the latter two groups individually have better lung function, slower rate of decline in FEV1, older age at diagnosis, better nutritional status, reducing infection with P. aeruginosa and B. cepacia complex, reduced burden of care and improved pancreatic status and glucose tolerance. Login to comment
61 The R117H mutation is commonly associated with the genetic polymorphism of the polypyrimidine tract in intron 8 giving rise to variable amounts of functional CFTR. This polymorphism exists on an intron-8 polythymidine sequence (IVS8) as a 5-, 7- or 9-thymidine (T) variant. Login to comment
62 These alleles cause intron Table 1 Genotype details of the 101 CF patients Group Genotype Patients (n) 1 F508del/F508del 61 2 G551D/F508del 11 G551D/621+1G!T 1 G551D/3659delC 1 3 R117H/F508del 22 R117H/E60X 1 4 G551D/R117H 4 8 to be incorrectly spliced leading to mRNA lacking exon 9 and so a reduced amount of normal CFTR transcript. Login to comment
63 R117H with the 5T variant are most severely affected.3 Each mutation, the missense mutation R117H in exon 4 and the 5T polymorphism in intron 8, have a mild phenotypic effect unless they are present on the same chromosome. Login to comment
65 In contrast to the number of T repeats, high numbers of TG repeats will result in a reduced amount of functional CFTR.16 The incidence of R117H on an IVS8-5T background was much higher in our cohort in comparison to a multicentre study of patients with the R117H/C mutation (39 with the R117H and 2 with the R117C mutation). Login to comment
66 In this study of 41 patients, 16 had the R117H mutation on an IVS8-5T background, and 25 on an IVS8-7T background.17 TG repeats were not determined in this study. Login to comment
68 In our study, the lack of any significant CF phenotype in patients compound for R117H/G551D compared with R117H/F508del mutations is intriguing. Login to comment
69 Compound heterozygosity for G551D/R117H mutations was associated with normal spirometry, BMI, no chronic infection and no symptoms. Login to comment
73 Only 52% of patients who are compound heterozygotes for R117H, where the second mutation was a severe mutation, were pancreatic sufficient. Login to comment
74 In the Cystic Fibrosis Genotype-Phenotype Consortium, 87% of patients with the R117H/F508del mutation had pancreatic sufficiency2 ; however, the older age in our cohort may account for this difference (31.7 Æ 1.8 vs. 23.5 Æ 9.6 years). Login to comment
76 In addition, the particularly high incidence of R117H on an IVS8-5T background in our centre, with its associated Table2PhenotypicvariablesforGroups1-4(genderratio,meanvalueÆSDandrangeforcontinuousvariables,percentagewithORforcategoricalvariables) Group1:F508del homozygote Group2:G551D+ severemutation Group3:R117H+ severemutation Group4: R117H/G551D Male/Female41/207/614/92/2 Age(years)27.6Æ6.9(17.7to48.2)26.3Æ4.5(20.1to35.5)31.7Æ13.3(19.8to76.6)35.3Æ3.2(31.3to39) Ageatdiagnosis(years)3.9Æ8.1(3to26)3.9Æ5.7(0.1to19)16.4Æ19.1(0to73.4)ÃÃ 13.8Æ16.7(0to29.3) PercentagepredictedFEV156.3%Æ22(19to110)77.5%Æ18.8(50to110)Ã 83.4%Æ21.2(27to116)ÃÃ 100%Æ2.4(97to102) YearlyrateofdeclineofFEV1(%/year)1.6Æ0.9(À0.5to4.0)0.9Æ0.7(À0.3to2.4)Ã 0.5Æ0.7(À0.7to1.8)Ã 0Æ0.1(0to0.1) BMI(kg/m2 )21.4Æ2.8(15.1to29.9)23.7Æ3.0(17.5to28.4)Ã 24.7Æ3.5(18.3to30.6)ÃÃ 26.6Æ1.1(25.2to28) InfectionwithP.aeruginosa75%62%(OR:0.5)26%(OR:0.1)ÃÃ 0% CultureofB.cepaciacomplex16%0%0%0% Useofazithromycin56%54%(OR:0.9)35%(OR:0.4)0% UseofrhDNase61%39%(OR:0.4)22%(OR:0.2)Ã 0% NumberofdaysofIVAb21.8Æ24.3(0to98)8.7Æ17.4(0to60)4.7Æ12.3(0to42)Ã 0(0) IGT/CFRD23%8%4%0% Useofinhaledantibiotic74%31%(OR:0.5)26%(OR:0.4)0% Pancreaticinsufficient97%69%(OR:0.07)Ã 48%(OR:0.03)ÃÃ 25%(OR:0.02)Ã Ã ComparedtoGroup1(P<0.05);ÃÃ ComparedtoGroup1(P<0.001);OR:OddsratiorelativetoGroup1. Login to comment
82 Many of the patients in this study will have started taking pancreatic-enzyme supplementation immediately after diagnosis and so our data will be an overrepresentation of the overall amount of PI, particularly in G551D and R117H patients. Login to comment

PMID: 19737283 [PubMed] Chiang HS et al: "CFTR (TG)m(T)n polymorphism in patients with CBAVD in a population expressing low incidence of cystic fibrosis."

No. Sentence Comment

79 F508del or R117H, which causes the development of CBAVD in Caucasian populations (15). Login to comment

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

No. Sentence Comment

65 Class III mutations cause defective protein regulation due to alterations of NBD1 and NBD2 that prevent channel activation by cyclic adenosine monophosphate (cAMP) or adenosine triphosphate (ATP).6-8 Additionally, some mutations within this class alter the function of ion channels regulated by CFTR such as the outwardly rectifying chloride chan- nel26 and the ROMK2 potassium channel.27 Class IV mutations, such as R347P, R117H, and R334W, yield conduction abnormalities resulting in diminished chloride conductance. Login to comment
96 More thorough DNA analysis now demonstrates that CF mutation carriers with chronic idiopathic pancreatitis (CIP) are likely to be compound heterozygotes with a severe and mild mutation or homozygous for commonly causing CF mutations.36,37 Cohn et al, for example, demonstrated an association between chronic pancreatitis and several CFTR mutations: ~F508, N1303K, and R117H. Login to comment
99 They also found an association with ~F508 and R117H in addition to Q493X, R560T, R553X, and 621 þ 1(G!T).34 Noone et al found an association between chronic pancreatitis and the 5T allele associated with complex alleles or in CFTR compound heterozygotes, but no significantly increased frequency has been found with the 5T allele alone.36,39 Finally, there appears to be an additive effect with being a CFTR compound heterozygote and the presence of N34S mutations of the pancreatic secretory trypsin inhibitor (PSTI).36,39 These studies demonstrate the increased risk of chronic pancreatitis due to an abnormally functioning CFTR protein (but may be due to just one mutant CFTR allele37 ). Login to comment
105 DNA analysis in $40 to 85% of patients reveals an autosomal recessive pattern including either a severe and mild CF mutation or two mild mutations.13,41,42 Most patients are compound heterozygotes, and ~F508 is present on one allele in $40% of this group.42,43 Other common mutations include R117H (3 536 SEMINARS IN RESPIRATORY AND CRITICAL CARE MEDICINE/VOLUME 30, to 14%) and the 5T variant of the polythymidine tract of the intron 8 (IVS8) acceptor splice site. Login to comment

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

No. Sentence Comment

92 In an attempt to define which class this mutation might belong to, we compared S1118F-CFTR with other well-defined classes of CFTR-mutations such as DF508-CFTR (Class II), G551D-CFTR (Class III) and R117H-CFTR (Class IV) and the data is shown in Figure 1D. It is likely that S1118F-CFTR is a trafficking mutant with impaired maturation. Login to comment
114 D: HEK-293cells weretransiently transfected with pCDNA3 containing WT-, S1118F-, R117H-, G551D- or DF508-CFTR cDNA, lysed 48 hr later, immunoprecipitated (a 24-1 mab) and western blotted for CFTR (a 24-1 mab). Login to comment
149 G551D-CFTR (Class III; regulation mutant) and R117H (Class IV; permeation mutant) are mutations with partial loss of channel function. 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: 19846789 [PubMed] Van Goor F et al: "Rescue of CF airway epithelial cell function in vitro by a CFTR potentiator, VX-770."

No. Sentence Comment

19 Although less common, CFTR mutations that primarily impair the ability of CFTR at the cell surface to open (e.g., G551D) or conduct Cl- or HCO3 - (e.g., R117H) are also found in CF patients (5, 18). Login to comment

PMID: 19865788 [PubMed] Reddy MM et al: "PKA mediates constitutive activation of CFTR in human sweat duct."

No. Sentence Comment

9 Keywords CFTR Á DF508 CFTR Á R117H CFTR Á PKA Á PKG Á G proteins Á Glutamate Á a-toxin Á Okadaic acid Introduction Generally, epithelial ion channels are thought to be activated by neurohumoral stimuli in response to electrolyte transport demand but to remain inactive in the absence of such stimuli. Login to comment
91 Sweat Ducts from DF508/DF508 CF Subjects Sweat ducts from homozygous (DF508/DF508) or heterozygous (DF508/R117H) CF subjects were initially perfused with 150 mM NaCl in the bath and 150 mM NaCl ? Login to comment
97 Sweat Ducts from R117H/DF508 CF Subjects We noticed significant depolarization of transepithelial potential of heterozygous (DF508/R117H) CF ducts when bath NaCl was replaced with KGlu (Fig. 3b), although the magnitude of depolarization of these compound heterozygous CF ducts was relatively smaller compared to that of normal ducts (Figs. 1a, 3b). Login to comment
98 In contrast to the lack of electrical response of DF508 homozygous CF ducts, the application of a-toxin induced qualitatively similar electrical responses in heterozygous (DF508/R117H, i.e., gradual increase in transepithelial resistance corresponding with pore formation and loss of intracellular messengers) as observed in normal ducts (Figs. 1a, 3b). Login to comment
119 b In contrast to the homozygous CF ducts, heterozygous CF ducts with R117H/DF508 mutations showed a small but consistent depolarization to the imposed Cl-gradient. Login to comment
121 These results are consistent with the fact that R117H CF mutation retains residual Cl-conductance. Login to comment
220 (C) and (L) represent cytosolic bath and lumen, respectively (Fig. 3a) or significantly smaller (in heterozygous R117H/ DF508 CF ducts that partially express CFTR activity) (Reddy and Quinton 2003) (Fig. 3b) compared to non-CF ducts (Fig. 1). Login to comment
221 Furthermore, permeabilization of the basolateral membrane with a-toxin either had no effect in homozygous DF508 CF ducts (Fig. 3a) or had qualitatively similar but quantitatively smaller effects on transepithelial potential or conductance of R117H/DF508 CF ducts, which is consistent with reduced gCFTR in these ducts. Login to comment

PMID: 19880712 [PubMed] Thauvin-Robinet C et al: "The very low penetrance of cystic fibrosis for the R117H mutation: a reappraisal for genetic counselling and newborn screening."

No. Sentence Comment

1 Phenotypic variability associated with certain mutations makes genetic counselling difficult, notably for R117H, whose disease phenotype varies from asymptomatic to classical CF. Login to comment
2 The high frequency of R117H observed in CF newborn screening has also introduced diagnostic dilemmas. Login to comment
3 The aim of this study was to evaluate the disease penetrance for R117H in order to improve clinical practice. Login to comment
4 Methods: The phenotypes in all individuals identified in France as compound heterozygous for R117H and F508del, the most frequent CF mutation, were described. Login to comment
5 The allelic prevalences of R117H (pR117H), on either intron 8 T5 or T7 background, and F508del (pF508del) were determined in the French population, to permit an evaluation of the penetrance of CF for the [R117H]+[F508del] genotype. Results: Clinical details were documented for 184 [R117H]+[F508del] individuals, including 72 newborns. Login to comment
8 The theoretical number of [R117H;T7]+[F508del] individuals in the French population was estimated at 3650, whereas only 112 were known with CF related symptoms (3.1%). Login to comment
9 The penetrance of classical CF for [R117H;T7]+[F508del] was estimated at 0.03% and that of severe CF in adulthood at 0.06%. Login to comment
10 Conclusions: These results suggest that R117H should be withdrawn from CF mutation panels used for screening programmes. Login to comment
13 The R117H mutation was initially considered as a mutation causing mild CF with pancreatic sufficiency,10 in keeping with a residual CFTR function supported by in vitro studies.11 R117H was then considered as predominantly associated with isolated CBAVD,4 12-14 generally in compound heterozygosity with F508del, the most frequent CF mutation. Login to comment
14 Incidentally, the [R117H]+[F508del] genotype was observed in asymptomatic individuals.15 Phenotypic variability was mostly attributed to the presence of a polypyrimidine variant in the intron 8 acceptor splice site (T5 or T7) in cis with R117H, leading to R117H;T5 or R117H;T7 alleles. Login to comment
15 While the T7 variant is considered neutral, the T5 variant was shown to affect exon 9 splicing reducing the amount of CFTR protein, probably causing a more severe phenotype.15 16 It was therefore suggested to consider R117H as a CF mutation only in the context of the R117;T5 complex allele.17 However, early pulmonary manifestations were reported in patients carrying a severe CF mutation and R117H;T7.16 18-20 The implementation of systematic CF newborn screening (CFNBS) since 2002 in France, relying on determination of immunoreactive trypsinemia (IRT) and subsequent screening for 30 common CFTR mutations when IRT is above 65 mg/l, led to observe a much higher frequency of R117H;T7 in this population than in CF patients,21 adding further to the diagnostic dilemma.16 21-24 To assist with genetic counselling and to improve diagnostic practice, we implemented a large collaborative study to: (1) delineate the overall disease phenotype associated with R117H, and (2) evaluate the penetrance of CF in carriers of the [R117H]+[F508del] genotype-that is, the probability of individuals with this genotype to develop CF. Login to comment
16 Another issue was to determine to what extent CFNBS methods select for [R117H]+[F508del] newborns. Login to comment
17 SUBJECTS AND METHODS Cross-sectional phenotypic study of individuals compound heterozygous for R117H and F508del All individuals known to the French CF Laboratory Network before 1 January 2008 who were heterozygous for R117H and F508del were included. Login to comment
18 These were part of a larger record of all individuals carrying two CFTR mutations with R117H at least on one allele (manuscript in preparation). Login to comment
21 Genotype data, including the intron 8 poly(T) variant in cis of R117H, were collected by the French CF Laboratory Network. Login to comment
25 Epidemiological study in the French general population The allelic prevalence of R117H (pR117H) and F508del (pF508del) and 95% confidence interval (CI) were determined by allele counting in a sample of healthy adult individuals of the French general population. Login to comment
26 Data were compiled from the French CF Laboratory Network as results of screening for about 30 frequent CFTR mutations (including R117H and F508del), performed between 2002 and 2006 in healthy partners of CF carriers or CF patients. Login to comment
28 Based on pR117H and pF508del and assuming Hardy-Weinberg equilibrium, the number of individuals expected to carry the [R117H]+[F508del] genotype in the French population was estimated to be p[R117H]+[F508del] = 26pR117H6pF508del. Login to comment
29 Evaluation of the penetrance of CF in individuals with the [R117H]+[F508del] genotype The penetrance was defined as the observed number of [R117H]+[F508del] patients with clinical CF, divided by the expected number of individuals with the [R117H]+[F508del] genotype, calculated as defined above. Login to comment
30 Epidemiological record in newborns screened for CF To determine whether elevated IRT selects for [R117H]+[F508del] newborns, the number of [R117H]+[F508del] newborns identified through elevated IRT was compared with the total number of newborns expected to carry this genotype regardless of IRT, based on 26pR117H6pF508del. Login to comment
31 Exhaustive data on newborns screened for CF from the 2002-2006 period, provided by the French Association for the Screening and Prevention of Infant Handicaps (AFDPHE), comprised: (1) the total number of newborns screened (NBS); (2) the number of newborns with elevated IRT; (3) the number of newborns with elevated IRT and the [R117H]+[F508del] genotype; (4) intron 8 poly(T) alleles in these children; (5) the number of newborns with elevated IRT and the F508del homozygous genotype. RESULTS Phenotypic description of patients compound heterozygous for R117H and F508del Among 278 individuals carrying two CFTR mutations with R117H at least on one allele, 193 [R117H]+[F508del] individuals were identified: 121 were referred for diagnosis request or positive family history and 72 were discovered through CFNBS (fig 1A). Login to comment
33 The poly(T) genotype was known in 173/184 (94.0%) individuals: 166/173 (96.0%) carried T7 and seven (4.0%) T5 in cis with R117H. Login to comment
40 The probabilities of occurrence of different symptoms with age were determined by Kaplan-Meyer analysis for the 166 [R117H;T7]+[F508del] patients (table 2). Login to comment
45 Comprehensive CFTR gene analysis failed to identify a further mutation or large gene rearrangement in cis with R117H;T7 in this child. Login to comment
46 The low number of patients with the T5 variant precluded any comparison of the phenotypes associated with R117H;T5 and R117H;T7. Login to comment
48 Of these, 151 carried one mutation (observed carrier frequency: 1/34.7), including 111 F508del (pF508del = 1.06%, 95% CI 0.87% to 1.27%) and 30 R117H (pR117H = 0.29%, 95% CI 0.19% to 0.41%) (fig 2A). Login to comment
50 The intron 8 poly(T) variant was determined in 28/30 R117H carriers: all had the T7 variant. Login to comment
52 Based on these data, and in the absence of selective mortality associated with the [R117H;T7]+[F508del] genotype, the expected p[R117H;T7]+[F508del] is 1/17 470 (260.010660.0027, 95% CI 0.0001% to 0.032%), equivalent to 3650 individuals in the French population of 63 750 000 inhabitants. Login to comment
53 Evaluation of the penetrance of CF in individuals with the [R117H;T7]+[F508del] genotype As R117H;T5 was not detected in the sample of 5245 healthy adult individuals, the penetrance was evaluated only for the [R117H;T7]+[F508del] genotype. Login to comment
54 While 3650 French individuals would be expected to carry the [R117H;T7]+[F508del] Figure 1 Cross-sectional phenotypic study in [R117H]+[F508del] compound heterozygous individuals. Login to comment
60 In total, 120 patients carrying the [R117H]+[F508del] genotype were recorded with cystic fibrosis (CF) or CFTR related disorders (CFTR-RD) symptoms, of whom 112 had the R117H;T7 allele. Login to comment
62 Table 1 Clinical presentations in the 184 [F508del]+[R117H] compound heterozygous individuals, according to the poly(T) variant NBS children (n = 72) Non-NBS individuals (n = 112) Asymptomatic (No. of individuals) CF/CFTR-RD symptoms (No. of individuals) Asymptomatic (No. of individuals) CF/CFTR-RD symptoms (No. of individuals) R117H;T7 (n = 166) 47 14: 7 98: - 1 classical CF - 1 severe DB +CRS +CBAVD - 3 moderate pulmonary + nasopharyngeal - 1 severe DB+CRS - 7 moderate pulmonary - 2 DB+CBAVD - 3 nasopharyngeal - 2 DB - 7 moderate pulmonary+CRS+CBAVD - 9 moderate pulmonary+CBAVD - 4 moderate pulmonary+CRS - 1 moderate pulmonary+pancreatic+CBAVD - 7 moderate pulmonary - 6 CRS+CBAVD - 3 pancreatic+CBAVD - 1 CRS - 2 pancreatic - 52 isolated CBAVD R117H;T5 (n = 7) 2 1: 1 3: - 1 nasopharyngeal - 1 severe DB+CRS - 1 moderate pulmonary - 1 isolated CBAVD R117H;T? Login to comment
63 { (n = 11) 6 2: 1 2: - 1 moderate pulmonary - 2 isolated CBAVD - 1 pancreatic Total 55 17 9 103 CBAVD, congenital bilateral absence of vas deferens; CRS, chronic rhinosinusitis; DB, disseminated bronchiectasis; NBS, newborn screened; Non-NBS, non-newborn screened (individuals who were not referred through newborn screening); R117H;T?, cases where the poly(T) variant was not determined or documented. genotype, only 112 (3.1%) with CF related symptoms were counted in the record of the French CF Laboratory Network, comprising 14 NBS and 98 non-NBS (table 1). Login to comment
67 Based on the allele frequencies determined in the general population, 202 newborns with [R117H;T7]+[F508del] and 396 with [F508del]+[F508del] were expected among these newborns, irrespective of IRT values. Login to comment
69 Of these, 52 were compound heterozygous for R117H and F508del (included in the 72 NBS children of the phenotypic study) and 332 homozygous for F508del. Login to comment
70 All R117H alleles were found on the intron 8 T7 background (fig 2B). Login to comment
71 Consequently, an Table 2 Probability of occurrence of clinical features at specific age in 166 French [F508del]+[R117H;T7] compound heterozygous individuals NBS children (n = 61) Non-NBS individuals (n = 105) No. of affected cases/no. of patients with available data Frequency (%) Penetrance of clinical features (%)* at age (years) No. of affected cases/no. of patients with available data Frequency (%) Penetrance of clinical features (%)* at age (years) 2 (99% CI) 2 (99% CI) 10 (99% CI) 30 (99% CI) Pulmonary symptoms 10/59 17 21 (10 to 42) 29/96 30 8 (3 to 19) 16 (8 to 28) 28 (17 to 42) Asthma 7/59 12 15 (6 to 37) 9/96 9 4 (1 to 14) 8 (4 to 20) 10 (4 to 21) Disseminated bronchiectasis 0/59 0 0 (NA) 7/96 7 0 (NA) 0 (NA) 5 (1 to 16) Nasopharyngeal symptoms 7/59 12 14 (5 to 37) 18/92 20 5 (2 to 16) 9 (4 to 21) 20 (11 to 34) Chronic sinusitis 7/59 12 14 (5 to 37) 13/92 14 5 (2 to 16) 10 (4 to 22) 15 (8 to 28) Nasal polyposis 0/59 0 0 (NA) 7/92 8 0 (NA) 0 (NA) 8 (3 to 21) Pancreatic symptoms 1/59 2 2 (0 to 20) 7/84 8 0 (NA) 0 (NA) 8 (3 to 23) Pancreatic insufficiency 1/59 2 2 (0 to 20) 2/84 2 0 (NA) 0 (NA) 2 (0 to 19) Chronic pancreatitis 0/59 0 0 (NA) 0/84 0 0 (NA) 0 (NA) 0 (NA) Acute pancreatitis 0/59 0 0 (NA) 5/84 6 0 (NA) 0 (NA) 4 (1 to 18) Staphylococcus aureus positive sputum/oropharyngeal cultures{ 19/49 39 37 (21 to 59) 10/37 27 0 (NA) 12 (3 to 36) 31 (13 to 63) Pseudomonas aeruginosa positive sputum/oropharyngeal cultures{ 6/49 12 13 (4 to 35) 1/39 3 0 (NA) 0 (NA) 0 (NA) NA, not applicable; NBS, newborn screened; non-NBS, individuals who were not referred through newborn screening. Login to comment
74 For clarity, data regarding frequent mutations other than R117H and F508del are not indicated. Login to comment
77 R117H;T? Login to comment
79 Letter to JMG J Med Genet 2009;46:752-758. doi:10.1136/jmg.2009.067215 estimated 25.7% (95% CI 19.9% to 32.3%) of newborns carrying the [R117H;T7]+[F508del] genotype were identified through CFNBS, as compared with 83.8% (95% CI 79.8% to 87.3%) of F508del homozygous newborns (p,0.001). Login to comment
80 DISCUSSION A very low disease penetrance for R117H Because of the need for accuracy in genetic counselling, diagnosis and follow-up in newborns carrying R117H and a CF causing mutation, a national collaborative study in France was set up to establish the overall phenotype associated with R117H and to evaluate the disease penetrance of the [R117H]+[F508del] genotype. Login to comment
81 The measured prevalence of F508del and R117H alleles in the French general population were very similar to those found in a US population (pR117H = 0.29% vs 0.3% and pF508del = 1.06% vs 1.2%).27 Moreover, according to the overall incidence of CF recently reassessed in France at 1/4136 and F508del frequency at 67.2% of CF chromosomes,21 pF508del in the general population would be expected to be 1.05%, which is also very close to the value we determined. Login to comment
83 The prevalences of F508del and R117H;T7 thus permitted the estimation of the number of individuals expected to carry the [R117H;T7]+[F508del] genotype in the French general population at 3650. Login to comment
84 Our study revealed that only 3.1% (112/3650) of the individuals expected to carry the [R117H;T7]+[F508del] genotype have been tested for CFTR mutations because of clinical CF or CFTR-RD symptoms. Login to comment
93 Phenotypic variability is not fully explained by the IVS8 poly(T) variation The very low frequency of R117H;T5 in our population (but not T5 in isolation)31 has precluded any correlation between phenotype and the poly(T) variation in cis with R117H. Login to comment
94 The presence in our study of a severe CF case associated with R117H;T7 and the previously described overlap between patients carrying R117H;T5 and R117H;T7 show that the commonly cited correlation between phenotype and the poly(T) variant in cis with R117H has limitations.16 18-20 32 However, as R117H;T5 seems to be more frequent in Australian and UK populations and has been associated with a more severe phenotype than R117H;T7,15 16 determination of the poly(T) variant may still be recommended whenever R117H is detected and R117H;T5 cautiously be considered as a mild CF mutation. Login to comment
95 Interestingly, five of the seven cases with R117H;T5 originated from Normandy, a north-western area of France which may have common ancestry with the UK. Login to comment
96 To what extent does CFNBS detect newborns with R117H? Login to comment
97 Based on pR117H;T7 and pF508del in the general population, one quarter of [R117H;T7]+[F508del] newborns appear to have elevated IRT and be identified through CFNBS, as compared with 83.7% of expected F508del homozygous newborns. Login to comment
99 Furthermore, given the low disease penetrance detected in the present study for the [R117H;T7]+[F508del] genotype, we could hypothesise that only a minority of the newborns would develop clinical CF symptoms. Login to comment
100 These data show that the [R117H;T7]+[F508del] genotype is selected by CFNBS and provide further evidence that not only classical CF but also equivocal cases, CFTR-RD and a number of asymptomatic cases are selected by CFNBS.21 33 Implications for CFNBS and genetic counselling The pertinence of including R117H and mild CF mutations in CFNBS mutation panels has been debated because of the consequences of making a genetic diagnosis of CF in newborns who might not become symptomatic for years, if at all.16 19 22-24 26 34 35 Bearing in mind that the aim of CFNBS is the earlier diagnosis of classical forms of CF, our results provide strong Key points c The penetrance of classical cystic fibrosis (CF) for the [R117H;T7]+[F508del] genotype was evaluated at 0.03%, and that of severe CF in adulthood at 0.06%. Login to comment
101 c It was estimated that only 3.1% of individuals expected to carry the [R117H;T7]+[F508del] genotype in the French population have been tested for CFTR mutations because of clinical CF or CFTR-RD symptoms or a positive family history. Login to comment
102 c R117H on an intron 8 T7 background should be considered principally as a CFTR-RD-associated mutation with reduced penetrance. Login to comment
104 c Withdrawal of R117H from CF mutation panels used for screening programmes should be considered. Login to comment
105 arguments in favour of removing R117H from CFNBS mutation panels. Login to comment
106 However, as withdrawal of R117H would lead to further CFTR testing in NBS children with abnormal neonatal IRT and a positive or borderline sweat test, inclusion of R117H in a second-step panel would be a good compromise. Login to comment
107 With regard to diagnosis and genetic counselling, R117H;T7 should be considered principally as a CFTR-RD associated mutation with reduced penetrance. Login to comment
109 Moreover, removal of R117H from CF mutation panels used for carrier screening should be considered, as healthy carriers of R117H could wrongly be considered CF carriers and prenatal diagnosis be improperly performed. Login to comment
111 Author affiliations: 1 Centre de Ge´ne´tique, Hoˆpital d`Enfants, CHU de Dijon, Dijon, France; 2 AFDPHE, Paris, France; 3 French CF Care Centres, France; 4 CRCM - Service de gastro-ente´rologie-mucoviscidose et nutrition pe´diatriques, Hoˆpital Robert Debre´, APHP, Paris, France; 5 CRCM - Service de Pe´diatrie 1, Hoˆpital d`Enfants, CHU Dijon, Dijon, France; 6 Inserm U794 et Fondation Jean Dausset/CEPH, Paris, France; 7 INED, Paris, France; 8 Unite´ INSERM U866 CIE1, Faculte´ de me´decine de Dijon, CHU Dijon, Dijon, France; 9 French CF Laboratory Network, France; 10 Laboratoire de Ge´ne´tique Mole´culaire et d`Histocompatibilite´, CHU de Brest, Brest, France; 11 Poˆle de Biochimie et Biologie Mole´culaire, Centre de Biologie Pathologie, CHU de Lille, Lille, France; 12 Laboratoire de Ge´ne´tique Mole´culaire, IURC, CHU de Montpellier, Montpellier, France; 13 Laboratoire de Biochimie-Ge´ne´tique, Hoˆpital Cochin, APHP, Paris, France; 14 Laboratoire de Biochimie Ge´ne´tique, Hoˆpital Robert Debre´, APHP, Paris, France; 15 Service de Ge´ne´tique Me´dicale, Laboratoire de Ge´ne´tique Mole´culaire, CHU Hoˆtel Dieu, Nantes, France; 16 Service d`Endocrinologie Mole´culaire et Maladies rares, Centre de Biologie et Pathologie Est, CHU de Lyon, Bron, France; 17 Laboratoire de Biochimie et Biologie Mole´culaire, Hoˆpital d`Enfants Armand Trousseau, APHP, Paris, France; 18 Laboratoire Pol Bouin, UF Biologie Cellulaire, Hoˆpital de la Maison Blanche, CHU de Reims, Reims, France; 19 Service de Ge´ne´tique Me´dicale, Hoˆpital Purpan, CHU de Toulouse, Toulouse, France; 20 Laboratoire de Ge´ne´tique Mole´culaire, Groupe Hospitalier Pellegrin, CHU de Bordeaux, Bordeaux, France; 21 Laboratoire SESEP, Centre hospitalier de Versailles, Le Chesnay, France; 22 Service de Biochimie-Ge´ne´tique et Inserm U955 e´quipe 11, Groupe Henri Mondor-Albert Chenevier, APHP, Cre´teil, France; 23 CRCM - Service de Pneumologie, Hoˆpital Cochin, APHP, Paris, France; 24 CRCM - Service de Me´decine interne, Centre hospitalier Lyon sud, Pierre-Be´nite, France; 25 CRCM - Service de Pe´diatrie ge´ne´rale, Hoˆpital Necker-Enfants-Malades, APHP, Paris, France; 26 CRCM - Centre de Perharidy, Roscoff, France; 27 Service de Ne´onatologie, SIHCUS - CMCO, Schiltigheim, France; 28 CRCM - Service de pneumologie et immunoallergologie, CHRU de Lille, Lille, France; 29 CRCM - Clinique de pe´diatrie, CHRU de Lille, Lille, France; 30 CRCM Lyon Pe´diatrie, Groupement Hospitalier Lyon Est, Bron, France; 31 CRCM - Unite´ de transplantation thoracique, CHU Hoˆpital Guillaume et Rene´ Lae¨nnec, Nantes, France; 32 CRCM - Service de Pe´diatrie, CHI de Cre´teil, France; 33 CRCM - Service de pneumologie pe´diatrique, Hoˆpital d`Enfants Armand-Trousseau, APHP, Paris, France; 34 Centre d`Epide´miologie Clinique, Hoˆpital Robert Debre´, APHP, Paris, France; 35 Laboratoire de Diagnostic mole´culaire, Service de Me´decine Ge´ne´tique, Hoˆpitaux Universitaires, Geneva, Switzerland; 36 CRCM - De´partement de me´decine de l`enfant et de l`adolescent, CHU de Rennes - Hoˆpital Sud, Rennes, France Other members of the Collaborating Working Group on R117H: Referring molecular geneticists of the French CF Laboratory Network (34 molecular genetics laboratories): Dr A Bazin (Saint-Ouen l`Aumoˆne), Dr M Blayau (Rennes), Dr JP Bonnefont (Paris), Dr J Bouligand (Le Kremlin Biceˆtre), Dr M Che´ry (Nancy), Dr F Chevalier-Porst (Lyon), Dr JM Costa (Saint-Ouen l`Aumoˆne), Dr M Coude (Le Mans), Dr I Creveaux (Clermont-Ferrand), Dr V Dalstein (Reims), Dr A de Becdelie`vre (Cre´teil), Dr F Gerson (Nantes), Dr S Gobin-Limballe (Paris), Dr AM Gouget (Besanc¸on), Pr A Kitzis (Poitiers), Dr C Lagier-Tourenne (Strasbourg), Dr C Magdelaine (Limoges), Dr MC Malinge (Angers), Dr P Malzac (Marseille), Dr H Mittre (Caen), Dr V Petit (Epinal), Dr C Philippe (Vandoeuvre-les-Nancy), Dr P Ray (Grenoble), Dr M Raynaud (Tours), Dr C Ronsin (Ivry-sur-Seine), Dr S Schmitt (Nantes). 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

103 Compound Heterozygotes Among Pancreatic Cancer Cases CFTR Mutations Sex Age at Diagnosis, y Ever/Never Smoker Family History of Pancreatic Cancer Pancreatitis ‡3 Years Before Cancer Diagnosis df508/S42F M 70 Nonsmoker No No R117H/E528E (splice site) M 75 Smoker Yes No df508/S912L W 56 Smoker No No df508/N1088S W 73 Smoker No No df508/M1191I M 79 Smoker No No df508/S1235R M 73 Smoker No No df508/F1052V M 49 Smoker No No df508/5T M 60 Smoker No No Man indicates man; W, woman. 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
76 For example, the compound heterozygote ΔF508/R117H, previously reported to occur commonly in CBAVD and infertile patients [20,21], was also a frequent genotype in our study (Table 2b). Login to comment
89 Mutations found in the homozygous (n=2) and heterozygous (n=20) diagnosed foetuses are the following: ΔF508/ΔF508 (n=1), 711+5G→A/711+5G→A (n=1), ΔF508/P5L (n=1), 2183AA→G/S42F (n=1), ΔF508/ D1445N (n=1), 711+5G→A/ΔF508 (n=1), G542X/E527G (n=1), N1303K/1717-1 G→A (n=1), R117H/E527G (n=1), ΔF508/2183AA→G (n=1), ΔF508/D1152H (n=1), R347H/ ΔF508 (n=1), ΔF508/G542X (n=2), ΔF508/N1303K (n=2), R1162X/ΔF508 (n=3), N1303K/D1152H (n=3). Login to comment
97 CF mutation General adult population MAR population n=1879 n=236 ΔF508 42.6 45.7 2183AA→G 5.9 5.9 R1162X 5.7 8.2 N1303K 5.4 5.9 G542X 4.2 3.7 D1152H 3.9 5.0 R553X 3.7 3.1 R117H 3.3 1.8 711+5G→A 2.8 4.1 Q552X 2.8 0.4 2789+5G→A 2.2 3.1 1717-1G→A 2.6 2.8 E527G 2.4 - G85E 2.4 0.9 R334Q 0.9 0.4 W1282X 0.7 0.9 R334W 0.6 - 1898+3A→G 0.5 0.4 R1158X 0.4 - R1066H 0.4 0.4 T338I 0.4 1.8 3849+10Kb C→T 0.4 1.3 3272-26 A→G - 0.9 3132delTG - 0.9 3659 del C - 0.4 4016 ins T - 0.4 1717-8G→A - 0.4 R347H - 0.4 ΔI507 - 0.4 R1070Q - 0.4 Other (16) 5.4 - Table 2a List of CFTR compound heterozygotes in the adult general population. Mutation Health status Disorder Gender Age (years) Notes and refs ΔF508/A238V Infertile CBAVD M 36 (A) ΔF508/R352W Infertile CBAVD M 45 (A) R553X/R334Q M 38 ΔF508/R347H M 53 [17] S42F/D372E (1251T→G) M 39 (A) (B) ΔF508/D110H Infertile M 38 ΔF508/L1414S (4373T→C) Infertile CBAVD M 44 (A) (B) ΔF508/V201M, D1270N & R74W Infertile CBAVD M 44 (A) [18,19] 2183AA→G/L206W Infertile CBAVD M 40 (A) 711+5G→A/ L206W Infertile CBAVD M 40 (A) Table 2b List of CFTR compound heterozygotes in the population enrolled for medically assisted reproduction. Login to comment
98 Mutation Disorder Gender Age (years) Notes and refs ΔF508/R117H M 47 (C) [20,21] ΔF508/R117H F 36 (C) [20,21] ΔF508/R117H M 43 (C) [20,21] G542X/D1152H M 40 (C) R1162X/2789+5G→A CBAVD M 44 (C) R117H/2789+5G→A CBAVD M 42 (C) N1303K/D110H CBAVD M 32 (C) N1303K/D1152H M 40 (C) 2789+5G→A/R1066H M 40 (C) Abbreviations: CBAVD: Congenital Bilateral Absence of the Vas Deference; M: Male; F: Female. Login to comment
105 Among the subjects tested, 9 resulted to be compound heterozygotes: ΔF508/R117H (n=3), G542X/D1152H (n=1), R1162X/2789+5G→A (n=1), R117H/2789 + 5G→A (n = 1), N1303K/D110H (n = 1), N1303K/D1152H (n = 1), 2789 + 5G→A/R1066H (n = 1) (Table 2b). Login to comment
106 The identification of 3 subjects with ΔF508/ R117H confirmed findings from other studies reporting high frequencies of ΔF508/R117H compound heterozygotes in males with infertility problems [20,21]. Login to comment
135 The most striking example is the length of the intron 8 polythydimine tract on exon 9 splicing as genetic modifier of the severity of the R117H mutation. 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

396 For example, patients who have a single R117H CFTR allele (a class IV mutation) have less severe reduction of apical plasma membrane anion permeability (Reddy & Quinton, 2003; Sheppard et al., 1993) and generally have milder disease than CF patients in whom CFTR function is absent, such as those homozygous for a class I or II mutation. Login to 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: 19914431 [PubMed] Munck A et al: "The importance of sweat testing for older siblings of patients with cystic fibrosis identified by newborn screening."

No. Sentence Comment

32 Thus, if we consider our 7 symptom-free siblings, 2 had mutations associated with classical CF disease, 1 with variable phenotype expression (an intermediate chloride ST: 50 mmol/L, F508del/R347H) and 4 children (from 3 families) combined a severe mutation with R117H against a background polythymidine sequence of intron 8 7 T-9 T, with 2 ST that were positive. Login to comment
33 Although the R117H mutation combined with a severe mutation is associated with phenotypic variability, these children require clinical monitoring in a CF care center.4 Many of these individuals may never express the disease,5 but, on rare occasions, patients may show classical CF manifestations6-8 ; therefore correlations between phenotype and the poly (T) variant in cis have limitations. Login to comment

PMID: 19914443 [PubMed] Borowitz D et al: "Cystic Fibrosis Foundation practice guidelines for the management of infants with cystic fibrosis transmembrane conductance regulator-related metabolic syndrome during the first two years of life and beyond."

No. Sentence Comment

57 Up to 7% of infants screened with a trypsinogen/DNA multimutation algorithm in which 2 mutations are identified will have 1 CF-causing mutation and R117H-T7.6 Some individuals with a CF-causing mutation on 1 allele and R117H associated with the T7 intron-8 polythymidine sequence on the other allele may have development of CF-like symptoms (although symptoms are rarely seen in early childhood and may not develop until adulthood.7,8 Others will not develop symptoms.9,10 Some CFTR mutations, including D1152H, have widely variable phenotypes.11 If mutations such as D1152H are found in trans with other phenotypically variable CFTR mutations, such as R117H-T7, an already confounded picture becomes more complicated. Login to comment
58 Mutations such as D1152H and R117H, when compound heterozygous with a disease-causing CFTR mutation may lead to isolated symptoms later in life, such as pancreatitis.12 Intronic Mutations that Affect Splicing Efficiency. Login to comment
198 However, males with CRMS who have a genotype that includes the R117H mutation are likely to have absence of the vas deferens. 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: 20021716 [PubMed] Gallati S et al: "Cystic fibrosis transmembrane conductance regulator mutations in azoospermic and oligospermic men and their partners."

No. Sentence Comment

67 In CAVD patients and azoospermic men without CAVD, respectively, the most common mutation was F508del (18.0% and 7.3%) followed by the mild mutations 5T (16.0% and 6.0%) and R117H (8.0% and 1.3%). Login to comment
113 The three most common mutations are F508del (65.00%), 3905insT (4.81%) and R553X (3.78%) in the CF patient cohort, F508del (18.00%), 5T (16.00%) and R117H (8.00%) in CAVD patients and 5T (4.56%), F508del (3.68%) and S1235R (1.05%) in infertile non-CAVD men, exemplifying the disease specificity of the mutation patterns illustrated in Table 1. Login to comment

PMID: 20059485 [PubMed] Dorfman R et al: "Do common in silico tools predict the clinical consequences of amino-acid substitutions in the CFTR gene?"

No. Sentence Comment

156 While p.R117H-5T is common in CF-PS patients, p. R117H-7T is usually found in individuals with other CFTR-related disorders. Login to comment
155 Prediction tools would not be capable of predicting the variable penetrance of the p.R117H mutation, which is dependent for it`s splicing efficiency, on the length of the poly-T-tract in intron 8 (IVS8-5T, 7T and 9T) (26-28). Login to comment

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

No. Sentence Comment

50 A ''mild`` CFTR allele that maintains partial ion channel activity, R117H, is associated with the 5Tallele in CF and 7T in CBAVD (20). Login to comment
68 Portuguese CFTR alleles Spanish CFTR alleles Turkish CFTR alleles 5T 22 F508del 11 5T 20 F508del 14 5T 9 D1152H 14 R334W 5 D443Ya 3 D110H 3 R117H 3 G576Aa 3 F508del 2 S1235R 3 R668Ca 3 3041-11del7 2 N1303K 2 G542X 2 1767del6 2 P205S 2 R117H 2 2789þ5G>A 2 D614G 2 V232D 2 CFTRdele2(ins186) 2 G542X 1 L997F 1 3120þ1G>A 1 L206W 1 H609R 1 G1130A 1 V562I 1 N1303H 1 M952I 1 I507del 1 L206W 1 365insT 1 3272-26A>G 1 3272-26A/G 1 E585X 1 2789þ5G>A 1 L15P 1 2752-15C>G 1 G576Aa 1 R347H 1 R334Q 1 R668Ca 1 2689insG 1 R347H 1 CFTRdele2,3 1 R1070W 1 E831X 1 L1227S 1 I 1027T 1 R1070W 1 E831X 1 3272-26A>G 1 L997F 1 I853F 1 A349V 1 6T 1 Note: CFTR ¼ cystic fibrosis transmembrane conductance regulator. Login to comment

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

No. Sentence Comment

49 1G [ T, F508del, S549 N, I507del, S549R, 2184delA, G551D, G85E, N1303 K, R560T, R117H, R347H, R347P, R334 W, 2789 ? Login to comment
116 Five had also PRSS1 mutations as mentioned above, three a CFTR mutation, two of these were women (1 F508del and 1IVS8-5T) and one was a man (1 R117H). Login to comment
118 Two women and 1 man had a F508del mutation, 5 women an IVS8-5T mutation and 2 women and 1 man a R117H mutation. Login to comment
119 One woman both had a R117H and an IVS8-5T mutation. 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
157 Moreover, 11 patients had at least one mutation (D1152H, 3849110kbC.T, IVS8-5T, R117H) that has been associated with normal or borderline sweat chloride level (36). Login to comment

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

No. Sentence Comment

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

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

No. Sentence Comment

104 It has been reported that in newborns carrying DF508 or G542X, a higher incidence of MI is found, whereas G551D and R117H are associated with a decreased MI incidence (19,21,22). Login to comment

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

No. Sentence Comment

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

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

No. Sentence Comment

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

PMID: 20478977 [PubMed] Muchekehu RW et al: "A new role for bicarbonate secretion in cervico-uterine mucus release."

No. Sentence Comment

150 An example of this might be the case of two infertile sisters with significantly abnormal cervical mucus who were found to be compound heterozygote carriers of the cystic fibrosis F508 and R117H/7T mutations (Schoyer et al. 2008). Login to comment

PMID: 20487541 [PubMed] Fang D et al: "Increased plasma membrane cholesterol in cystic fibrosis cells correlates with CFTR genotype and depends on de novo cholesterol synthesis."

No. Sentence Comment

8 Results: Membrane cholesterol measurements are elevated in both R117H and ΔF508 mouse nasal epithelium compared to age-matched sibling wt controls demonstrating a genotype correlation to membrane cholesterol detection. Login to comment
29 Data demonstrate a clear CFTR genotype correlation with ΔF508 CFTR mice exhibiting higher membrane cholesterol content and increased de novo cholesterol synthesis relative to R117H CFTR mice. Login to comment
35 These cells were grown at 37°C in 95% O2-5% CO2 on Falcon 10 cm diameter tissue culture dishes in LHC-8 Basal Medium (Biofluids Camarillo, CA) with 5% FBS. Mice Mice homozygous for the ΔF508 CFTR mutation were described previously [12], as were mice carrying the R117H CFTR mutation [13]. Login to comment
91 In order to determine if membrane cholesterol measurement correlates with Cftr genotype, membrane cholesterol was measured in nasal epithelium isolated from mice homozygous for either the R117H (R/ R) or the ΔF508 (ΔF/ΔF) CFTR mutations. Login to comment
98 WT mice from the ΔF508 colony and the R117H colony were directly compared and no difference in membrane cholesterol measurement was observed. Login to comment
117 A, C) Representative traces of membrane cholesterol determination in excised nasal epithelium from Cftr R117H/R117H (R/R) mice and Cftr ΔF508/ΔF508 (ΔF/ΔF) mice, respectively, compared to sibling Cftr +/+ (wt) mice. B, D) Quantification of responses between CftrR/R and sibling Cftr+/+(wt) nasal tissue and CftrΔF/ΔF nasal tissue compared to Cftr+/+ (wt) siblings. Login to comment
122 E) Representative traces of wt mice from the ΔF508 (ΔF) and R117H colonies. Login to comment
123 Mean response for wt mice in the ΔF and R117H colonies are 54.5 +/- 0.5 pC and 55.7 +/- 1.5 pC, respectively. Login to comment

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

No. Sentence Comment

58 When found in cis to the R117H mutation, (ie, is on the same chromosome), the effect can be identical to a ''severe`` mutation, and thus if this combination exists in conjunction with a classic CFTR mutation, one would predict full manifestations of classic CF. Login to comment
59 If the R117H mutation exists with the normal 7T (or 9T) allele, the effect is dampened. Login to comment
63 However, it is important to perform poly-T analysis if the R117H mutation is identified, as this combination (in cis) is considered a ''severe`` CF mutation. Login to 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
111 The ACMG guidelines on CF carrier testing state that intron 8 poly-T analysis should be reported only as a reflex if the R117H allele is found (see section on ''severe`` versus ''mild`` alleles). Login to comment
112 Despite the lack of predictable or consistent phenotype associated with the 5T intron 8 allele in conjunction with any mutation other than R117H, a considerable number of laboratories performing carrier testing for CF in the United States still report the 5T allele on all specimens.16 This activity has led to unnecessary invasive prenatal testing whereby parents are not at risk of having a child with CF, and misunderstand the significance (or lack thereof) of the 5T allele.17,18 While such situations are generally rare, these events reflect the complexity of carrier testing strategies for this particular disorder, and the continued need for provider education. Login to comment

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

No. Sentence Comment

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

PMID: 20522854 [PubMed] Sermet-Gaudelus I et al: "Measurement of nasal potential difference in young children with an equivocal sweat test following newborn screening for cystic fibrosis."

No. Sentence Comment

91 Of the three patients with two CFTR mutations in the HIRT-Nl group, one carried a mutation without any clinical consequence (3849+45G/A), while the other two carried F508del in trans with the R347H broad-spectrum mutation, or the CFTR-RD-associated mutation R117H. Login to comment
92 Five patients with HIRTwere compound heterozygous for the CF-causing mutations F508del and R117H on an intron 8 T7 background. Login to comment
121 Five children carrying the F508del/R117H;T7 genotypes were investigated. Login to comment
124 Although we cannot rule out a mutation in a non-coding region or in the promoter region, despite extensive genotyping, these findings suggest that the rare association of CFTR-related clinical symptoms with the F508del/ R117H;T7 genotype may be assessed by NPD measurements.24 25 CONCLUSION Although the clinical significance of CFTR dysfunction in the newborns with HIRT can only be definitively determined through systematic long-term follow-up, our results suggest Table 2 Clinical characteristics of children with hypertrypsinaemia (HIRT) at birth and at follow-up according to the diagnostic score cut-off HIRT-Nl HIRT-CF NPD diagnosis score >0.27 #0.27 p Value No. Login to comment
130 Table 3 Genotypes of the children with HIRT according to the diagnostic score cut-off in the 21 patients with reliable NPD tests; results after extensive genetic analysis CFTR genotypes Diagnosis score >0.27 (8 patients) £0.27 (13 patients) A/A 0 F508del/621+3A/G F508del/Q1291R A/AB F508del/R347H F508del/R117H;T7 W846X/R117C n¼2 F508del/R1070W 2183AA/G/L206W F508del/3272-26A/G F508del/R117H;T7; n¼4 A/D 0 F508del/R933G G551D/R352Q B/D G622D/3849+45G/A 0 A/0 F508del/0 n¼2 0 0/0 3 0 0, no identified mutation; A, CF-causing mutation; B, mutation associated with cystic CFTR-related disorders; C, mutation with no clinical consequence ; D, mutation of unknown or uncertain clinical relevance; AB, mutation that is associated with a wide phenotypic spectrum that might belong to either group A or B. CFTR, cystic fibrosis transmembrane conductance regulator; HIRT, hypertrypsinaemia; NPD, nasal potential difference. 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
14 Alternatively, R117H/DF508 compound heterozygotes tend to exhibit pancreatic sufficiency with varying pulmonary manifestations.9 N1303K has been associated with yet another phenotype: the early onset of pancreatic insufficiency and a wide spectrum of pulmonary disease.10 Experts have hypothesized that there are gene-environment interactions that may explain the variable pulmonary phenotype observed across the spectrum of CFTR genotypes.12,13 For example, in 2008, Collaco and colleagues12 demonstrated that any secondhand tobacco exposure had a negative long-term effect on lung function in CF patients. Login to comment
15 These adverse effects were amplified in the presence of variants in a CF modifier gene, transforming growth factor b1 (TGFb1), thus providing support for gene-environment interactions.14 Another well-studied phenotypic variant is the R117H mutation and its association with the 5T/7T/9T polymorphism in intron 8 of the same allele. Login to comment
16 R117H paired with the 7T variant (in cis) and R117H paired with the 5T variant (in trans) have been observed in infertile but otherwise healthy men with congenital bilateral absence of the vas deferens (CBAVD).15,16 When this same mutation is paired with the 5T variant (in cis), signs and symptoms of classical CF are observed.17 This has led to extensive debate as to whether the R117H mutation should even be included in the prenatal screening panel Fig. 1. Login to comment
19 Despite this fact, the R117H mutation remains a part of the standard prenatal carrier screening panel, with a reflex test for the 5T/7T/9T variant performed if positive for this mutation. Login to comment
51 When a patient is positive for R117H, a reflex test for the 5T/7T/9T variant is sent. Login to comment
52 If positive for 5T, determination as to whether the polymorphism is in cis or in trans with the R117H allele is undertaken.22 As discussed previously, R117H in combination with the 5T variant in trans manifests as CBAVD, but if in cis with the 5T variant, classical CF is expressed. Login to comment
53 Given that 5% of the general population will test positive for the 5T polymorphism alone, this test is recommended only as a reflex to a positive R117H result.22,23 Non CF-causing variants, including I506V, I507V, and F508C, can mistakenly cause a false-positive result based on laboratory and testing methodologies. 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

PMID: 20691141 [PubMed] Tomaiuolo AC et al: "Clinical hallmarks and genetic polymorphisms in the CFTR gene contribute to the disclosure of the A1006E mutation."

No. Sentence Comment

64 Some haplotypes contain loci mutually influencing the gene function, such as the R117H-poly-T association;12-14 others are neutral or ameliorative. 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

103 In vivo findings and, in some cases, in vitro functional characterizations have been reported for [F508C; S1251N],38 [R347H; D979A],39,40 [R74W; D1270N],41 [G628R; S1235R],42,43 [M470V; S1235R],42 [S912L; G1244V],44 [R117H; (TG)mTn],45-47 [R117C; (TG)mTn],46 [S1235R; (TG)mT5],48 [G576A; R668C],10,49 [V562I; A1006E],49 [R352W; P750L],49 [1198_1203del TGGGCT; 1204GϾA],49 [V754M; CFTRdele3_10,14b_16],50 and [F508del; I1027T].51 These complex alleles have been found in patients with either CF or CFTR-RD, although more often in the former. Login to comment
108 Five different CFTR mutations of the 117 CFTR amino acid are known: R117C, R117G, R117H, R117L, and R117P.37 All these mutations have previously been reported to be more likely to cause CFTR-RD than CF.13,37,46,56 However, R117H and R117C have been shown to yield high sweat test values and CF, even severe, if cis-acting with the T5 variant tract in CFTR intron 8.45,46 If we bear in mind that the pH range of airway surface fluid is pH 6.7-7.0,57,58 these mutations of the R117 CFTR residue represent both conservative and nonconservative substitutions. Login to comment

PMID: 20717170 [PubMed] Rene C et al: "p.Ser1235Arg should no longer be considered as a cystic fibrosis mutation: results from a large collaborative study."

No. Sentence Comment

69 Of these, eight were compound heterozygous for p.Phe508del, and two for mutations associated with CF-related diseases,3,27 (p.Arg117His;T7) and p.Arg1070Trp (http://www.genet.sickkids.on.ca/cftr/). Login to comment
95 of subjects Allele 1 Allele 2 p.Ser1235Arg;p.Arg785X p.Phe508del Severe CF 2 p.Ser1235Arg;p.Arg785X NAa Severe CF 1 p.Ser1235Arg;875+1G4A (c.743+1C4A) 3629delT (c.3497delT) Severe CF 1 p.Ser1235Arg;p.Arg785X p.Gly542X Severe CF 1 p.Ser1235Arg;(TG)13(T)5 p.Gly551Asp Mild CF 1 p.Ser1235Arg;(TG)13(T)5 p.Phe508del CBAVD 6 p.Ser1235Arg;(TG)13(T)5 p.Arg1070Trp CBAVD 1 p.Ser1235Arg;(TG)13(T)5 p.Arg117His; (T)7 CBAVD 1 p.Ser1235Arg p.Phe508del CBAVD 1 p.Ser1235Arg - CBAVD 1 p.Ser1235Arg;(TG)13(T)5 p.Phe508del CUAVD 1 Suspicion CF/mild phenotype: p.Ser1235Arg - Genital symptoms 5 p.Ser1235Arg - Respiratory symptoms 16 p.Ser1235Arg;(TG)13(T)5 p.Phe508del Respiratory symptoms 2 p.Ser1235Arg 406-6T4C (c.274-6T4C) Respiratory symptoms 1 p.Ser1235Arg p.Tyr1092X Respiratory symptoms 1 p.Ser1235Arg p.Glu831X Respiratory symptoms 1 p.Ser1235Arg p.Gln493X Respiratory symptoms 1 p.Ser1235Arg p.Ile507del Respiratory symptoms 1 p.Ser1235Arg - Digestive symptoms 13 p.Ser1235Arg p.Gly542X Digestive symptoms 1 p.Ser1235Arg - Hyperechogenic fetal bowel 5 p.Ser1235Arg p.Arg668Cys; p.Arg576Ala Hyperechogenic fetal bowel 1 p.Ser1235Arg p.Val920Met Hyperechogenic fetal bowel 1 p.Ser1235Arg p.Phe508del Hyperechogenic fetal bowel 1 aNA: not available; we could only test the mother and a healthy sister (the patient was deceased and the father`s DNA was not available). Login to comment

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

No. Sentence Comment

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

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

No. Sentence Comment

24 Class III and IV CFTR mutations are characterized by full-length CFTR that reaches the cell surface but exhibit reduced ion transport activity owing to abnormal channel gating (Class III, e.g. G551D) or reduced conductivity of the ion channel pore (Class IV, e.g. R117H). Login to comment

PMID: 20846557 [PubMed] Sutton JM et al: "Total pancreatectomy and islet cell autotransplantation as a means of treating patients with genetically linked pancreatitis."

No. Sentence Comment

117 Patient demographics Descriptive statistics Data mean (SEM) Range Age, y 32 (3) 15-59 Weight, kg 73 (6) 39-127 Body mass index, kg/m2 24 (2) 15-35 Chronic pancreatitis, y 14 (2) 3-47 Sex Male, n = 8 Female, n = 8 Previous pancreatic operations Puestow, n =3 Whipple, n = 3 Genetic mutations and loci, n (%) CFTR 10 (62.5) R297Q 2 DF508 + R117H 1 R553X + M470V 1 DF508 1 R117H 1 P750L 1 D1152H 1 R31C 1 S1235R 1 PRSS1 4 (25) R122H 3 Unknown* 1 SPINK1 2 (12.5) N34S 2 *One patient was identified as having a PRSS1 mutation, but the specific locus mutation was unknown at the time of publication. Login to comment
181 Among these patients, 9 separate mutations were discovered, the most common of which were DF508, R297Q, and R117H. 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
67 Conversely, PIP scores of well-established mild mutations such as R117H, 3849 ϩ 10kbCϾT, and R334W ranged from 0.00 to 0.25. 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: 21097845 [PubMed] Sheridan MB et al: "CFTR transcription defects in pancreatic sufficient cystic fibrosis patients with only one mutation in the coding region of CFTR."

No. Sentence Comment

15 Most PS-CF patients have two mutations in the coding regions of the CFTR gene.5 6 At least one mutation permits residual CFTR function, allowing the patient to escape the classic CF phenotype.7 8 While the 23 mutation ACMG panel includes several mutations frequently associated with PS-CF (eg, R117H [p.Arg117His], A455E [p.Arg455Glu], 2789+5G/A [c.2657+5G/A], and 3849+10kbC/T [c.3717+12191C/T]), it is not uncommon for a PS-CF patient to carry a rare CFTR mutation that is not present in the panel.9 Detection of less common mutations can be accomplished by use of extended mutation panels10 or by comprehensive analysis of the coding regions of the CFTR gene using scanning11e13 or DNA sequencing methods.14 Scanning techniques detect 85e99% of CFTR mutations15e17 while DNA sequencing has a higher sensitivity because it allows analysis of individual nucleotides.18 19 However, these techniques do not identify gene rearrangements and mutations in non-coding regions that affect splicing or expression of RNA transcripts. Login to comment

PMID: 21108631 [PubMed] Cuthbert AW et al: "New horizons in the treatment of cystic fibrosis."

No. Sentence Comment

165 Class 4 mutations allow the CFTR protein to be correctly translocated to the cell membrane but with reduced ion fluxes and altered selectivity because of mutations affecting the pore region of the channel, as in R117H. Login to comment
225 VX-770 was chosen on its ability to potentiate several forms of CFTR, including CFTR, G551D and R117H. 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: 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

1265 G551D and R117H mutations appeared to be negatively correlated with MI. 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

33 The Elucigene CF29Tm v2 Kit is capable of detecting the following mutations: p.Asp1152His (c.3454 GNC), c.1585-1 GNA, p.Gly542X (c.1624 GNT), p.Trp1282X (c.3846 GNA), p.Asn1303Lys (c.3909 C NG), p.Phe508del (c.1521_ 1523delCTT), c.3717+12191 CNT, p.Leu88IlefsX22 (c.262_ 263delTT), c.489+1 GNT, p.Ser1251Asn (c.3752 GNA), p.Gly551Asp (c.1652 GNA), p.Arg117His (c.350 GNA), p.Arg1162X (c.3484 CNT), p.Arg334Trp (c.1000 CNT), p.Ala455Glu (c.1364 CNA), p.Lys684SerfsX38 (c.2051_ 2052delAAinsG), p.Lys1177SerfsX15 (c. Login to comment

PMID: 21299497 [PubMed] Zhang W et al: "Functional regulation of cystic fibrosis transmembrane conductance regulator-containing macromolecular complexes: a small-molecule inhibitor approach."

No. Sentence Comment

185 The data also imply that: (i) targeting PDZ domain-based protein-protein interactions within the CFTR-NHERF2-LPA2-containing macromolecular complexes can locally regulate CFTR Cl-channel function, which might provide potential therapeutic targets for treating CFTR-related diseases; and (ii) compound CO-068 could be a seed compound for developing improved leads to augment CFTR function in CF patients who have CFTR mutants with impaired channel function, such as G551D or R117H. Login to comment
235 To further study the regulatory roles of PDZ domain-based protein-protein interactions within the macromolecular complexes on regulating CFTR Cl-channel function, and to explore the potential therapeutic value of using such an approach to treat diseases associated with dysfunctional CFTR protein (e.g. G551D-CFTR and R117H-CFTR), we screened a specially designed chemical library and identified a compound (compound CO-068) that preferentially disrupts the LPA2-NHERF2 interaction. Login to comment
255 Moreover, the present study suggests that by targeting different PDZ domain-based protein-protein interactions within the macromolecular complexes, we can modulate CFTR channel function on a use-dependent mode for treating different diseases, that is, targeting the LPA2-NHERF2 interaction to potentiate CFTR Cl-channel function for drug development to treat CF (especially those due to the presence of G551D- or R117H-CFTR); and targeting the CFTR-NHERF2 interaction to down-regulate CFTR Cl-channel function for drug development to treat CFTR-mediated secretory diarrhoea. Login to comment

PMID: 21372122 [PubMed] Narasimhan M et al: "New and investigational treatments in cystic fibrosis."

No. Sentence Comment

145 VX-770 (Vertex pharmaceuticals) is a compound that increases cyclic-AMP-dependent chloride secretion in cell cultures, and is a potent and selective CFTR potentiator of wild-type, G551D, F508del and R117H forms of CFTR. Login to comment
146 In a small phase 2 clinical trial, VX-770 administered twice daily in 39 patients with the G551D mutation over a 14-day or 28-day period improved lung function, nasal potential difference measures, and sweat chloride levels [Accurso et al. 2010]. 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

73 Nevertheless, an important issue in decisions regarding CFTR mutation panels relates to the clinical consequences of mutant alleles, as has been pointed out for R117H [22]. Login to comment
75 CFTR mutationa Proportion of allele Frequency of allele (%) Cumulative detection (%)b F508del 137/214 64.02 92.52 3849+10KbCNT 6/214 2.80 92.52c G542X 5/214 2.34 94.39 N1303K 4/214 1.87 98.13 R117H 4/214 1.87 99.07 R553X 3/214 1.40 99.07 1717-1GNA 2/214 0.93 99.07 G551D 1/214 0.47 100 R347P 1/214 0.47 100 A455E 1/214 0.47 100 W1282X 1/214 0.47 100 621+1GNT 1/214 0.47 100 a The other 11 mutations in ACMG 23 mutation panel are G85E, 711+1GNT, R334W, I507del, R560T, 1898+1GNA, 2184delA, 2789+5GNA, 3120+1GNA, R1162X and 3659delC. Login to comment

PMID: 21427159 [PubMed] Yu J et al: "Association of genetic variants in CFTR gene, IVS8 c.1210-12T[5_9] and c.1210-35_1210-12GT[8_12], with spermatogenetic failure: case-control study and meta-analysis."

No. Sentence Comment

145 The most common mutations detected in Caucasian CBAVD males are c.1521_1523delCTT, T[5] variant and c.350G>A (usual R117H). Login to comment
159 The most common mutations detected in Caucasian CBAVD males are c.1521_1523delCTT, T[5] variant and c.350G.A (usual R117H). 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

176 Additionally, in contrast to our analysis, Strom et al. do not include carriers of R117H plus 7T in their analysis, thereby lowering their overall carrier frequency. Login to 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
73 CFTR intron 8 poly(T) variant analysis was performed for all samples positive for p.R117H. Login to comment
91 p.F508del accounted for 57.7% of all mutations, followed by p.R117H (8.9%). Login to comment
92 Of the 841 individuals who carried a single p.R117H mutation, 3 females carried 2 copies of the 5T allele, whereas the majority (n ϭ 757) did not carry a 5T allele in cis with the p.R117H mutation on the basis of the poly(T) results of 7T/7T, 7T/9T, or 7T/11T. Login to comment
93 The poly(T) background of the p.R117H mutation could not be determined for the remaining 81 individuals who carried 5T/7T or 5T/9T. Login to comment
95 Twenty-one of these individuals carried at least 1 copy of p.R117H (Table 1). Login to comment
96 Twenty of the 21 individuals carried either 7T/7T or 7T/9T, and 1 individual, a 32-year-old woman, carried 5T/9T and p.R117H/ p.F508del. Login to comment
98 Of these mutations, p.R117H, c.3717ϩ 12191CϾT, and p.R347P are included in the ACMG panel, a finding consistent with that panel`s inclusion of mutations associated with mild or severe disease (19). 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
152 Ninety-four percent of the p.R117H-positive individuals with a second mutation did not carry a 5T allele. Login to comment
153 p.R117H in cis with 5T generally confers moderate to severe CF, whereas p.R117H in cis with 7T may confer a mild form of CF, a later CF onset, CBAVD, or no apparent disease (35-37). Login to comment

PMID: 21507732 [PubMed] de Nooijer RA et al: "Assessment of CFTR function in homozygous R117H-7T subjects."

No. Sentence Comment

0 Original Article Assessment of CFTR function in homozygous R117H-7T subjects R.A. de Nooijer a,⁎, J.M. Nobel a , H.G.M. Arets b , A.G. Bot a , F. Teding van Berkhout a , Y.B. de Rijke c , H.R. de Jonge a,d , I. Bronsveld a a Department of Pulmonology, University Medical Centre Utrecht, P.O. Box 85500, 3508 GA Utrecht, The Netherlands b Department of Paediatric Pulmonology, Wilhelmina Children's Hospital, University Medical Centre Utrecht, P.O. Box 85090, 3508 AB Utrecht, The Netherlands c Department of Clinical Chemistry, Erasmus MC Sophia, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands d Department of Biochemistry, Erasmus Medical Center, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands Received 2 January 2011; received in revised form 4 March 2011; accepted 22 March 2011 Abstract Background: R117H is a frequent missense mutation included in most CFTR mutation panels. Login to comment
1 However knowledge about the residual function of R117H-CFTR channels in cystic fibrosis-affected organs, e.g. airways, intestines and sweat glands is presently lacking. Login to comment
2 Methods: We evaluated clinical CF symptoms and assessed CFTR function by sweat tests, nasal potential difference and intestinal current measurements in 2 homozygous R117H individuals (7T variant). Login to comment
5 Conclusions: The lack of impact of the R117H mutation on chloride secretion in intestine and nose contrasts with the ~80% loss of CFTR activity reported in patch clamp studies. Login to comment
8 Keywords: Cystic fibrosis; R117H; NPD; ICM; CFTR 1. Login to comment
13 However, some atypical mutations, such as R117H, are less suitable for this classification because their phenotypical manifestations are more sensitive to variations in other genetic and epigenetic factors or environmental factors such as a certain lifestyle [3]. Login to comment
14 The R117H mutation is a relatively frequent mutation in cystic fibrosis (CF) patients worldwide [4]. Login to comment
17 R117H can occur in cis with either the polypyrimidine stretch T5 or T7 [6]. Login to comment
19 Therefore only 10% of the CFTR protein produced by an allele with the 5T variant may be functional, and the combined effect of R117H and T5 on the same chromosome, with e.g. a F508del mutation on the other allele, results in classic CF. Login to comment
21 Whereas much is known about the phenotypic variation among compound heterozygotes for F508del and R117H, www.elsevier. Login to comment
26 doi:10.1016/j.jcf.2011.03.009 Please cite this article as: de Nooijer RA, et al, Assessment of CFTR function in homozygous R117H-7T subjects, J Cyst Fibros (2011), doi:10.1016/j. Login to comment
27 jcf.2011.03.009 Journal of Cystic Fibrosis xx (2011) xxx-xxx JCF-00675; No of Pages www.elsevier.com/locate/jcf present information about the phenotype of the individual R117H mutation is restricted to expression studies in heterologous host cells [5,8]. Login to comment
29 This report describes 2 rare index cases of individuals who are homozygous for the R117H-7T CFTR mutation. Login to comment
30 In vivo and ex vivo assays to measure residual CFTR function in both patients, i.e. the sweat test, the nasal potential difference (NPD), and intestinal current measurements (ICM) in freshly excised rectal suction biopsies were applied to gain insight into the phenotype of the R117H mutation. Login to comment
34 A 33-year old female had no clinical symptoms but was recognized by mutation analysis after her son was identified with F508del/R117H by newborn screening. Login to comment
35 Both individuals were homozygous for the R117H-7T CFTR mutation, diagnosed on the basis of mutation analysis at the CFTR locus. Login to comment
57 2 R.A. de Nooijer et al. / Journal of Cystic Fibrosis xx (2011) xxx-xxx Please cite this article as: de Nooijer RA, et al, Assessment of CFTR function in homozygous R117H-7T subjects, J Cyst Fibros (2011), doi:10.1016/j. Login to comment
64 Four rectal biopsies were obtained in both R117H-7T homozygous individuals. Login to comment
79 CFTR mutation analysis Both subjects were tested homozygous for the R117H-7T CFTR mutation by INNO-LiPA which was subsequently confirmed by direct sequence analysis. Login to comment
92 NPD tracings of the R117H-7T homozygotes. Login to comment
98 4 R.A. de Nooijer et al. / Journal of Cystic Fibrosis xx (2011) xxx-xxx Please cite this article as: de Nooijer RA, et al, Assessment of CFTR function in homozygous R117H-7T subjects, J Cyst Fibros (2011), doi:.1016/j. Login to comment
102 Therefore, both R117H-7T homozygotes showed a normal electrophysiological phenotype in their upper airways, not indicative of CF disease. Login to comment
107 In both R117H-7T individuals the Isc responses to secretagogues (Fig. 4), and the cumulative value of the Clse- cretory responses (=ΔIsccarbachol +ΔIscforskolin/cAMP +ΔIschistamine ) were normal and far above the CF range (Fig. 4, legend; Table 1). Login to comment
108 According to the new criterium [21], both R117H homozygotes would therefore belong to the "CF unlikely" group. Login to comment
113 This indicates that CFTR activity is reduced but not absent in at least one tissue, the sweat duct, in line with the substantial loss of CFTR conductance of the R117H mutant (70-85%) reported in heterologous expression systems in vitro [5,8]. Login to comment
115 Discussion In this study we describe both clinical and electrophysiological findings in two R117H-7T homozygous subjects. Login to comment
117 Because these assays measure the basic defect in CF, i.e. abnormalities in CFTR-mediated chloride transport in epithelial tissues, there is a clear discrepancy between the apparently normal CFTR chloride channel function in airways and intestine reported here and the findings in patch clamp studies of the R117H CFTR channel in heterologous host cells in vitro, showing a loss of Cl-conductance of ~70-85% [5,8]. Login to comment
118 This loss of function results for a minor part from a small reduction in pore conductance for Cl- (14%) but is mainly due to a strong reduction in channel open probability (~72%), indicating that the R117H mutation affects both the pore properties and the gating of the CFTR channel, i.e. it has mixed class III and class IV properties [5]. Login to comment
119 The intracellular processing of the R117H channel, and its trafficking to the cell surface are not affected by the mutation, ensuring normal levels of mature CFTR protein in the apical membrane of the epithelial tissues. Login to comment
120 In addition, the normal bioelectrical phenotype in the nasal epithelium of the R117H homozygous subjects contrasts with the elevated sodium absorption and minimal Cl-conductance reported in NPD measurements for CF patients carrying the A455E mutation [22]. Login to comment
123 ICM tracing of the R117H-7T homozygotes. Login to comment
128 5R.A. CBAVD in males [24], have distinct effects on the bioelectrical phenotype of the airways, ranging from normal (R117H) to severe (A455E). Login to comment
130 Why the in vitro and in vivo phenotypes do not match is not clear but several mechanisms could be involved: first, rescue mechanisms may operate in native epithelium which are completely or partially lacking in the heterologous host cells in vitro.For example, functional rescue of a class III regulatory mutant including R117H may depend on the expression of stimulating co-factors such as the IRBIT (Inositol 1,4,5-triphosphate receptor-binding protein released with Inositol 1,4,5-triphosphate) that reduces channel mean close time or the NHERF1 (Na+ /H+ exchange regulatory factor 1) scaffolding protein that drives CFTR dimerization and is known to increase the open probability of the CFTR channel [26,27]. Login to comment
133 The lack of an intestinal bioelectrical phenotype in both R117H homozygous individuals may likewise result from intestine-specific rescue mechanisms but is also readily explained by the known insensitivity of the intestinal current measurements to a partial loss of CFTR function [30-32]. Login to comment
136 The R117H (and the A455E) CFTR mutants may therefore behave as borderline cases in which the homozygous expression is associated with a normal ICM pattern (≥20% residual CFTR conductance) whereas compound heterozygotes carrying a second more severe mutation (e.g. F508del) show a more variable residual CFTR Cl- current in the intestine ranging from normal to severely reduced, but not absent [24,33]. Login to comment
137 Still another explanation can be given for the lack of pancreatic insufficiency noted in both R117H homozygotes and compound heterozygotes for this mutation. Login to comment
138 Despite the severe loss of Cl-channel function of the R117H mutant CFTR, its bicarbonate transport function is not impaired [8] or even enhanced [34], in clear contrast to all known mutations associated with pancreatic insufficiency [8]. Login to comment
139 The finding of pancreatic sufficiency in both R117H homozygous subjects therefore confirms the notion that the loss of HCO3 - transport function is of more importance for the pathogenesis of CF in the pancreas than the loss of Cl-transport function. Login to comment
140 In conclusion, the only CFTR-associated abnormalities found in the R117H-7T homozygous subjects in this study were a slightly elevated sweat Cl- and CBAVD in the male individual. Login to comment
25 doi:10.1016/j.jcf.2011.03.009 Journal of Cystic Fibrosis 10 (2011) 326-332 www.elsevier.com/locate/jcf present information about the phenotype of the individual R117H mutation is restricted to expression studies in heterologous host cells [5,8]. Login to comment
28 In vivo and ex vivo assays to measure residual CFTR function in both patients, i.e. the sweat test, the nasal potential difference (NPD), and intestinal current measurements (ICM) in freshly excised rectal suction biopsies were applied to gain insight into the phenotype of the R117H mutation. Login to comment
32 A 33-year old female had no clinical symptoms but was recognized by mutation analysis after her son was identified with F508del/R117H by newborn screening. Login to comment
33 Both individuals were homozygous for the R117H-7T CFTR mutation, diagnosed on the basis of mutation analysis at the CFTR locus. Login to comment
61 Four rectal biopsies were obtained in both R117H-7T homozygous individuals. Login to comment
76 CFTR mutation analysis Both subjects were tested homozygous for the R117H-7T CFTR mutation by INNO-LiPA which was subsequently confirmed by direct sequence analysis. Login to comment
89 NPD tracings of the R117H-7T homozygotes. Login to comment
103 In both R117H-7T individuals the Isc responses to secretagogues (Fig. 4), and the cumulative value of the Clse- cretory responses (=ΔIsccarbachol +ΔIscforskolin/cAMP +ΔIschistamine ) were normal and far above the CF range (Fig. 4, legend; Table 1). Login to comment
104 According to the new criterium [21], both R117H homozygotes would therefore belong to the "CF unlikely" group. Login to comment
109 This indicates that CFTR activity is reduced but not absent in at least one tissue, the sweat duct, in line with the substantial loss of CFTR conductance of the R117H mutant (70-85%) reported in heterologous expression systems in vitro [5,8]. Login to comment
111 Discussion In this study we describe both clinical and electrophysiological findings in two R117H-7T homozygous subjects. Login to comment
114 This loss of function results for a minor part from a small reduction in pore conductance for Cl- (14%) but is mainly due to a strong reduction in channel open probability (~72%), indicating that the R117H mutation affects both the pore properties and the gating of the CFTR channel, i.e. it has mixed class III and class IV properties [5]. Login to comment
116 In addition, the normal bioelectrical phenotype in the nasal epithelium of the R117H homozygous subjects contrasts with the elevated sodium absorption and minimal Cl- conductance reported in NPD measurements for CF patients carrying the A455E mutation [22]. Login to comment
124 CBAVD in males [24], have distinct effects on the bioelectrical phenotype of the airways, ranging from normal (R117H) to severe (A455E). Login to comment
127 For example, functional rescue of a class III regulatory mutant including R117H may depend on the expression of stimulating co-factors such as the IRBIT (Inositol 1,4,5-triphosphate receptor-binding protein released with Inositol 1,4,5-triphosphate) that reduces channel mean close time or the NHERF1 (Na+ /H+ exchange regulatory factor 1) scaffolding protein that drives CFTR dimerization and is known to increase the open probability of the CFTR channel [26,27]. Login to comment
134 Still another explanation can be given for the lack of pancreatic insufficiency noted in both R117H homozygotes and compound heterozygotes for this mutation. Login to comment
135 Despite the severe loss of Cl- channel function of the R117H mutant CFTR, its bicarbonate transport function is not impaired [8] or even enhanced [34], in clear contrast to all known mutations associated with pancreatic insufficiency [8]. Login to comment

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

No. Sentence Comment

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

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

No. Sentence Comment

10 One patient with the F508del/R117H/7T genotype was reassigned the diagnosis of CF after he had a positive OP culture for Pa, and his follow up sweat Cl at 1 year of life was 73 mmol/L. Login to comment
57 However, since the New York state panel includes all the CF causing mutations (Group A),1,5 a mutation identified on sequencing would not have affected the diagnosis of CRMS. Three CRMS patients had the F508del/R117H/ 7T genotype, which has been associated with a variable CF phenotype.6-8 Compared to CF infants, CRMS infants` mean fecal elastase values were normal, and none of the CRMS infants had pancreatic insufficiency. Login to 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
74 This infant carried the F508del/R117H/ 7T genotype and had a Pa positive OP culture; his diagnosis was subsequently changed to CF. Login to comment
77 However, one infant who carried the F508del/R117H/7T genotype subsequently had a Pa positive OP culture and elevated follow up sweat Cl level, leading to a change in diagnosis to CF. Login to comment
78 TABLE 3- Clinical Features and Outcomes of the CRMS Infants Patient number Gender Race/ ethnicity Mean age at 1st sweat (weeks) Mean sweat chloride (range) CFTR gene mutations identified Follow up time (months) Fecal elastase (mcg/gm stool) History of Pa infection History of hospitalization 1 Male Caucasian 4 46 (38-54) F508del/R117H/7T 36 303 Yes No 2 Male Caucasian 5 40 (40-43) F508del/R117H/7T 60 500 Yes No 3 Female Caucasian 3 29 (27-31) F508del/R117H/7T 60 488 No No 4 Male Caucasian 3 34 (33-38) F508del/none 26 383 No No 5 Male Caucasian 3 45 (40-50) F508del/none 72 424 No No 6 Female Caucasian 3 35 (32-38) F508del/none 9 454 No No 7 Male Caucasian 3 41 (36-46) F508del/none 39 462 No No 8 Female Caucasian 5 50 (46-52) F508del/none 72 440 No Yes 9 Male Caucasian 4 43 (41-45) F508del/Y1032C 14 401 No No 10 Male Caucasian 3 52 (50-54) G542X/none 21 500 No No 11 Female Caucasian 8 34 (30-38) R560T/none 9 433 No No 12 Female Hispanic 6 36 (32-40) R334W/R117H/7T 24 500 Yes No Mean sweat chloride levels represent the mean of all tests performed in the neonatal period. Login to comment
101 Infants with the F508del/R117H/7T genotype represent a subgroup of CRMS, and the relationship between TABLE 5- Nutritional Outcomes in CF and CRMS Patients Age (years) Weight for Age Z score Height for age Z score 1 2 3 4 3 4 CF N 27 24 20 16 20 16 Mean (SD) À0.49 (1.02) À0.16 (0.97) 0.02 (1.06) 0.05 (1.116) À0.01 (0.94) À0.04 (0.94) CRMS N 12 9 6 4 6 4 Mean (SD) 0.41 (0.99) 0.88 (0.91) 1.07 (1.14) 0.76 (.74) 0.56 (0.53) 0.63 (0.63) Data represent the mean of all measurements obtained in a given year. Login to comment
58 However, since the New York state panel includes all the CF causing mutations (Group A),1,5 a mutation identified on sequencing would not have affected the diagnosis of CRMS. Three CRMS patients had the F508del/R117H/ 7T genotype, which has been associated with a variable CF phenotype.6-8 Compared to CF infants, CRMS infants` mean fecal elastase values were normal, and none of the CRMS infants had pancreatic insufficiency. 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
75 This infant carried the F508del/R117H/ 7T genotype and had a Pa positive OP culture; his diagnosis was subsequently changed to CF. Login to comment
79 TABLE 3- Clinical Features and Outcomes of the CRMS Infants Patient number Gender Race/ ethnicity Mean age at 1st sweat (weeks) Mean sweat chloride (range) CFTR gene mutations identified Follow up time (months) Fecal elastase (mcg/gm stool) History of Pa infection History of hospitalization 1 Male Caucasian 4 46 (38-54) F508del/R117H/7T 36 303 Yes No 2 Male Caucasian 5 40 (40-43) F508del/R117H/7T 60 500 Yes No 3 Female Caucasian 3 29 (27-31) F508del/R117H/7T 60 488 No No 4 Male Caucasian 3 34 (33-38) F508del/none 26 383 No No 5 Male Caucasian 3 45 (40-50) F508del/none 72 424 No No 6 Female Caucasian 3 35 (32-38) F508del/none 9 454 No No 7 Male Caucasian 3 41 (36-46) F508del/none 39 462 No No 8 Female Caucasian 5 50 (46-52) F508del/none 72 440 No Yes 9 Male Caucasian 4 43 (41-45) F508del/Y1032C 14 401 No No 10 Male Caucasian 3 52 (50-54) G542X/none 21 500 No No 11 Female Caucasian 8 34 (30-38) R560T/none 9 433 No No 12 Female Hispanic 6 36 (32-40) R334W/R117H/7T 24 500 Yes No Mean sweat chloride levels represent the mean of all tests performed in the neonatal period. Login to comment
102 Infants with the F508del/R117H/7T genotype represent a subgroup of CRMS, and the relationship between TABLE 5- Nutritional Outcomes in CF and CRMS Patients Age (years) Weight for Age Z score Height for age Z score 1 2 3 4 3 4 CF N 27 24 20 16 20 16 Mean (SD) À0.49 (1.02) À0.16 (0.97) 0.02 (1.06) 0.05 (1.116) À0.01 (0.94) À0.04 (0.94) CRMS N 12 9 6 4 6 4 Mean (SD) 0.41 (0.99) 0.88 (0.91) 1.07 (1.14) 0.76 (.74) 0.56 (0.53) 0.63 (0.63) Data represent the mean of all measurements obtained in a given year. Login to comment

PMID: 21547723 [PubMed] Clunes MT et al: "Introduction to section I: overview of approaches to study cystic fibrosis pathophysiology."

No. Sentence Comment

49 Milder forms of CF pathophysiology are observed in which mutated CFTR channels are inserted into the membrane and allow some secretory function, e.g., R117H mutation (8). Login to comment

PMID: 21547726 [PubMed] Ziady AG et al: "Methods for evaluating inflammation in cystic fibrosis."

No. Sentence Comment

75 Some commonly used mouse models bred into the C57BL/6 background are the UNC knockout mouse (B6.129P2-Cftrtm1Unc) and mutant murine Cftr mice such as the R117H mutant mouse (B6.129S6-Cftrtm2Mrc). Login to comment
295 Evaluation of inflammatory response in R117H mutant CF mice. Login to comment
598 For example, when bred into the C57BL/6 background R117H mutant mice exhibit CF defects similar in magnitude to those observed in mice bearing the F508del or S489X mutation. Login to comment

PMID: 21594800 [PubMed] Cai Z et al: "Application of high-resolution single-channel recording to functional studies of cystic fibrosis mutants."

No. Sentence Comment

305 Using biochemical (N) and functional Table 27.1 Comparison of predicted apical membrane Cl- current and measured cAMP-activated apical membrane Cl- current for wild-type and mutant CFTRs CFTR N (%) i (%) Po (%) N × i × Po (%) ICFTR (apical) (%) Wild-type 100 100 100 100 100 F508del 4 100 30 1.2 0 G551D 100 100 2.5 2.5 1.5 R117H 100 86 28 24 15 P574H 15 100 139 21.1 17 N, the number of Cl-channels in the apical membrane; i, single-channel current amplitude; Po, open probability; N × i × Po, the predicted apical membrane Cl- current; ICFTR (apical), measured cAMP-activated apical membrane Cl- current. Login to comment
312 Table 27.1 compares the predicted values of N × i × Po with the observed values of ICFTR(apical) measured in FRT epithelia for F508del-CFTR and the CF mutants, R117H, G551D and P574H, which disrupt CFTR function by different mechanisms (33, 37, 59, 64, 65). 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

78 The G551D missense mutation causes a glycine-to-aspartate substitution at residue 551. Login to comment
79 G551D-CFTR is adequately folded and inserts appropriately into the plasma membrane, but thereafter, it fails to open because of defective regulation. Login to comment
82 R117H, among the most common class IV mutations, occurs at a worldwide frequency approaching 0.5% (www.genet.sickkids.on.ca). Login to comment
83 The R117H missense mutation causes an arginine-to-histidine substitution at residue 117. Login to comment
84 R117H-CFTR R domain is normally phosphorylated, and the NBD binds ATP, but channel open time and thus chloride transport are reduced.60 Additionally, the degree of R117H-CFTR function depends on the length of the polythymidine tract in intron 8 on the same chromosome (which influences splicing efficiency) such that the longer thymidine tracts (9T.7T.5T) produce more functional R117H-CFTR. Login to comment
85 Clinical disease typically requires the R117H mutation in cis with 5T.61 Class V Mutations Found in ,1% of patients with CF, class V mutations produce normal plasma membrane CFTR. Login to comment
80 R117H-CFTR R domain is normally phosphorylated, and the NBD binds ATP, but channel open time and thus chloride transport are reduced.60 Additionally, the degree of R117H-CFTR function depends on the length of the polythymidine tract in intron 8 on the same chromosome (which influences splicing efficiency) such that the longer thymidine tracts (9T.7T.5T) produce more functional R117H-CFTR. Login to comment
81 Clinical disease typically requires the R117H mutation in cis with 5T.61 Class V Mutations Found in ,1% of patients with CF, class V mutations produce normal plasma membrane CFTR. Login to comment

PMID: 21658634 [PubMed] Wilke M et al: "Mouse models of cystic fibrosis: phenotypic analysis and research applications."

No. Sentence Comment

67 Unfortunately, there is no Table 1 CFTR mutant mice Mouse Mutation Cftr mRNA Genetic Survival to Body wt Contact References background maturity Null mutations Cftrtm1Unc S489X Ex10 R Not detectable* C57Bl/6 <5% 10-25% reduction BH Koller/Jax Labs [113,158] Cftrtm1Cam R487X Ex10 R Not detectable 129S6/Sv/Ev <5% 20% reduction WH Colledge [159] Cftrtm1Hsc M1X Ex1 R Not detectable CD1 x 129 25% Delayed LC Tsui [160] Cftrtm3Bay Ex2 R Not detectable C57Bl/6 x 129 40% Reduced AT Beaudet [161] Cftrtm3Uth Y122X Ex4 R Not detectable C57Bl/6 25% 25-50% reduction M Capecchi/PB Davis [113,162] Hypomorphic mutations Cftrtm1Hgu ** Ex10 I 10% of wt MF1 x 129 90% No reduction J Dorin [113] Cftrtm1Bay Ex3 I <2% wt C57Bl/6 x 129 40% 70% reduction AL Beaudet [163] F508del mutations Cftrtm2Cam F508del R 30% of wt 129S6/Sv/Ev <5% 10-20% reduction WH Colledge [164] Cftrtm1Kth F508del R Low in intestine C57Bl/6 x 129 40% 10-50% reduction KR Thomas/Jax labs [165] Cftrtm1Eur F508del (H&R) Normal levels FVB/129; FVB 90% 10-20% reduction BJ Scholte [9] C57Bl/6 Other point mutations Cftrtm2Hgu G551D R 50% of wt CD1/129 65% 30-50% reduction J Dorin [11] Cftrtm3Hgu G480C (H&R) Normal levels C57Bl/6/129 Normal No reduction J Dorin [166] Cftrtm2Uth R117H R 5-20% of wt C57/Bl6 95% 10-25% reduction M Capecchi/PB Davis [113,162] Transgenes Mouse Transgene Promoter Expression Phenotype References Tg(FABPCFTR) CFTR Rat intestinal fatty acid Intestinal villus epithelia Rescue of CF intestinal pathology [167] binding protein Tg(CCSPScnn1b) Scnn1b Clara cell secretory Airway surface epithelia Na+ hyperabsorption [13] protein (CCSP) Reduced airway surface fluid volume Mucus accumulation, CF-like lung disease; 40% survival. Login to comment
450 The synthetic triterpenoid CDDO reduced the hyper inflammatory phenotype of a R117H mutant mouse model, presumably through inhibition of the NF-κB pro-inflammatory pathway [147]. Login to comment

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

No. Sentence Comment

129 Occasionally, rare variants of IVS8-Tn alleles have been identified in CBAVD males, including for example cases of IVS8-T3-TG12 in trans with F508C [54], IVS8-T2- TG13 in trans with R117H-TG11T9 [63] and IVS8-T6 [64,65]. Login to comment
56 Moreover, this list is too loose, because it includes the p.R117H mutation that is most often associated with no disease when identified by newborn screening [14]. Login to comment
64 The example of the p.R117H mutation demonstrates clearly that it is inappropriate to rely solely on IRT results and mutation analysis [14]. Login to comment
106 The two most common compound heterozygous genotypes found in European males with CBAVD are p.F508del in trans with IVS8-5T (28%) and p.F508del in trans with p.R117H (6%). Login to comment
120 The IVS8-5T allele is also a genetic modifier of the mild mutation p.R117H when they are associated in cis. Login to comment
121 Thus, the combination p.R117H-7T is often found in CBAVD, p.R117H-5T is frequently found in CF-PS patients, whereas p.R117H-9T is generally not associated with disease [58]. Login to comment
323 Using biochemical (N) and functional (i and Po) data, the apical CFTR Cl- current generated by the CF-PI mutant p.F508del-CFTR and the CF-PS mutants p.R117H-, p.R334W-, p.R347P-, p.A455E- and p.P574H-CFTR were predicted [166,167]. 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

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
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

PMID: 9518736 [PubMed] Briel M et al: "Cl- transport by cystic fibrosis transmembrane conductance regulator (CFTR) contributes to the inhibition of epithelial Na+ channels (ENaCs) in Xenopus oocytes co-expressing CFTR and ENaC."

No. Sentence Comment

35 The following CFTR mutations were generated: CF-associated mutations such as ÄF508, G551D and R117H as well as artificial mutations within MSD1 such as R347E and K335E (Hipper et al. 1995). Login to comment
104 Another mutant examined contains a mutation in the first extracellular loop (R117H) and was described as a mild form of CF (Dean et al. 1990). Login to comment
110 In contrast, other mutations, which still activated whole-cell Cl¦ conductance (R117H, R347E, K335E) downregulated ENaC currents. 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

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

No. Sentence Comment

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

PMID: 9660057 [PubMed] Schaedel C et al: "Mild cystic fibrosis mutations in Southern Sweden with special reference to S549I and T338I."

No. Sentence Comment

22 Two patients (one with R117H/394delTT and another with R117ClAF508) were diagnosed as having CF during an infertility investigation, and except for age at diagnosis no clinical data were available; they were therefore excluded from further comparisons of clinical variables. Login to comment
23 One patient with the R117H genotype was excluded because the other mutation was unknown. Login to comment
36 The most frequent ones were T338I (5), R117C (3) and R117H (2), accounting for 2.2, 1.4and 0.9% of the C F alleles, respectively. Login to comment
55 Five patients had the relatively common R117H and R117C mutations with clinical pictures of mild or no lung symptoms, pancreatic sufficiency and male infertility as reported in several publications. Login to comment
56 Four of the patients with the R117C or R117H mutations were heterozygous 7T/9T for the IVS8 polymorphism and one patient with R117H/unknown mutation was homozygous for the 7T allele. Login to comment

PMID: 9708232 [PubMed] Davidson DJ et al: "Genetics and pulmonary medicine. 1. The genetics of cystic fibrosis lung disease."

No. Sentence Comment

17 However, under permissive conditions in vitro, such as reduced temperature, correct localisation of mature protein can occur where it can function normally (in the case of G480C), or suboptimally (in the case of F508), or (3) defective ion channel function, such as G551D or R117H, in which case some of the mutant protein becomes correctly localised but results in either very little residual function (in the case of G551D) or a substantially reduced level of ion transport (in the case of R117H). Login to comment
24 The G551D mutation, although also "severe" and conferring pancreatic insuYciency, is observed to be associated with a much lower incidence of meconium ileus, while the R117H mutation is a "mild" mutation in which pancreatic suYciency is generally observed. Login to comment
28 Furthermore, individuals carrying the R117H allele are typically more severely aVected if the R117H mutation is in cis with the 5T polymorphism as opposed to the 7T variant, the associated IVS8-T affecting the amount of already functionally impaired CFTR that is correctly spliced to influence the phenotype.7 Thus, detailed studies of the pathophysiological consequences of diVerent mutations and splicing abnormalities have provided some insight into the eVects of specific alterations in the quality or quantity of CFTR and it has been possible to correlate the level of CFTR function with phenotype in an organ specific manner. Login to comment

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

No. Sentence Comment

97 Molecular consequences of cftr gene mutations Several classification systems have been developed in an attempt to define the large number of cftr gene mutations on 43 I =ON 4o0 o 00 4O0 40 40 I II 111 IV V Normal NOmAfl Missnso G542X Missmnse Missense Missense A455E Fremeshift AA dIeIIOn 05510 R117H Allerndve 39soTT AF508 spiRlng Spl$oeJunculon 3849t10kbC4T1717-1G-4A Figure 4 Molecular consequences of cystic fibrosis transmembrane conductance regulator mutations. Login to comment
117 Class IV mutations produce protein that reaches the apical membrane, are capable of generating a cAMP regulated apical membrane chloride current, but have altered ionic properties resulting in a reduction in the amount of current; an example is the R117H mutation. 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: 9724814 [PubMed] Naren AP et al: "Syntaxin 1A inhibits CFTR chloride channels by means of domain-specific protein-protein interactions."

No. Sentence Comment

136 Those CFTR mutants that produce full-length translation products can be classified into three categories (2): (i) ER processing mutants that inefficiently traffic to the Golgi apparatus (e.g., the most common allele, ⌬F508); (ii) regulation mutants that mature normally but are refractory to activation by ATP (e.g., G551D); and (iii) conduction mutants that also mature normally but exhibit reduced single-channel conductances (e.g., R117H). 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
66 * PATIENT NO.† SEX MUTANT ALLELE POLYT GENOTYPE AGE AT ONSET OF PANCREATITIS AGE AT STUDY ENTRY EXOCRINE STATUS AND CALCULI‡ ALCOHOLISM »10 CIGARETTES/ DAY SWEAT TESTING BASE-LINE NASAL POTENTIAL DIFFERENCE SODIUM CHLORIDE yr mmol/liter mV 1 M DF508 9T/7T 8 27 PS0 No No 43.5 32.0 12.5 2 F DF508 9T/5T 15 34 PS1 No No 55.0 47.5 ND 3 M R117H 7T/7T 18 21 PS0 No Yes 44.0 33.0 ¡9.7 4 M DF508 9T/7T 18 26 PI3 No No ND ND ND 5 M DF508 9T/7T 18 30 PI3 No Yes ND ND ND 6 F Q493X 7T/5T 19 21 PS3 No Yes 51.5 41.0 ND 7 F DF508 9T/7T 20 31 PS3 No No 35.0 23.0 ¡10.8 8 M 621+1(G→T) 9T/7T 21 37 PS3 Yes Yes 72.0 48.5 5.0 9 M R560T 7T/7T 21 39 PI0 Yes Yes 103.0 76.0 ¡4.4 10 M DF508 9T/5T 22 36 PI3 Yes No 53.0 34.0 ¡17.6 11 M DF508 9T/7T 31 45 PS3 No Yes 55.0 34.0 ¡11.5 12 M R117H 7T/7T 35 38 PI2 Yes No ND ND ND 13 F DF508 9T/7T 36 39 PS3 No Yes 60.0 39.0 ¡10.2 14 F R553X 7T/5T 37 56 PI3 No Yes ND ND ND 15 F DF508 9T/7T 45 47 PI3 Yes Yes 104.0 80.0 ¡8.3 16 M DF508 9T/7T 49 52 PS1 Yes Yes ND ND ND 17 F DF508 9T/7T 64 76 PI3 No No 69.0 50.0 ¡10.3 18 F DF508 9T/9T 75 79 PS3 No No 34.5 19.0 ¡14.7 or radiologic abnormalities in 133 patients. Login to comment
92 CFTR Genotype and the Pancreatic Phenotype Among patients with cystic fibrosis, mutations have been described that result in pancreatic insufficiency (e.g., ∆F508), necessitating enzyme supplementation, or in disease that does not affect pancreatic function to the same extent (e.g., R117H),29 Figure 1. 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
47 Three different mutations were detected: ∆F508 in five patients, R117H in two, and N1303K in one, for a total of eight. Login to comment
58 SEX CFTR GENOTYPE POLYT GENOTYPE AGE AT DIAGNOSIS RESULTS OF PANCREATOGRAPHY† 1 M DF508/R117H 9T/7T 45 Moderately abnormal 2 F DF508/WT 9T/5T 32 Moderately abnormal 3 F DF508/WT 9T/5T 48 Moderately abnormal 4 F DF508/WT 9T/7T 40 Moderately abnormal 5 F DF508/WT 9T/7T 15 Mildly abnormal 6 F R117H/WT 7T/7T 32 Moderately abnormal 7 M N1303K/WT 7T/9T 43 Moderately abnormal 8 M WT/WT 5T/7T 33 Moderately abnormal 9 F WT/WT 5T/7T 29 Normal 10 F WT/WT 5T/7T 12 Moderately abnormal 11 F WT/WT 7T/7T 16 Severely abnormal 12 M WT/WT 7T/7T 22 Mildly abnormal 13 M WT/WT 7T/7T 31 Normal 14 F WT/WT 7T/7T 43 Mildly abnormal 15 F WT/WT 7T/7T 12 Severely abnormal 16 F WT/WT 7T/7T 54 Moderately abnormal 17 F WT/WT 7T/7T 47 Moderately abnormal 18 F WT/WT 7T/7T 65 Mildly abnormal 19 F WT/WT 7T/7T 12 Not done‡ 20 F WT/WT 7T/7T 59 Moderately abnormal 21 F WT/WT 7T/7T 42 Mildly abnormal 22 F WT/WT 7T/7T 33 Severely abnormal 23 F WT/WT 7T/7T 32 Not done 24 F WT/WT 7T/7T 54 Mildly abnormal 25 F WT/WT 7T/7T 54 Severely abnormal 26 F WT/WT 7T/9T 47 Normal 27 F WT/WT 7T/9T 21 Severely abnormal A total of 10 patients had CFTR mutations or the 5T allele or both (Table 1). Login to comment
64 The genotypes of these three patients (∆F508/wild type, 9T/5T in two and ∆F508/R117H, 9T/7T in one) are the two most common in patients with congenital absence of the vas deferens.10-12,27 These genotypes do not typically cause lung disease. Login to comment
65 In contrast, lung disease is present in patients with a genotype of ∆F508/R117H, 9T/5T.28 The three patients with abnormalities of both CFTR alleles were further evaluated to determine whether they had unrecognized cystic fibrosis-related lung disease (Table 3). Login to comment
74 The first assumption is based on data for U.S. whites,6 and the other three assumptions are based on data for whites tested at our medical center.22,25 †Three mutations causing cystic fibrosis were identified: ∆F508 in five patients, R117H in two, and N1303K in one. Login to comment
76 §Two patients had a genotype of ∆F508/wild type, 9T/5T, and one patient had a genotype of ∆F508/R117H, 9T/7T. Login to comment
99 GENOTYPE SWEAT CHLORIDE NASAL POTENTIAL DIFFERENCE FEV1 OTHER FINDINGS mmol/liter mV % of predicted 1 ∆F508/R117H, 9T/7T 28, 30 ¡24 86 Congenital absence of the vas deferens 2 ∆F508/WT, 9T/5T 44, 39 ¡23 106 Smoker (1 pack/day) 3 ∆F508/WT, 9T/5T 56, 62 ¡21 58 Smoker (2 packs/day) data. 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
49 The B-tube contains ARMS primers specific for the 621+1 G>T, R553X, G551D, R117H, R1162X and R334W 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
99 1: 1717-1G>A/+; 2: G542X/+; 3: W1282X/+; 4: N1303K/+; 5: ∆F508/+; 6: 3849+10kbC>T/+; 7: +/+; 8: +/+; 9: ∆F508/∆F508; 10: 621+1G>T/+; 11: R553X/+; 12: G551D/+; 13: R117H/+; 14: R1162X/ +; 15: R334W/+; 16: +/+; 17: +/+; 18: ∆F508/∆F508; 19: ∆F508/+. Login to comment
102 1: +/+; 2: 1717-1G>A/+; 3: G542X/+; 4: W1282X/+; 5: N1303K/+; 6: ∆F508/+; 7: 3849+10kbC>T/+; 8: 621+1G>T/+; 9: R553X/+; 10: G551D/+; 11: R117H/+; 12: R1162X/+; 13: ∆F508/∆F508; 14: R334W/+. Login to comment
104 15: +/+; 16: +/+; 17: R553X/+; 18: +/+; 19: ∆F508/+; 20: +/+; 21: +/+; 22: R117H/∆F508; 23: ∆F508/∆F508; 24: +/+: 25: G542X/N1303K; 26: no deoxyribonucleic acid (DNA) control. Login to comment
107 The CF(12)m test screens for the CF mutations 1717-1G>A, G542X, W1282X, N1303K, ∆F508, 3849+10kbC>T, 621+ 1G>T, R553X, G551D, R117H, R1162X and R334W, the most common CF mutations in Caucasians and Ashkenazi Jews. Login to comment

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

No. Sentence Comment

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

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

No. Sentence Comment

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

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

No. Sentence Comment

40 The screening procedures of 17 other known CF mutations included detection of mutations in the PCR products of positive controls and samples by: a) direct analysis on PAGE for A1507 and 1677delTA, simultaneously to AF508; b) hybridization with ASOs for mutation R117H (21), 1717-1GdA (22), G542X (22), N1303K (23), and W1316X (24), and c) restriction digestion `followed by agarose or polyacrylamide gel electrophoresis (exon 3 PCR product digested with HinfI for CUE, exon 4 with HinfI for 444delA, exon 5 with RsaI for 711 + 5G --*A,exon 7 with HhaI for R347H or with RsaI for Q359K/T360, exon 11 with HincII for both G551D and R553X, exon 19 with DdeI for R1162X or with HphI for 3849G+A, a 175 bp PCR fragment of exon 13 with HaeIII for 2556insAT) (4). Login to comment

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

No. Sentence Comment

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

PMID: 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: 9917235 [PubMed] Ren CL et al: "Mutations of the cystic fibrosis gene and pancreatitis."

No. Sentence Comment

246 His sweat chloride and base-line potential-difference values were normal, and he had one mutation that causes cystic fibrosis (DF508, 9T) and one mutation that ordinarily does not (R117H, 7T).1,2 None of these findings establish a firm diagnosis of cystic fibrosis. Login to comment

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

No. Sentence Comment

129 The coexistence of two independent DNA alterations in the same CFTR allele might modulate the phenotype.30 Variations in intronic signals for splicing of CFTR transcripts, such as the 5T allele in intron 8 of the CFTR gene, were shown to affect the disease severity of patients carrying the R117H mutation.31 However, in our study no other CFTR mutation was found in the same CFTR alleles of the 3849ϩ10kb C-ϾT mutation that were in all the patients associated with the 7T variant. Login to comment
132 Therefore, the extrapolation of our results onto other populations who have a higher incidence of other mild mutations such as R117H requires further studies. Login to comment

PMID: 9921909 [PubMed] Bombieri C et al: "Complete mutational screening of the CFTR gene in 120 patients with pulmonary disease."

No. Sentence Comment

61 Of these 22 mutations, 14 (R75Q, P111L, R117H, I148T, Y301C, ∆F508, E585X, V754M, L997F, R1066C, M1137V, 3667ins4, D1270N, 4382delA) are listed by the Cystic Fibrosis Genetic Analysis Consortium (CFGAC) as CF mutations (CFGAC website), even if their role in CF disease remains to be proven, as is the case for R75Q, P111L, V754M, L997F, and D1270N. Login to comment
88 of cases CFTR gene PolyTb status tested mutationa DBE 23 1 G576A-R668C/L997F 7/9 1 ∆F508/L997F 9/9 1 ∆F508/- 7/9 1 R1066C/- 5/7 1 3667ins4/- 5/7 1 R75Q/- 7/7 1 M1137V/- 7/7 1 -/- 5/5 3 -/- 5/7 10 -/- 7/7 2 -/- 7/9 CB 27 1 P111L/- 7/7 1 R117H/- 7/7 1 E585X/- 7/7 1 P1072L/- 7/7 1 -/- 5/7 15 -/- 7/7 6 -/- 7/9 1 -/- 9/9 E 25 1 R668C/- 7/7 6 -/- 5/7 16 -/- 7/7 6 -/- 7/9 S 8 1 E826K/- 7/7 1 ∆F508/- 7/9 1 4382delA/- 7/7 1 L997F/- 7/9 1 V754M/- 7/9 3 -/- 7/7 LC 26 1 I148T/- 5/7 1 D1270N-R74W 5/7 1 D651N/- 7/7 1 Y301C/- 7/7 1 -/- 5/7 16 -/- 7/7 5 -/- 7/9 TB 4 1 -/- 5/7 1 -/- 7/7 2 -/- 7/9 Pneumonia 5 4 -/- 7/7 1 -/- 5/7 Pnx 2 2 -/- 7/7 Controls 68 1 L997F/- 7/9 1 R31C/- 7/7 1 I506V/- 5/7 1 -/- 5/7 1 -/- 5/9 23 -/- 7/7 4 -/- 7/9 1 -/- 9/9 2 ? Login to comment

PMID: 9922375 [PubMed] Sheppard DN et al: "Structure and function of the CFTR chloride channel."

No. Sentence Comment

157 When expressed in heterologous epithelial cells, R117H was cor-folding, and there was little Cl0 channel function measured (27). Login to comment
159 In addition, R117H had an altered sensitivity to external pH, suggesting thatof human CFTR (36, 149). Login to comment
161 R117H caused a small decrease in single-channel conductance but a dramatic change informs a cAMP-stimulated Cl0 current (46, 58, 61). Login to comment
169 These results suggest that ICL2 and ICL3 may be located close to the intracellular mouth of the CFTR characterized by a shortened open time, similar to that of R117H (95). Login to comment

PMID: 9922376 [PubMed] Dawson DC et al: "CFTR: mechanism of anion conduction."

No. Sentence Comment

593 Sheppard et al. (137) reported that R117H CFTR exhibitedbut also of larger pore-occluding molecules such as DPC, DIDS, and organic anions (see sect. V). Login to comment

PMID: 9922378 [PubMed] Schultz BD et al: "Pharmacology of CFTR chloride channel activity."

No. Sentence Comment

326 (0)-p-Bromotetramisole and IBMX also activated wild-type and the disease-are needed before one can conclude the stimulatory effects of milrinone are mediated by inhibition of class III causing mutant CFTR, R117H, G551D, and DF508 in cell-attached patches. Login to comment

PMID: 9950763 [PubMed] Clancy JP et al: "Adenosine and its nucleotides activate wild-type and R117H CFTR through an A2B receptor-coupled pathway."

No. Sentence Comment

6 It is published 12 times aAJP - Cell Physiology Adenosine and its nucleotides activate wild-type and R117H CFTR through an A2B receptor-coupled pathway JOHN P. CLANCY,1,2 FADEL E. RUIZ,1 AND ERIC J. SORSCHER2,3 Departments of 1Pediatrics and 3Medicine and 2Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama at Birmingham, Birmingham, Alabama 35294-0005 Clancy, John P., Fadel E. Ruiz, and Eric J. Sorscher. Login to comment
7 Adenosine and its nucleotides activate wild-type and R117H CFTR through an A2B receptor-coupled pathway. Login to comment
15 We also present data showing that this pathway can activate clinically significant mutant CFTR molecules such as R117H. Login to comment
32 We also show that the same receptor is present in human airway epithelial cells and provide the first example of activation of a clini- 0363-6143/99 $5.00 Copyright ௠ 1999 the American Physiological Society C361 cally important CFTR mutation (R117H) through this receptor-coupled pathway. Login to comment
37 After vaccinia infection, wtCFTR or R117H CFTR under control of the T7 promoter in the pTM-1 vector was introduced into cells in complex with 1,2-dioleoyl-3-trimethylammonium-propane/1,2- dioleoyl-sn-glycero-3-phosphoethanolamine (DOTAP/DOPE; 20 µg DOTAP/DOPE and 5 µg pTM-1 CFTR per 5 ϫ 105 cells) for 4 h. wtCFTR in the pTM-1 vector was the generous gift of Dr. S. Cheng (Genzyme, Cambridge, MA); R117H CFTR in the pTM-1vectorwasthegenerousgiftofDr.MichaelWelsh(Howard Hughes Medical Institute, University of Iowa, Iowa City, IA). Login to comment
100 CA2B AR-COUPLED ACTIVATION OF WILD-TYPE AND R117H CFTR meability in the COS-7 and HeLa cell lines following transient expression. Login to comment
166 CA2B AR-COUPLED ACTIVATION OF WILD-TYPE AND R117H CFTR ity influences ADO nucleotide-activated Cl-secretion by metabolizing ADO phosphates to ADO (37, 38, 40, 41). Login to comment
178 We chose to study the R117H CFTR, which is known to localize to the cell surface and maintain normal PKA-dependent activation but which has reduced single-channel Cl-conductance (34, 43). Login to comment
179 Figure 9 compares 10 µM ADO- and 10 µM forskolin-stimulated halide permeability in COS-7 cells expressing R117H CFTR, indicating similar strong responses. Login to comment
181 Furthermore, activation of R117H CFTR byADO is qualitatively similar to that obtained by pharmacologic stimulation of adenyl cyclase. Login to comment
232 R117H CFTR is activated by ADO (10 µM) or forskolin (10 µM). Login to comment
233 Expression of R117H CFTR was performed as described (see METHODS). Login to comment
235 CA2B AR-COUPLED ACTIVATION OF WILD-TYPE AND R117H CFTR lowing conversion to ADO by surface-localized CD73 (ecto-5Ј-nucleotidase) in T84 cells (25, 37, 38). Login to comment
238 A2B receptor stimulation of COS-7 cells expressing either wtCFTR or R117H CFTR indicates that this G protein-coupled receptor can effectively activate CFTR-dependent halide transport (Fig. 9). Login to comment
239 The R117H CFTR represents a class IV CFTR mutation, characterized by intact protein production, maturation, surface localization, and regulation but defective single-channel Cl- conduction (34, 43). Login to comment
241 The phenotype of patients possessing the R117H mutation is unusual. Login to comment
243 It has therefore been suggested that the R117H mutation may rest at the boundary of required CFTR function in two organ systems, providing adequate function to protect the exocrine pancreas but failing to provide the necessary function in the lungs to protect the airways from the pulmonary manifestations of cystic fibrosis. Login to comment
244 Although Cl-transport in cells expressing the common ⌬F508 CFTR trafficking mutant may not be expected to be stimulated by A2B AR activation, our studies raise the possibility that the function of R117H CFTR and possibly other class IV surface-localized CFTR mutations might be augmented through pharmacologic activation of A2B AR. Login to comment
246 In summary, these experiments are the first to describe 1) AR-coupled CFTR activation by ADO and adenosine mono-, di-, and triphosphates in a cell line devoid of endogenous competing Cl-transport pathways, 2) A2B AR regulation of CFTR-dependent halide transport, 3) A2B AR protein in COS-7 and native human bronchial epithelia, and 4) A2B receptor activation of R117H CFTR. Login to comment
247 The findings help clarify the positive regulatory effects that ADO and its nucleotides can confer to wtCFTR and R117H CFTR through the A2B AR. Login to comment

PMID: 15287992 [PubMed] Claustres M et al: "Are p.I148T, p.R74W and p.D1270N cystic fibrosis causing mutations?"

No. Sentence Comment

15 The most striking exemple is the length of the intron 8 polythymidine tract (7, 9, or 5 thymidines) on exon 9 splicing as a genetic modifier of the severity of the p.R117H mutation [1]. Login to comment

PMID: 15744523 [PubMed] Clain J et al: "A neutral variant involved in a complex CFTR allele contributes to a severe cystic fibrosis phenotype."

No. Sentence Comment

103 The length of a polythymidine tract in the 3' splice site of intron 8 modulates the clinical presentation of the p.R117H missense mutation because of a dramatic decrease in the amount of p.R117H-CFTR transcript (Kiesewetter et al. 1993). Login to comment

PMID: 16128988 [PubMed] Larriba S et al: "Molecular evaluation of CFTR sequence variants in male infertility of testicular origin."

No. Sentence Comment

51 CFTR analysis We identified 14 different, potential disease-causing CFTR sequence variants, 11 of them are translated into missense amino acid changes (p.R75Q, p.P111L, p.R117H, p.I148T, p.R334W, p.M348K, p.G576A, p.R668C, p.D1270N, p.S1235R and p.S1426F), one deletion (p.F508del) and two alleles affecting exon splicing [IVS8-6(5T), c.1716G>A] in 30 of 83 infertile patients (Table 1) giving a frequency of 36.1%. Login to comment
72 Description of genetic abnormalities and other risk factors of infertile and fertile CFTR carrier individuals No. Phenotype CFTR genotype Associated factors Testicular histologya b c Infertile individuals 1 NOb (SO) p.R75Q No Severe hypospermatogenesis 2 NOb (SO) p.R75Q No nd 3 NOb (A) p.P111L AZFb,c del Sertoli cell only 4 NOb (A) p.R117H AZFc del Severe hypospermatogenesis 5 NOb (SO) p.I148T No Severe hypospermatogenesis 6 NOb (A) p.R334W No Primary spermatocyte arrest 7 NOb (SO) p.M348K UV grade III Primary spermatocyte arrest 8 NOb (A) p.F508del No Sertoli cell only 9 NOb (A) p.F508del No Primary spermatocyte arrest 10 NOb (A) p.G576A, p.R668C No Severe hypospermatogenesis, Leydig cell hyperplasia 11 NOb (SO) p.G576A, p.R668C No Primary spermatocyte arrest (unilateral) 12 NOb (SO) p.G576A, p.R668C No Severe hypospermatogenesis 13 NOb (A) p.R668C UC Sertoli cell-only (incomplete) 14 NOb (SO) p.D1270N No nd 15 NOb (SO) p.S1235R No Severe hypospermatogenesis 16 NOb (SO) p.S1426F* UC Sertoli cell only 17 NOb (A) (T)5-(TG)12 No Severe hypospermatogenesis, Sertoli cell only (80%) 18 NOb (A) (T)5-(TG)12 No Sertoli cell only 19 NOb (SO) (T)5-(TG)11 UV grade III Bilateral moderate hypospermatogenesis 20 NOb (SO) (T)5-(TG)11 UV grade II Severe hypospermatogenesis 21 NOb (A) (T)5-(TG)11 No nd 22 NOb (SO) c.1716 G>A Dysplasia SV Severe hypospermatogenesis, Sertoli cell only (95%) 23 NOb (A) c.1716 G>A No nd 24 NOb (A) c.1716 G>A No Primary spermatocyte arrest (bilateral) 25 NOb (SO) c.1716 G>A No Sertoli cell only (95%) 26 NOb (SO) c.1716 G>A No Severe hypospermatogenesis 27 NOb (SO) c.1716 G>A UV grade III Severe hypospermatogenesis 28 NOb (SO) c.1716 G>A No nd 29 NOb (SO) c.1716 G>A No nd 30 NOb (SO) c.1716 G>A AZFc del Severe hypospermatogenesis Fertile individuals 1 F1 p.R75Q No nd 2 F1 p.F508del No nd 3 F1 p.F508del No nd 4 F1 p.G576A, p.R668C/ c.1716 G>A No nd 5 F1 p.D836Y No nd 6 F1 p.S1235R/c.1716 G>A No nd 7 F1 c.1716 G>A No nd 8 F1 c.1716 G>A No nd 9 F1 c.1716 G>A No nd 10 F1 c.1716 G>A No nd 11 F1 c.1716 G>A No nd 12 F2 p.R75Q No nd the expected CF carrier frequency in the local population (Van der Ven et al., 1996; Larriba et al., 2001; Dohle et al., 2002) or with the general population (Jakubiczka et al., 1999; Pallares-Ruiz et al., 1999; Ravnik-Glavac et al., 2001) and not normospermic fertile individuals, the latter considered as adequate controls. Login to comment
77 Most of the changes identified, except p.F508del, p.R117H, p.I148T and p.R334W, are known to behave as benign mutations being present in milder phenotypes of CFTR-related pathologies (http:// www.genet.sickkids.on.ca) and/or because of the results of the performance of functional studies. 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

52 Mutation 0.46-0.35 9 c.1078delT #, p.R347P # 8 p.G85V, c.621 + 1G > T #, p.S549R (T > G) #, p.R553X #, c.3849 + 10kbC > T # 7 p.R347H #, c.1812-1G > A, p.R709X 0.30-0.10 6 p.H199Y, p.P205S, 5 p.R117H #, p.G551D #, p.W1089X, p.Y1092X, CFTR50kbdel 4 c.296 + 3insT, c.1717-1G > A #, c.1949del84, c.3849 + 1G > A 3 p.E92K, c.936delTA, c.1717-8G > A, c.1341G > A, p.A561E, c.2603delT, p.G1244E, [p.D1270N; p.R74W] 2 p.Q2X, p.P5L, CFTRdele2,3, p.S50P, p.E60K, c.405 + 1G > A, c.1677delTA, p.L558S, p.G673X, p.R851X, p.Y1014C, p.Q1100P, p.M1101K, p.D1152H, CFTRdele19, p.G1244V, p.Q1281X, p.Y1381X <0,1 1 c.124del23bp, p.Q30X, p.W57X, c.406-1G > A, p.Q98R, p.E115del, c.519delT, p.L159S, c.711 + 3A > T, p.W202X, c.875 + 1G > A, p.E278del, p.W361R, c.1215delG, p.L365P, p.A399D, c.1548delG, p.K536X, p.R560G, c.1782delA, p.L571S, [p.G576A; p.R668C], p.T582R, p.E585X, c.1898 + 1G > A, c.1898 + 3A > G, c.2051delTT, p.E692X, p.R851L, c.2711delT, c.2751 + 3A > G, c.2752-26A > G, p.D924N, p.S945L, c.3121-1G > A, p.V1008D, p.L1065R, [p.R1070W; p.R668C], [p.F1074L; 5T], p.H1085R, p.R1158X, c.3659delC #, c.3667del4, c.3737delA, c.3860ins31, c.3905insT #, c.4005 + 1G > A, p.T1299I, p.E1308X, p.Q1313X, c.4095 + 2T > A, rearrangements study (n = 4) Mutations identified in CF families with mixed European origin: c.182delT, p.L1254X, c.4010del4. Login to comment

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

No. Sentence Comment

66 Table 1 Assessment of CF risk Couples with PGD (n ¼ 47) Couples without PGD (n ¼ 22) All couples (n ¼ 69)(%) CF risk assessment Affected child or foetus 23 14 37 (53.6) CBAVD (without other CF complaints) 7 3 10 (14.5) During fertility work-up (not CBAVD) 10 10 (14.5) Positive family history 3 2 5 (7.2) CF patient (with CBAVD in males) 4 4 (5.8) Unknown 2 2 (2.9) Preconceptual screening 1 1 (1.4) Table 2 Reasons for choosing PGD Couples with PGD (n ¼ 47) Couples without PGD (n ¼ 22) All couples (n ¼ 69) Reason for choosing/informing about PGD Fertility problems 24 7 31 (44.9%) Objection to abortion 15 2 17 (24.6%) History of termination of pregnancy 8 1 9 (13%) Unknown 11 11 (15.9%) Other 1 1 (1.4%) Table 3 Genotypes of the couples with PGD cycles Female partner Male partner Number of couples with this genotype p.F508del/- p.F508del/- 17 p.F508del/- p.R117H/- (7T/9T) 1 p.2789+5G4A/- p.D110H/p.D110H 1 p.G542X/- p.F508del/- 1 p.R334Q/- p.F508del/- 1 p.R553X/- p.F508del/- 2 p.1717-1G4A p.2183AA4G/5T 1 p.F508del/- p.F508del/? Login to comment
67 2 p.1303K/- p.G542X/p.R117H 1 p.F508del/- 5T/? Login to comment
68 1 p.F508del/- p.G194T/5T 1 p.F508del/ p.3272-26A4G p.R1162X/- 1 p.F508del/- p.F508del/ p.R117H (7T/9T) 1 p.F508del/- p.F508del/ p.F508del 1 p.R334W/- p.F508del/ p.F508del 1 p.F508del/- p.F508del/ p.M265R 1 p.F508del/- ?/? 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
85 Out of 122 patients, 25 (20.49%, 95% CI 13.94-28.95) had SPINK1 mutations (24 p.N34S mutations and 1 p.P55S mutation), and 10 (40%) of these had additional mutations that could partially or completely cause pancreatitis; in addition to those already mentioned, 4 had CFTR mutations (1 p.R117H, 2 dF508del, and 1 IVS8-5T mutations). Login to comment
86 Out of 122 patients, 14 (11.48%, 95% CI 6.65-18.82) had CFTR mutations (4 dF508del, 4 p.R117H, 1 394delTT, and 5 IVS8-5T); and 5 (35.7%) of these had an additional mutation as mentioned above. Login to comment
87 As the mutation 394delTT belonged to mutation class I, dF508del to mutation class II, and the mutations p.R117H and IVS8-5T to classes IV and V, respectively, 64.3% of the patients with CFTR mutations had mutations coming from classes IV and V. Login to comment

PMID: 20607857 [PubMed] Bareil C et al: "UMD-CFTR: a database dedicated to CF and CFTR-related disorders."

No. Sentence Comment

15 Several sequence changes initially reported as causing disease have subsequently been reported to be neutral sequence variants (a typical illustration is the variant p.Ile148Thr) [Claustres et al., 2004; Rohlfs et al., 2004] or mutations with reduced penetrance (only some patients will develop CF or CFTR-related disorder; example: p.Arg117His) [Kiesewetter et al., 1993; Rosenstein and Cutting, 1998; Thauvin-Robinet et al., 2009] or mutations with variable expressivity (some patients develop mild rather than severe symptoms; examples include p.Leu206Trp [Desgeorges et al., 1995; Rozen et al., 1995] or p.Asp1152His [Burgel et al., 2010; Mussaffi et al., 2006]). Login to comment
81 Mutation p.Arg117His, for example (c.350G4A according to the recommended nomenclature), whose disease phenotype varying from asymptomatic to classical CF [Munck et al., 2009; Thauvin-Robinet et al., 2009], can partially be explained by its association in cis with the polyT alleles (T[5] or T[7]), was only found in CBAVD patients in our series. Login to comment
82 In all cases (19 alleles found in 18 patients, one male being homozygous), p.Arg117His was associated in cis with T[7] allele and (when the segregation analysis could be performed) with TG[10] repeats in 68.42% (13 alleles/19) (Fig. 3). Login to comment
115 Example of p.Arg117His mutation in CBAVD patients. 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

50 Seven mutations had not been previously reported in the Chilean population (p.1078delT, pG85E, c.3120+1 GNA, c.711+1 GNT, p.R117H, p.A455E, and p.I148T). Login to comment
81 Mutation This study Rios et al. [4] Molina et al. [5] Repetto et al. [6] Perez et al. [13] CFGAC [2] (n=578) (%) (n=72) (%) (n=36) (%) (n=100) (%) (n=4102) (%) (n=43,849) (%) Chile Chile Chile Chile Latin-Americaa Worldwide Unknown 58.0 66.6 61.1 34.0 36.7 22.7 p.F508del 30.6 29.2 30.6 45.0 47.1 66.0 p.R334W 3.1 - - 2.0 0.8 0.1 p.G542X 2.4 0 8.3 7.0 5.0 2.4 c.3849+10Kb CNT 1.7 - - 3.0 0.3 0.2 p.R553X 1.2 4.2 0 1.0 0.4 0.7 p.R1162X 0.9 - - 2.0 1.0 0.3 p.1078delT 0.5 - - 0 b0.1 0.1 p.G85E 0.5 - - - 0.8 0.2 p.W1282X 0.2 - - 5.0 1.0 1.2 c.3120+1 GNA 0.2 - - - 0.3 - c.711+1 GNT 0.2 - - - 0.1 0.1 p.R117H 0.2 - - 0 b0.1 0.3 p.A455E 0.2 - - 0 0 0.1 p.I148T 0.2 - - - - - p.G551D 0 0 0 1.0 0.1 1.6 p.N1303K 0 0 0 0 1.8 1.3 c.621+1 GNT 0 - - 0 0.2 0.7 c.1717-1 GNA 0 - - 0 0.3 0.6 p.I507del 0 - - 0 0.2 0.2 p.R347P 0 - - 0 0 0.2 c.2789+5 GNA 0 - - - 0.2 0.1 c.1898+1 GNA 0 - - - 0.1 0.1 c.2184delA 0 - - - b0.1 0.1 p.S549N 0 - 0 - 0.1 0.1 c.3659delC 0 - - 0 0.1 0.1 p.R560T 0 - - - 0 0.1 c.1811+1.6Kb ANG 0 - - - 0.4 - c.2183AANG 0 - - 0 0.1 - p.S549R 0 - - - 0.1 - c.3272-26 ANG 0 - - - 0.1 - c.3199del6 0 - - - b0.1 - p.E60X 0 - - 0 0 - c.3905insT 0 - - - 0 - p.S1251N 0 - - 0 - - CFTRdele2,3 0 - - - - - p.R347H 0 - - - - - p.V520F 0 - - - - - p.Q552X 0 - - - - - c.394delTT 0 - - - - - c.711+1 GNA 0 - - - - - c.2143delT 0 - - - - - c.3876delA 0 - - - - - a Data from Chilean patients published in Rios et al., Molina et al., and Repetto et al. [4-6] included in this publication were excluded in this table to avoid repetition. Login to comment

PMID: 21547743 [PubMed] Sosnay PR et al: "Evaluation of the disease liability of CFTR variants."

No. Sentence Comment

81 For example, the disease liability of the ACMG mutation p.Arg117His is dependent on polythymidine variants in the flanking exon (28). Login to comment
82 When this mutation is associated with the "5T" polythymidine tract, p.Arg117His has a higher penetrance for CF, whereas longer polythymidine tracts ("7T" or "9T") are associated with obstructive azoospermia or no disease at all. Login to comment

PMID: 18358580 [PubMed] Vailly J et al: "The expansion of abnormality and the biomedical norm: neonatal screening, prenatal diagnosis and cystic fibrosis in France."

No. Sentence Comment

98 For instance, the mutation referred to as R117H, which turns out to be the second most common mutation in France, indiscriminately entails classic forms of CF, attenuated forms or else simple forms of infertility, or even no symptoms at all. Login to comment
99 More precisely, R117H leads preferentially to CF when it is associated with another genetic marker called 5T, and preferentially to infertility when it is associated with the marker called 7T. Login to comment
102 Currently, the R117H mutation represents 8.5% of the mutations detected in the screened population, whereas before NSCF was implemented, it accounted for only 0.3% of the mutations in patients on record in tertiary care centres (ONM, 2001). Login to comment
173 In 2004, a study conducted by AFDPHE (2004) showed that a CF diagnosis had been established for 18 children that were homozygous (two identical mutations) or compound heterozygous (two different mutations) for the R117H mutation while having a normal sweat test. Login to comment
188 e''At [X], we have an experience with a child that has [an] R117H [mutation] and is ST negative, while his older brother is ST positive`` (Paediatrician 4, Observation 1). Login to comment
233 Situation 2 Bastien and Isabelle are the parents of little Zoe, who was given a sweat test according to the same procedure used for Lea, after a positive IRT level result and detection of a mutation e the famous so-called mild R117H mutation e were discovered during neonatal screening. Login to comment
237 shows that you are a carrier of the R117H mutation (associated with alleles 7T, 7T of intron 8). Login to comment
256 One of the three geneticists surveyed in the centre told me during a conversation I had with him concerning borderline forms: e''Whenever a mutation is found [by neonatal screening], even the R117H, people are sent to genetic counselling.. That`s the way it is, the machinery is in motion whether or not it is justified, I don`t know [he sighs]. 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
159 In addition, the 5T allele may modify the phenotype of the R117H mutation. Login to comment
160 Although the majority of CFTR mutations occur in cis (i.e. on the same chromosome) with the 7T and 9T alleles, R117H may occur in cis with 5T or 7T. Login to comment
161 As expected, R117H-7T is generally milder than R117H-5T. Login to comment

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

No. Sentence Comment

366 AF508/AF508 G551D/G551D G542X/G458V G542X/G542X R553X/W1316X N369X/unknown R553X/R553X G551S/G551S G368Xlunknown AF508/R117H PI PI PI PI PI PI PI PS PS PS Severe 116 Severe 181 Severe 49 Mild 49 Mild 50 Mild 102 Moderate-Severe 13 Mild 181 Mild 102 Mild 55 Comparison of genotype with phenotype for some CF-associated mutations. Login to comment

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

No. Sentence Comment

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

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

No. Sentence Comment

42 Arg117His previously termed R117H] V Splicing defect: leads to decreased amount of CFTR protein at the cell surface [eg 3849+10 kb C>T] VI Functional but unstable with decreased half life at the cell surface [eg Gln1412X previously termed Q1412X] R.M. Thursfield, J.C. Davies / Paediatric Respiratory Reviews (2012) 215-219216 difference (nPD) measurement. Login to comment

PMID: 22678879 [PubMed] El-Seedy A et al: "CFTR mutation combinations producing frequent complex alleles with different clinical and functional outcomes."

No. Sentence Comment

105 [2002C>T;3718-2477C>T] p.Gln689X 2 CSD Nasal polyposis 14 y,16 y NA, 29 p.[Gly576Ala;Arg668Cys] NI 3 IP 35-39 y NA p.[Asp443Tyr;Gly576Ala;Arg668Cys] NI 1 IP Bronchitis 49 y NA p.[Gly576Ala;Arg668Cys] p.PheF508del 1 IP 42 y NA p.[Gly576Ala;Arg668Cys] p.Arg668Cys 1 IP NA NA p.[Gly576Ala;Arg668Cys] c.1210_34TG[12]T[5] 4 IP 19-69 y NA p.[Gly576Ala;Arg668Cys] NI 1 Cholestasis 60 y NA p.[Gly576Ala;Arg668Cys] c.1584G>A 33 CBAVD 27-50 y 9-82 p.[Asp443Tyr;Gly576Ala;Arg668Cys] p.Phe508del 2 CBAVD 30 y,36 y NA p.[Asp443Tyr;Gly576Ala;Arg668Cys] c.2051_2052delAAinsG 1 CBAVD 34 y 72 p.[Asp443Tyr;Gly576Ala;Arg668Cys] p.Trp1282X 1 CBAVD NA NA p.[Asp443Tyr;Gly576Ala;Arg668Cys] p.Asn1303Lys 1 CBAVD 35 y 65-66 p.[Asp443Tyr;Gly576Ala;Arg668Cys] p.Ser549Asn 1 CBAVD NA NA p.[Asp443Tyr;Gly576Ala;Arg668Cys] c.3605delA 1 CBAVD 30 y 41-69 p.[Asp443Tyr;Gly576Ala;Arg668Cys] p.Gln1411X 1 CBAVD 31 y NA p.[Asp443Tyr;Gly576Ala;Arg668Cys] p.Arg347His 3 CBAVD 29 y, 34 y, NA NA p.[Asp443Tyr;Gly576Ala;Arg668Cys] p.Gly542X 1 CBAVD 35 y NA p.[Asp443Tyr;Gly576Ala;Arg668Cys] c.946delT 1 CBAVD 26 y NA p.[Asp443Tyr;Gly576Ala;Arg668Cys] c.4242_4242+1delGGinsT 1 CBAVD 41 y 31 p.[Asp443Tyr;Gly576Ala;Arg668Cys] p.Arg117His 1 CBAVD 32 y NA p.[Asp443Tyr;Gly576Ala;Arg668Cys] p.Thr338Ile 1 CBAVD NA NA p.[Asp443Tyr;Gly576Ala;Arg668Cys] p.Glu379Lys 1 CBAVD NA NA p.[Asp443Tyr;Gly576Ala;Arg668Cys] p.Met1137Val 1 CBAVD NA NA p.[Asp443Tyr;Gly576Ala;Arg668Cys] p.Thr1246Ile 2 CBAVD NA NA p.[Asp443Tyr;Gly576Ala;Arg668Cys] NI 1 CBAVD 34 NA p.[Gly576Ala;Arg668Cys] p.Asn1303Lys 8 CBAVD 30-42 y NA p.[Gly576Ala;Arg668Cys] NI 1 CBAVD 27 y NA p.Arg668Cys p.Phe508del 1 CBAVD 30 y NA p.Arg668Cys NI 1 CUAVD NA NA p.[Asp443Tyr;Gly576Ala;Arg668Cys] p.Phe508del 1 CUAVD NA NA p.[Gly576Ala;Arg668Cys] NI 1 CUAVD Renal agenesis NA NA p.[Gly576Ala;Arg668Cys] NI 1 Hypofertility (not CBAVD) CF carrier`s partner NA NA p.[Gly576Ala;Arg668Cys] p.Asp1152His 1 FBA Mild CF considered possible, 2 older brothers with the same genotype, one with a very mild phenotype, the other being asymptomatic 22 wg NA p.[Asp443Tyr;Gly576Ala;Arg668Cys] p.Asn1303Lys 1 FBA TOP for de novo chromosomal translocation; not CF 21 wg NA p.[Asp443Tyr;Gly576Ala;Arg668Cys] p.Arg31Cys 1 FBA Not CF at birth 28 wg <30 p.[Gly576Ala;Arg668Cys] p.Phe508del 1 FBA Unknown outcome 23 wg NA p.[Gly576Ala;Arg668Cys] p.Phe508del 1 FBA Not CF at birth 21 wg <30 p.[Gly576Ala;Arg668Cys] p.Trp846X (Continued) Table 1. 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

20 Class III (e.g., G551D, 4%) and class IV (e.g., R117H) mutations impair the CFTR channel opening-closing (or gating) cycle and conductance, respectively, without recognizable conformational or trafficking defects. Login to comment

PMID: 22390181 [PubMed] Grzegorczyk V et al: "Management of male infertility due to congenital bilateral absence of vas deferens should not ignore the diagnosis of cystic fibrosis."

No. Sentence Comment

48 The most common mutation in patients with CBAVD are the main CF-associated defect F508del (21-40%), the T5 variant of the polypyrimidin tract of the intron eight (19-37%) which pathogenicity depends on the adjacent TG-repeat, and R117H (3-14%) and the most frequent genotype is F508del/R117H (40%) (De Braekeleer & Fe´rec, 1996; Je´ze´quel et al., 2000; Ratbi et al., 2007). 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

25 DF508, the most common CFTR mutation worldwide, was detected in 61 patients, and the R117H missense mutation and the splice variant IVS8-5T were found in 22 patients each. Login to comment
29 Two mutations were found in 42 patients; the most frequently detected genotype was the compound heterozygous combination DF508/R117H in 17 patients with CBAVD (40%), followed by DF508/IVS8-5T in 13 patients (31%). Login to comment
30 In the heterozygous condition (n = 37 patients), DF508 mutation (21 patients, 57%) was followed by the IVS8-5T splice variant (six patients, 16%) and R117H mutation (six patients, 16%) (Table 2). 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
46 Table 2 Frequency of genotypes detected in patients with CBAVD DF508/R117H DF508/IVS8-5T Others DF508 IVS8-5T R117H Others 17 patients with CBAVD (40)a 13 patients with CBAVD (31) 12 patients with CBAVD (29) 21 patients with CBAVD (57) 6 patients with CBAVD (16) 6 patients with CBAVD (16) 4 patients with CBAVD (11) a Percentages in brackets refer to genotypes with two mutations (n = 42) or one mutation (n = 37) detected. 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: 22960984 [PubMed] Rowe SM et al: "Progress in cystic fibrosis and the CF Therapeutics Development Network."

No. Sentence Comment

30 Ivacaftor will also be tested in the archetype conductance mutation R117H, which could establish whether potentiation of CFTR gating is sufficient to partially ameliorate non-gating mutations, setting the stage for other studies involving rare mutations localised to the cell surface. Login to comment
48 Since then, newer agents with improved pharmacokinetic and pharmacodynamic properties have been developed, and early phase trials have been conducted to test Table 2 CFTR-based therapies completed or in progress within the Therapeutics Development Network CFTR mutation Proportion of patients with causative mutation (%) Therapeutic approach Status G551D/other 4 Ivacaftor FDA approved, age ≥6 Age 3-5 planned Non-G551D gating/other 1 Ivacaftor Phase II/III R117H/other 5 Ivacaftor Phase III F508del/ F508del 49 Lumacaftor+ ivacaftor Phase II; phase III planned VX-661+ ivacaftor Phase II PTC/other 10 Ataluren Phase III (primary endpoint negative) CF, cystic fibrosis; CFTR, CF transmembrane conductance regulator; PTC, premature termination codon. Login to comment

PMID: 22842702 [PubMed] Ni WH et al: "The CFTR polymorphisms poly-T, TG-repeats and M470V in Chinese males with congenital bilateral absence of the vas deferens."

No. Sentence Comment

8 It is estimated that about one in 20-25 Caucasians carries a mutation of the CFTR gene.2 In contrast, CF is very rare in Asian populations including Chinese.3-5 However, congenital bilateral absence of the vas deferens (CBAVD) is not uncommon in Asian populations.6 CBAVD accounts for approximately 6% of cases of obstructive azoospermia7 and is responsible for 1%-2% of all infertility in males.6 It is well known that CBAVD is also present in nearly 95% of all CF males.6 To date, more than 1000 mutations have been identified in the CFTR gene in classic and atypical CF patients worldwide.8 Mutations of the CFTR gene have also been frequently reported in patients with CBAVD.6 In the majority of cases, CBAVD can be considered to be an atypical, genital phenotypic presentation of CF, presenting without other clinical manifestations of CF.9 The 5T allele, R117H and F508del, are the most common CFTR mutations in Caucasian CBAVD patients.2 The poly(T) sequence located in the splicing acceptor site of intron 8 (IVS8 poly(T)) has three variants, with five, seven or nine thymidines (the 5T, 7T and 9T alleles, respectively).10 The 7T or 9T allele generate a predominantly normal mRNA transcript, whereas the 5T variant affects splicing efficiency and results in reduced levels of normal mRNA due to deletion of exon 9.11 The protein product of the CFTR transcript lacking exon 9 is devoid of cyclic adenosine monophosphate-activated chloride conductance, and therefore, the 5T allele is now considered as a mild mutation with an incomplete penetrance.11,12 Prior studies have demonstrated that the disease penetrance of 5T depends on the copy number of its adjacent TG repeats.13,14 The number of TG repeats immediately adjacent to 5T is associated with a variable efficiency of exon 9 splicing.15,16 The different alleles at (TG)m(T)n polymorphic loci at the 39 end of human CFTR intron 8 determine the exon 9 splicing efficiency.17,18 In other respects, the M470V (1540A/G in exon 10) polymorphism is one of the most common polymorphisms in the CFTR gene.19 By in vitro studies, it was shown that the CFTR gene carrying the V allele yielded a lower functional CFTR protein rate than those carrying the M allele, independently of the intron 8 Tn genotype.15 de Meeus et al.19 reported that strong linkage disequilibrium was observed between the 5T allele and the V allele of the M470V polymorphism in the CBAVD population, but not in the normal population. Login to comment
50 The frequency of IVS8-5T in our patients was higher than in Portuguese (27.4%),24 Iranian (25.94%),25 Chinese residents of Taiwan (29.2%)26 and Turkish patients (19.6%).27 The compound heterozygote with a major mutation of CFTR such as F508del or R117H, which causes the development of CBAVD in Caucasian populations, determined the pathogenic 5T allele.10 However, no major CFTR mutations, such as F508del, were found in Japanese and Chinese residents of Taiwan subjects with CBAVD.6 In our study, we also found no F508del mutation in Chinese population with CBAVD. 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

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

74 [1521_1523delCTT]+[350G>A;1210-12T[7]] genotype (legacy name: F508del/R117H-IVS-8 T(7)) had negative sweat test results. Login to comment
75 The R117H-T7 complex allele is usually considered a CFTR-related disorder mutation [5,24] and when found in compound heterozygosity with a CF-causing mutation, it results in variable phenotypes ranging from mild form of CF, obstructive azoospermia, or to no disease at all [5]. Login to comment
77 However, the R117H mutation is an integral part of the Elucigene assay and thus could not have been disregarded. Login to comment
78 The two newborns carrying R117H-T7 allele, were not diagnosed with CF. Login to 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: 22739718 [PubMed] Pettit RS et al: "Cystic fibrosis transmembrane conductance regulator-modifying medications: the future of cystic fibrosis treatment."

No. Sentence Comment

116 Future research for ivacaftor includes use in other gating CFTR mutations (class III mutations),20 use in patients between ages 2 and 5 years, and patients with at least 1 copy of R117H mutation, a class IV mutation.21 Clinicians should monitor the literature to determine whether ivacaftor should be used in patients with CF and other genotypes. Login to comment

PMID: 22483971 [PubMed] Li H et al: "Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) in Chinese patients with congenital bilateral absence of vas deferens."

No. Sentence Comment

71 ΔF508 and R117H are the most common CBAVD mutations in Northern European population, but none of these was found in this study. Login to comment
119 △F508 R117H Mutation genotypes IVS8-Tn n (%) Two mutations detected Neg Neg I556V/I556V 7T/7T 1(1.3) Neg Neg I556V/1209+2 G-C 5T/7T 1(1.3) Neg Neg I556V/726delATT 5T/5T 1(1.3) Neg Neg I556V/- 5T/5T 1(1.3) Neg Neg I556V/- 5T/7T 1(1.3) Neg Neg G970D/- 5T/7T 1(1.3) Neg Neg C592F/- 5T/5T 1(1.3) Neg Neg 1209+1 G-C/- 5T/7T 1(1.3) Neg Neg R553X/- 5T/7T 1(1.3) Neg Neg Q1352H/- 5T/7T 1(1.3) Neg Neg S485C/- 5T/7T 1(1.3) Neg Neg A357T/- 5T/7T 1(1.3) Neg Neg E217G/- 5T/7T 1(1.3) Neg Neg R347H/- 5T/7T 1(1.3) Neg Neg G451K/- 5T/7T 1(1.3) Neg Neg L558S/- 5T/7T 1(1.3) Neg Neg 3635delT/Q1352H 7T/7T 1(1.3) Neg Neg A1136T/G970D 7T/7T 1(1.3) Neg Neg 870-1 G-C/- 5T/7T 1(1.3) Neg Neg 520-2 A-G/- 5T/7T 1(1.3) Neg Neg R419I/- 5T/7T 1(1.3) Neg Neg C491F/Q1643Q 7T/7T 1(1.3) Neg Neg Q1352H/- 5T/7T 1(1.3) Neg Neg R851X/- 5T/7T 1(1.3) Neg Neg P750L/G970D 7T/7T 1(1.3) One mutation detected Neg Neg -/- 5T/7T 2(2.7) Neg Neg -/- 5T/7T 3(4.1) Neg Neg -/- 5T/7T 5(6.8) Neg Neg -/- 5T/5T 2(2.7) Neg Neg -/- 5T/5T 1(1.3) Neg Neg G970D/- 7T/7T 2(2.7) Neg Neg D993Y/- 7T/7T 1(1.3) Neg Neg I556V/- 7T/7T 1(1.3) Neg Neg T388R/- 7T/7T 1(1.3) No mutation detected Neg Neg -/- 7T/7T 8(10.9) Neg Neg -/- 7T/7T 15(20.5) Neg Neg -/- 7T/9T 2(2.7) Neg Neg -/- 7T/7T 4(5.5) Neg: Negative. Login to comment
70 ƊF508 and R117H are the most common CBAVD mutations in Northern European population, but none of these was found in this study. Login to comment
118 b3;F508 R117H Mutation genotypes IVS8-Tn n (%) Two mutations detected Neg Neg I556V/I556V 7T/7T 1(1.3) Neg Neg I556V/1209+2 G-C 5T/7T 1(1.3) Neg Neg I556V/726delATT 5T/5T 1(1.3) Neg Neg I556V/- 5T/5T 1(1.3) Neg Neg I556V/- 5T/7T 1(1.3) Neg Neg G970D/- 5T/7T 1(1.3) Neg Neg C592F/- 5T/5T 1(1.3) Neg Neg 1209+1 G-C/- 5T/7T 1(1.3) Neg Neg R553X/- 5T/7T 1(1.3) Neg Neg Q1352H/- 5T/7T 1(1.3) Neg Neg S485C/- 5T/7T 1(1.3) Neg Neg A357T/- 5T/7T 1(1.3) Neg Neg E217G/- 5T/7T 1(1.3) Neg Neg R347H/- 5T/7T 1(1.3) Neg Neg G451K/- 5T/7T 1(1.3) Neg Neg L558S/- 5T/7T 1(1.3) Neg Neg 3635delT/Q1352H 7T/7T 1(1.3) Neg Neg A1136T/G970D 7T/7T 1(1.3) Neg Neg 870-1 G-C/- 5T/7T 1(1.3) Neg Neg 520-2 A-G/- 5T/7T 1(1.3) Neg Neg R419I/- 5T/7T 1(1.3) Neg Neg C491F/Q1643Q 7T/7T 1(1.3) Neg Neg Q1352H/- 5T/7T 1(1.3) Neg Neg R851X/- 5T/7T 1(1.3) Neg Neg P750L/G970D 7T/7T 1(1.3) One mutation detected Neg Neg -/- 5T/7T 2(2.7) Neg Neg -/- 5T/7T 3(4.1) Neg Neg -/- 5T/7T 5(6.8) Neg Neg -/- 5T/5T 2(2.7) Neg Neg -/- 5T/5T 1(1.3) Neg Neg G970D/- 7T/7T 2(2.7) Neg Neg D993Y/- 7T/7T 1(1.3) Neg Neg I556V/- 7T/7T 1(1.3) Neg Neg T388R/- 7T/7T 1(1.3) No mutation detected Neg Neg -/- 7T/7T 8(10.9) Neg Neg -/- 7T/7T 15(20.5) Neg Neg -/- 7T/9T 2(2.7) Neg Neg -/- 7T/7T 4(5.5) Neg: Negative. 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
71 Mutation I148T, which is still part of this test, was ignored since this mutation is not considered disease-causing anymore. 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

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: 22366207 [PubMed] Haverkamp MH et al: "Pulmonary Mycobacterium abscessus: a canary in the cystic fibrosis coalmine."

No. Sentence Comment

1 After exclusion of genetic immune disorders known to cause NTM susceptibility, we found compound heterozygosity of two mutations, F508del and R117H in CFTR. Login to comment
51 In the absence of defects in the IL-12/IFN-g pathway, we sequenced all 27 exons of the CFTR gene and found mutations in exon 10, c.1521-1523delCTT leading to F508del, and exon 4, c.482G>A leading to R117H (Fig. 1AeC). Login to comment
52 The length of a polythymidine stretch in intron 8, which precedes the exon 9 splice acceptor site, influences the amount of functional CFTR protein with the R117H mutation.5 We found 7 thymidines on the R117H allele (Fig. 1D). Login to comment
59 Factor Examples Lung disorders COPD, fibrosis due to systemic diseases, malignancy Prior (lung) infections HIV, tuberculosis, NTM, histoplasmosis Genetic disorders Cystic fibrosis, a 1-antitrypsin deficiency, ciliary motility disorder, Lady Windermere Syndrome, MSMD Endocrine disorders Cushing Syndrome, panhypopituitarism Aspiration Hypersensitivity heterozygosity for F508del and R117H;T7 as in the patient. Login to comment
60 The other siblings were heterozygous for R117H;T7, but lacked the F508del mutation. Login to comment
65 6 Mild mutations in CFTR with residual function of the protein, like R117H, often appear in compound heterozygosity with F508del. Login to comment
66 R117H/F508del (estimated carrier rate 1/ 17,470 persons) can lead to adult onset isolated chronic pathology of the pulmonary, digestive or reproductive tracts (penetrance of delayed severe CF symptoms 0.06%), but also to classical childhood CF (penetrance 0.03%) or absence of all CF symptoms. Login to comment
67 7 The activity of an R117H CFTR protein is further dependent on the length of a polythymidine stretch in intron 8. Login to comment
68 Individuals with the R117H mutation and a T5 or T7 variant have lower levels of functional CFTR than individuals with T9 (the normal variant), because of reduced splicing of exon 9. Login to comment
70 5 R117H;T7 has only recently been classified as a mutation that causes CF. Login to comment
71 8 The broad clinical spectrum of F508del/R117H;T7, illustrated by genotypeephenotype relations in our patient`s relatives, makes genetic counseling difficult. Login to comment
75 10,11 Mutations in CFTR, including F508del and R117H, are found in 36.5% of these patients, 10 but overall this seems to be a milder disease than even the attenuated forms of CF. Login to comment
78 Furthermore, childhood bronchitis, the cholecystectomy, infertility and her family history could have been interpreted as Figure 1 F508del, R117H and the length of a polythymidine stretch in intron 8 of the Cystic Fibrosis Transmembrane Conductance Regulator protein (CFTR). Login to comment
81 The localization of the common F508del mutation in the first cytoplasmic Nucleotide Binding Domain and the milder R117H mutation in the first membrane spanning domain is indicated. Login to comment
87 The heterozygous missense mutation c.482G>A (R117H) in exon 4 leading to the replacement of Arginine (R) at residue 117 by Histidine (H). Login to comment
53 The length of a polythymidine stretch in intron 8, which precedes the exon 9 splice acceptor site, influences the amount of functional CFTR protein with the R117H mutation.5 We found 7 thymidines on the R117H allele (Fig. 1D). Login to comment
61 The other siblings were heterozygous for R117H;T7, but lacked the F508del mutation. Login to comment
69 Individuals with the R117H mutation and a T5 or T7 variant have lower levels of functional CFTR than individuals with T9 (the normal variant), because of reduced splicing of exon 9. Login to comment
72 8 The broad clinical spectrum of F508del/R117H;T7, illustrated by genotypeephenotype relations in our patient`s relatives, makes genetic counseling difficult. Login to comment
76 10,11 Mutations in CFTR, including F508del and R117H, are found in 36.5% of these patients, 10 but overall this seems to be a milder disease than even the attenuated forms of CF. Login to comment
79 Furthermore, childhood bronchitis, the cholecystectomy, infertility and her family history could have been interpreted as Figure 1 F508del, R117H and the length of a polythymidine stretch in intron 8 of the Cystic Fibrosis Transmembrane Conductance Regulator protein (CFTR). Login to comment
82 The localization of the common F508del mutation in the first cytoplasmic Nucleotide Binding Domain and the milder R117H mutation in the first membrane spanning domain is indicated. Login to comment
88 The heterozygous missense mutation c.482G>A (R117H) in exon 4 leading to the replacement of Arginine (R) at residue 117 by Histidine (H). Login to comment

PMID: 22293084 [PubMed] Yu H et al: "Ivacaftor potentiation of multiple CFTR channels with gating mutations."

No. Sentence Comment

138 For example, R117H-CFTR is delivered to the cell surface in normal amounts, but exhibits a ~20% reduction in CFTR channel conductance and a ~75% reduction in the channel open probability, resulting in residual CFTR function both in vitro and clinically [28]. Login to comment
139 Other CFTR gene mutations associated with residual CFTR function include A445E, R347H, D1152H, and certain splice mutations (3849 +10kbC→T) [4,29-30]. 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: 22271776 [PubMed] Vernooij-van Langen AM et al: "Novel strategies in newborn screening for cystic fibrosis: a prospective controlled study."

No. Sentence Comment

105 Three of these infants had equivocal sweat test results (chloride 33, 34, 36 mmol/litre; all had R117H-7T as a second mutation), the other 10 had normal sweat tests (F508del/394delTT/ S1251N/R553X combined with R117H-7T n¼8, F508del/L967S, F508del/Q1352H) (table 3). Login to comment
136 CF, cystic fibrosis; IRT, immunoreactive trypsinogen; PAP, pancreatitis-associated protein. Table 3 Immunoreactive trypsinogen and pancreatitis-associated protein concentrations, CFTR gene mutation analysis and sweat tests for all infants with an equivocal diagnosis IRT (mg/litre) PAP (mg/litre) Mutation 1 Mutation 2 Sweat test chloride (mmol/litre) 1 199 1.4 E60X R117H-7T 36 2 139 0.8 394delTT R117H-7T/9T 21 3 123 0.6 F508del R117H-7T 22 4 89 1.4 S1251N R117H-7T 29 5 79 1.6 F508del R117H-7T 26 6 77 2.4 R553X R117H-7T 22 7 76 0.8 F508del R117H-7T 34 8 73 0.5 F508del R117H-7T 25 9 70 1.0 F508del R117H-7T 22 10 69 1.1 F508del R117H-7T 33 11 67 2.7 F508del R117H-7T 17 12* 174 3.8 F508del L967S 19 13* 84 3.2 F508del Q1352H 17 Equivocal diagnosis¼two CFTR gene mutations of which one has unclear clinical significance, and a normal or equivocal sweat test result. Login to comment
164 Eleven of the 13 infants with an equivocal diagnosis in the IRT/DNA/sequencing strategy had R117H-7T as a second mutation. Login to comment
166 The Dutch CF Registry showed only 10 patients (1196 registered patients in 2008) with a R117H-7T mutation, and only four of them were diagnosed under the age of 18 years. Login to comment
168 This indicates that this mutation mostly acts as a non-disease-causing variant.30 31 Many experts on NBS for CF therefore advise exclusion of this mutation.31 If R117H-7Twere to be excluded from the panel, only two infants with an equivocal diagnosis would have been identified with this strategy. Login to comment
104 Three of these infants had equivocal sweat test results (chloride 33, 34, 36 mmol/litre; all had R117H-7T as a second mutation), the other 10 had normal sweat tests (F508del/394delTT/ S1251N/R553X combined with R117H-7T n&#bc;8, F508del/L967S, F508del/Q1352H) (table 3). Login to comment
135 CF, cystic fibrosis; IRT, immunoreactive trypsinogen; PAP, pancreatitis-associated protein. Table 3 Immunoreactive trypsinogen and pancreatitis-associated protein concentrations, CFTR gene mutation analysis and sweat tests for all infants with an equivocal diagnosis IRT (mg/litre) PAP (mg/litre) Mutation 1 Mutation 2 Sweat test chloride (mmol/litre) 1 199 1.4 E60X R117H-7T 36 2 139 0.8 394delTT R117H-7T/9T 21 3 123 0.6 F508del R117H-7T 22 4 89 1.4 S1251N R117H-7T 29 5 79 1.6 F508del R117H-7T 26 6 77 2.4 R553X R117H-7T 22 7 76 0.8 F508del R117H-7T 34 8 73 0.5 F508del R117H-7T 25 9 70 1.0 F508del R117H-7T 22 10 69 1.1 F508del R117H-7T 33 11 67 2.7 F508del R117H-7T 17 12* 174 3.8 F508del L967S 19 13* 84 3.2 F508del Q1352H 17 Equivocal diagnosis&#bc;two CFTR gene mutations of which one has unclear clinical significance, and a normal or equivocal sweat test result. Login to comment
163 Eleven of the 13 infants with an equivocal diagnosis in the IRT/DNA/sequencing strategy had R117H-7T as a second mutation. Login to comment
165 The Dutch CF Registry showed only 10 patients (1196 registered patients in 2008) with a R117H-7T mutation, and only four of them were diagnosed under the age of 18 years. Login to comment
167 This indicates that this mutation mostly acts as a non-disease-causing variant.30 31 Many experts on NBS for CF therefore advise exclusion of this mutation.31 If R117H-7Twere to be excluded from the panel, only two infants with an equivocal diagnosis would have been identified with this strategy. 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
111 Except one (p.R117H (7T/7T)/p. S1235), these compound heterozygotes were excluded in the overall computations, because CFTR variant p.R75Q, p.I148T, 5T or p.E528E was present in at least one allele. Login to comment
140 Variant distribution in patients aged >20 and <20 years In younger patients, overall PRSS1 variants were 2.9-fold more common (>20 years: 9/239, 3.8%; <20 years: 46/421, 10.9%; p¼0.001, OR 3.1, 95% CI 1.5 to 6.5), whereas overall SPINK1 variants were similarly distributed (56/239, 23.4%; 73/421, Table 2 CFTR variants detected by melting curve analysis Gene Variant Patients Controls p Value OR (95% CI) CFTR (CF-causing, severe) p.F508del 44/660 (6.7%) 48/1758 (2.7%) <0.0001 2.5 (1.7 to 3.9) p.R117H (5T/7T) 2/660 (0.3%) 1/1758 (0.06%) NS e p.G542X 1/660 (0.2%) 1/1758 (0.06%) NS e c.1717-1G>A 3/660 (0.5%) 1/1758 (0.06%) NS e p.E585X 0/660 1/1758 (0.06%) NS e c.2183AA>G 0/660 1/1758 (0.06%) NS e p.R1158X 1/660 (0.2%) 0/1758 NS e p.R1162X 1/660 (0.3%) 0/1758 NS e p.N1303K 3/660 (0.5%) 0/1758 NS e Total 55/660 (8.3%) 53/1758 (3%) <0.0001 2.9 (2 to 4.3) CFTR (CF-causing mild) p.R117H (7T/7T) 13/660 (2%) 8/1758 (0.5%) 0.0009 4.4 (1.8 to 10.7) p.R117H (7T/9T) 3/660 (0.5%) 1/1758 (0.06%) NS e p.R347H 1/660 (0.2%) 0/1758 NS e p.R347P 1/660 (0.2%) 0/1758 NS e p.A455E 1/660 (0.2%) 0/1758 NS e c.2657+5G>A 1/660 (0.2%) 0/1758 NS e p.D1152H 3/660 (0.5%) 5/1758 (0.3%) NS e Total 23/660 (3.5%) 14/1758 (0.8%) <0.0001 4.5 (2.3 to 8.8) CFTR (non CF-causing) p.R74Q 2/660 (0.3%) 0/1758 NS e p.R75Q (het)* 29/660 (4.4%) 59/1758 (3.4%) NS e p.R75Q (hom)* 2/660 (0.3%) 1/1758 (0.06%) NS e p.Y84H 0/660 1/1758 (0.06%) NS e p.A120T 0/660 1/1758 (0.06%) NS e p.I148T* 4/660 (0.6%) 11/1758 (0.6%) NS e p.I507V 1/660 (0.2%) 2/1758 (0.1%) NS e p.F508C 1/660 (0.2%) 0/1758 NS e c.1716+12T>C 0/660 1/1758 (0.06%) NS e p.E528E (het)* 36/660 (5.5%) 82/1758 (4.7%) NS e p.E528E (hom)* 0/660 2/1758 (0.1%) NS e c.1898+8C>G 0/660 1/1758 (0.06%) NS e p.H667Y 1/660 (0.2%) 0/1758 NS e p.R668C 5/660 (0.8%) 3/1758 (0.2%) NS e p.G691R 0/660 1/1758 (0.06%) NS e p.L997F 5/660 (0.8%) 6/1758 (0.3%) NS e p.S1235R 10/660 (1.5%) 18/1758 (1.0%) NS e Total (excluded)* 25/660 (3.8%) 45/1758 (2.6%) NS e CFTR (CF-causing) Total (all) 78/660 (11.8%) 67/1758 (3.8%) <0.0001 3.4 (2.4 to 4.8) CFTR (all) Total (excluded)* 103/660 (15.6%) 112/1758 (6.4%) <0.0001 2.7 (2 to 3.6) The table is divided into three parts. Login to comment
150 Table 4 Homozygous and compound heterozygous patients and controls with at least two CFTR, SPINK1 or CTRC variants Gene Variant Patients Controls p Value OR (95% CI) CFTR (CF-causing severe or CF-causing mild/CF-causing mild) p.F508del/p.R117H (7T/9T) 2/660 (0.3%) 1/1758 (0.06%) NS e p.F508del/p.R347H 1/660 (0.2%) 0/1758 NS e p.F508del/p.D1152Hy 1/660 (0.2%) 0/1758 NS e p.R117H (7T/7T)/c.2657+5G>A 1/660 (0.2%) 0/1758 NS e p.R117H (7T/7T)/p.R1158X 1/660 (0.2%) 0/1758 NS e p.R117H (7T/7T)/c.1717-1G>A 1/660 (0.2%) 0/1758 NS e p.R117H (7T/9T)/p.N1303K 1/660 (0.2%) 0/1758 NS e p.D1152Hy/p.N1303K 1/660 (0.2%) 0/1758 NS e Total 9/660 (1.4%) 1/1758 (0.06%) 0.002 16.1 (1.9 to 134.2) CFTR (CF-causing severe or CF-causing mild or non-CF-causing/Non-CF-causing) p.F508del/p.R75Q* 0/660 1/1758 (0.06%) NS e p.F508del/5T* 2/660 (0.3%) 1/1758 (0.06%) NS e p.F508del/p.E528E* 2/660 (0.3%) 2/1758 (0.1%) NS e p.R75Q*/5T* 1/660 (0.2%) 1/1758 (0.06%) NS e p.R75Q*/p.E528E* 2/660 (0.3%) 2/1758 (0.1%) NS e p.R117H (7T/7T)/p.R75Q* 1/660 (0.2%) 0/1758 NS e p.R117H (7T/7T)/p.E528E* 1/660 (0.2%) 0/1758 NS e p.R117H (7T/7T)/p.S1235R 1/660 (0.2%) 0/1758 NS e p.I148T*/5T* 0/660 1/1758 (0.06%) NS e p.R347P/p.E528E* 1/660 (0.2%) 0/1758 NS e p.E528E*/5T* 1/660 (0.2%) 4/1758 (0.23%) NS e p.H667Y/5T* 1/660 (0.2%) 0/1758 NS e p.L997F/5T* 1/660 (0.2%) 0/1758 NS e p.L997F/p.E528E* 0/660 1/1758 (0.06%) NS e p.D1152Hy/5T* 1/660 (0.2%) 0/1758 NS e p.S1235R/5T* 2/660 (0.3%) 1/1758 (0.06%) NS e Total 17/660 (2.6%) 14/1758 (0.8%) 0.001 3.3 (1.6 to 6.7) CFTR Total (all, excluded)* 10/660 (1.5%) 1/1758 (0.06%) <0.0001 27 (3.5 to 211.7) SPINK1 p.N34S (hom) 17/660 (2.6%) 0/1758 <0.0001 95.6 (5.7 to 1594) p.N34S (het)/c.(1-215G>A;194+2T>C) 7/660 (1.1%) 0/1758 <0.0001 40.4 (2.3 to 708.2) Total 24/660 (3.6%) 0/1758 <0.0001 135.4 (8.2 to 2231) CTRC p.R254W (hom) 1/546 (0.2%) 0/1700 NS e p.R254W/p.V235I 1/546 (0.2%) 0/1700 NS e Total 2/546 (0.4%) 0/1700 NS e For CFTR compound heterozygous carriers, calculations were performed for patients and controls carrying a combination of one CF-causing severe or a CF-causing mild in addition with one CF-causing mild variant (upper section). Login to comment
152 All compound heterozygotes in this section except one (p.R117H (7T/7T)/p.S1235R) carry CFTR variants that were not over-represented in patients on at least one allele. Login to comment
162 p.R254W 1/546 (0.2%) 0/1700 NS e p.L14P p.R254W 1/546 (0.2%) 0/1700 NS e p.N34S (het) p.R254W 1/546 (0.2%) 0/1700 NS e p.N34S (het) p.R254W p.R117H (7T/7T)/ p.R75Q 1/546 (0.2%) 0/1700 NS e p.N34S (het) p.K247_R254del p.E528E* 1/546 (0.2%) 0/1700 NS e p.N34S (het) p.R254W p.E528E* 1/546 (0.2%) 0/1700 NS e c. Login to comment
163 (1-215G>A; 194+2T>C) p.F508del 1/660 (0.2%) 0/1758 NS e p.N34S (hom) p.I507Vy 1/660 (0.2%) 0/1758 NS e p.N34S (hom) p.S1235Ry 1/660 (0.2%) 0/1758 NS e p.N34S (het) p.R117H (5T/7T) 1/660 (0.2%) 0/1758 NS e p.N34S (het) p.F508del/ p.R117H (7T/9T) 1/660 (0.2%) 0/1758 NS e p.N34S (het) p.F508del/p.E528E 1/660 (0.2%) 1/1758 (0.06%) NS e p.N34S (het) p.F508del/ p.E528E/5T/7T 0/660 1/1758 (0.06%) NS e p.N34S (het) p.R117H (7T/7T) 1/660 (0.2%) 0/1758 NS e p.N34S (het) p.F508del 8/660 (1.2%) 0/1758 <0.0001 45.8 (2.6 to 795.4) p.N34S (het) p.R668Cy 1/660 (0.2%) 0/1758 NS e p.N34S (het) p.S1235Ry 3/660 (0.5%) 0/1758 0.03 18.7 (1 to 363.2) p.N34S (het) p.N1303K 1/660 (0.2%) 0/1758 NS e p.R254W p.R117H (7T/7T)/ c.1717-1G>A 1/546 (0.2%) 0/1700 NS e p.R254W p.R668Cy 0/546 1/1700 (0.06%) NS e p.R254W p.L997Fy 1/546 (0.2%) 0/1700 NS e Total (all) 43/660 (6.5%) 3/1667 (0.2%) <0.0001 38.7 (12 to 125.1) Total (CF-causing) 33/660 (5%) 2/1667 (0.1%) <0.0001 43.8 (10.5 to 183.2) p.N29I p.R75Q 1/660 (0.2%) 0/1758 NS e p.R122C 5T/9T 1/660 (0.2%) 0/1758 NS e p.R122H p.R75Q 2/660 (0.3%) 0/1758 NS e p.R122H 5T/7T 2/660 (0.3%) 0/1758 NS e p.R122H p.E528E 3/660 (0.5%) 0/1758 0.03* 18.7 (1 to 363.2) p.N34S (het)/ c. 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
107 Except one (p.R117H (7T/7T)/p. S1235), these compound heterozygotes were excluded in the overall computations, because CFTR variant p.R75Q, p.I148T, 5T or p.E528E was present in at least one allele. Login to comment
135 Variant distribution in patients aged >20 and <20 years In younger patients, overall PRSS1 variants were 2.9-fold more common (>20 years: 9/239, 3.8%; <20 years: 46/421, 10.9%; p&#bc;0.001, OR 3.1, 95% CI 1.5 to 6.5), whereas overall SPINK1 variants were similarly distributed (56/239, 23.4%; 73/421, Table 2 CFTR variants detected by melting curve analysis Gene Variant Patients Controls p Value OR (95% CI) CFTR (CF-causing, severe) p.F508del 44/660 (6.7%) 48/1758 (2.7%) <0.0001 2.5 (1.7 to 3.9) p.R117H (5T/7T) 2/660 (0.3%) 1/1758 (0.06%) NS e p.G542X 1/660 (0.2%) 1/1758 (0.06%) NS e c.1717-1G>A 3/660 (0.5%) 1/1758 (0.06%) NS e p.E585X 0/660 1/1758 (0.06%) NS e c.2183AA>G 0/660 1/1758 (0.06%) NS e p.R1158X 1/660 (0.2%) 0/1758 NS e p.R1162X 1/660 (0.3%) 0/1758 NS e p.N1303K 3/660 (0.5%) 0/1758 NS e Total 55/660 (8.3%) 53/1758 (3%) <0.0001 2.9 (2 to 4.3) CFTR (CF-causing mild) p.R117H (7T/7T) 13/660 (2%) 8/1758 (0.5%) 0.0009 4.4 (1.8 to 10.7) p.R117H (7T/9T) 3/660 (0.5%) 1/1758 (0.06%) NS e p.R347H 1/660 (0.2%) 0/1758 NS e p.R347P 1/660 (0.2%) 0/1758 NS e p.A455E 1/660 (0.2%) 0/1758 NS e c.2657+5G>A 1/660 (0.2%) 0/1758 NS e p.D1152H 3/660 (0.5%) 5/1758 (0.3%) NS e Total 23/660 (3.5%) 14/1758 (0.8%) <0.0001 4.5 (2.3 to 8.8) CFTR (non CF-causing) p.R74Q 2/660 (0.3%) 0/1758 NS e p.R75Q (het)* 29/660 (4.4%) 59/1758 (3.4%) NS e p.R75Q (hom)* 2/660 (0.3%) 1/1758 (0.06%) NS e p.Y84H 0/660 1/1758 (0.06%) NS e p.A120T 0/660 1/1758 (0.06%) NS e p.I148T* 4/660 (0.6%) 11/1758 (0.6%) NS e p.I507V 1/660 (0.2%) 2/1758 (0.1%) NS e p.F508C 1/660 (0.2%) 0/1758 NS e c.1716+12T>C 0/660 1/1758 (0.06%) NS e p.E528E (het)* 36/660 (5.5%) 82/1758 (4.7%) NS e p.E528E (hom)* 0/660 2/1758 (0.1%) NS e c.1898+8C>G 0/660 1/1758 (0.06%) NS e p.H667Y 1/660 (0.2%) 0/1758 NS e p.R668C 5/660 (0.8%) 3/1758 (0.2%) NS e p.G691R 0/660 1/1758 (0.06%) NS e p.L997F 5/660 (0.8%) 6/1758 (0.3%) NS e p.S1235R 10/660 (1.5%) 18/1758 (1.0%) NS e Total (excluded)* 25/660 (3.8%) 45/1758 (2.6%) NS e CFTR (CF-causing) Total (all) 78/660 (11.8%) 67/1758 (3.8%) <0.0001 3.4 (2.4 to 4.8) CFTR (all) Total (excluded)* 103/660 (15.6%) 112/1758 (6.4%) <0.0001 2.7 (2 to 3.6) The table is divided into three parts. Login to comment
144 Table 4 Homozygous and compound heterozygous patients and controls with at least two CFTR, SPINK1 or CTRC variants Gene Variant Patients Controls p Value OR (95% CI) CFTR (CF-causing severe or CF-causing mild/CF-causing mild) p.F508del/p.R117H (7T/9T) 2/660 (0.3%) 1/1758 (0.06%) NS e p.F508del/p.R347H 1/660 (0.2%) 0/1758 NS e p.F508del/p.D1152Hy 1/660 (0.2%) 0/1758 NS e p.R117H (7T/7T)/c.2657+5G>A 1/660 (0.2%) 0/1758 NS e p.R117H (7T/7T)/p.R1158X 1/660 (0.2%) 0/1758 NS e p.R117H (7T/7T)/c.1717-1G>A 1/660 (0.2%) 0/1758 NS e p.R117H (7T/9T)/p.N1303K 1/660 (0.2%) 0/1758 NS e p.D1152Hy/p.N1303K 1/660 (0.2%) 0/1758 NS e Total 9/660 (1.4%) 1/1758 (0.06%) 0.002 16.1 (1.9 to 134.2) CFTR (CF-causing severe or CF-causing mild or non-CF-causing/Non-CF-causing) p.F508del/p.R75Q* 0/660 1/1758 (0.06%) NS e p.F508del/5T* 2/660 (0.3%) 1/1758 (0.06%) NS e p.F508del/p.E528E* 2/660 (0.3%) 2/1758 (0.1%) NS e p.R75Q*/5T* 1/660 (0.2%) 1/1758 (0.06%) NS e p.R75Q*/p.E528E* 2/660 (0.3%) 2/1758 (0.1%) NS e p.R117H (7T/7T)/p.R75Q* 1/660 (0.2%) 0/1758 NS e p.R117H (7T/7T)/p.E528E* 1/660 (0.2%) 0/1758 NS e p.R117H (7T/7T)/p.S1235R 1/660 (0.2%) 0/1758 NS e p.I148T*/5T* 0/660 1/1758 (0.06%) NS e p.R347P/p.E528E* 1/660 (0.2%) 0/1758 NS e p.E528E*/5T* 1/660 (0.2%) 4/1758 (0.23%) NS e p.H667Y/5T* 1/660 (0.2%) 0/1758 NS e p.L997F/5T* 1/660 (0.2%) 0/1758 NS e p.L997F/p.E528E* 0/660 1/1758 (0.06%) NS e p.D1152Hy/5T* 1/660 (0.2%) 0/1758 NS e p.S1235R/5T* 2/660 (0.3%) 1/1758 (0.06%) NS e Total 17/660 (2.6%) 14/1758 (0.8%) 0.001 3.3 (1.6 to 6.7) CFTR Total (all, excluded)* 10/660 (1.5%) 1/1758 (0.06%) <0.0001 27 (3.5 to 211.7) SPINK1 p.N34S (hom) 17/660 (2.6%) 0/1758 <0.0001 95.6 (5.7 to 1594) p.N34S (het)/c.(1-215G>A;194+2T>C) 7/660 (1.1%) 0/1758 <0.0001 40.4 (2.3 to 708.2) Total 24/660 (3.6%) 0/1758 <0.0001 135.4 (8.2 to 2231) CTRC p.R254W (hom) 1/546 (0.2%) 0/1700 NS e p.R254W/p.V235I 1/546 (0.2%) 0/1700 NS e Total 2/546 (0.4%) 0/1700 NS e For CFTR compound heterozygous carriers, calculations were performed for patients and controls carrying a combination of one CF-causing severe or a CF-causing mild in addition with one CF-causing mild variant (upper section). Login to comment
146 All compound heterozygotes in this section except one (p.R117H (7T/7T)/p.S1235R) carry CFTR variants that were not over-represented in patients on at least one allele. Login to comment
155 p.R254W 1/546 (0.2%) 0/1700 NS e p.L14P p.R254W 1/546 (0.2%) 0/1700 NS e p.N34S (het) p.R254W 1/546 (0.2%) 0/1700 NS e p.N34S (het) p.R254W p.R117H (7T/7T)/ p.R75Q 1/546 (0.2%) 0/1700 NS e p.N34S (het) p.K247_R254del p.E528E* 1/546 (0.2%) 0/1700 NS e p.N34S (het) p.R254W p.E528E* 1/546 (0.2%) 0/1700 NS e c. Login to comment
156 (1-215G>A; 194+2T>C) p.F508del 1/660 (0.2%) 0/1758 NS e p.N34S (hom) p.I507Vy 1/660 (0.2%) 0/1758 NS e p.N34S (hom) p.S1235Ry 1/660 (0.2%) 0/1758 NS e p.N34S (het) p.R117H (5T/7T) 1/660 (0.2%) 0/1758 NS e p.N34S (het) p.F508del/ p.R117H (7T/9T) 1/660 (0.2%) 0/1758 NS e p.N34S (het) p.F508del/p.E528E 1/660 (0.2%) 1/1758 (0.06%) NS e p.N34S (het) p.F508del/ p.E528E/5T/7T 0/660 1/1758 (0.06%) NS e p.N34S (het) p.R117H (7T/7T) 1/660 (0.2%) 0/1758 NS e p.N34S (het) p.F508del 8/660 (1.2%) 0/1758 <0.0001 45.8 (2.6 to 795.4) p.N34S (het) p.R668Cy 1/660 (0.2%) 0/1758 NS e p.N34S (het) p.S1235Ry 3/660 (0.5%) 0/1758 0.03 18.7 (1 to 363.2) p.N34S (het) p.N1303K 1/660 (0.2%) 0/1758 NS e p.R254W p.R117H (7T/7T)/ c.1717-1G>A 1/546 (0.2%) 0/1700 NS e p.R254W p.R668Cy 0/546 1/1700 (0.06%) NS e p.R254W p.L997Fy 1/546 (0.2%) 0/1700 NS e Total (all) 43/660 (6.5%) 3/1667 (0.2%) <0.0001 38.7 (12 to 125.1) Total (CF-causing) 33/660 (5%) 2/1667 (0.1%) <0.0001 43.8 (10.5 to 183.2) p.N29I p.R75Q 1/660 (0.2%) 0/1758 NS e p.R122C 5T/9T 1/660 (0.2%) 0/1758 NS e p.R122H p.R75Q 2/660 (0.3%) 0/1758 NS e p.R122H 5T/7T 2/660 (0.3%) 0/1758 NS e p.R122H p.E528E 3/660 (0.5%) 0/1758 0.03* 18.7 (1 to 363.2) p.N34S (het)/ c. Login to comment

PMID: 22423042 [PubMed] Gonska T et al: "Role of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) in patients with chronic sinopulmonary disease."

No. Sentence Comment

66 All P values are two-sided with a Table 2-CFTR Genotypes Identified in Subjects With Idiopathic Sinopulmonary Disease CF Causing/CF Causing CF Causing/CFTR Mutation CFTR Mutation/CFTR Mutation CF Causing/Unknown CFTR Mutation/Unknown F508del/A455E 3x F508del /D1152H 2x D579G/D579G 2x F508del /26x R764X/2 F508del/S1251N R75X/V456A 758delC/2 F508del/L967S 1716G.A/5T 1716G.A/2 F508del/5T R75Q/5T R117H (7T)/23x F508del/3212T.C 5T/23x G542X/D1152H 1717-1G.A/Q1291H Patients are grouped according to the identified CFTR alterations on allele 1/allele 2. Login to comment

PMID: 22398597 [PubMed] Ledford H et al: "Cystic fibrosis drug Vertex's latest triumph."

No. Sentence Comment

17 A pediatric study will evaluate the drug in patients between two and five years old, another trial will seek to expand use of the drug in other CFTR gating mutations and a third will specifically target a class of mutations called R117H, which also affects gating but retains some degree of chloride ion transport. Login to comment

PMID: 21847140 [PubMed] Viart V et al: "Functional analysis of a promoter variant identified in the CFTR gene in cis of a frameshift mutation."

No. Sentence Comment

10 The mutation R117H occurring in cis with the 5-thymidine (5T) tract variant in intron 8 generally results in pancreatic sufficient CF and as such, is considered as a mild mutation, whereas R117H in cis with the 7T is mainly considered as a CFTR-related disease-associated mutation with low penetrance.7 Complex alleles may also involve alterations in the CFTR promoter region, as is the case for the (À102T4A;S549R)+(F508del) genotype for which the promoter sequence variation is associated with an increase in CFTR expression and a moderate clinical phenotype.8 Here we report the functional analysis of a promoter variant associated in cis with a frameshift mutation (48C4G;3532AC4 GTA)+(F508del) identified in a patient with a classic form of CF as characterized by a positive sweat test, pulmonary symptoms, digestive manifestations and pancreatic insufficiency. Login to comment

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

No. Sentence 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
109 Molecular analysis of the R117H mutation The R117H mutation, known to be variable in its disease expression, was found in three specimens. Login to comment
111 The third R117H predicted haplotype contained a 7T variant and multiple differences from the other two R117H haplotypes. Login to comment
112 The haplotype containing the R117H mutation with the 7T variant was identical to the 1717-1G→A containing haplotype; however the significance is unknown since each is only found in one chromosome (Table 3). Login to comment
113 A single CF-related metabolic syndrome chromosome containing the 5T variant in the absence of R117H had a unique haplotype quite different from all other R117H containing haplotypes. Login to comment
138 Researchers found that the phenotypic severity of a CF-causing mutation could be impacted by the genomic context of the CFTR gene as seen when R117H is in cis with the 5T variant and when S1251N is in cis with F508C [33,34]. Login to comment
140 For example, when a newborn specimen is positive for R117H and either F508del, G542X or N1303K, and also carries both an 5T and a 9T variant, a clinician could use haplotype information to proceed with a strong probability that the 9T variant is in cis with F508del, G542X or N1310K and not R117H (Table 3). Login to comment
141 This study also shows that R117H may reside on the opposite chromosome from nearly all of the listed mutations in Table 3 because it has a different polymorphism background. Login to comment

PMID: 22256939 [PubMed] Massie RJ et al: "Lessons learned from 20 years of newborn screening for cystic fibrosis."

No. Sentence Comment

30 Where possible, all patients with a diagnosis of CF had further CFTR mutation analysis performed in an attempt to clarify the genotype (p.A455E, p.S549N, p.R347H, p.R1162X, p.R347P, p.R334W, p.R117H). Login to comment
94 The term CFTR-related metabolic syndrome has been developed in the US to allow a systematic approach to follow-up of these infants.15 Many years of clinical follow-up with repeat sweat tests and more extensive CFTR genotype analyses will be required to establish how many of these infants have CF.10,16 Other lessons learned from our screening program include the lack of value in testing infants with a markedly elevated initial IRT level in the absence of a CFTR mutation - a practice advocated by some centres.17 We have previously demonstrated the difficulty of including the R117H mutation in the screening panel, and deliberately avoided it in our newborn screening and carrier screening programs.18-20 This decision has been supported by French data highlighting the low penetrance of this mutation.21 In addition, we have shown a modest reduction in the live-birth prevalence of CF since the introduction of screening, because families use prenatal testing for subsequent pregnancies.22,23 Emerging issues in newborn screening have been well described in a recent review.24 Of key importance to Australia is whether newborn screening strategies should switch to IRT/pancreatitis-associated peptide to avoid detection of carriers altogether.25 There are a number of trials of this in progress around the world, including in South Australia. Login to comment
137 Genetic counselling after carrier detection by newborn screening when one parent carries DeltaF508 and the other R117H. Login to comment
139 19 Massie RJ, Poplawski N, Wilcken B, et al. Intron-8 polythymidine sequence in Australasian individuals with CF mutations R117H and R117C. Login to comment
144 21 Thauvin-Robinet C, Munck A, Huet F, et al. The very low penetrance of cystic fibrosis for the R117H mutation: a reappraisal for genetic counselling and newborn screening. Login to comment
140 Genetic counselling after carrier detection by newborn screening when one parent carries DeltaF508 and the other R117H. Login to comment
142 19 Massie RJ, Poplawski N, Wilcken B, et al. Intron-8 polythymidine sequence in Australasian individuals with CF mutations R117H and R117C. Login to comment
147 21 Thauvin-Robinet C, Munck A, Huet F, et al. The very low penetrance of cystic fibrosis for the R117H mutation: a reappraisal for genetic counselling and newborn screening. Login to comment

PMID: 22081250 [PubMed] Yu J et al: "CFTR mutations in men with congenital bilateral absence of the vas deferens (CBAVD): a systemic review and meta-analysis."

No. Sentence Comment

7 Moreover, the common heterozygous F508del/5T and F508del/R117H were observed in 17 and 4% of CBAVD cases respectively, and the allele frequency in CBAVD was 17% for F508del, 25% for 5T and 3% for R117H. Login to comment
24 In particular, several large studies that extensively screened CFTR mutations in CBAVD demonstrated that the most common mutations are F508del, 5T (c.1210-12T[5]) and R117H (c.350G . Login to comment
31 Generally speaking, F508del/5T and F508del/ R117H are the two most common kinds of compound heterozygote, in men with CBAVD, which clearly differs from those observed in typical CF (De Braekeleer and Ferec, 1996; Claustres et al., 2000; Claustres, 2005). Login to comment
89 Summary analysis demonstrated that two common heterozygous genotypes, F508del/5T and F508del/R117H, were observed in CBAVD cases with frequency of 17 and 4%, respectively (Figs 3 and 4). Login to comment
90 As for the frequent mutant alleles, the frequency was 17% for F508del, 25% for 5T and 3% for R117H, respectively (Figs 5-7). Login to comment
97 However, the frequency of cases with two mutations was higher in Figure 4 Forest plot for meta-analysis of F508del/R117H frequency in CBAVD patients. For details see Fig. 2. Login to comment
109 The results demonstrate a high frequency of overall CFTR mutations, as well as heterozygous genotype F508delt/5T and F508del/R117H, in CBAVD patients and indicate a potential association of CFTR mutations with CBAVD. Login to comment
114 Figure 7 Forest plot for meta-analysis of R117H frequency in CBAVD patients. For details see Fig. 2. results are consistent with the assumption that severe mutations such as F508del would result in typical CF while the mild variant 5T might be responsible for atypical CF symptoms such as CBAVD (Cuppens and Cassiman, 2004; Claustres, 2005). 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: 22438829 [PubMed] Henderson LB et al: "Variation in MSRA modifies risk of neonatal intestinal obstruction in cystic fibrosis."

No. Sentence Comment

112 Intestinal obstruction in a null CF mouse model (C57BL/ 6J Cftr2/2 ) leads to high mortality (.80% [17]) by 40 days of age while lower rates of mortality [44] occur in a CF mouse model (C57BL/ 6JR117H/R117H ) with a targeted knock-in of a missense mutation (p.Arg117His) associated with residual CFTR function [45,46] and very low rates of MI in humans with CF [47]. Login to comment
113 Mice heterozygous for the Cftr null (Cftr+/2 ) or p.Arg117His allele (Cftr+/R117H ) were crossed to mice with one or two Msra null alleles to produce CF mice (Cftr2/2 or CftrR117H/R117H ) with wild-type (+/+), heterozygous (+/2), and null (2/2) Msra genotypes. Login to comment
119 As anticipated, CftrR117H/ R117H mice displayed reduced mortality, notably through the weaning period, compared to Cftr-null mice (64.3% of Msra+/+ mice alive at 40 days, n = 14; Figure 3B). Login to comment
126 B. CF mice homozygous for a missense Cftr allele (CftrR117H/R117H ) and wild-type for Msra display a low rate of mortality due to intestinal obstruction around the time of weaning (n = 14). Login to comment
127 Survival is not affected in CftrR117H/R117H mice lacking one (n = 51) or two (n = 51) Msra alleles compared to wild-type. Login to comment
148 Our hypothesis was that the CF null model (with high rates of obstruction) would reveal whether loss of Msra function decreased obstruction while the p.Arg117His model (with lower rates of obstruction) would reveal whether loss of Msra function increased obstruction. Login to comment
150 The lack of effect in the p.Arg117His CF mice suggested that the modifying effect of Msra did not exceed the reduction in obstruction conferred by residual function of CFTR bearing p.Arg117His. Login to comment
245 Mouse studies Mice heterozygous for a Cftr null allele, B6.129P2-Cftrtm1Unc [17] or for the Cftr missense allele p.Arg117His, B6.129S6-Cftrtm2Uth [44], and either homozygous or heterozygous for a null allele of Msra [51] were generated as breeders to produce CF mice carrying the three genotypes of Msra (+/+, +/2, and 2/2) used in this study. Login to comment
246 Mouse studies Mice heterozygous for a Cftr null allele, B6.129P2-Cftrtm1Unc [17] or for the Cftr missense allele p.Arg117His, B6.129S6-Cftrtm2Uth [44], and either homozygous or heterozygous for a null allele of Msra [51] were generated as breeders to produce CF mice carrying the three genotypes of Msra (+/+, +/2, and 2/2) used in this study. Login to comment

PMID: 22768130 [PubMed] Sloane PA et al: "A pharmacologic approach to acquired cystic fibrosis transmembrane conductance regulator dysfunction in smoking related lung disease."

No. Sentence Comment

105 CFTR Genetics CFTR genetic testing (50 mutation analysis) was performed on all airway tissue samples and NPD participants at a commercially accredited facility (Baylor Medical Genetics, Houston, TX), and included the 23 mutations recommended by the American College of Medical Genetics (ACMG) and reflex testing of the 5T allele upon detection of the R117H mutation. Login to comment
106 CFTR Genetics CFTR genetic testing (50 mutation analysis) was performed on all airway tissue samples and NPD participants at a commercially accredited facility (Baylor Medical Genetics, Houston, TX), and included the 23 mutations recommended by the American College of Medical Genetics (ACMG) and reflex testing of the 5T allele upon detection of the R117H mutation. Login to comment

PMID: 22058188 [PubMed] Elborn JS et al: "Fixing cystic fibrosis CFTR with correctors and potentiators. Off to a good start."

No. Sentence Comment

17 The most common of these mutations is the R117H mutation, which when found in cis with a 5Tsplice variant (IVS8-T5) and a second severe CF mutation results in classic CF.13 Further studies are required in this larger patient group. Login to comment

PMID: 21875427 [PubMed] Field PD et al: "CFTR mutation screening in an assisted reproductive clinic."

No. Sentence Comment

9 R117H / c.350G>A was significantly increased in this infertile population and accounted for 13.8% of all mutations identified. Login to comment
17 For example, patients with homozygous F508del/c.1521_1523delCTT usually have the most severe phenotype affecting the lungs, pancreas and intestinal tract and causing infertility in over 95% of male patients; in contrast, the affect of a R117H/c.350G>A mutation is associated with absence of the vas deferens in some male patients. Login to comment
37 Table 1 A breakdown of the CFTR mutations identified in the infertile patient population, the percentage of those mutations identified, the percentage of the infertile population screened, the percentage of the same mutations identified in the antenatal population by Massie et al. and figures published by Bobadilla et al. for the corresponding CFTR mutations in a global population study 'Legacy Mutation Name` and HGVS convention nomenclature* Number of mutations identified in infertile population Percentage of mutations identified in infertile population (%) Percentage of mutations identified in antenatal population4 (%) Percentage of mutations identified in a global population5 (%) F508delCTT / c.1521_1523delCTT 185 70.9 88.89 75.48 R117H / c.350G>A 36 13.8 0.63 G551D / c.1652G>A 12 4.6 2.78 3.82 G542X / c.1624G>T 6 2.3 0.93 1.83 N1303K / c.3909C>G 4 1.5 0.93 0.95 621+1G>T / c.489+1G>T 5 1.9 0.93 0.96 I507del / c.1519-1521delATC 2 0.8 0.53 3659delC / c.3528delC 2 0.8 R1162X / c.3484C>T 1 0.4 0.20 3120+1G>A / c.2988+1G>A 1 0.4 2184-delA / c.2052delA 1 0.4 3849+10kbC>T / c.3717-2477C>T 1 0.4 4.63 2789+5G>A / c.2657+5G>A 1 0.4 0.93 R347P / c.1040G>A 1 0.4 0.16 1717-1G>A / c.1585-1G>A 1 0.4 0.81 R553X / c.1657C>T 1 0.4 S549R / c.1647T>G 1 0.4 Total CFTR mutations identified 261 Total patients screened 5600 Incidence of CF carriers at QFG 1 in 21.5 (4.66%) CF, cystic fibrosis; CFTR, CF transmembrane receptor. Login to comment
40 R117H/c.350G>A, the CFTR mutation previously linked to infertility in male patients, was identified at 13.8% of all mutations identified in our population of ART patients (12.2% in women and 18.5% in men) compared with the global population of 0.6%.5,6 Twelve carrier couples were identified during this study with nine of those couples progressing to at least one cycle of PGD for CF. Login to comment
42 Discussion In a worldwide analysis of CFTR mutation rates, Bobadilla et al. published mutation rates by continent and country, giving a global snapshot of CFTR mutations in many populations5 (see Table 1), which is mirrored by results published by the WHO.6 Screening of 5600 patients presenting for infertility treatment identified a CFTR mutation carrier rate that is elevated when compared to that identified in a comparable Australian antenatal population screen4 as well as global populations.5,6 Our results are biased with regard to the sex of mutation carriers as mostly female ART patients (84%) were screened; however, this is comparable with the percentage of female patients included in the antenatal population from the published data set of Massie et al.4 Our data suggest a link between female infertility and some of the less common CFTR mutations eg R117H/c.350G>A. Login to comment
43 Male carriers of the R117H/c.350G>A mutation have been shown to have an increased association with congenital absence of vas deferens (CAVD) with 22%7 and 24%8 carrier rates reported in men affected with CAVD, but the link between R117H/c.350G>A and infertility has never been shown with female patients. Login to comment
44 Radpour et al. investigated the link between CFTR mutations and congenital absence of the uterus and vagina but only identified links between CAVD and CFTR mutations in male carrier patients.9 Female patients affected with CF are known to have reduced fertility, not only owing to tenacious impermeable cervical mucus, but affected female patients also have some ovarian dysfunction as well as reduced nutrition.10 We believe that the increased incidence of R117H/c.350G>A mutation in this study being at 13.8%, compared to a background population level of under 0.65%, shows some association with both female and male infertility. Login to comment
47 Only one other major study reported a similar level of R117H/c.350G>A at a rate of 16% of all mutations identified (carrier rate of one in 27 in a 12 mutation panel) in 5161 pregnant patients from California.13 A larger study of 57 999 patients screened for CFTR mutations over a ten-year period has shown that medically assisted reproduction couples had a carrier rate of one in 22 compared to the antenatal population incidence of one in 32 but found a much lower incidence of R117H/c.350G>A in their ART patients.14 Studies have shown that when a carrier screening program for CFTR mutations is implemented, the live birth rate of babies affected by CF has been reduced.15-18 A screening study in New South Wales, Australia, screened 1000 patients and found that those patients at highest risk of having a CF-affected child altered their reproductive plans to avoid having an affected baby.19 The study published after screening 3000 female antenatal patients in Victoria, Australia, identified nine carrier couples, six of those couples chose to terminate their pregnancy because of a prenatal result showing their baby was affected.4 From the patients screened at this clinic, we were able to identify 12 carrier couples, nine of which went on to have at least one cycle of PGD for CFTR mutations. 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
115 The p.R117H mutation has a variable penetrance as its splicing efficiency is affected by the length of the poly-T-tract in intron 8 (IVS8-5T, 7T and 9T), therefore the genotyping scoring tools are probably inadequate for evaluation of this mutation (24-26). 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
41 ARMS PCR program for ΔF508, N1303K, G542X,R117H began with a 5 min incubation at 94°C,andProceeded with 28 cycles, each containing 15 s of denaturation at 94°C,30 s of annealing at appropriate temperature and 30 s of extension at 72°C;with a 10 min incubation at 72°C completing the amplification. Login to comment
43 Results Heterozygote frequency for ΔF508 mutation has been 5/53 (%9.43) and for G542X mutation, it has been 4/53(%7.55) in all patients tested where as other common mutations (R117H, W1282X, N1303K) were not detected in our samples. Login to comment

PMID: 21837768 [PubMed] Lukowski SW et al: "Disrupted post-transcriptional regulation of the cystic fibrosis transmembrane conductance regulator (CFTR) by a 5'UTR mutation is associated with a CFTR-related disease."

No. Sentence Comment

265 Also, heterozygosity for other CFTR mutations, such as ∆F508, R117H and R75Q, has been linked to the development of CBAVD and bronchiectasis [Wilschanski, et al., 2006; Ziedalski, et al., 2006]. 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: 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

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: 21966101 [PubMed] Prasad R et al: "Molecular basis of cystic fibrosis disease: an Indian perspective."

No. Sentence Comment

98 25 mutation Table 2 CFTR mutation identified in Indian population with classical CF [25] Genotype No. of subjects Delta F508/Delta F508 5 Delta F508/3849?10kb C-T 1 Delta F508/S549 2 Delta F508/Y138H 1 Delta F508/15251G-A 1 V520F/R117H 2 1530L/1530L 1 876-6del4/876-6del4 1 1792insA/1792insA 1 3986-3987delC/3986-3987delC 1 Delta F508/U 10 1161delC/U 2 L69H/U 1 R117H/U 1 Q493L/U 1 Y517C/U 1 S549N/U 3 G551D/U 1 E1329Q/U 1 N1303K/U 1 Y1381H/U 1 L218X/U 1 R553X/U 1 1525-1G-A/U 3 3120?1G-A/U 2 3849?10kbC-T/U 2 U/U 1 U unidentified panel were detected in our population at a combined frequency of (10%). Login to comment
126 In the CAVD patients with normal renal development, the initial screening identified one extra, R117H mutation in three chromosomes. Login to comment
128 Other identified mutations R117H, 3120?1[G-A and P1021S have been described previously in studies of patients with CAVD. Login to comment
130 Table 3 CFTR mutations identified and characterized in the Indian patients with CAVD [12] Mutation Nucleotide change No. of alleles T5 Reduction of oligo T tract to 5T at 1342-6 25 F508del Deletion of 3 bp(CTT or TTT) between 1652 and 1655 11 L69H T to A at 338 1 F87I T to A at 391 1 R117H G to A at 482 3 G126S G to A at 508 1 F157C T to G at 602 1 E543A A to C at 1760 1 Y852F A toT at 2687 1 3120?1G-A G to A 3120?1 1 P1021S CtoT at 3193 1 D1270E T to A at 3942 1 We documented NBD1 and NBD2 as the hotspot identified in the CFTR protein in Indian CF population, whereas the regions known to alter chloride permeability (transmembrane regions) and delta F508 mutation in NBD1 are the hot spot for mutation identification in our genital form of CF cases (obstructive azoospermia). 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: 19318035 [PubMed] Seia M et al: "Borderline sweat test: Utility and limits of genetic analysis for the diagnosis of cystic fibrosis."

No. Sentence Comment

59 In order to evaluate the relationship between the presence of CFTR mutation and sweat chloride concentration, we focused our attention on the 91 individuals (11.8%) in whom borderline sweat chloride values (31-59 mEq/l) were recorded (mean sweat electrolyte value was 40.0 mEq/l): 25 refused to be referred to the local Table 2 Demographic and clinical features of subjects with positive DNA analysis Patient Initials Gender Age at test years/ months Sweat chloride mEq/l Clinical indication DNA results IRT Right arm Left arm 1 CA M 49y5m 34 34 CBAVD G542X/5T-TG12 ND 2 SA M 45y2m 45 43 Pancreatitis F508del/R117H-7T ND 3 PD F 43y7m 33 38 Recurrent bronchitis F508del/5T-TG12 ND 4 CA M 36y1m 31 29 CBAVD R117H-7T/R117C-7T ND 5 SC M 36y1m 33 40 Pneumonia F508del/D1152H ND 6 MG M 25Y5m 41 45 CBAVD Q552X/D1152H NEG 7 SG M 18y5m 49 54 Pancreatitis 4016insT/dupl.prom.-3 ND 8 LS F 10y4m 41 38 Pancreatitis D1152H/L997F NEG 9 CM M 8y3m 30 31 Pneumonia F1052V/A120T NEG 10 PT M 7y3m 41 39 Positive screening F508del/Y1032C POS 11 ME F 7y1m 44 44 Positive screening 2789+5GNA/5T-TG12 POS 12 PM F 6y4m 35 36 Positive screening 2183AANG/5T-TG12 POS 13 BM F 6y3m 36 39 Positive screening F508del/5T-TG12 POS 14 CD M 5y8m 40 41 Chronic bronchitis 5T-TG12/5T-TG12 NEG 15 CG F 4y5m 33 37 Recurrent bronchitis R553X/L997F POS 16 CS F 3y8m 53 58 Family history G542X/D614G POS 17 VA M 4y2m 49 43 Pneumonia E831X/5T-TG12 ND 18 SC M 3y4m 39 39 Positive screening R352Q/G213E POS 19 CC F 2y3m 31 31 Positive screening F508del/5T-TG12 POS 20 CA F 2y5m 51 52 Recurrent bronchitis E831X/5T-TG12 ND 21 MR F 3y+7m 29 31 Family history G542X/5T-TG12 POS 22 CM F 2y3m 60 58 Pneumonia T338I/L997F POS 23 LM F 2y1m 50 52 Positive screening F508del/E1473X POS 24 CGE F 0y8m 46 47 Positive screening E92K/5T-TG13 POS 25 NF M 0y7m 32 30 Positive screening F508del/P5L POS 26 RG M 0y7m 45 40 Positive screening N1303K/P5L POS 27 PE M 47y4m 60 58 Nasal polyposis R1066H/UN ND 28 LS M 39y9m 39 38 Azoospermy N1303K/UN ND 29 TM M 38y4m 40 45 Azoospermy N1303K/UN ND 30 DF M 34y2m 52 58 Bronchiectasis 3849+10 kbCNT/UN ND 31 TV F 30y5m 35 34 Recurrent bronchitis L997F/UN ND 32 FA F 18y7m 53 49 Family history Del es.2/UN NEG 33 DG M 17y8m 43 47 Recurrent bronchitis 5T-TG12/UN NEG 34 LN F 13y7m 54 53 Nasal poliposis, malnutrition R74W-V855I/UN NEG 35 FKT M 15y4m 54 53 Chronic bronchitis R352Q/UN NEG 36 BM M 10y9m 48 51 Chronic bronchitis T1263I/UN NEG 37 SV F 11y1m 60 58 Chronic bronchitis R347H/UN NEG 38 CV F 10y10m 38 39 Recurrent bronchitis 5T-TG12/UN NEG 39 BF F 9y10m 37 38 Chronic bronchitis L997F/UN NEG 40 CA M 8y2m 33 32 Pneumonia F508del/UN NEG 41 RX F 8y7m 29 31 Chronic bronchitis V920L/UN NEG 42 MG F 4y3m 51 51 Positive screening F508del/UN POS Sweat chloride concentration and mutations/variants detected are also reported. Login to comment
92 It is known that some mutations as D1152H and R117H-7T/R117C-7Tare associated with negative or borderline sweat chloride value. Login to comment
57 In order to evaluate the relationship between the presence of CFTR mutation and sweat chloride concentration, we focused our attention on the 91 individuals (11.8%) in whom borderline sweat chloride values (31-59 mEq/l) were recorded (mean sweat electrolyte value was 40.0 mEq/l): 25 refused to be referred to the local Table 2 Demographic and clinical features of subjects with positive DNA analysis Patient Initials Gender Age at test years/ months Sweat chloride mEq/l Clinical indication DNA results IRT Right arm Left arm 1 CA M 49y5m 34 34 CBAVD G542X/5T-TG12 ND 2 SA M 45y2m 45 43 Pancreatitis F508del/R117H-7T ND 3 PD F 43y7m 33 38 Recurrent bronchitis F508del/5T-TG12 ND 4 CA M 36y1m 31 29 CBAVD R117H-7T/R117C-7T ND 5 SC M 36y1m 33 40 Pneumonia F508del/D1152H ND 6 MG M 25Y5m 41 45 CBAVD Q552X/D1152H NEG 7 SG M 18y5m 49 54 Pancreatitis 4016insT/dupl.prom.-3 ND 8 LS F 10y4m 41 38 Pancreatitis D1152H/L997F NEG 9 CM M 8y3m 30 31 Pneumonia F1052V/A120T NEG 10 PT M 7y3m 41 39 Positive screening F508del/Y1032C POS 11 ME F 7y1m 44 44 Positive screening 2789+5GNA/5T-TG12 POS 12 PM F 6y4m 35 36 Positive screening 2183AANG/5T-TG12 POS 13 BM F 6y3m 36 39 Positive screening F508del/5T-TG12 POS 14 CD M 5y8m 40 41 Chronic bronchitis 5T-TG12/5T-TG12 NEG 15 CG F 4y5m 33 37 Recurrent bronchitis R553X/L997F POS 16 CS F 3y8m 53 58 Family history G542X/D614G POS 17 VA M 4y2m 49 43 Pneumonia E831X/5T-TG12 ND 18 SC M 3y4m 39 39 Positive screening R352Q/G213E POS 19 CC F 2y3m 31 31 Positive screening F508del/5T-TG12 POS 20 CA F 2y5m 51 52 Recurrent bronchitis E831X/5T-TG12 ND 21 MR F 3y+7m 29 31 Family history G542X/5T-TG12 POS 22 CM F 2y3m 60 58 Pneumonia T338I/L997F POS 23 LM F 2y1m 50 52 Positive screening F508del/E1473X POS 24 CGE F 0y8m 46 47 Positive screening E92K/5T-TG13 POS 25 NF M 0y7m 32 30 Positive screening F508del/P5L POS 26 RG M 0y7m 45 40 Positive screening N1303K/P5L POS 27 PE M 47y4m 60 58 Nasal polyposis R1066H/UN ND 28 LS M 39y9m 39 38 Azoospermy N1303K/UN ND 29 TM M 38y4m 40 45 Azoospermy N1303K/UN ND 30 DF M 34y2m 52 58 Bronchiectasis 3849+10 kbCNT/UN ND 31 TV F 30y5m 35 34 Recurrent bronchitis L997F/UN ND 32 FA F 18y7m 53 49 Family history Del es.2/UN NEG 33 DG M 17y8m 43 47 Recurrent bronchitis 5T-TG12/UN NEG 34 LN F 13y7m 54 53 Nasal poliposis, malnutrition R74W-V855I/UN NEG 35 FKT M 15y4m 54 53 Chronic bronchitis R352Q/UN NEG 36 BM M 10y9m 48 51 Chronic bronchitis T1263I/UN NEG 37 SV F 11y1m 60 58 Chronic bronchitis R347H/UN NEG 38 CV F 10y10m 38 39 Recurrent bronchitis 5T-TG12/UN NEG 39 BF F 9y10m 37 38 Chronic bronchitis L997F/UN NEG 40 CA M 8y2m 33 32 Pneumonia F508del/UN NEG 41 RX F 8y7m 29 31 Chronic bronchitis V920L/UN NEG 42 MG F 4y3m 51 51 Positive screening F508del/UN POS Sweat chloride concentration and mutations/variants detected are also reported. Login to comment
90 It is known that some mutations as D1152H and R117H-7T/R117C-7Tare associated with negative or borderline sweat chloride value. Login to comment

PMID: 19208501 [PubMed] Balascakova M et al: "Pilot newborn screening project for cystic fibrosis in the Czech Republic: defining role of the delay in its symptomatic diagnosis and influence of ultrasound-based prenatal diagnosis on the incidence of the disease."

No. Sentence Comment

54 The diagnosis of CF could not be unambiguously established in one patient bearing the complex allele p.F508del/p.R117H-IVS8 T(7), who had mean sweat chloride concentration of 20.4 mM/L [12]. Login to comment
52 The diagnosis of CF could not be unambiguously established in one patient bearing the complex allele p.F508del/p.R117H-IVS8 T(7), who had mean sweat chloride concentration of 20.4 mM/L [12]. 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: 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

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
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
57 We identified one patient apparently harbouring three mutations in the CFTR gene; the genotype is F508del/F508del/ R117H. 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
92 Regarding the mutations detected, we noted a moderate heterogeneity with 21 mutations detected, the Table 3 Distribution of genotypes in CF patients from Romania (n=128; 256 chromosomes) Genotype Number Ethnicity F508del/F508del 46 Romanian 42 Hungarian 3 Gypsy 1 F508del/x 25 Romanian 23 Hungarian 1 Turkish-Romanian 1 F508del/G542X 8 Romanian F508del/CFTRdele2,3(21 kb) 4 Romanian 3 Hungarian 1 F508del/W1282X 3 Romanian F508del/F508del/R117H 1 Romanian F508del/R334W 1 Romanian F508del/621+1GNT 1 Romanian F508del/N1303K 1 Romanian F508del/2183AANG 1 Romanian F508del/3849+10 kb(CNT) 1 Romanian F508del/3272-26ANG 1 Romanian F508del/R1162X 1 Romanian F508del/R785X 1 Romanian F508del/1717-2ANG 1 Romanian F508del/2789+5GNA 1 Romanian G542X/G542X 1 Romanian W1282X/W1282X 1 Romanian N1303K/457TATNG 1 Romanian 621+1GNT/2183AANG 1 Romanian W1282X/x 1 Romanian R1070Q/E585X 1 Romanian R1070Q/x 1 Romanian E831X/x 1 Gypsy R735K/x 1 Romanian 1677delTA/x 1 Romanian x/x 21 Romanian 18 Hungarian 2 Gypsy 1 presence of common mutations (excepting the Celtic mutation G551D), and a similarity with the mutations detected in Italy, France and Spain [5]. Login to comment

PMID: 18243066 [PubMed] Ratbi I et al: "Cystic fibrosis carrier frequency and estimated prevalence of the disease in Morocco."

No. Sentence Comment

27 We screened for 32 CFTR gene mutations (G85E, 394delTT, R117H, 621+1GNT, 711+1GNT, R334W, R347P, R347H, 1078delT, A455E, I507del, F508del, V520F, 1717-1GNA, G542X, G551D, R553X, R560T, S549R(TNG), S549N, 1898+1GNA, 2183AANG, 2184delA, 2789+5GNA, 3120 + 1G NA, R1162X, 3659delC, 3849 + 10kbC NT, W1282X, 3905insT, 3876delA, N1303K) and the (T)5 splicing variant of intron 8, using a commercial kit (CF v3 Genotyping Assay, Abbott, Rungis, France). Login to comment

PMID: 18796364 [PubMed] Chiang HS et al: "CFTR mutation analysis of a Caucasian father with congenital bilateral absence of vas deferens, a Taiwanese mother, and twins resulting from ICSI procedure."

No. Sentence Comment

0 736 J Formos Med Assoc | 2008 • Vol 107 • No 9 CASE REPORT Although cystic fibrosis (CF) is one of the most common autosomal recessive diseases in Caucasians, it is very rare in Asian populations.1,2 Congenital bilateral absence of the vas deferens (CBAVD) is a newly recognized primarily genital phenotype of CF; however, it is relatively common in our practice among male infertility patients with obstructive azoospermia.3 A recent survey on a small number of Asian patients with CF transmembrane conductance regulator (CFTR) gene mutations revealed mostly unique mutations that have never been reported in Caucasian CF patients.2 Our previous study also showed that none of the major CFTR gene mutations such as ⌬F508 or p.R117H could be identified in 27 Taiwanese males with CBAVD. Login to comment
140 Special characteristics of the lower frequency of CFTR gene mutations (36%) with none of the major CFTR gene mutations, such as ⌬F508 or p.R117H, were found in our previous screening of Taiwanese patients for CBAVD. Login to comment
141 Special characteristics of the lower frequency of CFTR gene mutations (36%) with none of the major CFTR gene mutations, such as èc;F508 or p.R117H, were found in our previous screening of Taiwanese patients for CBAVD. Login to comment

PMID: 18687795 [PubMed] Audrezet MP et al: "Validation of high-resolution DNA melting analysis for mutation scanning of the cystic fibrosis transmembrane conductance regulator (CFTR) gene."

No. Sentence Comment

51 Sequences of the Primers Used for CFTR Analysis by HRM, GC Size, Amplicon Length, Number of Positive Controls Validated for Each Exon, and Positive Controls for Routine Analysis Exon Primer Sequences GC length Amplicon length (bp) Introns Number of heterozygous- positive controls Number of homozygous- positive controls Recommended control 1 LSCFE1Fmod 5Ј-CCGCCGCCGTTGAGCGGCAGGCACC-3Ј 8 200 bp 74 4 125GϾC LSCFE1Rmod 5Ј-CCGCCGCCGGCACGTGTCTTT CCGAAGCT-3Ј 8 19 M1I 2 2i5b 5Ј-CAAATCTGTATGGAGACC-3Ј 0 194 bp 39 5 R31C 2i3Љ 5Ј-CAACTAAACAATGTACATGAAC-3Ј 0 4 296ϩ1GϾT 3 LSCFe3Fmod LSCFe3Rmod 5Ј-CGCCGTTAAGGGAAATAGGACAA CTAAAATA-3Ј 5 276 bp 44 10 2 R75Q 5Ј-CCGCCGATTCACCAGATTTCGTAGTC-3Ј 6 66 G85V 4 LSCFe4FmodC 5Ј-CCGCCGCCGCCCGTGTTGAAATT CTCAGGGT-3Ј 12 361 bp 52 14 1 R117H LSCFe4RmodC 5Ј-CCGCCGCCCACATGTACGATAC AGAATATATGTGCC-3Ј 9 26 574delA 5 LSCFE5Fmod 5Ј-CCGCCGGTTGAAATTATCTAACTTTCC-3Ј 6 201 bp 13 8 624delT LSCFE5Rmod 5Ј-CCGAACTCCGCCTTTCCAGTTGT-3Ј 3 48 711ϩ1GϾT 6a LSCF6aFmod2 5Ј-CCGCCGGGGTGGAAGAT ACAATGACACCTG-3Ј 5 317 bp 25 8 C225X LSCF6aRmod2 5Ј-CCGCCGCCGCGATGCATAGAG CAGTCCTGGTT-3Ј 11 66 L206W 6b LSCFE6bFmod 5Ј-CGCGCCGCCGGATTTAC AGAGATCAGAGAG-3Ј 10 239 bp 0 2 1 R258G LSCFE6Brmod 5Ј-CCGCCGCCGAGGTGGA GTCTACCATGA-3Ј 8 66 1001ϩ11CϾT 7 LSCFE7Fmod2 5Ј-CCGCCGCCCTCTCCCTGAATTT TATTGTTATTGTTT-3Ј 13 326 bp 7 11 1078delT LSCFE7Rmod2 5Ј-CCCGCCGCCCTATAATGCAG CATTATGGT-3Ј 10 7 1248ϩ1GϾT 8 LSCFE8Fmod 5Ј-CCGGAATGCATTAATGCTAT TCTGATTC-3Ј 4 199 bp 32 7 W401X LSCFE8Rmod 5Ј-CCCGCAGTTAGGTGTTTAG AGCAAACAA-3Ј 4 18 1249-5AϾG 9 LSCFe9Fmod2 5Ј-CCGCCGCCGGGAATTATTTGAGAA AGCAAAACA-3Ј 8 279 bp 0 3 D443Y LSCFe9Rmod2 5Ј-CCGCCGCGAAAATACCTTCCAG CACTACAAACTAGAAA-3Ј 8 57 A455E 10 LSCF10FmodD 5Ј-CGCCGTTATGGGAGAACTGG AGCCTTCAGAG-3Ј 5 275 bp 0 15 1 F508del LSCF10RmodD 5Ј-CCGCAGACTAACCGATTGAAT ATGGAGCC-3Ј 4 68 E528E 11 h11i5 5Ј-TGCCTTTCAAATTCAGATTGAGC-3Ј 0 197 bp 42 13 2 G542X 11i3ter 5Ј-ACAGCAAATGCTTGCTAGACC-3Ј 0 17 G551D 12 LSCFE12Fmod 5Ј-CGCGTCATCTACACTAGATGACCAG-3Ј 4 244 bp 43 15 G576A 1898 ϩ 1GϾALSCFE12Rmod 5Ј-CCGGAGGTAAAATGCAATCTATGATG-3Ј 3 63 13 LSCF13AFmod 5Ј-CCGCCGCCGGAGACATATTG CAATAAAGTAT-3Ј 9 38 20 I601F LSCF13ARmod 5Ј-GCCTGTCCAGGAGACAGGA GCATCTC-3Ј 2 R668C LSCF13BFmod 5Ј-CCGCCGCAATCCTAACTGAG ACCTTACACCG-3Ј 2 R668C LSCF13BRmod 5Ј-CCGCCGATCAGGTTCAGGA CAGACTGC-3Ј 3 346 bp 2184insA LSCF13CFmod 5Ј-CCGCGGTGATCAGCACTGGCCC-3Ј 6 301 bp 77 L749L LSCF13CRmod 5Ј-CCGCGCGCGCGGCCAGTTTCTTG AGATAACCTTCT-3Ј 13 259 bp V754M LSCF13DFmod 5Ј-CGTGTCACTGGCCCCTCAGGC-3Ј 1 221 bp I807M LSCF13DRmof 5Ј-CCGCCGCCGCTAATCCTATGA TTTTAGTAAAT-3Ј 9 220 bp 2622ϩ1GϾA LSCf13FFmod 5Ј-CGCGGTGCAGAAAGAAGAAAT TCAATCCTAACTG-3Ј 4 R668C LSCF13FRmod 5Ј-CCGCCGTGCCATTCATTTGT AAGGGAGTCT-3Ј 6 2184insA 14a LSCF14aFmodB 5Ј-CCGACCACAATGGTGGCAT GAAACTG-3Ј 3 239 bp 35 7 1 T854T LSCF14aRmodB 5Ј-CCGCCGACTTTAAATCCAGTAAT ACTTTACAATAGAACA-3Ј 6 7 W846X 14b LSCF14bFmod 5Ј-CCGGAGGAATAGGTGAAGAT-3Ј 2 179 bp 38 4 2752-5GϾT LSCF14bRmodb 5Ј-CCGTACATACAAACATAGTGGATT-3Ј 3 59 2789ϩ5GϾT 15 LSCFE15Fmod 5Ј-CGCGCCGTGTATTGGAAA TTCAGTAAGTAACTTTGG-3Ј 7 412 bp 33 16 T908S LSCFE15Rmod 5Ј-CCGCAGCCAGCACTGCCAT TAGAAA-3Ј 4 68 S945L (table continues) phisms that we have chosen to exclude. Login to comment
75 In addition to heterozygous variants, 10 homozygote samples carrying F508del, 394delT, R117H, G542X, S549R, 4016inT homozygous mutations, and R75Q, T854T, 1001ϩ11 CϾT, and Q1463Q homozygous variants, were also tested. Login to comment
76 Only mutations 394delT, R117H, G542X, 4016insT, and variants R75Q and 1001ϩ11 CϾ T provided positive results (Figure 5). Login to comment
119 However, under the preferred DHPLC conditions, the frequent mutation R117H of exon 4 was not detected, and the percentage of false-positive results was significant, suggesting that analytical conditions were not fully optimized. 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: 18666218 [PubMed] Sheth VR et al: "Monitoring infection and inflammation in murine models of cystic fibrosis with magnetic resonance imaging."

No. Sentence Comment

36 MATERIALS AND METHODS Mouse Models C57BL/6 congenic B6.129S6-Cftrtm2Mrc male mice bearing the R117H mutation were inoculated with P. aeruginosa-laden agarose beads on Day 0, directing the infection into the right mainstem bronchus. Login to comment

PMID: 18507830 [PubMed] Fajac I et al: "Could a defective epithelial sodium channel lead to bronchiectasis."

No. Sentence Comment

75 In Group 2, 2 patients were heterozygous for the p.F508del, 2 for the p.R117H-7T mutation, 3 for the IVS8-5T allele, and 1 for the c.1717G>A (p.E528E) variant. 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: 17572159 [PubMed] Loumi O et al: "CFTR mutations in the Algerian population."

No. Sentence Comment

73 It has previously been reported by Claustres in a CBAVD patient associated with the R117H mutation [25] and seems to confer a CF phenotype when it is associated with 2183AA/G and 621+3A/G mutations in our case. 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

32 The Inno Lipa™ CFTR17 assay contains normal and mutant probes for 17 other CFTR mutations (394delTT, G85E, 621+1G→T, R117H, 1078delT, R347P, R334W, E60X, 711+5G→A, 2789 + 5G→ A, R1162X, 3659delC, 3849 + 10kbC→ T, 2143delT, A455E, 2183AA→G, 2184delA) (Innogenetics). 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

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

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

48 The mutation R117H was found in patients 12, 23, 24, 34 and 39, with patient 12 presenting both alleles with this mutation and IVS8- 7T status. Login to 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
57 When we compared the mutations detected by the present study with those found in fibrocystic patients in our region, we verify that among fibrocystics the most frequent mutations are: DF508, G542X, G551D, R553X and N1303K (Bernardino et al., 2000; Martins et al., 1993; Raskin et al., 1999), while in the present study they were the DF508, IVS8-5T, R117H and N1303K. Login to comment

PMID: 16157443 [PubMed] Stipoljev F et al: "Cytogenetic analysis of azoospermic patients: karyotype comparison of peripheral blood lymphocytes and testicular tissue."

No. Sentence Comment

61 T, R117H; exon 7: 1078delT, R347P, R334W; exon 13: 2143delT, 2183AA ! Login to comment

PMID: 16436646 [PubMed] Heaney DL et al: "Detection of an apparent homozygous 3120G>A cystic fibrosis mutation on a routine carrier screen."

No. Sentence Comment

66 Similar to I148T influencing 3199del6 in cis18,19 or R117H being influenced by the 5T variant,20 there could be an additional mutation on the same chromosome causing different phenotypes for those who have the same apparent genotype. Login to comment

PMID: 16412743 [PubMed] Schulz S et al: "Increased frequency of cystic fibrosis transmembrane conductance regulator gene mutations in infertile males."

No. Sentence Comment

45 Mutations R117H, R347P, G542X, G551D, R553X, 3849ϩ10kbCϾT, and N1303K were analyzed by PCR and restriction enzyme cleavage. Login to comment
47 Among CFTR mutations detected in the German population, F508del, R117H, R347P, G542X, G551D, R553X, 3849ϩ10kbCϾT, N1303K, and CFTR2,3dele(21kb) occur with a frequency of 72%, 1%, 1.2%, 1.2%, 0.9%, 2%, 1%, 1.8%, and 1.2%, respectively (9-11). Login to comment
62 The only 3 mutations identified were F508del (26 cases), R117H (5 cases), and CFTRdele2,3 (3 cases). Login to comment
98 Patients (n) IVS8T alleles 5/5 5/7 5/9 7/7 7/9 9/9 Oligozoospermia 13 - - - 10 N/N 2 N/N 1 F508del/N - Asthenozoospermia 39 - 1 N/N - 27 N/N 6 N/N 5 F508del/N - Asthenoteratozoospermia 7 - 1 N/N - 5 N/N 1 N/N - Oligoasthenozoospermia 138 - 11 N/N 1 N/N 94 N/N 2 R117H/N 24 N/N 5 F508del/N 1 N/N Oligoasthenoteratozoospermia 282 - 16 N/N 3 N/N 196 N/N 2 R117H/N 2 Ex2,3/N 53 N/N 9 F508del/N 1 N/N Cryptozoospermia 51 - 1 N/N - 38 N/N 9 N/N 1 Ex2,3/N 2 N/N Azoospermia 67 - 3 N/N 3 F508del/N 45 N/N 1 R117H/N 11 N/N 3 F508del/N 1 N/N Total 597 Note: Semen defects were classified according to WHO guidelines (1992): oligozoospermia less than 20 ϫ 106 spermatozoa/mL; asthenozoospermia less than 50% spermatozoa with forward progression (categories a and b) and less than 25% spermatozoa with category a; teratozoospermia less than 30% spermatozoa with normal morphology; oligoasthenoteratozoospermia signifies disturbances of all three variables. Login to comment

PMID: 16275171 [PubMed] Braun AT et al: "Cystic fibrosis mutations and genotype-pulmonary phenotype analysis."

No. Sentence Comment

80 Thereafter, the longitudinal patterns of WCXR and BCXR for the two patients with novel mutations (i.e., G1047R and 1525-2AYG) were superimposed on the Table 1 Summary of patient characteristics Characteristics F508del homozygote group (n =38) Pancreatic sufficiency groupa (n =19) Sex Male 25 8 Female 13 11 Center Madison 21 12 Milwaukee 17 7 Group Screened 38 3 Control 0 14 Other 0 2 Meconium ileus Yes 6 0 No 32 19 Mean age at diagnosis (weeks)TS.D. 7.15T2.4 193.1T192 Mean sweat Cl mEq/lTS.D. Login to comment
81 101.0T9.5 83.5T21.2 CXR scores at diagnosis WCXR 2.48T32b 4.68T71 BCXR 21.9T0.3 21.1T.48 Pulmonary function at 8 years FEV1 (%)c 97T4 104T2 FVC (%)c 103T3 103T2 FEV1/FVC% 0.92T0.03 0.98T.01 FEF25 - 75% 99T11 104T5 a Mild pancreatic phenotype mutations include: R117H occurring with F508del (n =5) and G542X (n =1); R117C with F508del (n =2); R347P with F508del (n =1), R1066H (n =1) and 2184insA (n À1), 2789+5G>A with F508del (n =3); 3272À26A>G with F508del (n =1); 3849+10kbC>T with F508del (n =1); L138ins with 3272À26A>G (n =1); R352Q with F508del (n =1); and 1336K with F508del (n =1). Login to comment

PMID: 16266832 [PubMed] Peckham D et al: "Delayed diagnosis of cystic fibrosis associated with R117H on a background of 7T polythymidine tract at intron 8."

No. Sentence Comment

2 In each case two CFTR gene mutations were identified, including R117H on a background of a poly T genotype of 7T/ 9T. Login to comment
3 Patients with two identified CFTR mutations which include the R117H/7T anomaly should be followed up routinely as they remain susceptible to severe lung disease. Login to comment
5 Keywords: Cystic fibrosis; Late diagnosis; R117H; 7T; Bronchiectasis 1. Login to comment
9 We report late diagnoses of CF in two elderly men, both of whom had an R117H mutation on a background of a poly T genotype of 7T/9T. Login to comment
28 Genetic analysis demonstrated N1303K and R117H with a poly T genotype 9T/7T. Login to comment
42 CFTR genotype analysis revealed delta 508 and R117H with a poly T genotype 9T/7T. Login to comment
46 Discussion Doubts have been expressed over the diagnosis of cystic fibrosis in patients with R117H with a background 7T polythymidine tract at intron 8. Login to comment
51 The presence of R117H/DF508 on a background of 5T is associated with elevated or borderline sweat test, moderate lung disease, pancreatic exocrine sufficiency and male infertility while R117H/DF508 in association with 7T is associated with a normal, borderline or elevated sweat test and variable clinical presentation [1-4,6-8] R117H in association with 9T is very unusual but has been reported [5]. Login to comment
53 While R117H is associated with a broad phenotype, it is often associated with a normal or borderline sweat test despite the presence of sino pulmonary disease. Login to comment
55 Taylor et al. reported the cases of three infants with DF508/R117H genotype on a 7T/9T background identified through routine screening. Login to comment
59 Conclusion The presence of two CF mutations including R117H with a 7T allele can be associated with late presentation and severe lung disease. Login to comment

PMID: 16798544 [PubMed] Kerem E et al: "Atypical CF and CF related diseases."

No. Sentence Comment

42 One such mutation is the R553Q which when being present together with DF508 mutation on the same CFTR allele, is believed to have an attenuating effect on the clinical presentation of CF.9 Likewise, the 5T allele was shown to affect the disease severity of patients carrying the mutation R117H.10 In patients carrying the R117H mutation when the allele also contained the 5T variant the phenotype was mild CF whereas in patients carrying R117H together with the 7T variant the phenotype was CBAVD only. Login to comment

PMID: 16798543 [PubMed] Davies JC et al: "New tests for cystic fibrosis."

No. Sentence Comment

46 A very small number of mutations which appear to confer a mild pulmonary phenotype have been described, such as A455E and R117H. Login to comment

PMID: 16051530 [PubMed] Kinnunen S et al: "Spectrum of mutations in CFTR in Finland: 18 years follow-up study and identification of two novel mutations."

No. Sentence Comment

6 G542X, R1162X, R117H, 3732delA, 1898+3A>C, S1196X, S945L, W57R, 774insT and S589T were each identified in a number of chromosomes from one to three. Login to comment
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
68 Both of the R117H mutations were situated in Northern Finland. Login to comment
94 394delTT has been suggested to have a Table 1 Spectrum of CFTR mutations in Finland Mutation Recommended nomenclature/nucleotide Recommended nomenclature/protein Exon/Intron N % F508del c.1520_1522delTCT p.Phe508del E 10 37 36 394delTT c.262_263delTT p.Leu88fs E 3 36 35 CFTRdele2,3(21kb) E2 and E3 6 5.9 3659delC c.3528delC p.Lys1177fs E 19 6 5.9 1898+3A>C c.1766+3A>C I 12 3 2.9 R117H c.350G>A p.Arg117His E 4 2 2 S945L c.2834C>T p.Ser945Leu E 15 2 2 W57R c.169T>C p.Trp57Arg E 3 1 1 774insT c.642_643insT p.Ile215fs E 6a 1 1 G542X c.1624G>T p.Gly542X E 11 1 1 S589T c.1766G>C p.Ser589Thr E 12 1 1 R1162X c.3484C>T p.Arg1162X E 19 1 1 S1196X c.3587C>G p.Ser1196X E 19 1 1 3732delA c.3600delA p.Asp1201fs E 19 1 1 Unknown 2.9 Total 102 100 Reference sequence is Genbank NM_000492.2. Login to comment
111 Some other rare mutations that were detected in Finland also reach relatively high frequencies in specific areas: 3732delA in Russia; R117H in Norway and in the Celtic countries; R1162X in Northern Italy (although multi- ethnicity and recurrence has been demonstrated for this mutation) [3,14]. Login to comment
120 The other two patients were both from northern Finland and carried R117H on the other chromosome. Login to comment
121 Both R117H mutations were in combination with 7T variant on the T-tract of 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
69 Both of the R117H mutations were situated in Northern Finland. Login to comment
95 394delTT has been suggested to have a Table 1 Spectrum of CFTR mutations in Finland Mutation Recommended nomenclature/nucleotide Recommended nomenclature/protein Exon/Intron N % F508del c.1520_1522delTCT p.Phe508del E 10 37 36 394delTT c.262_263delTT p.Leu88fs E 3 36 35 CFTRdele2,3(21kb) E2 and E3 6 5.9 3659delC c.3528delC p.Lys1177fs E 19 6 5.9 1898+3A>C c.1766+3A>C I 12 3 2.9 R117H c.350G>A p.Arg117His E 4 2 2 S945L c.2834C>T p.Ser945Leu E 15 2 2 W57R c.169T>C p.Trp57Arg E 3 1 1 774insT c.642_643insT p.Ile215fs E 6a 1 1 G542X c.1624G>T p.Gly542X E 11 1 1 S589T c.1766G>C p.Ser589Thr E 12 1 1 R1162X c.3484C>T p.Arg1162X E 19 1 1 S1196X c.3587C>G p.Ser1196X E 19 1 1 3732delA c.3600delA p.Asp1201fs E 19 1 1 Unknown 3 2.9 Total 102 100 Reference sequence is Genbank NM_000492.2. Login to comment
112 Some other rare mutations that were detected in Finland also reach relatively high frequencies in specific areas: 3732delA in Russia; R117H in Norway and in the Celtic countries; R1162X in Northern Italy (although multi- ethnicity and recurrence has been demonstrated for this mutation) [3,14]. Login to comment
122 Both R117H mutations were in combination with 7T variant on the T-tract of intron 8. Login to comment

PMID: 15936089 [PubMed] Li C et al: "Macromolecular complexes of cystic fibrosis transmembrane conductance regulator and its interacting partners."

No. Sentence Comment

738 Such syntaxin 1A-disrupting reagents will be beneficial to ¨5% of CF patients suffering from the partial loss of function CFTR mutants (e.g., G551D, R117H, etc.; Welsh et al., 1995). 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

51 Complete List of Mutations Detectable with the CF APEX Assay CFTR location Amino acid change Nucleotide change 1 E 1 Frameshift 175delC 2 E 2,3 Frameshift del E2, E3 3 E 2 W19C 189 GϾT 4 E 2 Q39X 247 CϾT 5 IVS 2 Possible splicing defect 296 ϩ 12 TϾC 6 E 3 Frameshift 359insT 7 E 3 Frameshift 394delTT 8 E 3 W57X (TAG) 302GϾA 9 E 3 W57X (TGA) 303GϾA 10 E 3 E60X 310GϾT 11 E 3 P67L 332CϾT 12 E 3 R74Q 353GϾA 13 E 3 R75X 355CϾT 14 E 3 G85E 386GϾA 15 E 3 G91R 403GϾA 16 IVS 3 Splicing defect 405 ϩ 1GϾA 17 IVS 3 Possible splicing defect 405 ϩ 3AϾC 18 IVS 3 Splicing defect 406 - 1GϾA 19 E 4 E92X 406GϾT 20 E 4 E92K 406GϾA 21 E 4 Q98R 425AϾG 22 E 4 Q98P 425AϾC 23 E 4 Frameshift 444delA 24 E 4 Frameshift 457TATϾG 25 E 4 R117C 481CϾT 26 E 4 R117H 482GϾA 27 E 4 R117P 482GϾC 28 E 4 R117L 482GϾT 29 E 4 Y122X 498TϾA 30 E 4 Frameshift 574delA 31 E 4 I148T 575TϾC 32 E 4 Splicing defect 621GϾA 33 IVS 4 Splicing defect 621 ϩ 1GϾT 34 IVS 4 Splicing defect 621 ϩ 3AϾG 35 E 5 Frameshift 624delT 36 E 5 Frameshift 663delT 37 E 5 G178R 664GϾA 38 E 5 Q179K 667CϾA 39 IVS 5 Splicing defect 711 ϩ 1GϾT 40 IVS 5 Splicing defect 711 ϩ 1GϾA 41 IVS 5 Splicing defect 712 - 1GϾT 42 E 6a H199Y 727CϾT 43 E 6a P205S 745CϾT 44 E 6a L206W 749TϾG 45 E 6a Q220X 790CϾT 46 E 6b Frameshift 935delA 47 E 6b Frameshift 936delTA 48 E 6b N287Y 991AϾT 49 IVS 6b Splicing defect 1002 - 3TϾG 50 E 7 ⌬F311 3-bp del between nucleotides 1059 and 1069 51 E 7 Frameshift 1078delT 52 E 7 Frameshift 1119delA 53 E 7 G330X 1120GϾT 54 E 7 R334W 1132CϾT 55 E 7 I336K 1139TϾA 56 E 7 T338I 1145CϾT 57 E 7 Frameshift 1154insTC 58 E 7 Frameshift 1161delC 59 E 7 L346P 1169TϾC 60 E 7 R347H 1172GϾA 61 E 7 R347P 1172GϾC 62 E 7 R347L 1172GϾT 63 E 7 R352Q 1187GϾA 64 E 7 Q359K/T360K 1207CϾA and 1211CϾA 65 E 7 S364P 1222TϾC 66 E 8 Frameshift 1259insA 67 E 8 W401X (TAG) 1334GϾA 68 E 8 W401X (TGA) 1335GϾA 69 IVS 8 Splicing changes 1342 - 6 poly(T) variants 5T/7T/9T 70 IVS 8 Splicing defect 1342 - 2AϾC Table 1. Continued CFTR location Amino acid change Nucleotide change 71 E 9 A455E 1496CϾA 72 E 9 Frameshift 1504delG 73 E 10 G480C 1570GϾT 74 E 10 Q493X 1609CϾT 75 E 10 Frameshift 1609delCA 76 E 10 ⌬I507 3-bp del between nucleotides 1648 and 1653 77 E 10 ⌬F508 3-bp del between nucleotides 1652 and 1655 78 E 10 Frameshift 1677delTA 79 E 10 V520F 1690GϾT 80 E 10 C524X 1704CϾA 81 IVS 10 Possible splicing defect 1717 - 8GϾA 82 IVS 10 Splicing defect 1717 - 1GϾA 83 E 11 G542X 1756GϾT 84 E 11 G551D 1784GϾA 85 E 11 Frameshift 1784delG 86 E 11 S549R (AϾC) 1777AϾC 87 E 11 S549I 1778GϾT 88 E 11 S549N 1778GϾA 89 E 11 S549R (TϾG) 1779TϾG 90 E 11 Q552X 1786CϾT 91 E 11 R553X 1789CϾT 92 E 11 R553G 1789CϾG 93 E 11 R553Q 1790GϾA 94 E 11 L558S 1805TϾC 95 E 11 A559T 1807GϾA 96 E 11 R560T 1811GϾC 97 E 11 R560K 1811GϾA 98 IVS 11 Splicing defect 1811 ϩ 1.6 kb AϾG 99 IVS 11 Splicing defect 1812 - 1GϾA 100 E 12 Y563D 1819TϾG 101 E 12 Y563N 1819TϾA 102 E 12 Frameshift 1833delT 103 E 12 D572N 1846GϾA 104 E 12 P574H 1853CϾA 105 E 12 T582R 1877CϾG 106 E 12 E585X 1885GϾT 107 IVS 12 Splicing defect 1898 ϩ 5GϾT 108 IVS 12 Splicing defect 1898 ϩ 1GϾA 109 IVS 12 Splicing defect 1898 ϩ 1GϾC 110 IVS 12 Splicing defect 1898 ϩ 1GϾT 111 E 13 Frameshift 1924del7 112 E 13 del of 28 amino acids 1949del84 113 E 13 I618T 1985TϾC 114 E 13 Frameshift 2183AAϾG 115 E 13 Frameshift 2043delG 116 E 13 Frameshift 2055del9ϾA 117 E 13 D648V 2075TϾA 118 E 13 Frameshift 2105-2117 del13insAGAA 119 E 13 Frameshift 2108delA 120 E 13 R668C 2134CϾT 121 E 13 Frameshift 2143delT 122 E 13 Frameshift 2176insC 123 E 13 Frameshift 2184delA 124 E 13 Frameshift 2184insA 125 E 13 Q685X 2185CϾT 126 E 13 R709X 2257CϾT 127 E 13 K710X 2260AϾT 128 E 13 Frameshift 2307insA 129 E 13 V754M 2392GϾA 130 E 13 R764X 2422CϾT 131 E 14a W846X 2670GϾA 132 E 14a Frameshift 2734delGinsAT 133 E 14b Frameshift 2766del8 134 IVS 14b Splicing defect 2789 ϩ 5GϾA 135 IVS 14b Splicing defect 2790 - 2AϾG 136 E 15 Q890X 2800CϾT 137 E 15 Frameshift 2869insG 138 E 15 S945L 2966CϾT 139 E 15 Frameshift 2991del32 140 E 16 Splicing defect 3120GϾA interrogation: ACCAACATGTTTTCTTTGATCTTAC 3121-2A3G,T S; 5Ј-ACCAACATGTTTTCTTTGATCTTAC A GTTGTTATTAATTGTGATTGGAGCTATAG-3Ј; CAACAA- TAATTAACACTAACCTCGA 3121-2A3G,T AS. Login to comment
73 Genomic DNA Samples Used for Mutation Evaluation on the APEX Array Mutations validated with native DNA CFTRdel 2,3 (21 kb) 394delTT G85E R75X 574delA Y122X R117C R117H 621 ϩ 1GϾT 621 ϩ 3AϾG 711 ϩ 1GϾT I336K R334W R347P IVS8-5T IVS8-7T IVS8-9T A455E ⌬F508 ⌬I507 1677delTA 1717 - 1GϾA G542X G551D R553X R560T S549N 1898 ϩ 1GϾA 1898 ϩ 1GϾC 2183AAϾG 2043delG R668C 2143delT 2184delA 2184insA 2789 ϩ 5GϾA S945L 3120 ϩ 1GϾA I1005R 3272 - 26AϾG R1066C G1069R Y1092X (CϾA) 3500 - 2AϾT R1158X R1162X 3659delC S1235R 3849 ϩ 10 kb CϾT W1282X primer. Login to comment

PMID: 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
92 The best temperature range for both heterozygous R117H (exon 4, 270 bp) (Figure 1; A to C) and the hard-to-discriminate mutation G551D heterozygous (exon 11, 175 bp) (Figure 1; D to F) is 50 to 55°C. Login to comment
113 In this 270-bp fragment, heterozygous R117H (G/T) is located 83 bp from the 5Ј end, heterozygous I148T (T/C) is located in the middle of the fragment, and heterozygous 621 ϩ 1 (G/T) is located at the end of the fragment (37 bp from the 3Ј end) (Figure 4, A to D; Table 1). Login to comment
114 Heterozygous 621 ϩ 1 (G/T) had the least distinct split-peak pattern when compared to heterozygous R117H and I148T (Figure 4; B to D). Login to comment
124 A: R117H heterozygous (exon 4, 270 bp) without dilution and injected at 5 kV for 30 seconds; B: R117H heterozygous (exon 4) without dilution and injected at 3 kV for 20 seconds. Login to comment
127 A: Wild-type control (exon 4, 270 bp); B: R117H heterozygous (exon 4) with 50 to 55°C gradient; C: R117H heterozygous (exon 4) with 55 to 60°C gradient; D: wild-type control (exon 11, 175 bp); E: G551D heterozygous (exon 11) with 50 to 55°C gradient; F: G551D heterozygous (exon 11) with 55 to 60°C gradient. Login to comment
146 A: Wild-type; B: R117H heterozygous (exon 4); C: I148T heterozygous (exon 4); D: 621 ϩ 1 G/T heterozygous sample 1 (intron 4); E: 621 ϩ 1 G/T heterozygous sample 2 (intron 4, from Coriell Repository); F: 621 ϩ 1 G/T heterozygous sample 3 (intron 4, from Coriell Repository). 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
28 b 5T in cis can modify the R117H phenotype or alone can contribute to congenital bilateral absence of vas deferens (CBAVD). Login to comment
29 5T analysis is performed only as a reflex test for R117H positives (4). Login to comment
94 Methods The methods described below include: (1) design of oligonucleotide capture probes, (2) design of PCR amplification primers and multiplexed PCR reactions, (3) preparation of the probe-conjugated microsphere sets, (4) verification 150 Dunbar and Jacobson xMAPTM Table 2 Oligonucleotide Capture Probesa Target Microsphere Probe sequence Modificationb Sequence 5' → 3' set Standard mutation panel 1c I507 & F508 5'-AmMC12 AACACCAAAGATGATATTTT 006 2B DI507 5'-AmMC12 ACACCAAAGATATTTTCTT 008 3B DF508 5'-AmMC12 AAACACCAATGATATTTTC 015 4B W1282 5'-AmMC12 CAACAGTGGAGGAAAGCC 012 5B W1282X 5'-AmMC12 CAACAGTGAAGGAAAGCC 020 6 1717-1G 5'-AmMC12 TTGGTAATAGGACATCTCCA 017 7 1717-1GÆA 5'-AmMC12 TTGGTAATAAGACATCTCCA 019 8B G542 5'-AmMC12 TATAGTTCTTGGAGAAGGTGGA 026 9B G542X 5'-AmMC12 TATAGTTCTTTGAGAAGGTGGA 028 10C G551 & R553 5'-AmMC12 AGTGGAGGTCAACGAGCAA 038 11B G551D 5'-AmMC12 GTGGAGATCAACGAGCAA 030 12C R553X 5'-AmMC12 GTGGAGGTCAATGAGCAA 032 13 R560 5'-AmMC12 CTTTAGCAAGGTGAATAACT 035 14 R560T 5'-AmMC12 CTTTAGCAACGTGAATAACT 039 15 R117 5'-AmMC12 AGGAGGAACGCTCTATCGCG 042 16 R117H 5'-AmMC12 AGGAGGAACACTCTATCGCG 025 17B I148 5'-AmMC12 CTTCATCACATTGGAATGCAGA 034 18B I148T 5'-AmMC12 CTTCATCACACTGGAATGCAGA 045 19C 621+1G 5'-AmMC12 TTTATAAGAAGGTAATACTTCCT 046 20E 621+1G→T 5'-AmMC12 ATTTATAAGAAGTTAATACTTCCTT 048 21 N1303 5'-AmMC12 GGGATCCAAGTTTTTTCTAA 051 22 N1303K 5'-AmMC12 GGGATCCAACTTTTTTCTAA 052 23B 1078T 5'-AmMC12 CACCACAAAGAACCCTGA 054 24C 1078delT 5'-AmMC12 ACACCACAAGAACCCTGA 061 25 R334 5'-AmMC12 ATATTTTCCGGAGGATGATT 063 26 R334W 5'-AmMC12 ATATTTTCCAGAGGATGATT 064 27B R347 5'-AmMC12 ACCGCCATGCGCAGAACAA 067 28B R347P 5'-AmMC12 ACCGCCATGGGCAGAACAA 053 29C 711+1G 5'-AmMC12 ATTTGATGAAGTATGTACCTAT 059 30C 711+1G→T 5'-AmMC12 ATTTGATGAATTATGTACCTAT 071 31 G85 5'-AmMC12 TGTTCTATGGAATCTTTTTA 066 32B G85E 5'-AmMC12 ATGTTCTATGAAATCTTTTTA 073 33 3849+10kbC 5'-AmMC12 GTCTTACTCGCCATTTTAAT 077 34 3849+10kbC→T 5'-AmMC12 GTCTTACTCACCATTTTAAT 075 35 A455 5'-AmMC12 CCAGCAACCGCCAACAACTG 011 36D A455E 5'-AmMC12 TCCAGCAACCTCCAACAACTG 036 37 R1162 5'-AmMC12 TAAAGACTCGGCTCACAGAT 060 38 R1162X 5'-AmMC12 TAAAGACTCAGCTCACAGAT 068 39B 3659C 5'-AmMC12 TTGACTTGGTAGGTTTAC 022 40C 3659delC 5'-AmMC12 TTGACTTGTAGGTTTACC 079 41B 2789+5G 5'-AmMC12 TGGAAAGTGAGTATTCCATGTC 074 42D 2789+5G→A 5'-AmMC12 TTGGAAAGTGAATATTCCATGTC 014 43E 2184A 5'-AmMC12 GAAACAAAAAAACAATC 007 44E 2184delA 5'-AmMC12 AGAAACAAAAAACAATC 018 45B 1898+1G 5'-AmMC12 TATTTGAAAGGTATGTTCTTTG 013 (Continued) of microsphere coupling, (5) direct hybridization of biotinylated PCR amplification products to the multiplexed probe-coupled microsphere sets, and (6) results and data analysis. Login to comment
106 Table 3 Reverse Complementary Oligonucleotide Targetsa Target Target sequence Modification Sequence 5' → 3' Standard mutation panel C1b I507 & F508 5'-Biotin AAAATATCATCTTTGGTGTT C2 ΔI507 5'-Biotin AAAGAAAATATCTTTGGTGT C3 ΔF508 5'-Biotin AGAAAATATCATTGGTGTTT C4 W1282 5'-Biotin GGCTTTCCTCCACTGTTGC C5 W1282X 5'-Biotin GGCTTTCCTTCACTGTTGC C6 1717-1G 5'-Biotin TGGAGATGTCCTATTACCAA C7 1717-1G→A 5'-Biotin TGGAGATGTCTTATTACCAA C8 G542 5'-Biotin CCACCTTCTCCAAGAACTAT C9 G542X 5'-Biotin CCACCTTCTCAAAGAACTAT C10 G551 & R553 5'-Biotin CTTGCTCGTTGACCTCCACT C11 G551D 5'-Biotin CTTGCTCGTTGATCTCCACT C12 R553X 5'-Biotin CTTGCTCATTGACCTCCACT C13 R560 5'-Biotin AGTTATTCACCTTGATAAAG C14 R560T 5'-Biotin AGTTATTCACGTTGCTAAAG C15 R117 5'-Biotin CGCGATAGAGCGTTCCTCCT C16 R117H 5'-Biotin CGCGATAGAGTGTTCCTCCT C17 I148 5'-Biotin CTGCATTCCAATGTGATGAA C18 I148T 5'-Biotin CTGCATTCCAGTGTGATGAA C19 621+1G 5'-Biotin GGAAGTATTACCTTCTTATA C20 621+1G→T 5'-Biotin GGAAGTATTAACTTCTTATA C21 N1303 5'-Biotin TTAGAAAAAACTTGGATCCC C22 N1303K 5'-Biotin TTAGAAAAAAGTTGGATCCC C23 1078T 5'-Biotin CTCAGGGTTCTTTGTGGTGT C24 1078delT 5'-Biotin TCTCAGGGTTCTTGTGGTGT C25 R334 5'-Biotin AATCATCCTCCGGAAAATAT C26 R334W 5'-Biotin AATCATCCTCTGGAAAATAT C27 R347 5'-Biotin ATTGTTCTGCGCATGGCGGT C28 R347P 5'-Biotin ATTGTTCTGCCCATGGCGGT C29 711+1G 5'-Biotin TAGGTACATACTTCATCAAA C30 711+1G→T 5'-Biotin TAGGTACATAATTCATCAAA C31 G85 5'-Biotin TAAAAAGATTCCATAGAACA C32 G85E 5'-Biotin TAAAAAGATTTCATAGAACA C33 3849+10kbC 5'-Biotin ATTAAAATGGCGAGTAAGAC C34 3849+10kbC→T 5'-Biotin ATTAAAATGGTGAGTAAGAC C35 A455 5'-Biotin CAGTTGTTGGCGGTTGCTGG C36 A455E 5'-Biotin CAGTTGTTGGAGGTTGCTGG C37 R1162 5'-Biotin ATCTGTGAGCCGAGTCTTTA C38 R1162X 5'-Biotin ATCTGTGAGCTGAGTCTTTA (Continued) Rapid CF Screening by xMAPTM 153 Table 3 (Continued) Target Target sequence Modification Sequence 5' → 3' C39 3659C 5'-Biotin GGTAAACCTACCAAGTCAAC C40 3659delC 5'-Biotin AGGTAAACCTACAAGTCAAC C41 2789+5G 5'-Biotin ACATGGAATACTCACTTTCC C42 2789+5G→A 5'-Biotin ACATGGAATATTCACTTTCC C43 2184A 5'-Biotin AAGATTGTTTTTTTGTTTCT C44 2184delA 5'-Biotin AAGATTGTTTTTTGTTTCTG C45 1898+1G 5'-Biotin AAAGAACATACCTTTCAAAT C46 1898+1G→A 5'-Biotin AAAGAACATATCTTTCAAAT C47 3120+1G 5'-Biotin TTTTTACATACCTGGATGAA C48 3120+1G→A 5'-Biotin TTTTTACATATCTGGATGAA Reflex panel CR2 I506V 5'-Biotin GAAAATGTCATCTTTGGTGT CR3 I507V 5'-Biotin GAAAATATCGTCTTTGGTGT CR4 F508C 5'-Biotin AAAATATCATCTGTGGTGTT CR5 5T 5'-Biotin TCCCTGTTAAAAACACACAC CR6 7T 5'-Biotin CCCTGTTAAAAAAACACACA CR7 9T 5'-Biotin CCTGTTAAAAAAAAACACAC a The position and sequence of the mutation or variation is indicated in bold type. b Target C1 (I507 & F508) is also used in the reflex panel. Login to comment
114 Using a small target DNA (approx 100-300 bp) minimizes the potential for steric hindrance to affect the xMAPTM Table 4 PCR Amplification Primers Size CFTR target Mutation(s) Primer 5' Modification Sequence 5' → 3' (bp) Exon 10 ΔI507, ΔF508, BE10U 5'-Biotin TTCTGTTCTCAGTTTTCCTGG 107 I506V, I507V, E10D None TTGGCATGCTTTGATGACG F508C Exon 20 W1282X E20U None TTGAGACTACTGAACACTGAAGG 126 BE20D 5'-Biotin TTCTGGCTAAGTCCTTTTGC Intron 10 1717-1G→A E11U None TCAGATTGAGCATACTAAAAGTGAC 89 BE11D2 5'-Biotin GAACTATATTGTCTTTCTCTGCAAAC Exon 11 G542X, G551D, E11U2 None AAGTTTGCAGAGAAAGACAATATAG 135 R553X, R560T BE11D 5'-Biotin GAATGACATTTACAGCAAATGC Exon 4 R117H E4U None TTTGTAGGAAGTCACCAAAGC 145 BE4D2 5'-Biotin GAGCAGTGTCCTCACAATAAAGAG Exon 4/intron 4 I148T, E4U2 None CTTCTCTTTATTGTGAGGACACTGC 169 621+1G→T BE4D 5'-Biotin ATGACATTAAAACATGTACGATACAG Exon 21 N1303K BE21U 5'-Biotin TGCTATAGAAAGTATTTATTTTTTCTGG 106 E21D None AGCCTTACCTCATCTGCAAC Exon 7 1078delT, BE7U 5'-Biotin GAACAGAACTGAAACTGACTCG 199 R334W, R347P E7D3 None CAGGGAAATTGCCGAGTG Intron 5 711+1G→T I5U None CAACTTGTTAGTCTCCTTTCC 99 BI5D2 5'-Biotin AGTTGTATAATTTATAACAATAGTGC Exon 3 G85E E3U None CTGGCTTCAAAGAAAAATCC 117 BE3D2 5'-Biotin TGAATGTACAAATGAGATCCTTACC Chromosome 7 3849+10kbC→T BC7U 5'-Biotin GACTTGTCATCTTGATTTCTGG 148 C7D None TTTGGTGCTAGCTGTAATTGC Exon 9 A455E BE9U 5'-Biotin TCACTTCTTGGTACTCCTGTCC 105 E9D None CAAAAGAACTACCTTGCCTGC Exon 19-I R1162X BE19U 5'-Biotin ATTGTGAAATTGTCTGCCATTC 167 E19Da None CAATAATCATAACTTTCGAGAGTTG Exon 19-II 3659delC BE19U2 5'-Biotin TTTAAGTTCATTGACATGCCAAC 91 E19Da None CAATAATCATAACTTTCGAGAGTTG Intron 14B 2789+5G→A I14BU None GTGTCTTGTTCCATTCCAGG 147 BI14BD 5'-Biotin TGGATTACAATACATACAAACATAGTGG Exon 13 2184delA E13U None AGATGCTCCTGTCTCCTGG 126 BE13D 5'-Biotin TGCACAATGGAAAATTTTCGTATAG Intron 12 1898+1G→A I12U None TTAGACTCTCCTTTTGGATACC 110 BI12D 5'-Biotin GTCTTTCTTTTATTTTAGCATGAGC Intron 16 3120+1G→A I16U None ATGACCTTCTGCCTCTTACC 118 BI16D 5'-Biotin ATGAAAACAAAATCACATTTGC Intron 8 5T/7T/9T I8U None TAATGGATCATGGGCCATGTGC 212 BI8D 5'-Biotin ACTGAAGAAGAGGCTGTCATCACC CFTR, cystic fibrosis transmembrane conductance regulator gene. Login to comment
118 Table 5 Genomic DNA Samples CFTR genotype Sourcea Normal/normal Sigma, D6537 ΔF508/normal Patient sample ΔF508/ΔF508 Coriell Cell Repositories, NA04540 ΔI507/normal Coriell Cell Repositories, NA11277 W1282/normal Coriell Cell Repositories, NA11723 1717-1G→A/normal Coriell Cell Repositories, NA12444 G542X/G542X Coriell Cell Repositories, NA11496B G542X/normal Coriell Cell Repositories, NA11497B ΔF508/G551D Coriell Cell Repositories, NA11274 ΔF508/R553X Coriell Cell Repositories, NA07469 G551D/R553X Coriell Cell Repositories, NA11761 ΔF508/R560T Coriell Cell Repositories, NA11284 ΔF508/R117H Coriell Cell Repositories, NA13591 I148T/normal Patient sample ΔF508/621+1G→T Coriell Cell Repositories, NA11281 N1303K/G1349D Coriell Cell Repositories, NA11472A ΔF508/1078delT Patient sample R334W/? Login to comment

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
68 of chromosomes (frequency %) p.M1V 1 1 (0.23) p.M1K 1 1 (0.23) c.300delA 3 1 (0.23) p.P67L 3 1 (0.23) c.359insT 3 1 (0.23) p.G85E 3 3 (0.70) c.394delTT 3 1 (0.23) p.Q98R 4 1 (0.23) p.R117H 4 2 (0.47) p.Y122X 4 2 (0.47) p.Y161N 4 1 (0.23) c.621+1GNT intron 4 1 (0.23) c.621+2TNG intron 4 1 (0.23) p.I175V 5 2 (0.47) c.711+1GNT intron 5 5 (1.16) p.L206W 6 3 (0.70) p.Q220X 6 1 (0.23) p.L227R 6 1 (0.23) c.1078delT 7 2 (0.47) p.R334W 7 7 (1.63) p.R347P 7 2 (0.47) c.1215delG 7 1 (0.23) c.T5 intron 8 1 (0.23) p.D443Y 9 1 (0.23) p.I506T 10 1 (0.23) p.I507del 10 4 (0.93) p.F508del 10 259 (60.23) p.F508C 10 1 (0.23) c.1677delTA 10 1 (0.23) c.1717-8GNA intron 10 1 (0.23) c.1717-1GNA intron 10 6 (1.40) p.G542X 11 23 (5.35) p.S549R 11 1 (0.23) p.G551D 11 2 (0.47) p.R553X 11 1 (0.23) c1811+1.6kbANG intron 11 4 (0.93) c.1812-1GNA intron 11 1 (0.23) p.T582I 12 1 (0.23) p.E585X 12 2 (0,47) c.1898+1GNA intron 12 1 (0.23) [c.1898+5GNA ;p.E725K] intron 12 1 (0.23) c.1898+73TNG intron 12 1 (0.23) c.2183AANG 13 4 (0.93) c.2184insA 13 1 (0.23) p.K710X 13 4 (0.93) c.2423delG 13 1 (0.23) p.S776X 13 1 (0.23) c.2493ins8 13 1 (0.23) p.R792X 13 1 (0.23) p.K830X 13 1 (0.23) p.D836Y 14a 1 (0.23) p.W846X1 14a 1 (0.23) c.2711delT 14a 1 (0.23) c.2789+5GNA intron 14b 3 (0.70) p.S945L 15 3 (0.70) p.D993Y 16 1 (0.23) c.3129del4 17a 1 (0.23) c.3195del6 17a 1 (0.23) c.3272-26ANG intron 17a 1 (0.23) [c.3395insA ;pI148T] 17b/4 1 (0,23) p.Y1092X 17b 3 (0.70) Table 1 (continued) Mutation Location exon/intron No. Login to comment
75 The IRT-1 concentrations were higher than the cutoff in 1299 samples (0.77%) and were followed by the genetic test which detected 11 cases with two mutations: eight were homozygous for the mutation p.F508del, two were compound heterozygotes (p.I507del+p.R334W and p.G542X+ p.R117H) and one was homozygous for the mutation p.R117H associated with the 7T allele in the intron 8 polythymidine sequence (IVS8) (Table 2). Login to comment
83 Table 2 Genotypes identified by newborn screening in 19 affected babies IRT (ng/ml) Genotypes 118 [p.F508del]+[p.F508del]a 163 [p.F508del]+[p.F508del]a N130 [p.F508del]+[p.F508del]b N130 [p.F508del]+[p.F508del]b N130 [p.F508del]+[p.F508del]b 155 [p.F508del]+[p.F508del]a 166 [p.F508del]+[p.F508del]a 109 [p.F508del]+[p.F508del]a 110 [p.F508del]+[p.F508del]a 136 [p.F508del]+[c.3007delG]a 160 [p.F508del]+[c.2622+1GNA]a 129 [p.F508del]+[c.3850-1GNA]a 151 [p.G542X]+[c.2380del8]a 131 [c.1078delT]+[p.K710X]a N130 [p.I507del]+[p.R334W]b 75 [p.G542X]+[p.R117H ;c1342-6 T7]b MI [p.E1104X]+[p.E1104X]b 84 [p.R117H; c1342-6 T7]+[p.R117H; c1342-6 T7]a 99 [c.2183AANG]+[p.Q220X]a IRT: Immunoreactive trypsinogen (cutoff: 65 ng/ml). Login to comment
89 The mutation was p.F508del (n=47), p.G542X (n=5), p.N1303K (n=4), p.G551D (n=2), p.R334W (n=2), c.1717- 1NA (n=1), p.I507del (n=1), p.R1162X (n=1), [p.R117H;IVS8-T7] (n=8) or [p.R117H;IVS8-T5] (n=1). Login to comment
131 The panel of 30 mutations (c.1717-1GNA, p.G542X, p.W1282X, p.N1303K, p.F508del, c.3849+10kbCNT, c.621+1GNT, p.R553X, p.G551D, p.R117H, p.R1162X, p.R334W, p.A455E, c.2183AANG, c.3659delC, c.1078delT, p.I507del, p.R347P, p.S1251N, p.E60X, p.Y1092X, c.394delTT, c.1811+1.6kbANG, c.3272-26ANG, c.2789+5GNA, c.3120+1GNA, c.711+ 1GNT, p.G85E, p.Y122X, p.W846X) should account for 83.32% of the CF alleles in L-R and 84.25% in the whole country. Login to comment
158 We found the frequency of mutation R117H (12.16%) higher in the heterozygous neonates than in the CF population in France (0.16%) or in L-R (0.47%). Login to comment
159 R117H- 7T is associated with a broad phenotypic range, from CF with suppurative lung disease to no clinical disease. Login to comment

PMID: 15533383 [PubMed] Fedder J et al: "Etiology of azoospermia in 100 consecutive nonvasectomized men."

No. Sentence Comment

29 We analyzed for the following CFTR mutations: ⌬F508 (exon 10), 394delTT (exon 3), R117H (exon 4), and IVS8-5T (intron 8) (4). Login to comment
60 Among the 28 patients with OA, 12 had at least one CFTR mutation. Two men were found to have a ⌬F508 mutation, and four were found to have a R117H mutation. Two were compound heterozygotes carrying both a ⌬508 and an R117H mutation and one carrying a 394delTT and an R117H mutation. Two men had an IVS8-5T mutation. Login to comment
70 Main group Specific etiology (subgroup) No. of patients in each subgroup (% of the main group) No. of patients with a history of cryptorchidism (% of the subgroup) Nonobstructive azoospermia Klinefelter`s syndrome (XXY) 6 (8) 1 (17) 46,XX karyotype/15,21 translocation 2 (3) 0 Y microdeletion/deletion 9 (13) 1 (11) Parotitis/orchitis/torsio testis/anabolic steroids 5 (7) 0 Hodgkin lymphoma/chemotherapy/radiotherapy 5 (7) 0 Unexplained 45 (63) 27 (60) Obstructive azoospermia CF-carriera (⌬F508, R117H, 284delA, IVS8-5T) 12 (43) 3 (25) Embryological cause (utricular cyst, malformation) 2 (7) 0 Epididymitis (Chlamydia trachomatis) 5 (18) 0 Surgical cause 2 (7) 0 Trauma (traffic accident, torture, accidental shot) 3 (11) 0 Unexplained 4 (14) 0 a Carrier of at least one mutation in the cystic fibrosis gene; two of these men also showed Sertoli cell-only syndrome in addition to absence of vasa deferentia. 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

12 For example, a polythymidine tract in intron 8, known as 5/7/9T, modifies the phenotype of the disease associated with the R117H polymorphism. Login to comment
13 The R117H polymorphism is associated with either classical CF or with congenital bilateral absence of the vas deferens (CBAVD) depending on the presence and chromosome location of 5T or 7T. Login to comment
14 The presence of 5T on the same allele (5T in cis-) with R117H is associated with classical CF; however, 7T in cis-with R117H is associated with infertility due to CBAVD in otherwise healthy men.7 The ambiguity arises when 5T is paired in a trans configuration with R117H and no other CF mutation is present, or if 5T is detected alone, because the phenotype is associated with CBAVD only.8 Testing for the R117H mutation and the intron 8 variant in a large population was recognized as a potential complication in CF screening program because it would expand the risk ascertainment beyond that for classical CF.2 Since the 5T variant alone occurs in about 5% of the US population,1 the combination of primary mutations and reflex variants in a single test can result in the detection of a 5T genotype without the R117H polymorphism. Login to comment
19 4, November 2004 Copyright (c) American Society for Investigative Pathology and the Association for Molecular Pathology 348 the guidelines for CF screening specify reflex testing for 5/7/9T only with the positive detection of R117H.1 However, the number of mutations and increased throughput requirements for CF screening resulted in many labs and vendors combining 5/7/9T and primary mutation panel testing in the same assay. Login to comment
33 This approach resolved issues associated with the detection of 5T without R117H and complied with ACOG guidelines for CF reflex testing. Login to 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: 15482777 [PubMed] Wong LJ et al: "The necessity of complete CFTR mutational analysis of an infertile couple before in vitro fertilization."

No. Sentence Comment

80 The more common mutation affecting the same amino acid is R117H, about 0.7% in the US white CF population (10), which is located at the external end of the second transmembrane domain of the CFTR protein (9). Login to comment
81 The partial penetrance of R117H mutation depends on the cis-located 5T tract in intron 8 and possibly also by nuclear modifier genes (7, 11-13). Login to comment
85 The substitution of the basic amino acid arginine with another basic amino acid histidine is predicted to be mild, as it has been observed in patients with the R117H mutation. 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
122 N1303K).8,9,11,34 -36 Mutants that have been shown previously to form plasma membrane Cl- channels with altered single-channel properties in heterologous cells (S108F, R117H, R334W, F1052V)10,34,35,37 were associated with residual cAMP-mediated Cl- secretion of ϳ12%-54% of control rectal epithelia. Login to comment

PMID: 15269305 [PubMed] Pont-Kingdon G et al: "Long-range (17.7 kb) allele-specific polymerase chain reaction method for direct haplotyping of R117H and IVS-8 mutations of the cystic fibrosis transmembrane regulator gene."

No. Sentence Comment

15 Two of these mutations, R117H in exon 4 and the 5T polymorphism of the polythymidine tract in intron 8 (IVS-8 5T polymorphism) have a phenotypic synergic effect. Login to comment
16 The mutation R117H which accounts for approximately 0.8% of mutant alleles, changes an arginine to an histidine in a transmembrane domain of the protein, altering the conductance of the ion channel.16 The IVS-8 polymorphism affects the splicing efficiency of intron 8.17,18 A tract of 7T or 9T at the 3Ј end of intron 8 insures proper splicing of the intron while a 5T results in a majority of mRNA lacking exon 9.19 -22 Each mutation is independently considered mild because in both cases, residual activity of the ion channel remains. Login to comment
17 Therefore, an individual carrying the R117H mutation and the IVS-8 5T polymorphism on two different chromosomes (in trans) is not affected by, nor considered a carrier of classic CF23 although this individual might present with atypical CF. Login to comment
18 In contrast, a gene with both R117H and IVS-8 5T (in cis) is severely affected.24 Both R117H and the IVS-8 5T variants have been found at higher frequencies in individuals with atypical CF than in the normal population.22,25-27 If an individual is heterozygous for both R117H and the IVS-8 5T variant, it is necessary to establish if both mutations are in cis or in trans to correctly analyze the Supported by the Institute for Clinical and Experimental Pathology, LLC, ARUP Laboratories. Login to comment
26 Since the R117H and IVS-8 loci are separated by 17.7 kilobases (Cystic Fibrosis Mutation database at http://genet.sickkids.on.ca/cftr), the assay described here is based on long-range allele-specific PCR. Login to comment
29 Materials and Methods Patient Samples Genomic samples previously genotyped as R117H heterozygous were selected for the development of this assay and de-identified following Institutional Review Board protocol. Login to comment
40 Determination of R117H and IVS-8 Haplotype Using Oligonucleotide Ligation Assay At the end of the PCR, products are analyzed using the Cystic Fibrosis Assay version 3.0 (Celera Diagnostics, Alameda, CA). Login to comment
49 The R117H and the IVS-8 polymorphism are analyzed concurrently using as template 1.5 ␮l of the 17.7-kb PCR product previously diluted with 3.5 ␮l of "diluent for purified DNA" buffer. Login to comment
52 The R117H and the IVS-8 loci are analyzed in the green channel. Login to comment
65 Results Long-Range Allele-Specific PCR Three independent long-range PCRs are performed per sample: one reaction amplifies both R117H alleles of the heterozygous R117H sample, while the other two are allele-specific (Figure 1). Login to comment
68 The forward primer of the "RH" PCR (R117H-F) anneals in exon 4, 5Ј of the mutation site. Login to comment
77 The sample shown in Figure 2 is heterozygous for the R117H mutation and carries the 5T/7T IVS-8 polymorphisms. Login to comment
85 "RH" is the PCR that amplifies both the wild-type and the R117H mutant allele. Login to comment
89 Primers Sequences PCR Primer Sequence Predicted Tm (°C) R allele H allele "RH" R117H-F 5Ј-TGTAGGAAGTCACCAAAGCAGTAC 58.2 58.2 "Halsp" Halsp-F 5Ј-CCCGGATAACAAGGAGGAACA 55.8 (1.9) 57.7 "Ralsp" Ralsp-F 5Ј-CCCGGATAACAAGGAGGAACG 58.1 55.8 (2.3) IVS8-R 5Ј-CAACCGCCAACAACTGTCC 57.7 57.7 Bold characters indicate the allele-specific nucleotide. Login to comment
101 Haplotyping of R117H Samples Sixteen samples with a variety of IVS-8 genotypes were haplotyped (Table 3). Login to comment
105 In addition to the R117H and IVS-8 loci, the OLA analysis reveals results for other CF mutation loci included in the CF version 3.0 kit from Celera. Login to comment
106 In the same channel as R117H and IVS-8, the two extra peaks correspond to the wild-type alleles of the 621 ϩ 1G Ͼ T and 711 ϩ 1G Ͼ T mutations. Login to comment
111 In this analysis, the samples shown in A and C (samples 1 and 4) carries the 5T allele on the wild-type chromosome (R117) therefore R117H and 5T are in trans. Login to comment
117 Genotypes of R117/R117H locus and the 5T/7T/9T locus were confirmed by sequencing the extremities of each PCR obtained from sample 1 and 2 (data not shown). Login to comment
118 Accuracy and Reproducibility Several methods are available for genotyping independently both R117H and IVS-827,31 but determination of the phase relies on family studies or unequivocal results such as homozygosity of the IVS-8 genotype or compound heterozygous with delF508-9T.24,27 Although R117H and the 5T IVS-8 polymorphism are found at relatively high frequency in populations affected with CF or with atypical CF,22,25-27 they are relatively rare in the normal population and we found only five R117H/5T-positive samples in more than 10000 CF tests. Login to comment
121 The parent carrying the R117H mutation is IVS-8-7T homozygous and the other parent has the 5T allele (data not shown). Login to comment
122 Thus, this linkage study confirms the molecular diagnosis that R117H and 5T are in trans in this sample. Login to comment
123 Additionally, sample 5 and 16 (Table 3) and the Coriell cell line control GM13591 (Bernacki SH, Beck JC, Muralidharan K, Schaefer F, Shrimpton AE, Pont-Kingdon G, Stenzel TT, submitted) are compound heterozygous R117H and DelF508. Login to comment
125 Molecular haplotyping determined the haplotypes as R117H-7T/DelF508-9T (sample 16) and R117H-5T/DelF508-9T (sample 5 and GM13591). Login to comment
131 Genotypes and Haplotypes of R117H Samples Sample Genotype Haplotype Interpretation R chromosome (wild type) H chromosome (mutant) 1 R117H-5T/7T R-5T H-7T Trans 2 R117H-5T/7T R-7T H-5T Cis 3 R117H-5T/9T R-9T H-5T Cis 4 R117H-5T/7T R-5T H-7T Trans 5 R117H/Del F508-7T/9T R-9T H-5T Cis 6 R117H-7T/7T failed H-7T na 7 R117H-7T/7T R-7T H-7T na 8 R117H-7T/9T R-9T H-7T na 9 R117H-7T/7T R-7T H-7T na 10 R117H-7T/7T failed H-7T na 11 R117H-7T/7T R-7T H-7T na 12 R117H-7T/7T R-7T H-7T na 13 R117H-7T/7T R-7T H-7T na 14 R117H-7T/9T R-9T H-7T na 15 R117H-7T/9T R-9T H-7T na 16 R117H/DelF508-7T/9T R-9T H-7T na 17 R117H/G542X-7T/9T R-9T H-7T na na, not applicable. Login to comment
133 Discussion This test allows the direct haplotyping of the R117H mutation and the 5T polymorphism of intron 8 of the CFTR gene. Login to comment
134 Both the R117H mutation and the IVS-8 variant have been found at a higher frequency in individuals affected with classic or atypical cystic fibrosis. Login to comment
136 If an individual is found to have the R117H mutation and the IVS-8 5T polymorphism, the molecular test can establish the cis/trans status of both mutations without the need to obtain DNA from parents. Login to comment
137 Haplotyping technologies have rarely been applied to clinical testing for several reasons: methods are labor intensive and highly sophisticated,12,32 rely on extreme dilution of DNA not practical in a clinical setting,5,11 are limited to short fragments of DNA,6,8 -10,13 or are not accurate enough to determine haplotypes from specific individuals.33 A recent, elegant molecular approach that uses post-PCR ligation has been described and would also allow the amplification and haplotyping of the R117H mutation and the IVS-8 5T polymorphism.15 This approach has the disadvantage of requiring additional post-PCR steps before analysis. Login to comment
154 The analysis of the R117H loci from each PCR provides an internal control. Login to comment
155 An additional probe set, distinguishing the R117H mutation from the wild type, could also be added to the FRET probe assay and multiplexed with the IVS-8 probe. 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
42 The greatest frequency of pancreatitis was reported in patients carrying at least 1 R334W mutation (19.0%), followed by patients with a 2789ϩ5GϾA mutation (14.9%), R117H mutation (11.7%), R347P mutation (11.6%), 3849ϩ10kbCϾT mutation (9.0%), A455E mutation (8.3%), or G85E mutation (8.0%; Table 1). Login to comment
47 This sex difference was unique for R334W and was not apparent for patients with other pancreatitis-related genotypes (R347P, R117H, G85E, 2789ϩ5GϾA, or 3849ϩ10kbCϾT) or for patients with pancreatitis in the PI group. Login to comment
56 Four of 54 patients (7.4%) with an R117H mutation and 2 of the remaining patients with PS (1.7%) developed pancreatitis. Login to comment
59 Other mutants, such as R117H, R334W, and R347P, which are correctly processed and retain some residual apical chloride channel function, are associated with a milder form of the disease.20,21 However, the vast majority of CF centers in Europe and the United States do not formally assess pancreatic function at diagnosis, and many assume that a patient with a diagnosis of CF has PI and requires enzyme supplements. Login to comment
64 of patients Patients with pancreatitis At least 1 attack of pancreatitis Ն2 attacks of pancreatitis All genotyped patients with CF 17,871 364 (2.0) - - Pancreas insufficienta 12,997 114 (0.9) 1.0 (reference) 1.0 (reference) Pancreas sufficientb 868 103 (11.9) 9.3 (6.7-12.8) 14.8 (8.2-26.8) 3849ϩ10kbCϾT/anyc 256 23 (9.0) 5.3 (3.1-9.0) 7.1 (2.8-18.3) R117H/anyc 249 29 (11.7) 8.9 (5.5-14.5) 14.1 (6.1-32.7) 2789ϩ5GϾA/anyc 134 20 (14.9) 13.2 (7.3-23.8) 10.4 (3.1-35.5) R347P/anyc 95 11 (11.6) 11.1 (5.3-23.1) 26.6 (9.1-77.4) R334W/anyc,d 79 15 (19.0) 25.8 (13.2-50.5) 43.6 (15.3-124) A455E/anyc 60 5 (8.3) 3.4 (2.6-4.4) 18.3 (5.0-67.9) Genotype incompletely determinede 4006 147 (3.7) 3.4 (2.6-4.4) 6.3 (3.8-10.5) NOTE. Values expressed as number (percent) or odds ratio (95% confidence interval). Login to comment
68 bPatients with pancreas sufficiency (PS) carrying at least 1 PS mutation (3849ϩ10kbCϾT, R117H, 2789ϩ5GϾA, R347P, R334W, A455E). Login to comment
82 The R334W mutation also has been found in 3.9% of patients with CF in Uruguay, another country with massive historical immigration from Spain.26 Several study groups have identified an excess of the R117H and other mild CFTR mutations in patients with idiopathic pancreatitis, but failed to identify patients with the R334W mutation. Login to comment

PMID: 15039235 [PubMed] Durie PR et al: "Characteristic multiorgan pathology of cystic fibrosis in a long-living cystic fibrosis transmembrane regulator knockout murine model."

No. Sentence Comment

23 The first murine model of CF was established by gene targeting of embryonic stem cells to disrupt the murine cftr gene.15 Other murine models have been developed to model human mutations, including the most common CFTR gene mutation ⌬F508 (confers loss of phenylalanine) and models carrying common missense mutations (G551D, R117H).16 -20 Most of these animals develop a range of intestinal pathology that may cause fatal complications after bowel obstruction at birth or when weaned to solid chow. 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

94 Class IV mutations (R117H, and was not replaced with mature protein. Login to comment
95 Cyclic R334W, R347P) result in a CFTR that reaches the AMP activated chloride conductance was present for plasma membrane but has reduced chloride conduct- cells grown at 30 8C but not at 37 8C. Login to comment

PMID: 12454843 [PubMed] Durno C et al: "Genotype and phenotype correlations in patients with cystic fibrosis and pancreatitis."

No. Sentence Comment

105 CFTR Genotypes Among CF Patients With PS With and Without Pancreatitis Two mutations (n) ⌬F508/R117H (9) ⌬F508/(5T) (6) ⌬F508/3272-26A 3 G (4) ⌬F508/R347H (2) ⌬F508/P574H (2) ⌬F508/875 ϩ 1G Ͼ C (2) ⌬F508/3849 ϩ 10kb C 3 T (1) ⌬F508/A455E (1) ⌬F508/D614G (1) ⌬F508/G85E (1) ⌬F508/R347P (1) ⌬F508/S1251N (1) ⌬F508/⌬F508a (1) ⌬F508/3120G Ͼ A (1) ⌬F508/G551Da (1) G542X/R117H (1) R560T/L206W (1) R117H/R117H (1) R31L/P67L (1) 1461ins4 (AGAT)/G85E (1) G551D/(5T) (1) R1066C/3849 ϩ 10kb C Ͼ T (1) G551D/3849 ϩ 10kb C Ͼ T (1) R334W/R334W (1) R334W/681delC (1) W1282X/3489 ϩ 10kb C Ͼ T (1) One mutation (n) ⌬F508/- (18) L1077P/- (1) W1282X/- (1) M1137V/- (1) G551D/- (1) R347H/- (1) Q30X1/- (1) G1244E/- (1) R117H/- (1) 621 ϩ 2G621 ϩ 1G 3 T/- (1) NOTE. Login to comment
124 of episodes of pancreatitis Genotype 1 0.3 12 21.7 2 ⌬F508/S1251N 2 0.3 34 30.0 1 ⌬F508/R347H 3 4.4 13 42.5 3 / 4 4.4 21 36.5 1 ⌬F508/ 5 7.3 26 40.8 10 ⌬F508/P67L 6 9.6 29 29.9 (D) 1 ⌬F508/ 7 12.0 18 39.9 1 ⌬F508/R347P 8 12.9 37 40.9 2 G542X/D1152H 9 13.0 30 50.3 1 ⌬F508/3849 ϩ 10Kbc Ͼ T 10 14.7 13 21.5 1 DF508/R117H 11 15.6 34 40.8 1 ⌬F508/2789ϩ5G Ͼ T 12 15.6 10 26.0 10 ⌬F508/R117H 13 16.0 10 22.0 14 ⌬F/508/3849 ϩ 10kbC Ͼ T 14 16.0 18 21.2 (D) 1 R1066C/3849 ϩ 10kbC Ͼ T 15 19.9 15 40.8 5 No DNA 16 23.2 19 23.2 15 ⌬F508/11234V 17 24.1 40 47.6 (D) 1 No DNA 18 26.9 25 43.3 12 No DNA 19 27.4 35 50.3 (D) 2 ⌬F508/A455E NOTE. Login to comment

PMID: 12127423 [PubMed] Girodon E et al: "Cystic fibrosis transmembrane conductance regulator (CFTR) gene defects in patients with primary sclerosing cholangitis."

No. Sentence Comment

78 Four additional subjects (3.5%) carried one of the following mild defects: R117H, R347H, R74W-D1270N and R668C-G576A. 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: 12054472 [PubMed] Tan AL et al: "Biochemical implications of sequence comparisons of the cystic fibrosis transmembrane conductance regulator."

No. Sentence Comment

91 Furthermore, if histidine is assigned a full positive charge, then the net charge of the segment would be )3 in rat, )2 in primates, )1 in other mammals, 0 in toad, )1 in frog, +1 in dogfish, and 0 in teleost fishes. It should be noted that the mutant R117H exhibited altered sensitivity to pH and a reduced chloride current [32]. 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
81 Three patients had two CFTR gene mutations: two had the severe mutation ⌬F508 associated with the mild mutation R117H, and one had two mild mutations (R117H and R347H). Login to comment
108 Patient Mutations Intron 8 Phenotype Seminal vesicle Epididymis Testicular volume (right/left) (mL) Comments 1 ⌬F508/R117H 7T/9T BAVD A/D C/C 20/20 2 ⌬F508/R117H 7T/9T BAVD A/A E/C 15/12 3 R117H/R347H 7T/9T BAVD A/D E/E 15/15 Compound heterozygote 4 ⌬F508/o 5T/7T BAVD A/h C/C 10/13 Compound heterozygote 5 ⌬F508/o 5T/9T BAVD A/A E/E 16/17 Compound heterozygote 6 ⌬F508/o 5T/9T BAVD A/D E/E 15/15 7 ⌬F508/o 5T/9T BAVD A/A E/E 11/9 8 ⌬F508/o 5T/9T BAVD h/h E/E 20/20 9 ⌬F508/o 5T/9T BAVD A/A C/C 17/9 10 ⌬F508/o 5T/9T BAVD D/A E/E 15/12 11 ⌬F508/o 5T/9T BAVD A/D E/E 10/12 12 ⌬F508/o 7T/9T BAVD A/N C/E 20/20 13 ⌬F508/o 7T/7T BAVD A/A E/E 20/18 14 ⌬F508/o 7T/7T BAVD h/h E/E 10/9 15 ⌬F508/o 9T/9T BAVD A/D C/C 23/26 16 1612delTT/o 7T/9T BAVD A/D C/C 8/7 17 D1270N/o 7T/7T BAVD A/A E/E 12/13 18 R117H/o 7T/7T BAVD A/D E/E 20/18 19 2789ϩ5GBA/o 7T/7T BAVD A/A C/C 18/13 20 o/o 5T/5T BAVD D/A E/E 8/10 21 o/o 5T/9T BAVD A/A C/E 20/18 22 o/o 5T/7T BAVD A/A E/E 20/20 23 o/o 5T/9T BAVD A/A E/E 9/10 24 o/o 5T/7T BAVD A/D E/E 10/10 25 o/o 5T/7T BAVD A/A E/E 9/10 26 o/o 5T/9T BAVD A/D E/A 12/0 Left testicular atrophy 27 o/o 5T/7T BAVD A/A C/E 9/8 28 o/o 7T/7T BAVD A/A E/E 15/15 29 o/o 7T/7T BAVD A/h E/E 11/11 30 o/o 9T/9T BAVD h/h C/C 7/8 31 o/o 7T/7T BAVD h/A E/E 12/12 32 o/o 7T/7T BAVD A/A E/C 10/10 33 o/o 7T/9T BAVD A/A E/E 11/12 34 o/o 7T/7T BAVD h/A C/C 9/9 35 o/o 7T/7T BAVD A/D C/A 10/11 Bilateral dilatation of rete testis 36 o/o 7T/7T BAVD A/D C/C 12/12 37 o/o 7T/9T BAVD A/A C/E 15/15 38 o/o 7T/7T BAVD D/A C/C 12/15 39 o/o 7T/7T BAVDϩURA A/A C/C 12/12 40 o/o 7T/7T BAVDϩURA D/A A/C 0/20 Right testis absent 41 o/o 5T/9T UAVD D/A E/E 13/13 42 o/o 5T/7T UAVD D/A E/C 8/10 Right testicular hypotrophy 43 o/o 5T/7T UAVD h/N E/E 7/8 44 o/o 7T/7T UAVD A/D E/A 12/0 Left cryptorchidism 45 o/o 7T/7T UAVD D/A E/E 4/5 Bilateral testicular hypotrophy 46 o/o 7T/7T UAVD h/h E/E 8/8 47 o/o 7T/7T UAVDϩURA D/A E/E 15/15 Note: A ϭ absent; D ϭ dilated; C ϭ caput only; E ϭ whole; h ϭ hypotrophic; N ϭ normal; o ϭ no detected mutation; BAVD ϭ bilateral absence of the vas deferens; UAVD ϭ unilateral absence of the vas deferens; URA ϭ unilateral renal agenesis. Robert. Absence of the vas deferens. Login to comment
116 Mutation Cystic fibrosis chromosome (n ϭ 950) (%) CBAVD chromosome (n ϭ 54) (%) CUAVD chromosome (n ϭ 6) (%) General population (%)a ⌬F 508b 69 25.9 0 1.4 G542Xb 4.6 0 0 - N1303Kb 2.7 0 0 - 1717-1GϾAb 0.9 0 0 - R117H 0.3 7.4 0 - 5T - 31.5 50 5.2 Note: CBAVD ϭ congenital bilateral absence of the vas deferens; CUAVD ϭ congenital unilateral absence of the vas deferens. 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

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

103 b 3905insT, 1811+1.6kbA>G, S945L, S1251N, Y122X, 2711delT, R117H, E60X, 2184insA, E585X, L558S, S1235R, D1152H, K710X, Q493X, A455E, G178R, I148T, 574delA. Login to comment
115 The most frequent were F508del (21.75%), the 5T allele (16.31%), and R117H (4.37%), followed by D1152H (1.19%), and D443Y (0.93%). Login to comment
119 Compound heterozygosity was the rule, but 10 patients were found to be homozygotes for one CFTR mutation [5T/5T (n=7), R117H/R117H (n=2), R74W+D1270N/R74W+ FIGURE 2. Geographic distribution of the most common mutations responsible for CF in 12 regions in France, as given by the area of residence of parents and/or grandparents. Login to comment
124 The most common compound heterozygous genotypes were F508del/5T (28.44%) and F508del/R117H (5.6%). Login to comment
130 All R117H alleles whose data at locus IVS8(T)n were communicated to us were found on a 7T background. Login to comment
171 CFTR Mutation Genotypes Identified Both in Cystic Fibrosis (CF) and in Congenital Bilateral Absence of the Vas Deferens (CBAVD) CF CBAVD F508del/5T 3 143 F508del/2789+5G>A 53 1 F508del/3272-26A>G 17 4 F508del/R117H* 10 39 F508del/R117C 2 2 F508del/L206W 12 4 F508del/R347H 10 5 F508del/R347L 1 1 F508del/D443Y 1 5 F508del/Y569C 1 1 F508del/P574H 3 1 F508del/G628R(G>A) 2 1 F508del/V920M 1 1 F508del/R1070W 2 3 F508del/D1152H 6 8 F508del/S1235R 3 1 F508del/T1246I 1 1 F508del/D1270N+R74W 2 3 F508delN1303I 1 1 3659delC/R347H 1 1 G542X/T338I 2 2 R347H/R1066H 1 1 *The only case with CF whose alleles at IVS8(T)n were reported had mutation R117H associated with a 5T allele. Login to comment
172 In the group of CBAVD patients, 26 were reported with a 7T allele associated with mutation R117H. 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: 10649490 [PubMed] Girodon-Boulandet E et al: "Screening practices for mutations in the CFTR gene ABCC7."

No. Sentence Comment

175 For instance, the R117H mutation, for which most commercial kits test, is now considered to be a CF mutation only when it is associated in ciswith the IVS8-5T variant or when sweat test or nasal potential difference values are abnormal [Rosenstein and Cutting, 1998]. Login to comment
176 This would imply that laboratories should routinely analyse the IVS8-6 polyvariant site once R117H has been detected, which is especially important for genetic counseling of the patients themselves and their relatives. Login to comment

PMID: 10571016 [PubMed] Scanlin TF et al: "Terminal glycosylation in cystic fibrosis."

No. Sentence Comment

650 Some mutations (e.g., G542X) produce a truncated transcript and no protein, while other mutations (e.g., R117H) produce a protein that has impaired conduction properties. Login to comment

PMID: 10386624 [PubMed] Fanen P et al: "Structure-function analysis of a double-mutant cystic fibrosis transmembrane conductance regulator protein occurring in disorders related to cystic fibrosis."

No. Sentence Comment

113 This fraction, as well as that of D1270N-CFTR (38%), resembles the pattern of responses of R117H-CFTR, another mild mutant associated with CBAVD [11]. Login to comment
115 The R117H mutation produces di¡erent phenotypes, depending on the presence or absence of the 5T allele on the same chromosome [17]. Login to comment
116 When R117H occurs on a 5T background, the physiology of the vas deferens, lungs and sweat glands is impaired, de'ning a complete but mild CF. Login to comment
117 When R117H occurs on a 7T background, only the physiology of the vas deferens is impaired. Login to comment
121 Thus, this double-mutant strongly resembles the R117H mutation when it is associated with the 7T background. Login to comment
123 The contribution of each mutant to this phenotype may be as follows: R74W is a polymorphism which may slightly reduce the normal amount of CFTR protein (67% of responding cells versus 81^89%) in vivo and D1270N has a cAMP-responsive anion conductance with di¡erent ratios between fast and slow responder cells, as for the R117H mutation. Login to comment

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

No. Sentence Comment

16 The mutation ⌬F508, associated with pancreatic insufficiency and diagnosis at younger age, is classified as a "severe" mutation (6), whereas others such as R117H and A455E are considered to be "mild" mutations. Login to comment
93 Three of them had a mild mutation (R117H or A455E) and were clinically classified as class 0 (n ϭ 2) or class 1 (n ϭ 1). Login to comment
94 The fourth patient had undergone sinus surgery and was ⌬F508 negative (G542X/unidentified). Login to comment
120 of Patients in Surgical Group ⌬F508 Genotype Homozygosity 69 61 22 Compound heterozygosity 33 29 5 Negative 11 10 1 Mutations ⌬F508 171 75.7 27 Non-⌬F508 55 24.3 6 R117H (4) C276X (1) 394delT (1) W401X (2,† ) A455E (1) G542X (4,‡ ) G551D (1) R553X (1) G628R(G→C) (1) Y1092X (1) D1152H (1) S1251N (1) W1282X (3) N1303K (8) W1310X (1) 1717-1G→A (3,† ) 1898ϩ1G→C (1) 2183AA-G (3,†† ) 3659delC (2) 3272-26A→G (2,† ) 4218-insT (2) unknown (11,‡ ) * The genotype and mutations are given for the 113 patients with CF. Login to comment
121 of Patients in Surgical Group DF508 Genotype Homozygosity 69 61 22 Compound heterozygosity 33 29 5 Negative 11 10 1 Mutations DF508 171 75.7 27 Non-DF508 55 24.3 6 R117H (4) C276X (1) 394delT (1) W401X (2,ߤ ) A455E (1) G542X (4,ߥ ) G551D (1) R553X (1) G628R(G࢐C) (1) Y1092X (1) D1152H (1) S1251N (1) W1282X (3) N1303K (8) W1310X (1) 1717-1G࢐A (3,ߤ ) 189811G࢐C (1) 2183AA-G (3,ߤߤ ) 3659delC (2) 3272-26A࢐G (2,ߤ ) 4218-insT (2) unknown (11,ߥ ) * The genotype and mutations are given for the 113 patients with CF. Login to comment

PMID: 10232317 [PubMed] Johnson DW et al: "Sunshine, sweating, and main d'accoucheur."

No. Sentence Comment

16 Screening for ten of the common cystic fibrosis transmembrane conductance regulator gene (CFTR) mutations (⌬F508, G551D, R553X, G542X, N1303K, A455E, 621+1, Delta I507 and R117H), showed a single delta F508 mutation. Login to comment

PMID: 9915972 [PubMed] Castellani C et al: "Cystic fibrosis mutations in heterozygous newborns with hypertrypsinemia and low sweat chloride."

No. Sentence Comment

9 Three of these mutations (R117H, Y301C, and E527G) are thought to be disease causing in CF or in CBAVD, since they determine the substitution of an amino acid in evolutionarily conserved residues and therefore are tentatively classified, on the basis of the Cystic Fibrosis Genetic Analysis Consortium (CFGAC) database, as "mutations"; the other four mutations (1716 G/A, 2622ϩ14 G/A, 3041-71 G/C, and 4002 A/ G) are not believed to be disease causing in CF and CBAVD, either because they do not determine any amino acid substitutions (in the case of 1716 G/A and 4002 A/ G) or because they occur in noncoding regions that, as determined by sequence-analysis software, produce no apparent alteration (in the case of 2622ϩ14 G/A and 3041-71 G/C) and therefore are tentatively classified, on the basis of the CFGAC database, as CF "polymorphisms." Login to comment
16 Am. J. Hum. Genet. 64:303-304, 1999 Table 1 Sweat Chloride Concentration and CFTR Genotypes CASE SWEAT CHLORIDE (mEq/liter) MUTATION Allele 1a Allele 2b 1 10 R1162X 3041-71G/C,c 4002A/Gc 2 14 DF508 3 30 R1162X R117H 4 21 DF508 E527G 5 8 DF508 6 12 N1303K, 2622ϩ14G/Ad 7 6 DF508 8 20 DF508 1716G/Ac 9 16 DF508 10 10 DF508 11 19 R1162X 12 19 N1303K 13 12 G542X 1716G/Ac 14 32 DF508 15 14 DF508 16 26 N1303K 2622ϩ14G/Ac 17 18 DF508 Y301C 18 18 2183AArG a First mutation found, assigned to one gene. Login to comment

PMID: 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
242 Of interest, one of these mutations near predicted membrane-spanning ␣-helix 1 of TMD1 of CFTR, R117H, correlates with high incidence to a second disorder, congenital bilateral absence of the vas deferens (CBAVD), which causes infertility in males (94-96). Login to comment

PMID: 9545412 [PubMed] Grody WW et al: "Diversity of cystic fibrosis mutation-screening practices."

No. Sentence Comment

30 For example, 13 of the laboratories do not test for R117H, which many would feel is one of the relatively more common and important mutations, associated with both classical CF and congenital bilateral absence of the vas deferens (Jezequel et al. 1995). Login to comment
31 And only two of the other laboratories specifically indicated that they include testing for the intronic 5/7/9T polymorphism that markedly affects phenotypic expression of R117H and some other CFTR mutations (Kiesewetter et al. 1993; Chillon et al. 1995). Login to 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

PMID: 9591500 [PubMed] Tuerlings JH et al: "Mutation frequency of cystic fibrosis transmembrane regulator is not increased in oligozoospermic male candidates for intracytoplasmic sperm injection."

No. Sentence Comment

2 The three most frequent cystic fibrosis (CF)-causing CFTR mutations in the Dutch population (⌬F508, A455E, and G542X) and the three most frequent CFTR mutations potentially causing congenital bilateral absence of the vas deferens (CBAVD) in the Dutch population (⌬F508, R117H, and IVS8-5T) were analyzed. Login to comment
65 The three most frequent CFTR mutations causing CF in the Dutch population (⌬F508, A455E, and G542X) and the three most frequent CFTR mutations potentially causing congenital bilateral absence of the vas deferens in the Dutch population (⌬F508, R117H, and IVS8-5T) were analyzed. Login to comment
68 Detection of R117H, A455E, and G542X mutations was performed with the use of allele-specific amplification tests, as described by Ferrie et al. (12) for G542X and R117H. Login to comment
91 The R117H and IVS8-5T frequencies per chromosome in the normal population of the Netherlands are approximately 0.009 (2 of 232 chromosomes of 116 unaffected, unrelated individuals) and 0.037 (8 of 212 chromosomes of 106 unaffected, unrelated individuals), respectively. Login to comment
108 (Ϯ SEM) of men without a CFTR mutation 15.0 (Ϯ 0.6) 3.7 (Ϯ 0.3) 2.9 (Ϯ 0.6) 7.8 17.3 (Ϯ 2.1) 63 (Ϯ 2) 16.5 (Ϯ 1.4) Patient 1 (⌬F508 mutation) 20 5.0 5 7.8 20 63 NT Patient 2 (⌬F508 mutation) 15 3.5 1 7.4 40 90 4.4 Patient 3 (R117H mutation) 13.5 8.3 0.1 7.8 1 95 13 Patient 4 (IVS8-5T stretch) 20 3.0 31 7.8 1 67 NT Note: NT ϭ not tested. Login to comment
111 The four mutations identified were ⌬F508 (twice; 1.3% of the chromosomes analyzed), R117H (once; 0.6% of the chromosomes analyzed), and IVS8-5T (once; 0.6% of the chromosomes analyzed) (Table 2). Login to comment
132 Mutation General population* (95% CI) Patients with OAT† (95% CI) Patients with CBAVD‡ Patients with CF§ ⌬F508 0.013 (0.011-0.015) 0.013 (0.0037-0.047) 0.169 0.777 R117H 0.009 (0.0027-0.030) 0.006 (0.0012-0.037) 0.305 Ͻ0.001 IVS8-5T 0.037 (0.019-0.073) 0.006 (0.0012-0.037) 0.055 ND A455E Ͻ0.001 (ND) 0 (ND) Ͻ0.001 0.026 G542X Ͻ0.001 (ND) 0 (ND) Ͻ0.001 0.015 ⌬I507 Ͻ0.001 (ND) 0 (ND) Ͻ0.001 Ͻ0.001 Total 0.005 (ND)࿣ 0.027 (0.010-0.067) 0.529 0.818 Note: OAT ϭ oligoasthenoteratozoospermia; CBAVD ϭ congenital bilateral absence of the vas deferens; ND ϭ not done. Login to comment
133 * Locally derived frequencies for ⌬F508, R117H, and IVS8-5T (n ϭ 21,544 chromosomes, n ϭ 232 chromosomes, and n ϭ 212 chromosomes, respectively); and theoretical estimates for A455E, G542X, and ⌬I507 based on a 3.3% carrier frequency and regionally derived mutation frequencies (H.S., unpublished data). Login to comment
136 § H.S., unpublished data (n ϭ 726 for ⌬F508, A455E, and G542X; n ϭ 272 for R117H; IVS8-5T not determined). Login to comment

PMID: 9499426 [PubMed] Mickle JE et al: "A mutation in the cystic fibrosis transmembrane conductance regulator gene associated with elevated sweat chloride concentrations in the absence of cystic fibrosis."

No. Sentence Comment

151 Mutation analysis Total genomic DNA was assayed for 16 common CFTR mutations (R117H, 621+1G→T, R334W, R349P, A455E, 1717-1G→A, ∆I507, ∆F508, G542X, S549N, G551D, R553X, R560T, 3849+10 kb C→T, W1282X, N1303K) by reverse dot-blot hybridization (46). Login to comment
152 Mutation analysis Total genomic DNA was assayed for 16 common CFTR mutations (R117H, 621+1G࢐T, R334W, R349P, A455E, 1717-1G࢐A, ࢞I507, ࢞F508, G542X, S549N, G551D, R553X, R560T, 3849+10 kb C࢐T, W1282X, N1303K) by reverse dot-blot hybridization (46). Login to comment

PMID: 9879057 [PubMed] Gallet X et al: "Topological model of membrane domain of the cystic fibrosis transmembrane conductance regulator."

No. Sentence Comment

232 Mutations associated with mild forms of cystic fibrosis (R117H, R334W, and R347P) implicate three of our inner pore residues in the chloride conductance.50 In other studies, basic amino acids of membrane helices were replaced by acidic residues (K95D, K335E, R347E, and R1030E). Login to comment
236 Mutations associated with mild forms of cystic fibrosis (R117H, R334W, and R347P) implicate three of our inner pore residues in the chloride conductance.50 In other studies, basic amino acids of membrane helices were replaced by acidic residues (K95D, K335E, R347E, and R1030E). Login to comment

PMID: 9580747 [PubMed] Wilmott RW et al: "Making the diagnosis of cystic fibrosis."

No. Sentence Comment

18 The mutation R117H on a 9T background does not meet the criteria for a CF mutation, but in conjunction with the 5T allele it often produces a clinical picture of CF with pancreatic sufficiency. Login to comment
20 However, the consensus panel determined that neither R117H alone, nor the presence of the 5T allele alone, is a CF mutation. Login to comment

PMID: 10837612 [PubMed] Alton E et al: "Cystic fibrosis clinical trials."

No. Sentence Comment

77 The chloride conductance of R347P and ments include the cDNA with appropriate promoter, R117H mutant CFTR has been assessed in vitro, and linked to a gene transfer agent (GTA). Login to comment
79 Thus patients promoters such as SV40, CMV and RSV, although who are R347P/delta F508 or R117H/delta F508 whether these function with equal efficiency in compound heterozygotes should demonstrate approx- differing cell types is far from clear. Login to comment

PMID: 9476862 [PubMed] Rubenstein RC et al: "A pilot clinical trial of oral sodium 4-phenylbutyrate (Buphenyl) in deltaF508-homozygous cystic fibrosis patients: partial restoration of nasal epithelial CFTR function."

No. Sentence Comment

169 Other mutations that affect channel conductance, but not CFTR trafficking, (25) such as R117H (substitution of histidine residue at position 117 for an arginine), are often present in CF patients with clinically mild lung disease and pancreatic sufficiency. Login to comment
170 We have examined the NPD of one such patient (genotype Ȳc;F508-R117H) who is pancreatic sufficient and has an elevated sweat chloride concentration. Login to comment
184 It is possible, even though R117H and A455E are both partially functional CFTR mutations, that their interactions with other (as yet undetermined) cellular constituents might differ, and thereby alter NPD responses. Login to comment
194 Patients with mutations that decrease, but do not eliminate, CFTR activity such as R117H, have elevated sweat chloride concentrations characteristic of CF, but are typically pancreatic sufficient and have relatively mild lung disease (25). Login to comment
195 In the Johns Hopkins Hospital Cystic Fibrosis Center, there are two patients with genotype R117H/⌬F508. 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

58 Class IV mutations result in a reduction in the amount of chloride current (e.g., R117H, R347P, S1251N mutations) while class V mutations result in a reduction in the amount of a normally functioning CFTR protein (e.g., A455E, 3849ϩ10kbC3T mutations). Login to 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
60 Class IV mutations result in a reduction in the amount of chloride current (e.g., R117H, R347P, S1251N mutations) while class V mutations result in a reduction in the amount of a normally functioning CFTR protein (e.g., A455E, 3849110kbC3T 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: 9755815 [PubMed] Meschede D et al: "Genetic diseases of the seminal ducts."

No. Sentence Comment

63 AF.508 and R117H are the two most prevalent CFTR mutations among Caucasians with CBAVD. Login to comment
64 While AF508 is a "severe" mutation, R117H can be classified with the "mild" ones. Login to comment
71 Along with AF508/R117H the AF508/T5 genotype is the most common one among CBAVD patients [6, 161. Login to comment
65 While AF508 is a "severe" mutation, R117H can be classified with the "mild" ones. Login to comment
72 Along with AF508/R117H the AF508/T5 genotype is the most common one among CBAVD patients [6, 161. 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
58 As the level of CFTR mRNA lacking exon 9 are determined by the variation at locus IVS8(T)n, the mutation R117H can cause CF with pancreatic sufficiency (CF-PS) or obstructive azoospermia, depending on the polyT allele of intron 8 that is associated (5T in CF-PS and 7T in CBAVD) (Kiesewetter et al. 1993). 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: 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: 9374552 [PubMed] Fanen P et al: "Cystic fibrosis phenotype associated with pancreatic insufficiency does not always reflect the cAMP-dependent chloride conductive pathway defect. Analysis of C225R-CFTR and R1066C-CFTR."

No. Sentence Comment

4 Immunoprecipitation and functional studies showed that cells transfected with C225R-CFTR exhibit cAMP-dependent chloride fluxes; C225R-CFTR protein is poorly expressed but fully glycosylated and can be compared with R117H-CFTR. Login to comment
23 Three mutants, C225R, R1066C, and R117H, were constructed. Login to comment
57 RESULTS Three mutated CFTR proteins (C225R-, R1066C-, and R117H-CFTR) and wild-type CFTR were transiently expressed in HeLa cells and analyzed at the mRNA, protein, and functional levels. Login to comment
58 Wild-type and R117H-CFTR were used as controls since both proteins are processed to the plasma membrane and function as cAMP-regulated chloride channels (3, 11). Login to comment
63 A, Northern blot analysis; B, immunoprecipitation assay using mAb 24-1 (Genzyme) of mock-transfected HeLa cells expressing wild-type and mutant CFTRs without (left panel) and with (right panel) sodium butyrate treatment at the same exposure time; C, immunoprecipitation assay of R1066C- and ⌬F508-transfected cells grown at 26 or 37 °C. TABLE I Summary of the MEQ assay results Cell type Wild-type R117H C225R R1066C C225R ϩ NaBd R1066C ϩ NaBd pECE All responding 60 (30)a 9 (16)a 8 (8)a 0 11 (22)a 0 0 Fast 30 (50)b 3 (33)b 0 0 3 (27)b 0 0 ⌬Fstim/⌬Fbasal 13.5 Ϯ 6.8c 8 Ϯ 1.7c 22.3 Ϯ 7.1c Range 6-27 6-9 16-30 Slow 30 (50)b 6 (66)b 8 (100)b 0 8 (73)b 0 0 ⌬Fstim/⌬Fbasal 3.4 Ϯ 1.0c 2.4 Ϯ 0.5c 2.9 Ϯ 1.4c 3.4 Ϯ 1.0c Range 2-5 2-3 1.5-5 1.5-5 Total 200 56 100 100 50 50 60 a Percentage of all cells. Login to comment
66 Fig. 1B shows that the fully processed form of wild-type CFTR protein was detected in HeLa cells as a diffuse band of approximate molecular mass of 170 kDa (band C) and that the core-glycosylated form appeared as a thin band of about 140 kDa (band B) on 5% SDS-PAGE; the pattern was almost identical for R117H-CFTR. Login to comment
70 The intensity of bands C and B of wild-type, R117H- and C225R-CFTR increased markedly, and the ratio of bands C/B was similar in treated wild-type, R117H-, and C225R-CFTR cells. Login to comment
80 Similar results were obtained with R117H-transfected cells (33% being fast responsive and 66% slow responsive cells) supporting the immunoprecipitation data, which suggested that wild-type and R117H-CFTR activate a cAMP-regulated chloride pathway. Login to comment
84 To determine if increased protein synthesis influenced the function of the C225R and R1066C mutants, we pretreated cells with 5 mM sodium butyrate for 18-20 h. R117H- and wild-type-CFTR were not tested since they were fully responsive in untreated conditions. Login to comment
93 A, HeLa cells transfected with wild-type (WT) CFTR, R117H-CFTR, or pECE (⌬Fstim/⌬Fbasal ϭ 21 for WT fast, 2 for WT slow, 6 for R117H, and 1 for pECE). Login to comment
96 CFTR Mutations Associated with Pancreatic Insufficiency atUniversityofNorthCarolinaatChapelHill,onOctober25,2012www.jbc.orgDownloadedfrom DISCUSSION We analyzed the structure-function relationships of two mutations, C225R and R1066C, that we had identified in CF patients with pancreatic insufficiency (6) and compared the properties of those mutations with those of wild-type-CFTR and R117H-CFTR. Login to comment
101 Six CF-associated mutations (P99L, R117H, P205S, R334W, R347P, and R347H) located in putative membrane-spanning domains that have already been analyzed for their functional properties (2-5) were all associated with a mild phenotype (pancreatic sufficiency, PS). Login to comment
105 The processing of C225R-CFTR resembles that of R117H-CFTR. Login to comment
107 Both mutants are associated with mild lung disease, but R117H is associated with PS whereas C225R is associated with PI. 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
26 It is common among men with CBAVD (De Braekeleer and Fe´rec 1996) and may here, Letters to the Editor Table 1 Summary of Mutation Analysis in CFTR Gene in 16 Men with IASV and in 7 Men with BEDO Diagnosis CFTR Genotypea T5/T7/T9 IASV ϩ/ϩ 7/7 IASV ϩ/ϩ 7/7 IASV ϩ/ϩ 7/7 IASV ϩ/ϩ 7/7 IASV ϩ/ϩ 7/7 IASV ϩ/ϩ 7/7 IASV ϩ/ϩ 7/9 IASV ϩ/ϩ 7/7 IASV ϩ/ϩ 7/7 IASV ϩ/ϩ 7/7 IASV ϩ/ϩ 7/7 IASV ϩ/ϩ 5/7 IASV ϩ/ϩ 7/7 IASV ϩ/ϩ 7/7 IASV I1139V/ϩ 7/9 IASV ϩ/ϩ 7/7 BEDO DF508/ϩ 9/5 BEDO DF508/R117H 9/7 BEDO ϩ/ϩ 7/9 BEDO DF508/R117H 9/7 BEDO R553X/ϩ 7/5 BEDO R347P/ϩ 7/7 BEDO DF508/ϩ 9/5 a A plus sign (ϩ) denotes the wild-type allele (i.e., no mutation was detected). Login to comment
33 Compound heterozygosity for DF508/R117H was detected in two patients, for DF508/T5 in another two, and for R553X/ T5 in one. Login to comment
36 His father carries the DF508 mutation, and his mother carries the R117H mutation, proving that in the index patient the two mutations are in the trans phase. Login to comment
44 R117H and the T5 allele are rarely found in full-blown CF, but they contribute to a major degree to the molecular pathology underlying both CBAVD (De Braekeleer and Fe´rec 1996) and BEDO with concomitant seminal-vesicle anomalies. 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
25 It is common among men with CBAVD (De Braekeleer and Fe &#b4;rec 1996) and may here, Letters to the Editor Table 1 Summary of Mutation Analysis in CFTR Gene in 16 Men with IASV and in 7 Men with BEDO Diagnosis CFTR Genotypea T5/T7/T9 IASV af9;/af9; 7/7 IASV af9;/af9; 7/7 IASV af9;/af9; 7/7 IASV af9;/af9; 7/7 IASV af9;/af9; 7/7 IASV af9;/af9; 7/7 IASV af9;/af9; 7/9 IASV af9;/af9; 7/7 IASV af9;/af9; 7/7 IASV af9;/af9; 7/7 IASV af9;/af9; 7/7 IASV af9;/af9; 5/7 IASV af9;/af9; 7/7 IASV af9;/af9; 7/7 IASV I1139V/af9; 7/9 IASV af9;/af9; 7/7 BEDO DF508/af9; 9/5 BEDO DF508/R117H 9/7 BEDO af9;/af9; 7/9 BEDO DF508/R117H 9/7 BEDO R553X/af9; 7/5 BEDO R347P/af9; 7/7 BEDO DF508/af9; 9/5 a A plus sign (af9;) denotes the wild-type allele (i.e., no mutation was detected). Login to comment
32 Compound heterozygosity for DF508/R117H was detected in two patients, for DF508/T5 in another two, and for R553X/ T5 in one. Login to comment
35 His father carries the DF508 mutation, and his mother carries the R117H mutation, proving that in the index patient the two mutations are in the trans phase. Login to comment
43 R117H and the T5 allele are rarely found in full-blown CF, but they contribute to a major degree to the molecular pathology underlying both CBAVD (De Braekeleer and Fe &#b4;rec 1996) and BEDO with concomitant seminal-vesicle anomalies. Login to comment

PMID: 9328474 [PubMed] Mak V et al: "Higher proportion of intact exon 9 CFTR mRNA in nasal epithelium compared with vas deferens."

No. Sentence Comment

80 For instance, the R117H mutation is associated with pancreatic-sufficient CF (CF-PS) (28). Login to comment
82 Not surprisingly, the mild R117H mutation has been identified in otherwise healthy males with CBAVD. Login to comment
83 However, further genetic analysis uncovered that individuals heterozygous for the R117H mutation on a 5T background (i.e., R117H and 5T on the same chromosome) and a 'severe` CFTR mutation (e.g., ∆F508, G551D) developed lung disease characteristic of CF, whereas the R117H mutation found in CBAVD men is associated exclusively with the more efficient splice acceptor 7T (i.e., R117H and 7T on the same chromosome) (23). Login to comment
84 It is also important to note that the R117H mutation gives rise to a partially functional CFTR protein (30). Login to comment
85 Therefore, the R117H/5T allele results in a low enough level of partially functioning CFTR in the lung and an even lower level in the reproductive tract such that both organs are affected. Login to comment
86 In contrast, the R117H/7T allele, although producing a sufficient level of partially functional CFTR in the lung to prevent disease, the lower level in the genital ducts results in characteristic pathologic changes. Login to comment
87 Therefore, the R117H/5T allele results in a low enough level of partially functioning CFTR in the lung and an even lower level in the reproductive tract such that both organs are affected. Login to comment
88 In contrast, the R117H/7T allele, although producing a sufficient level of partially functional CFTR in the lung to prevent disease, the lower level in the genital ducts results in characteristic pathologic changes. Login to comment

PMID: 9511929 [PubMed] Devidas S et al: "CFTR: domains, structure, and function."

No. Sentence Comment

41 For example, the Rl 17Hmutation,a missense substitution of a histidine for an arginine at position 117,is associated with mild pancreatic disease (Carroll et al., 1995b). Login to comment
42 The R117H mutation is a semiconservative change which preserves some positive charge in the residue immediately preceding the second proposed membrane-spanning segment of the first transmembrane domain of CFTR. Login to comment
44 Table I shows that the R117H mutation reduces both single-channel conductance and channel open probability without affecting channel selectivity. Login to comment
54 A119CFTR (the first 118 amino acids were deleted creating the next functional methionine at Met150 ), and MIV-M150V (both methionines at positions 1and 150 were Table I. Single Channel Characteristics of CFTR Channelsin Oocytes PS WT R117H 9.3 ±0.4(4) 6.5 ±0.5(4)* Po 0.65 ±0.02(7) 0.49±0.01(7)* Selectivity Br > Cl > I(4:3) Br > Cl > 1(5:4) * Denotes significantly different from wild type (WT). Login to comment
84 The mutant R117H, where a change in amino acid occurs in the first putative exofacial loop of CFTR, and all of the truncation mutants when activated by PKA and ATP have reduced open probabilities compared to wild type. Login to comment
87 This would explain why a mutation in an exofacial residue such as in the R117H mutation could affect processes of gating normally associated with intracellular domains. Login to comment

PMID: 9379167 [PubMed] Tabcharani JA et al: "Halide permeation in wild-type and mutant cystic fibrosis transmembrane conductance regulator chloride channels."

No. Sentence Comment

21 Mutations in CFTR that cause it to be mislocalized (i.e., ⌬F508) or unresponsive (i.e., G551D) are associated with severe forms of cystic fibrosis, whereas mutations that only partially reduce CFTR conductance (R347P,H, Sheppard et al., 1993; Tabcharani et al., 1993), open probability (R117H, Sheppard et al., 1993; Becq et al., 1994; intracellular loop IV mutants, Seibert et al., 1996), or processing (A455E, Sheppard et al., 1995) are associated with milder symptoms. Login to comment
24 Mutations in CFTR that cause it to be mislocalized (i.e., DF508) or unresponsive (i.e., G551D) are associated with severe forms of cystic fibrosis, whereas mutations that only partially reduce CFTR conductance (R347P,H, Sheppard et al., 1993; Tabcharani et al., 1993), open probability (R117H, Sheppard et al., 1993; Becq et al., 1994; intracellular loop IV mutants, Seibert et al., 1996), or processing (A455E, Sheppard et al., 1995) are associated with milder symptoms. 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, Ƞ6;F508/R117H, G551D/G551D) [12]. Login to comment
123 All, however, were pancreatic insufficient and were colonized by Pseudomonas spp. The only two pancreatic sufficient subjects were those who also showed the two highest values for chloride secretion ( genotypes A455E/∆F508 and R117H/∆F508). 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

7 Twenty-one German CAVD patients were compound heterozygous for ∆F508 and R117H, which was the most frequent CAVD genotype in our study group. Login to comment
8 Haplotype analysis indicated a common origin for R117H in our population, whereas another frequent CAVD mutation, viz. the "5T allele" was a recurrent mutation on different intragenic haplotypes and multiple ethnic backgrounds. Login to comment
43 This initial screening included the mutations ∆F508, G542X, R553X, G551D, N1303K, 1717-1 G→A, 3272-26 A→G, Y1092X, 2143delT, R347P, R347H, R334W, I336K, R117H, R117C, 2789+5 G→A, 3849+10kB C→T and the "5T" allele, the latter two splice variants being tested according to the instructions of Highsmith et al. (1994) and Chillón et al. (1995). Login to comment
56 Two CF mutations (∆F508 and R117H) and one splicing variant (the "5T" allele) were found to be particularly common in these patients. Login to comment
58 Missense substitution R117H was identified on 24 chromosomes (11%), which is an approximately 30-fold increase in allele frequency compared with German CF chromosomes (Dörk et al. 1994b). Login to comment
59 This frequency of R117H seems to be the highest number reported so far in a patient subpopulation and confirms a particular association of R117H with the CAVD phenotype in Mid-Europe (Gervais et al. 1993). Login to comment
60 All the R117H alleles were from patients of German or Austrian descent and carried the same diagnostic marker haplotype composed of four intragenic dimorphisms and the 7T allele (Table 1). Login to comment
61 This haplotype is otherwise rare on normal or CF chromosomes and accounts for less than 0.5% in the German population, suggesting a common origin of the R117H mutation, which occurs at a CpG dinucleotide, in Mid-European populations. Login to comment
68 Screening for the three mutations ∆F508, R117H and "5T" together allowed the identification of some 40% of mutations in our CAVD cohort. Login to comment
86 The V938G substitution was identified in two unrelated patients, one homozygote with unilateral ab- 368 Table 1A Frequency distribution and haplotypes of CFTR mutations in 106 CAVD patients Mutationa Nucleotide changesb Locationc Frequencyd Haplotypee Referencef 174delA deletion of A at 174 exon 1 1 D3 This study E56K G→A at 298 exon 3 1 B3 This study D58N G→A at 304 exon 3 1 C2 This study D110H G→A at 460 exon 4 2 C2 Dean et al. (1990) R117H G→A at 482 exon 4 24 B6 Dean et al. (1990) A120T G→A at 490 exon 4 1 n.p. Chillón et al. (1994) ̃L138 insertion of CTA after 546 exon 4 1 A2 This study L206W T→G at 749 exon 6a 1 B8 Claustres et al. (1993) M265R T→G at 926 exon 6b 1 A2 Schwarz et al. (pers. comm.) R297W C→T at 1021 exon 7 1 C2 This study 1078delT deletion of T at 1078 exon 7 1 C2 Claustres et al. (1992) R334W C→T at 1132 exon 7 1 B1 Gasparini et al. (1991) R334L G→T at 1133 exon 7 1 D3 This study I336K T→A at 1139 exon 7 1 A2 Cuppens et al. (1993) R347H G→A at 1172 exon 7 3 D1 Cremonesi et al. (1992) L375F A→C at 1257 exon 8 1 B3 Jézéquel et al. (1996) ∆F508 deletion of 3 bp between 1652-1655 exon 10 57 B1 Kerem et al. (1989) G542X G→T at 1756 exon 11 2 B1 Kerem et al. (1990) R553X C→T at 1789 exon 11 1 A4 Cutting et al. (1990) L568F G→T at 1836 exon 12 1 B3 This study 2184insA insertion of A at 2184 exon 13 1 D3 Dörk et al. (1994b) 2789+5 G→A G→A at 2789+5 intron 14b 4 D3 Highsmith et al. (1997) R933S A→T at 2931 exon 15 1 n.p. Login to comment
137 Complex alleles are indicated a One CF allele with R75X and 125G→C b One CBAVD allele with R75Q and R933S c One CBAVD allele with 5T and Q1352H d Two CF alleles with F508C and S1251N e One CF allele with 1716G→A and L619S f G576A and R668C were linked on two CBAVD and three CF alleles, whereas two additional CF alleles carried R668C together with the 3849+10kB C→T mutation (Dörk and Stuhrmann 1995) 371 Table 3 CFTR mutation genotypes in 106 males with CAVD Genotype PolyT Frequency Ethnic descent Diagnosis ∆F508/R117H 9/7 21 German, Austrian 20 CBAVD, 1 CUAVD ∆F508/5T 9/5 9 German, Austrian 8 CBAVD, 1 CUAVD ∆F508/F508C 9/7 3 German CBAVD ∆F508/R347H 9/9 2 German CBAVD ∆F508/1716 G→A 9/7 2 German CBAVD ∆F508/3272-26 A→G 9/7 2 German CBAVD ∆F508/E56K 9/7 1 German CBAVD ∆F508/M265R 9/7 1 German-Portuguese CBAVD ∆F508/R334W 9/9 1 German CBAVD ∆F508/T351S 9/9 1 German CBAVD ∆F508/L375F 9/7 1 Volga German CBAVD ∆F508/G576A & R668C 9/7 1 German CBAVD ∆F508/R933S 9/7 1 German CBAVD ∆F508/L997F 9/9 1 German CBAVD ∆F508/Y1032C 9/7 1 German CBAVD ∆F508/D1152H 9/7 1 German CBAVD ∆F508/K1351E 9/7 1 German CBAVD ∆F508/D1377H 9/7 1 Portuguese CBAVD ∆F508/L1388Q 9/7 1 German CBAVD ∆F508/unknown 9/7 4 German 3 CBAVD, 1 CUAVD 5T/5T 5/5 2 German CBAVD 5T/G542X 5/9 2 German, Turkish CBAVD 5T/D58N 5/7 1 Lebanese CBAVD 5T/̃L138 5/7 1 German-Polish CBAVD 5T/1078delT 5/7 1 German CBAVD 5T/R553X 5/7 1 German CBAVD 5T/2184insA 5/7 1 Turkish CBAVD 5T/D979A 5/7 1 Vietnamese CBAVD 5T/D1152H 5/7 1 Turkish CBAVD 5T/3659delC 5/7 1 German CBAVD 5T/S1235R 5/7 1 Greek CBAVD 5T/W1282X 5/7 1 German CBAVD 5T & Q1352H/ R297W & Q1352H 5/7 1 Vietnamese CBAVD 5T/unknown 5/7 1 German CBAVD R117H/L206W 7/9 1 German CBAVD R117H/2789+5 G→A 7/7 1 German CBAVD R117H/unknown 7/7 1 German CBAVD 2789+5 G→A/2789+5 G→A 7/7 1 Lebanese CBAVD 2789+5 G→A/L973F 7/7 1 German CBAVD V938G/V938G 7/7 1 Greek CBAVD V938G/174delA 7/7 1 German CBAVD D110H/D110H 7/7 1 Turkish CBAVD R334L/I336K 7/7 1 German CBAVD R347H/N1303K 9/9 1 German CBAVD L568F/D1152H 7/7 1 Turkish CBAVD 3272-26 A→G/V1153E 7/7 1 German CBAVD R75Q/unknown 7/7 1 German CBAVD A120T/unknown 9/7 1 German CBAVD 1716G→A/unknown 7/7 1 German CBAVD G576A & R668C/unknown 7/7 1 German CBAVD 2752-15 C→G/unknown 7/7 1 Iranian CBAVD Unknown/unknown 17 German, Turkish 7 CBAVD and 1 CUAVD without observed renal agenesis, 9 CBAVD with renal agenesis allele and the R297W mutation on a homozygous Q1352H background may then reduce CFTR function to a disease-causing level. Login to comment
144 Lung function tests indicated initial pulmonary deterioration in a few cases (FEV1 forced expiratory volume in 1 s, given as percent predicted) Subject Age Genotype Height Weight Sweat C1- Symptoms (years) (cm) (kg) (mM) 1 33 ∆F508/R117H 172 75 46 Dyspnoe 2 37 ∆F508/R117H 178 83 31 Nasal polyposis 3 31 ∆F508/R117H 181 91 n.d. Nasal polyposis 4 32 R117H/unknown 164 70 33 Recurrent infections 5 33 ∆F508/E56K 193 100 85 Sinusitis, recurrent bronchitis 6 31 ∆F508/M265R 192 112 59 Recurrent infections, pancreatitis 7 33 ∆F508/R334W 182 78 n.d. Recurrent infections, pneumonia 8 28 ∆F508/R347H n.d. n.d. n.d. Recurrent infections 9 32 ∆F508/F508C 192 98 32 Pneumonia 10 34 ∆F508/Y1032C n.d. n.d. n.d. Recurrent bronchitis 11 33 ∆F508/3272-26 A→G 172 82 125 Recurrent infections, maldigestion, FEVI 73% 12 28 ∆F508/unknown 185 95 n.d. Login to comment
152 By far the most frequent CAVD genotype in our population was the ∆F508/R117H genotype that was present in every fifth German male presenting with CBAVD. Login to comment
177 Two further CAVD missense mutations, viz. R117H and R347H, have been thoroughly studied in vitro and both were shown to result in a pH-sensitive decrease of chloride conductance (Sheppard et al. 1993; Tabcharani et al. 1993). Login to comment
186 Severe disease results when additional mild mutations such as R117H occur in cis on a "5T" allele in certain populations (Kiesewetter et al. 1993) and the joint effect of both mutations strongly supports the view of CBAVD as representing a partial form of CF. Login to comment
195 Previous studies have reported few homozygous CBAVD patients for mutations R117H, D1152H and "5T" (Costes et al. 1995; Rave-Harel et al. 1995; Zielenski et al. 1995). Login to comment
202 Thus, there seem to be two classes of mild CFTR mutations in males: those that primarily target the male genital tract (e.g. R117H, "5T", D1152H) and those that may leave the vas deferens patent but exert deleterious effects at a more advanced age and lead to late-onset disease of the pulmonary tract, as is often observed for the 3849+10kb C→T mutation. 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
76 So far only cases of 4pAll six were tested; three were found to be compound hetero-and 9p trisomies have been reported in children of parentszygotes, one with genotype Delta F508/R117H, one with with centric fission of chromosomes no. 4 and no. 9. Login to comment
77 Janke1717-1 ⇒A/R117H and one with Delta F508/5T. 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
80 So far only cases of 4p All six were tested; three were found to be compound hetero-and 9p trisomies have been reported in children of parents zygotes, one with genotype Delta F508/R117H, one with with centric fission of chromosomes no. 4 and no. 9. Janke 1717-1 d2;A/R117H and one with Delta F508/5T. Login to comment

PMID: 9271620 [PubMed] Kerem E et al: "A missense cystic fibrosis transmembrane conductance regulator mutation with variable phenotype."

No. Sentence Comment

146 The 5T allele is associated with the lowest levels of normal splicing of exon 9, and high levels of exon 9 skipping leading to a nonfunctional chloride channel.32 Furthermore, the 5T allele was shown to affect the disease severity of patients carrying the mutation R117H.33 In patients carrying the R117H mutation when the allele also contained the 5T variant the phenotype was mild CF, whereas in patients carrying R117H together with the 7T variant the phenotype was male infertility only. Login to comment

PMID: 9191467 [PubMed] Davies JC et al: "CFTR gene transfer reduces the binding of Pseudomonas aeruginosa to cystic fibrosis respiratory epithelium."

No. Sentence Comment

95 Twelve patients were homozygous for the dF508 mutation, six were compound heterozygotes with two identified mutations (d/G542X X 3, d/R347P, d/R117H, d/1717), 11 were heterozygous for dF508 with an unknown mutation, and in 3, the genotype was unknown. Login to comment

PMID: 9164776 [PubMed] Gregg RG et al: "Newborn screening for cystic fibrosis in Wisconsin: comparison of biochemical and molecular methods."

No. Sentence Comment

52 Polyacrylamide gel electrophoresis of PCR-amplified DNA served to identify the ⌬F508 mutation.14 Mutations S549N, R553X, and G551D were screened by PCR amplification of exon 11, followed by restriction enzyme digests that are diagnostic of each mutation. Login to comment
57 Mutations, G542X, W1282X, R117H, R553X, N1303K, 1717-1G3A, R560T, and 621ϩ1G3T were analyzed by the ARMS procedure using published primers and conditions.18 A total of 360 patients were studied by multimutation analysis (80% of the Wisconsin CF population). Login to comment
123 Tested) Frequency (%) Theoretical Cumulative Detection† (%) Patients Missed in One Year‡ ⌬F508§ 513/720 71.25 91.74 1.32 G542X 17/162 3.02 93.38 1.05 W1282X 7/102 1.97 94.36 0.90 R117H 6/101 1.71 95.14 0.77 R553X 11/197 1.61 95.82 0.66 G551D 9/195 1.33 96.35 0.58 N1303K 3/100 0.86 96.67 0.53 1717 - 1G 3 A 2/99 0.58 96.88 0.49 R560T 2/106 0.54 97.06 0.47 621 ϩ 1G 3 T 3/163 0.53 97.25 0.44 S549N 0/196 0.0 97.25 0.44 * Chromosomes were analyzed on blood or cheek cell specimens obtained from 360 patients (80% of the total Wisconsin CF population), all of whom had a positive sweat test. Login to comment
152 DNA Analysis of Genotyped CF Patients in the US* n Percent ⌬F508 12701 67.7 G542X 403 2.2 G551D 357 1.9 W1282X 240 1.3 N1303K 223 1.2 R553X 157 0.8 3849 ϩ 10kbC 3 T 102 0.5 621 ϩ 1G 3 T 147 0.8 1717 - 1G 3 A 101 0.5 R117H 101 0.5 R334W 36 0.2 ⌬I507 42 0.2 R347P 37 0.2 R560T 23 0.1 R1162X 44 0.2 2789 ϩ 5G 3 A 25 0.1 A455E 16 0.1 3120 ϩ IG 3 A 14 0.0 S549N 12 0.0 711 ϩ IG 3 T 9 0.0 Other 178 0.9 Unidentified 3814 20.3 Total 18782 99.7† Patient Genotypes Allele 1/Allele 2 n % of Genotype ⌬F508/⌬F508 4573 48.7 ⌬F508/Known 1511 16.1 ⌬F508/Unknown 2044 21.8 Known/unknown 310 3.3 Known/known 223 2.4 Unknown/unknown 730 7.8 Total 9391 100.0 *Data from Cystic Fibrosis Registry, 1995; Annual Report. Login to comment
118 Tested) Frequency (%) Theoretical Cumulative Detectionߤ (%) Patients Missed in One Yearߥ DF508&#a7; 513/720 71.25 91.74 1.32 G542X 17/162 3.02 93.38 1.05 W1282X 7/102 1.97 94.36 0.90 R117H 6/101 1.71 95.14 0.77 R553X 11/197 1.61 95.82 0.66 G551D 9/195 1.33 96.35 0.58 N1303K 3/100 0.86 96.67 0.53 1717 2 1G 3 A 2/99 0.58 96.88 0.49 R560T 2/106 0.54 97.06 0.47 621 1 1G 3 T 3/163 0.53 97.25 0.44 S549N 0/196 0.0 97.25 0.44 * Chromosomes were analyzed on blood or cheek cell specimens obtained from 360 patients (80% of the total Wisconsin CF population), all of whom had a positive sweat test. Login to comment
147 DNA Analysis of Genotyped CF Patients in the US* n Percent DF508 12701 67.7 G542X 403 2.2 G551D 357 1.9 W1282X 240 1.3 N1303K 223 1.2 R553X 157 0.8 3849 1 10kbC 3 T 102 0.5 621 1 1G 3 T 147 0.8 1717 2 1G 3 A 101 0.5 R117H 101 0.5 R334W 36 0.2 DI507 42 0.2 R347P 37 0.2 R560T 23 0.1 R1162X 44 0.2 2789 1 5G 3 A 25 0.1 A455E 16 0.1 3120 1 IG 3 A 14 0.0 S549N 12 0.0 711 1 IG 3 T 9 0.0 Other 178 0.9 Unidentified 3814 20.3 Total 18782 99.7ߤ Patient Genotypes Allele 1/Allele 2 n % of Genotype DF508/DF508 4573 48.7 DF508/Known 1511 16.1 DF508/Unknown 2044 21.8 Known/unknown 310 3.3 Known/known 223 2.4 Unknown/unknown 730 7.8 Total 9391 100.0 *Data from Cystic Fibrosis Registry, 1995; Annual Report. Login to comment

PMID: 9150159 [PubMed] Macek M Jr et al: "Identification of common cystic fibrosis mutations in African-Americans with cystic fibrosis increases the detection rate to 75%."

No. Sentence Comment

39 Mutation Analysis All patients were screened for the AF508 mutation and 15 common Caucasian CF mutations using a reverse dot strip hybridization system (Kawasaki et al. 1993) (R117H, 621+1G--T, R334W, R347P, A455E, A1507, 1717-1G-+A, G542X, S549N, GSS1D, R553X, R560T, 3849+10kbC-+T, W1282X, and N1303K) (Welsh et al. 1995) and a deep intron 11 splice-site mutation, 1811+1.6kbA-+G (Chillon et al. 1995). Login to comment
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

22 In comparison, the rate of R334W, 3849ϩ10 kb C→T, R117H, R347H and poly-T allelic congenital chromosomal abnormalities in newborns is 0.5% variants in intron 8. Login to comment
62 Results and importance of molecular genetic examinations of cystic fibrosis transmembrane regulator (CFTR) mutations Mutation detection Female Male Clinical findings Remaining risk for Couple number Nationality rate (%)a mutations mutations in the male CF/CBAVD I German 82 -/- dF508/dF508 CBAVD & CF 1:280 II German 82 -/- dF508/R347H CBAVD 1:280 III German 82 dF508/- R117H/- CBAVD 1:4 IV Turkish 32 -/- R117H/- CBAVD 1:150 V Turkish 32 -/- -/- CBAVD 1:5400 VI Italian 63 -/- -/- CBAVD 1:34 300 aThe percentage indicates the frequency of the identified mutations in the reference population, based on the difference in the distribution of CFTR mutations in different populations (according to the frequencies published by the Cystic Fibrosis Genetic Analysis Consortium, 1994). 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: 9068292 [PubMed] Wallis C et al: "Diagnosing cystic fibrosis: blood, sweat, and tears."

No. Sentence Comment

29 Pancreatic insuYciency appears to correlate with diVerent gene mutations at the CFTR locus21 (for example R117H, R334W, R347P, P574H), but to date there has not been a satisfactory correlation between a high chloride conduction (that is a high sweat test result )22 or severe pulmonary disease and genotyping.23 The most surprising finding to emanate from the numerous phenotype-genotype correlation studies that festoon the cystic fibrosis literature, is a new understanding of the wide phenotypic range that an individual, homozygous for a mutation in the CFTR gene, can present. Login to comment

PMID: 9401006 [PubMed] Shrimpton AE et al: "Cystic fibrosis mutation frequencies in upstate New York."

No. Sentence Comment

84 % Comment 3 G85E 1 1 0.5 4 R117H 1 1 0.5 i4 621 + 1,G>T 1 2 3 1.5 5 711 + 1,G>T 1 1 0.5 6b N287Y 1 1 0.5 Novel 7 1154insTC 2 2 1.0 8 1259insA 1 1 0.5 Novel 9 A455E 1 1 0.5 10 Delta F508 109 39 148 74.0 10 1609delCA 1 1 0.5 Spanish i10 1717-1,G>A 3 3 1.5 11 G542X 2 1 3 1.5 11 G551D 3 3 1.5 11 R553X 4 4 2.0 i12 1898+1,G>A 2 2 1.0 13 2143delT 1 1 0.5 13 2184delA+G>A 1 1 0.5 i14 2789+5,G>A 2 2 1.0 17b R1070P 1 1 0.5 Novel 17b Y1092X(C>A) 2 2 1.0 French Canadian (Rozen et al., 1992) 17b CF?20kbdel 14b-18 1 1 0.5 Novel (Shrimpton and Borowitz, 1997) i19 3849+10kb,C>T 1 1 0.5 20 W1282X 2 2 0.5 Ashkenazi 21 N1303K 3 3 6 3.0 Unknown 4/144 4/56 8/200 4.0 AL. 75 and 81 mMol/L. Login to comment

PMID: 9375855 [PubMed] Casals T et al: "Missense mutation R1066C in the second transmembrane domain of CFTR causes a severe cystic fibrosis phenotype: study of 19 heterozygous and 2 homozygous patients."

No. Sentence Comment

56 The current clinical data for missense mutations derived from a relatively large number of cases are limited to a few mutations: N1303K (Osborne et al., 1992; CF genotype-phenotype Consortium 1993), R117H (CF genotype-phenotype Consortium 1993), P205S (Chillón et al., 1993), A455E (Gan et al., 1995), L206W (Desgeorges et al., 1995), R334W (Estivill et al., 1995), and G85E (Vázquez et al., 1996). 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

0 HUMAN MUTATION 10:108115 (1997) (c) 1997 WILEY-LISS, INC. HUMU 769 RESEARCH ARTICLE 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 Kenneth J. Friedman,1,2* Ruth A. Heim,2 Michael R. Knowles,3 and Lawrence M. Silverman2 1 Curriculum in Genetics, University of North Carolina, Chapel Hill, North Carolina 27154 2 Department of Pathology, University of North Carolina, Chapel Hill, North Carolina 27154 3 Department of Medicine, University of North Carolina, Chapel Hill, North Carolina 27154 Communicated by Henry A. Erlich The CFTR intron 8 variable length polythymidine tract modulates the cystic fibrosis (CF) phenotype associated with the mutation R117H. Login to comment
3 Polythymidine alleles were identified for mutations either associated with a wide range of clinical phenotypes (R117H, R347P, G85E, D1152H, R334W, 2789+5 G>A, 3849+10kb C>T), and/or located at hypermutable CpG loci (R117H, 3849+10kb C>T, R553X, R334W, S945L and R75Q). Login to comment
4 R117H was detected in cis with each of three alleles (5T, 7T, 9T) at the intron 8 locus. Login to comment
5 The novel R117H-9T association was detected in a 10-month old African-American male with borderline-to-mildly elevated sweat chloride values (~50-66 mEq/L). Login to comment
9 In summary, the 5T allele was not found in cis with CF-causing mutations besides R117H, but an elevated 5T allele frequency in variant CF patients suggests 5T may be associated with disease in some situations. Login to comment
22 The exon 4 missense mutation, R117H, has been reported on at least two different genetic backgrounds defined by a polymorphic tract of thymidines in intron 8 (Kiesewetter et al., 1993). Login to comment
25 Compound heterozygotes with the ∆F508/ R117H genotype exhibit moderate lung disease, pancreatic exocrine sufficiency, borderline-to-high sweat electrolytes, and male infertility when R117H exists in cis to a 5T allele. Login to comment
26 In contrast, an R117H in cis to a 7T may give rise to little more than male infertility (Kiesewetter, 1993). Login to comment
28 The complex genotypes responsible for the variability of CF expression associated with R117H may have a similar impact on the clinical heterogeneity seen with other CFTR mutations. Login to comment
29 The mutations R117H, R347H, ∆F508, and 384910kb C>T exist in association with more than one intron 8 allele (Dörk et al., 1994; Chillón et al., 1995), but small numbers of any particular mutation-intron 8 combination make phenotypic conclusions difficult to establish. Login to comment
39 Mutation screening was performed for R553X (Cutting et al., 1990), R334W (Gasparini et al., 1991), G85E (Zielenski et al., 1991a), S945L (Claustres et al., 1993), 3849 + 10kb C>T (Highsmith et al., 1994), R117H and R347P (Dean et al., 1990), 2789+5G>A (Highsmith et al., 1997), D1152H (Highsmith, per. Login to comment
44 R117H, R347P, D1152H, and R75Q required electrophoresis at 230 V for 5 hr in a 10% polyacrylamide gel. Login to comment
55 None of these 73 patients bear two detected CF mutations or were heterozygous for R117H. Login to comment
74 Among the 14 R117H alleles we have studied, eight were associated with the 5T allele and five were on a 7T background. Login to comment
75 In each case, the phenotype observed was concordant with the observation (Kiesewetter et al., 1993) that the shorter polythymidine tract (5T) at this locus exacerbates the symptoms secondary to R117H. Login to comment
76 We also detected one R117H allele in cis to 9T, which has not been reported previously. Login to comment
78 His genotype was ∆F508/R117H and 9T,9T. Login to comment
90 None have two identified CFTR mutations, nor are any heterozygous for R117H. Login to comment
94 Association of Selected CFTR Mutations with Intron 8 Polythymidine Alleles Chromosomes In cis with In cis with In cis with Mutation Site CpG locus 5T 7T 9T R75Qa EXON 3 Y 0 8 0 G85E EXON 3 N 0 5 0 R117H EXON 4 Y 8 5 1 R334W EXON 7 Y 0 4 0 R347P EXON 7 N 0 7 0 R553X EXON 11 Y 0 7 0 2789+5 G>A INTRON 14B N 0 5 0 S945L EXON 15 Y 0 3 0 D1152H EXON 18 N 0 7 0 3849+10kb C>T INTRON 19 Y 0 15 2 a Sequence variant. Login to comment
130 We detected one R117H allele in association with a 9T in a patient who sweated heavily, had a low serum sodium level, and had borderline to mildly elevated sweat chloride values. Login to comment
131 This R117H-9T pairing has not been previously reported, although a similar clinical situation has been described in a man with a∆F508/R117H genotype in the absence of any pulmonary disease (Smith et al., 1995). Login to comment
132 Although we determined this individual to be a 5T,9T heterozygote, the intriguing possibility remains that R117H on a 9T background may at times be associated with a clinical scenario distinct from that commonly seen when R117H is associated with either 5T or 7T. Login to comment
140 In this study, the marked variability in phenotype associated with mutations other than R117H cannot be attributed to the 5T allele. Login to comment
145 The role of the 5T allele in eliciting pulmonary symptoms when not co-inherited with R117H has been difficult to define. Login to comment
157 Thus far, only R117H has been shown to owe its phenotypic heterogeneity to the presence of the 5T and 7T alleles. Login to comment
158 The R117H-9T association we have reported here may represent an extension of this correlation. 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: 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

36 PCR Amplification and DGGE Analysis Initial screening of Asian CF patients for the 16 most common caucasian CFTR mutations (R117H, TABLE 1. Login to comment

PMID: 8918588 [PubMed] Moss RB et al: "Reduced IL-10 secretion by CD4+ T lymphocytes expressing mutant cystic fibrosis transmembrane conductance regulator (CFTR)."

No. Sentence Comment

159 Southern hybridization blots of reverse transcriptase-polymerase chain reaction (RT-PCR) products of CFTR derived from cDNAs prepared from the T84 adenocarcinoma cell line (lane 1), water control (lane 2), a F508 homozygous CF-derived CD4 T cell clone (lane 3), a R117H homozygous CF-derived CD4 T cell clone (lane 4), two normal (wild type CFTR) T cell clones (lanes 5 and 6), a neuroblastoma cell line (lane 7), the HeLa cell line (lane 8), another water control (lane 9), and CFTR plasmid (lane 10). Login to comment
281 IL-10 production by concanavalin A-activated T cell clones Group IL-10 P Cystic fibrosis, total (n 83)* 684 6116 0.05 Control, total (n 97) 1565 6401 Atopic (n 92) 672 6173 0.026 Non-atopic (n 88) 1667 6417 CF, atopic (n 34) 417 6120 0.056 CF, non-atopic (n 49) 869 6175 Control, atopic (n 58) 821 6264 0.023 Control, non-atopic (n 39) 2670 6895 Non-atopic, control (n 39) 2670 6895 0.031 Non-atopic, CF (n 49) 869 6175 Atopic, control (n 58) 821 6264 NS Atopic, CF (n 34) 417 6120 Values are pg/ml per 106 cells, mean 6s:e:m: * Includes two clones from a non-atopic individual with congenital bilateral absence of the vas deferens but not clinical CF who is homozygous for R117H CFTR alleles. Login to comment

PMID: 8947061 [PubMed] Hubert D et al: "Genotype-phenotype relationships in a cohort of adult cystic fibrosis patients."

No. Sentence Comment

118 For the two genotypes, R117H/∆F508 and N1303K/∆F508, which would be classified as Group 3, the lack of difference in pulmonary involvement might be due to a selection bias created by mortality in this cross-sectional study and/or by the young age of the patients in most groups of this study, since the mean age of all groups but one was less than 15 yrs. Login to comment

PMID: 8810276 [PubMed] Price MP et al: "Function of Xenopus cystic fibrosis transmembrane conductance regulator (CFTR) Cl channels and use of human-Xenopus chimeras to investigate the pore properties of CFTR."

No. Sentence Comment

268 Assignment of this region as an extracellular loop is based on recognition of this region by an extracellular antibody (31), by insertion of a site that becomes glycosylated (32), and by effect of external pH on the R117H variant (13). Login to comment
269 We previously found that mutation of an adjacent residue (Arg117 mutated to His) did not alter anion permeability but did decrease single channel conductance and altered the response to changes in extracellular pH (13). Login to comment
270 Our data also suggest that this region influenced the pattern of gating; hX1-6 showed a pattern of gating characterized by a shortened open time, similar to that found in the R117H mutant. Login to comment
287 Assignment of this region as an extracellular loop is based on recognition of this region by an extracellular antibody (31), by insertion of a site that becomes glycosylated (32), and by effect of external pH on the R117H variant (13). Login to comment
288 We previously found that mutation of an adjacent residue (Arg117 mutated to His) did not alter anion permeability but did decrease single channel conductance and altered the response to changes in extracellular pH (13). Login to comment
289 Our data also suggest that this region influenced the pattern of gating; hX1-6 showed a pattern of gating characterized by a shortened open time, similar to that found in the R117H mutant. Login to comment

PMID: 9239681 [PubMed] De Braekeleer M et al: "Mutations in the cystic fibrosis gene in men with congenital bilateral absence of the vas deferens."

No. Sentence Comment

65 Indeed, studies on genotype-phenotype have now shown that some mutations and/or genotypes are associated with mild phenotypes (Dean et al., 1990; Strong et al, 1991; Varon Table I. Distribution of patients with congenital bilateral absence of the vas deferens (CBAVD) according to their genotype References No. of No. of No. of compound No. of No. of Remarks patients homozygotes (HH) heterozygotes (hh) heterozygotes (h) normal (N) 1 2/3 4 5/6 7/8/9 10/11 12/13/14/29 15/16 17/18/30 19/24 20/24 21 22 23 31 32 33 TOTAL 25 26 27 28 25* 10 18 59 8** 44 33*** 36" 70 67" 28° 1 35 26d 35 26 45 572 1 4 1 1 0 0 0 0 0 0 0 3 1 1 0 0 0 0 0 0 0 5 1 3 3 1 4 3 8 6 2 8 15 3 0 5 3 1 6 15 86 1 3 1 16 2 9 27 3 23 15 13 40 28 19 5 15 7 18 14 25 279 6 5 8 28 2 13 12 18 21 23 6 2 15 16 16 6 5 202 Most common mutations in the studied population Most common mutations in the studied population Most common mutations in the studied population Most common mutations in the studied population DNA sequencing of the coding regions and the splice junctions DNA sequencing of the coding regions and the splice junctions DNA sequencing of the coding regions and the splice junctions DNA sequencing of the coding regions and the splice junctions Most common mutations in the studied population DNA sequencing of the coding regions and the splice junctions DNA sequencing of the coding regions and the splice junctions Most common mutations in the studied population Only tested for AF508 and R117H DNA sequencing of the coding regions and the splice junctions Most common mutations in the studied population Most common mutations in the studied population DNA sequencing of the coding regions and the splice junctions Case report Case report Case report Case report •Including one congenital unilateral absence of the vas deferens (CUAVD). 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: 8869353 [PubMed] Alton EW et al: "A mild variant of cystic fibrosis."

No. Sentence Comment

59 In contrast "milder" mutations such as R117H (class 4) are generally associated with pancreatic sufficiency. Login to comment

PMID: 8663098 [PubMed] Becq F et al: "cAMP- and Ca2+-independent activation of cystic fibrosis transmembrane conductance regulator channels by phenylimidazothiazole drugs."

No. Sentence Comment

34 27, Issue of July 5, pp. 16171-16179, 1996 (c) 1996 by The American Society for Biochemistry and Molecular Biology, Inc. Printed in U.S.A. MATERIALS AND METHODS Cell Culture-CHO-K1 cells that had been stably transfected with pNUT vector alone (denoted CFTR(-)) or with wild-type CFTR (CFTR(ϩ)) or various mutated versions (G551D, R347D, R117H, and ⌬F508) in pNUT were used (8, 15). Login to comment
144 Functional Response of CFTR Channels with Disease-causing Mutations-Three CFTR mutations associated with severe (⌬F508 and G551D) or mild (R117H) forms of cystic fibrosis were studied after stable transfection into CHO cells. Login to comment
149 The basic biophysical properties of ⌬F508 and R117H versions of CFTR were similar to those reported previously (11, 28, 29). Login to comment
150 R117H had a slightly lower unitary conductance and significantly reduced Po (Table I). Login to comment
163 G551D channel activity in the presence of PKA and ATP was lower than wild-type CFTR (Po ϭ 0.17 Ϯ 0.06, n ϭ 2.6 Ϯ 0.57, n ϭ 3 patches) but was nevertheless increased 2-fold by addition of bromotetramisole in the presence of PKA (Po ϭ 0.36 Ϯ 0.08, n ϭ 6.2 Ϯ 0.56, n ϭ 7 patches). Login to comment
164 Although these values for Po may be overestimated because they are based on the estimated number of channels without locking all the channels open using AMP-PNP, the increase in open probability was consistent and was also observed with the mutants R117H and R347D (data not shown). Login to comment
194 Our results can be summarized as follows: (i) levamisole and bromotetramisole promote the opening of cell-attached CFTR channels in the absence of forskolin, (ii) elevation of intracellular cAMP and Ca2ϩ are not required for this stimulation, (iii) at least four mutant CFTRs (G551D, R117H, R347D, and ⌬F508) can also be activated on-cell by these drugs in the absence of forskolin, (iv) both phenylimidazothiazoles further enhance CFTR channel activity when excised patches were exposed to high levels of PKA, indicating that their target is associated with the membrane, and (v) activation by both drugs requires some kinase activity. Login to comment
206 Frequency Control Levamisole Number of channels Po g pS CFTR 0/15 20/23 12 Ϯ 2.80 0.47 Ϯ 0.05 6.8 Ϯ 0.20 G551D 0/10 31/43 3 Ϯ 0.27 0.35 Ϯ 0.07 5.3 Ϯ 0.30 R117H 0/5 9/13 2 Ϯ 0.32 0.14 Ϯ 0.10 5.7 Ϯ 0.15 R347D 0/4 6/10 4.6 Ϯ 0.40 0.40 Ϯ 0.02 2.8 Ϯ 0.30 ⌬F508 (37 °C) 0/10 0/15 ⌬F508 (23 °C) 0/5 5/8 2.1 Ϯ 0.03 0.13 Ϯ 0.02 6.8 Ϯ 0.14 they are uncompetitive inhibitors of alkaline phosphatase (26, 31, 37). Login to comment
143 Activation of CFTR by Phenylimidazothiazole Drugs Functional Response of CFTR Channels with Disease-causing Mutations-Three CFTR mutations associated with severe (DF508 and G551D) or mild (R117H) forms of cystic fibrosis were studied after stable transfection into CHO cells. Login to comment
148 The basic biophysical properties of DF508 and R117H versions of CFTR were similar to those reported previously (11, 28, 29). Login to comment
193 Our results can be summarized as follows: (i) levamisole and bromotetramisole promote the opening of cell-attached CFTR channels in the absence of forskolin, (ii) elevation of intracellular cAMP and Ca21 are not required for this stimulation, (iii) at least four mutant CFTRs (G551D, R117H, R347D, and DF508) can also be activated on-cell by these drugs in the absence of forskolin, (iv) both phenylimidazothiazoles further enhance CFTR channel activity when excised patches were exposed to high levels of PKA, indicating that their target is associated with the membrane, and (v) activation by both drugs requires some kinase activity. Login to comment
204 Frequency Control Levamisole Number of channels Po g pS CFTR 0/15 20/23 12 6 2.80 0.47 6 0.05 6.8 6 0.20 G551D 0/10 31/43 3 6 0.27 0.35 6 0.07 5.3 6 0.30 R117H 0/5 9/13 2 6 0.32 0.14 6 0.10 5.7 6 0.15 R347D 0/4 6/10 4.6 6 0.40 0.40 6 0.02 2.8 6 0.30 DF508 (37 &#b0;C) 0/10 0/15 DF508 (23 &#b0;C) 0/5 5/8 2.1 6 0.03 0.13 6 0.02 6.8 6 0.14 Activation of CFTR by Phenylimidazothiazole Drugs they are uncompetitive inhibitors of alkaline phosphatase (26, 31, 37). 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

7 One patient carried two CF mutations (AF508/R347H), and five were found to carry one CF mutation (four AF508; one R117H). Login to comment
63 DNA samples from ABPA patients were screened for nine additional mutations associated with pancreatic sufficient and atypical CF: R117H (ASO), R347P (NcoI digest) and R347H (HhaI digest), R334W (MspI digest), A455E (ASO and BamHI digest), G551S (ASO) (Strong et al. 1991), 2789+5G-*A (ASO), D1152H (ASO) (Tsui 1992), and 3849+10kbC-*T (ASO and HphI digest) (Highsmith et al. 1994). Login to comment
103 Her baseline NPD was -45 mV, which de- 59:45-S1, 1996 Table 2 Demographics and Genotype of ABPA Patients CFTR I.D. Race CF Mutations Polymorphismsa 1 Caucasianb AFS08/R347H 2 Caucasianb -/- M470V, 129G/C 3 Caucasianb AFS08/- ... 4 African-American -/- 5 Caucasian -5-ST, M470V 6 Caucasian &FS08/- R75Q, M470V 7 Caucasian -/- M470V 8 Caucasian R117H-7T/- R75Q 9 Caucasian AFS08/- M470V 10 Caucasian AFS08/- M470V 11 Caucasian -/- ST a The 5 thymidine variant (ST) does not cause CF (Chu et al. 1992) but has been associated with the CBAVD phenotype (Chill6n et al. 1995). Login to comment
107 The R117H mutation in patient 8 was identified by DGGE and confirmed by ASO and sequencing. Login to comment
133 Furthermore, one patient was found to carry R117H-7T on one allele, a mutation associated with pancreatic sufficient CF and CBAVD (Kiesewetter et al. 1993). Login to comment
135 However, the frequency of R117H-7T in the general 49 population is believed to be low (1/160) (Kiesewetter et al. 1993). Login to comment

PMID: 8663008 [PubMed] Sheppard DN et al: "Contribution of proline residues in the membrane-spanning domains of cystic fibrosis transmembrane conductance regulator to chloride channel function."

No. Sentence Comment

215 The present results complement and extend our previous study of mild CF mutants located in MSD1 (R117H, R334W, and R347P). Login to comment
223 The present results complement and extend our previous study of mild CF mutants located in MSD1 (R117H, R334W, and R347P). Login to comment

PMID: 8661502 [PubMed] Grygorczyk R et al: "CFTR channels expressed in CHO cells do not have detectable ATP conductance."

No. Sentence Comment

15 Thus, mutations that cause mislocalization (⌬F508; [11]) or inhibit responsiveness to secretagogues (G551D; [13]) are usually associated with severe disease symptoms, whereas mutations that only partially reduce open probability (R117H; [26, 5]), single channel conductance (R347P/H; [25, 26]), or targeting to the plasma membrane (A445E; [25]) correlate with milder disease symptoms [31]. Login to comment

PMID: 8644747 [PubMed] Witt DR et al: "Cystic fibrosis heterozygote screening in 5,161 pregnant women."

No. Sentence Comment

11 The incidence of R117H mutations was much higher than expected. Login to 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
145 Unexpectedly, R117H was present in very high frequency in Caucasians and accounts for 16% of all carriers in lab group B. Login to comment
150 Seven heterozygotes were identified: 4 F508s and 1 each of R117H, 1717G-A, and R560T. Login to comment
158 The compound heterozygote identified through screening was a 36-year-old woman with the F508 and R117H mutations. Login to comment
165 Mutation analysis revealed both boys to be compound heterozygotes for G551D and R117H. Login to comment
172 Factors that potentially contributed to the high rate of acceptance in this study included incorporation of pretest education into an ex- Table 8 Results of Prenatal Diagnosis in High-Risk Pregnancies CFTR MUTATIONSa COUPLE PRENATAL DIAGNOSIS Mother Father Fetus 1 No (miscarriage) GSS1D R117H N/GSS1D (abortus) 2 No (miscarriage) F508 1717G-A NA 3 No (miscarriage) F508 RS60T NA Yes (second pregnancy) N/N 4 Yes G542X F508 N/N S Yes F508 F508 N/F508 6 Yes (twins) F508 F508 F508/F508, F508/F508 7 Yes F508 F508 N/N 8b Yes F508 NA N/F508 9b Yes N1303K NA N/N1303K a NA = not available; and N = normal. Login to comment
208 This rate is higher than anticipated, largely because of the unexpected high frequency of R117H in 16% of carriers, which represents a 16-fold increase over that seen in CF Consortium data (Tsui 1992). Login to comment
209 Because the R117H missense mutation is associated with a milder so-called pancreatic sufficient phenotype (Kristidis et al. 1992; Gervais et al. 1993), it is possible that this allele is underrepresented in the Consortium data, which is comprised of clinically diagnosed CF patients. An additional explanation is suggested by the identification ofa variable poly T region at the CFTR splice site at exon 9, which modifies the functional efficiency of the protein (Chu et al. 1993). Login to comment
210 As has been reported elsewhere (Klesewetter et al. 1993), all of the R117H heterozygotes identified in our study have the more efficient 7T region, in contrast to a group of clinically diagnosed CF patients in which ST predominates. Login to comment
211 Thus, the lower frequency of R117H in the Consortium data may be a consequence of failure to ascertain most individuals with R117H and the more efficient splicing mechanism. Login to comment
213 The presence of the R117H mutation in all three of these individuals is consistent with its mild diminution in CFTR protein expression and the potential ameliorating effect of the variable exon 9 splice site (Chu et al. 1993; Chillon et al. 1995). Login to comment
271 Med Care 29:473-489 Gervais R, Dumur V, Rigot J-M, Lafitte J-J, Roussel P (1993) High frequency of the R117H mutation in patients with congenital absence of the vas deferens. N Engl J Med 328:446-447 Gilbert F (1990) Is population screening for cystic fibrosis appropriate now? Login to comment
207 This rate is higher than anticipated, largely because of the unexpected high frequency of R117H in 16% of carriers, which represents a 16-fold increase over that seen in CF Consortium data (Tsui 1992). Login to comment
212 The presence of the R117H mutation in all three of these individuals is consistent with its mild diminution in CFTR protein expression and the potential ameliorating effect of the variable exon 9 splice site (Chu et al. 1993; Chillon et al. 1995). Login to comment
270 Med Care 29:473-489 Gervais R, Dumur V, Rigot J-M, Lafitte J-J, Roussel P (1993) High frequency of the R117H mutation in patients with congenital absence of the vas deferens. N Engl J Med 328:446-447 Gilbert F (1990) Is population screening for cystic fibrosis appropriate now? 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: 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

6 The three major CF mutations in Northern Ireland are AF508, G551D, and R117H with respective frequencies of 68.O%, 5.19/0, and 4.1%. Login to comment
45 Prior to the DGGE study a variety of methods (see Tables 1 and 2) were used to screen for CFTR mutations, including single mutation assaysfor AF508, AI507, G55lD, G542X, R553X, R117H, R560T, 621+lG>T, and 3849+10kbC>T. Login to comment
53 35%) PAGE (278) Kerem et al.. 1989AF508 G551D R117H R560T G542X 621+1G>T A1507 E60X 3659delC R553X 3120G>A 1l54insTC 2789+5G>A N1303K MlI(G>T) QW P67L 557delT 711+3A>G L206W R297Q V520F V562L Y563N Y917C R1162X 3849G>A 3849 +10kbC>T 3850-1GBA W1282X 280 21 17 12 9 9 7 3 2 1 68.0 5.1 4.1 2.9 2.2 2.2 1.7 0.7 0.5 0.24 17-32-13 (38;27%j 17-31-13(24,17%) 16-07-17 16-30-13 plus14 rare haplotypes (29) 16-07-17 23-33-13 (4) 22-31-13 (2) 21-31-13 17-07-17 (5) 16-31-13 16-35-13 17-58-13 17-35-13 16-07-17 17-07-17 23-29-13 (1) 23-31-13 (1) 16-07-17 16-31-13 16-07-17 15-29-13 16-33-13 16-07-17 17-07-17 16-07-17 16-07-17 16-30-13 16-32-17 17-31-13 16-31-14 16-46-13 16-30-14 17-07-17 DGGE(2) ' RD ASO's (11) DGGE(6) RD AR (8) DGGE (1) RD PAGE (5) DGGE (2) SEQ SEQ (2) DGGE (1) RD DGGE DGGE DGGE SEQ DGGE DGGE DGGE SEQ DGGE DGGE SEQ DGGE DGGE DGGE DGGE DGGE SEQ RD DGGE DGGE Cutting et al.. 1990 Dean et al.. 1990 Kerem et al., 1990 Kerem et al.. 1990 Zielenski et al., 1991 Kerem et al.. 1990 Malone et al., CFGAC Kerem et al., 1990 Cutting et al., 1990 Zielenski et al., CFGAC lannuzzi et al., 1991 Highsmith et al., 1990 Osborne et al., 1991 this study Savov et al., 1994 Hamosh et al., CFGAC Graham et al., 1992 Petreska et al., CFGAC Claustres et al., 1993 Graham et al., 1991 Jones et al.. 1992 this study Kerem et al.. 1990 Edkins & Creegan, CFGAC Gasparini et al., 1991 Cutting et al.. 1992 Highsmith et al., 1994 Audriizet et al., 1993 Vidaud et al., 1990 "Numbers in parentheses after the microsatellite haplotypes refer to the number of alleles haplotyped when not all of the available chromosomeswere typed. Login to comment
73 G85E, L88S R117H, 621+1G>T, 435insA. Login to comment
89 G551D (5.1%), R117H (4.1%), R560T (2.9%), HUGHESET AL. Login to comment
108 There were four mutations, R117H, AF508, AI507, and G542X, on 11 CF alleles that were missed due to poor PCR amplification in their original screening methods (Table 1) but were detected using DGGE. Login to comment
110 Analysis of three intragenic CFTR microsatellites demonstratedthat all R117H and R560T alleles share the same respective haplotype: 16(IVS8CA)- 30(IVS17bTA)- 13(IVSl7bCA) for R117H and 16-07-17for R560T. Login to comment

PMID: 8889582 [PubMed] Hughes D et al: "Fluorescent multiplex microsatellites used to define haplotypes associated with 75 CFTR mutations from the UK on 437 CF chromosomes."

No. Sentence Comment

6 Ancient mutations, AF508, G542X, N1303K, were associated with several related haplotypes due to slippage during replication, whereas other common mutations were associated with the one respective haplotype (e.g., G551D and R560T with 16-7-17, R117H with 16-30-13,621+1G>T with 21-31-13,3659delC with 16-35-13). Login to comment
58 As the repeat number increasesbeyond 50, it probably becomes more disposed to the addition or deletion of dinucleotide repeats during replication as all other mutations where several alleles were tested gave the same respective 17bTA repeat number, i.e., G551D (17AT repeats = 7), R560T (7), G85E (24), R117H (30), 621+1G>T (31), 3659delC (354, 1898+lG>A (45). Login to comment
74 CF 8CA-17bTA-17bCA Mutation chromosomes % Normal Laboratoryb Reference' HaplotVpe 1)15-29-13 557delT Nl Graham et al.. 1992 21 16-07-17 MU (G>T) 3) 16-24-13 4) 16-25-13 5) 16-29-13 6) 16-30-13 7) 16-30-14 8) 16-31-13 9) 16-31-14 10) 16-32-13 12) 16-33-13 13) 16-34-13 14) 16-35-13 11)16-32-17 15)1645-13 16) 1646-13 17) 1646-14 19) 17-07-17 18)16-53-13 20)17-29-14 21) 17-31-13 22) 17-32-13 23) 17-35-13 24) 17-51-11 25) 17-55-13 27) 17-58-13 28) 21-31-13 29) 22-31-13 31)23-22-17 26) 17-56-13 30) 22-33-13 32) 23-29-13 33)23-31-13 34)23-32-13 35)23-33-13 36)23-34-13 37) 23-36-13 38)24-22-17 39) 24-31-13 182delT P67L R75X L206W 1154insTC 146linsAGAT Q493x V520F 1717-1G>A G551D R560T V562L R709X S1196X L1254X R1283M G85E 2184insA 711+lG>T 3495delA 4279insA SlOR L88S R117C R117H G178R 1717-1G>A Y563N W1098R G1123R 3850- 1G>A E6OX %%deIT 1138insG R34P 2183AA>G 2184delA R1158X 1078delT R1162X 3849G>A Q141W R347P Y917C G2iX 711+3A>G 441delA 3130de115 3659delC 1898+1G>A R709X 2711delT R1158X E92K 3849+lOkbC>T 2118delAACT 4048insCC 296+1 2 T S Q22OX R297Q A1507 2789+5G>A 3120+1G>A W128W 1811+lG>C AF508 E831X R116W AF508 W846X1 3120G>A R785X R553X R553X R553X 621+1G>T G542X G542X Y1182X N1303K AF508 G54W 3041delG 1525-1G>A N1303K G542X G542X G542X 394delTT R709X N1303K 1 1 1 2 1 1 4 2 3 4 2 26 8 1 1 1 1 1 8 1 1 1 1 1 1 1 19 1 2 1 1 1 1 7 1 1 2 1 1 2 1 1 1 1 1 1 1 1 2 1 1 7 4 1 2 1 1 2 1 1 4 Asian 1 2 1Asian 5 4 i Afro-Caribbean 5 1 42 (19%) 1 1 57 (26%) 1 2 1 1 1 2 12 2 11.4 0.4 4.9 16.3 1.1 3.8 1.9 10.6 2.3 1.5 2.3 1.5 2.7 4.5 0.4 0.8 0.8 0.4 0.8 0.4 1 2 1 7 1 1 1Asian 1 1.5 0.8 0.8 NI G NI, M M NI NI. Login to comment
83 G 23-31-13 2 NI,G 24-31-13 1 C R117H 16-30-13 19 16.3 NI.G, C 1717-1G>A 16-07-17 2 M, G 16-30-13 2 M, G R553X 17-55-13 1 M 17-56-13 1 C 17-58-13 1 0.4 NI 1898+1G>A 16-45-13 4 1.5 M E60X 0.2-0.5 16-31-13 7 3.8 NI.M G85E 16-24-13 8 M. G, C 1154insTC 16-07-17 4 NI, M, G A1507 17-07-17 5 4.5 NI R560T 16-07-17 8 N1 3659delC 16-35-13 7 2.3 NI. Login to comment
91 Other relativelycommon mutations (e.g., G551D, R560T, R117H, 3659delC, and 621+lG>T) were found associatedwith the one haplotype, suggesting that they emerged more recently. 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

91 Other mutations appeared in varioushaplotypes that were different at both microsatelliteand diallelic markers: R117H, H199Y, R347H, R347P, L558S, 2184insA, 3272-26A+G, R1162X, and 3849+10kbC-T (Table 4). 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
106 (1992) Dork et al. (1994a) Malone et al. (personal communication) Claustreset al. (1992) Ferec et al. (1992) Fanen et al. (1992) lvaschenko et al. (1991) T. Dork (personal communication) Dean et al. (1990) Dork et al. (1994a) Ferec et al. (1992) Bozon et al. (1994) Costes et al. (personal communication) Fanen et al. (1992) Audrezet et al. (personal communication) Zielenski et al. (1991a) Zielenski et al. (1991a) Granell et al. (1992) Highsmith et al. (1990) Mercier et al. (1993b) Vidaud et al. (1990) Fanen et al. (1992) Fanen et al. (1992) Dork et al. (1994b) (continued) HAPLOTYPESFOR 94 CF MUTATIONS TABLE2. CFTR HaplotvpesforDiallelic and Multiallelic DNA Markers for 94 CF Mutations"(Continued) ~~ ~ J44-GAIT- 8CA-17BTA- No. of TSU-TUB20 17BCA Mutation chromosomes % Normal Laboratory Reference 1-6-1-2 (9.1%) 1-6-2-2 (8.9%) 1-7-1-2 (3.4%) 1-7-2-2 (2.6%) 2-7-1-1 (1.2%) 2-7-2-2 (0.7%) 17-7-16 16-7-18 16-7-17 15-7-17 24-31-13 23-52-13 23-34-13 23-33-14 23-33-13 23-32-13 23-31-13 23-30-13 23-21-19 23-18-13 22-35-13 22-31-13 22-30-13 21-31-13 19-33-13 18-45-13 18-37-13 18-35-13 17-57-11 17-55-13 17-55-11 17-54-11 17-53-11 17-52-11 17-51-11 17-33-13 16-46-13 16-45-13 16-44-13 16-42-13 16-35-13 16-30-13 16-30-13 16-7-17 16-21-19 L107% L1077P 24ldelAT L719X A1507 3849+10kbC-T 2184insA 2991de132 G551D 1154insTC V520F R560T 4114ATA+lT 3667de14 435insA Q414X C225R Q39X N1303K R1162X H199Y G542X G542X w1204x R347H G542X AF50gb N1303K 2143delT 3849f 10kbC-T N1303K 681delC R347H A455E N1303K A120T 621+1 h T 574delA 1221delCT F311L R560K R553X R533X R553X Q552X R553X Q552X R116W R553X 1898+5 h T 3272-26A-G 1717-1hA 1342-2A-C A1507 2869insG 2869insG E92X 4374+1 h T 2183AA-G R117H 1609delCA I336K W1063X 1 1 1 1 6 1 3 1 1 22 17 1 1 1 1 1 1 1 1 1 1 1 1 1 17 1 1 4 157 7 1 2 2 1 1 2 2 1 9 1 1 1 1 1 1 6 1 1 1 2 1 3 2 1 3 1 1 1 4 2 4 1 1 - - 10.33 1.45 - - 0.48 1.45 - 0.24 1.45 0.24 - - - - 0.24 0.48 - - - - - - 0.49 0.48 - 0.24 0.24 0.24 - - - - - 0.72 0.24 0.72 - t h fP h b.fb,fP h b,fp.t t h b.fb.fp,h,t b.fb.fp,h,t t t t h b h h fP h fP fb b fP b.fb,fP,h.t fP fb b,fP,t b.fb,fp,h,t b.fb,h h h h,t t fb t b b b.fb.t fP fb fb tb h fP h h t t b h t h b b h h b,fb,h fP.h b h fP fP Bozon et al. (1994) Fanen et al. (1992) Dork et al. (1994a) Kerem et al. (1990) Dork et al. (1994~) Cutting et al. (1990) Kerem et al. (1990) lannuui et d. Login to comment
138 Nine mutations (R117H, H199Y, R347H, R347P, L558S, 2184insA, 3272-26A+G, R1162X, and 3849+10kbC+T) have been found associated with more than one haplotype for both diallelic and microsatellite markers. 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: 21374513 [PubMed] Schwarz M et al: "Methods for screening in cystic fibrosis."

No. Sentence Comment

34 As an extreme example, asample may betested for R560T and R117H by ARMS duplex (primers aredetailed in Table 3,p. Login to comment
38 Table2 Sequences,ProductSizes,andAnnealingTemperaturesofPCRPrimersUsedinCFAnalysis(seeNote1O)8 ExonPrimersequence5`to3`Name ProductAnnealing size,bptemperature,"C 3 4 7 9 10@al-Q G A10 11 12 13 14a 17b 19 CTTGGGTTAATCTCCTTGGA3i5 ATTCACCAGATTTCGTAGTC313 TCACATATGGTATGACCCTC4i5 TTGTACCAGCTCACTACCTA4i3 AGACCATGCTCAGATCTTCCAT7i5 GCAAAGTTCATTAGAACTGATC7i3 TAATGGATCATGGGCCATGT9i5 ACAGTGTTGAATGTGGTGCA9i3 GTTTTCCTGGATTATGCCTGGGCACC16B GTTGGCATGCTTTGATGACGCTTCC16D GCAGAGTACCTGAAACAGGAlOi CATTCACAGTAGCTTACCCAlOi CAACTGTGGTTAAAGCAATAGTGTlli5 GCACAGATTCTGAGTAACCATAATlli3 GTGAATCGATGTGGTGACCA1215 CTGGTTTAGCATGAGGCGGT1213 TGCTAAAATACGAGACATATTGCA13i5 ATCTGGTACTAAGGACAGCl-1M AAAAGGTATGCCACTGTTAAG14ai5 GTATACATCCCCAAACTATCT14ai3 TTCAAAGAATGGCACCAGTGT17bl5 ATAACCTATAGAATGCAGCA17bi3 GCCCGACAAATAACCAAGTGA1915 GCTAACACATTGCTTCAGGCT19i3 309 438 410 561 98 491 425 426 528 511 463 454 54 54 54 54 54 54 54 57 58 57 56 54 20 21 intron6a iniron8 intron17b intron17b mtron19 GGTCAGGATTGAAAGTGTGCA CTATGAGAAAACTGCACTGGA AATGTTCACAAGGACTCCA CAAAGTACCTGTTGCTCCA CAAGTCTTTCACTGATCTTC TGAGCAGTTGTTAATAGATAA TCTATCTCATGTTAATGCTG GTTTCTAGAGGACATGATC GACAATCTGTGTGCATCG GCTGCATTCTATAGGTTATC AAACTTACCGACAAGAGGA TGTCACCTCTTCATACTCAT AGGCTTCTCAGTGATCTGTTG GAATCATTCAGTGGGTATAAGCAG 20x547359 2Oi3 211547654 210 FC09106/l1057 6iRPT NURI22050 AT17R1.2201-30150 AT17D1.2 ACl7R214050 AC17D2 i19F43750 i19R "SequencesareprovidedcourtesyoftheCysticFibrosisGeneticAnalysisConsortium 106 Schwarz and Malone Table 3 Sequences and Product Sizes for ARMS Primers (23) Used to Detect the CF Mutations R560T and R117H in a Duplex Reactiona Mutatron Prnner Sequence 5` to 3` Product size, bp R560T RI 17H Common AAAATTTCAGCAATGTTGTTTTTGACCAAC Normal GCTTGCTAGACCAATAATTAGTTATTCAAC Mutant GCTTGCTAGACCAATAATTAGTTATTCAAG Common CACATATGGTATGACCCTCTATATAAACTC Normal CCTATGCCTAGATAAATCGCGATAGAACC Mutant CCTATGCCTAGATAAATCGCGATAGAAT 316 237 aAs for the CF(4)m test, a pan of tubes (A and B) is required for eachDNA sample. Login to comment
39 Tube A contams R560T and R117H common, R560T normal, and R117H mutant primers; tube B contams R560T and R117H common, R560T mutant and R117H normal, pnmers. Login to comment

PMID: 9156582 [PubMed] Gray MA et al: "Chloride channels and cystic fibrosis of the pancreas."

No. Sentence Comment

116 The first group involve missense mutations of arginine residues within the pore-forming domain MSD1 (R117H, R334W and R347P), which collectively account for approximatley 2% of CF patients. Login to comment
117 The second group involves residues within NBD1 (A455E and P574H) which are located close to the walker A (residues 458-464) and B (residues 568-572) motifs, crucial for ATP binding. Login to comment

PMID: 8825927 [PubMed] Cashman SM et al: "The Irish cystic fibrosis database."

No. Sentence Comment

4 Mutation AF508 is found in 72% ofIrish CF chromosomes, G551D in 6-9%, and R117H in 2%. Login to comment
29 The genotype of three of the mothers was AF508/G551D, AF508/R117H, and AF508/ AF508 respectively. Login to comment
30 The CF father is a 29 year old of genotype AI507/R117H. Login to comment
39 Care Table 2 Haplotypes associated with the most common CF mutations in Ireland, as well as with Irish CF chromosomes with unidentified mutations and non-CF chromosomes Mutation NmlNcf % X/Kt Mt Microsatellite§ No chrsll AF508 367/506 72-5 A 1 See table 3 2 B 2 116 C - 0 D 2 2 G551D 35/506 6-9 B 2 16-7-17 20 R117H 10/506 2-0 C 1 16-30-13 5 C 1 16-31-13 1 G542X 5/506 1-0 B 2 17-32-13 2 621 + 1G-T 4/506 0-8 B 2 21-7-17 2 B 2 21-31-13 2 R560T 4/506 0-8 D 2 16-7-17 1 D 2 16-31-17 1 1717-1G-A 3/506 0-6 C 1 16-32-13 2 A 2 17-32-13 1 N1303K 2/506 0-4 B 2 23-29-13 2 3659delC 2/506 0-4 C 1 16-35-13 2 AI507 2/506 0-4 ND ND R352Q 1/506 0-2 C 1 16-31-13 1 R553X 0/506 0 0 ND ND 1078delT 0/506 0.0 ND ND Total identified 435/506 85-6 Unidentified 71/506 14-4 A 1 See table 3 3 A 2 5 B 2 17 C 1 5 D 2 8 Normal A 1 See table 3 16 A 2 1 B 2 3 C 1 13 C 2 1 D 2 2 * Nm = number of chromosomes bearing the mutation. Login to comment
65 '0 Mutation R117H, found initially in a US patient of Anglo-Irish ancestry,32 occurs with the highest frequency in Ireland, and with much lower frequency or not at all elsewhere.4 The haplotype associations shown in table 2 could be useful for counselling in some cases, for instance in families where DNA from the affected child is unobtainable,33 or where a direct test for the less common mutations is not available. Login to comment
28 The genotype of three of the mothers was AF508/G551D, AF508/R117H, and AF508/ AF508 respectively. Login to comment
38 Care Table 2 Haplotypes associated with the most common CF mutations in Ireland, as well as with Irish CF chromosomes with unidentified mutations and non-CF chromosomes Mutation NmlNcf % X/Kt Mt Microsatellite&#a7; No chrsll AF508 367/506 72-5 A 1 See table 3 2 B 2 116 C - 0 D 2 2 G551D 35/506 6-9 B 2 16-7-17 20 R117H 10/506 2-0 C 1 16-30-13 5 C 1 16-31-13 1 G542X 5/506 1-0 B 2 17-32-13 2 621 + 1G-T 4/506 0-8 B 2 21-7-17 2 B 2 21-31-13 2 R560T 4/506 0-8 D 2 16-7-17 1 D 2 16-31-17 1 1717-1G-A 3/506 0-6 C 1 16-32-13 2 A 2 17-32-13 1 N1303K 2/506 0-4 B 2 23-29-13 2 3659delC 2/506 0-4 C 1 16-35-13 2 AI507 2/506 0-4 ND ND R352Q 1/506 0-2 C 1 16-31-13 1 R553X 0/506 0 0 ND ND 1078delT 0/506 0.0 ND ND Total identified 435/506 85-6 Unidentified 71/506 14-4 A 1 See table 3 3 A 2 5 B 2 17 C 1 5 D 2 8 Normal A 1 See table 3 16 A 2 1 B 2 3 C 1 13 C 2 1 D 2 2 * Nm = number of chromosomes bearing the mutation. Login to comment

PMID: 8553305 [PubMed] Gan KH et al: "Genetic and clinical features of patients with cystic fibrosis diagnosed after the age of 16 years."

No. Sentence Comment

41 DNA was analysed for the following mutations: E60X, R117H, A455E, AI507, AF508, G542X, S549N, G550X, G551D, R553X, R560T, R1162X, S1251N, W1282X, N1303K, 621 + 1G-+T, 1717-1G--+A. These mutations represent 80% ofthe expected cystic fibrosis mutations in The Netherlands. Login to comment

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

80 Identification of novel mutations The systematic screening of exons 7, 10, and I I performed on each positive Guthrie card during this period has led us to identify five new mutations in the CFTR 30 545 % of non AF508 mutations 20 9 1717-1G->A 10 & & i i Esox G91R I 621+1G->T R117H 6b[ 7 905delG 1078 del T R347H 1221 det CT F311L R347L i10 i11i12 13 14a~l ! Login to comment

PMID: 7472820 [PubMed] Wilschanski M et al: "Correlation of sweat chloride concentration with classes of the cystic fibrosis transmembrane conductance regulator gene mutations."

No. Sentence Comment

13 Abnormal function of the channel results in aber- cAMP CF CFTR NBF PI PS RT-PCR Cyclicadenosinemonophosphate Cysticfibrosis Cysticfibrosistransmembraneconductance regulator Nucleotidebindingfold Pancreaticinsufficiency Pancreaticsufficiency Restrictiontransferasepolymerasechainreaction rant chloride conductance across the apical membrane of epithelial cells in a variety of organs.l-5 Approximately 70% of the CF chromosomes harbor a three base-pair deletionre- 705 0 Wilschanski et al. The Journal of Pediatrics November 1995 I II Ill IV V Normal Nonsense Missense G542X Missense Missense Missense A455E Frameshift AA deletion G551D R117H Alternative 394delTT AF508 splicing Splice junction 3849+10kbC~T 1717-1G~A (a) (b) (c) (d) (e) (f) Figure. Login to comment
43 Defined mutations (each mutation cited in references 8, 23, and 24; numerals in parentheses indicate number of patients): Nonsense mutations-----class I: Frameshift mutations---class I: Splice site mutations-class I: Missense mutations---class HI: Missense mutations---class IV: Partially defective processing---class V: Alternative spficing-----classV: R1162X (3), Y1092X (3), G542X (21), Q552X (2), Q493X (2), w1282x (2), E1104X (1), R553X (6), E585X (l), (all PI) 3659delC (5), 2184delA (4), 4010de14 (1), 556delA (1), 3002delG (1) 3905insT (1), 4016insT (3), 1154insTC (l), 441delA (1), 2184insA (2), 1078delT (1), 4326delTC (3) (all PI) I717-1G--~A (4), 621+lG--*T (10), 711+IG--~T (3), 875+1G-+C (2), 3120+IG-~A (1) (18 PI, 2 PS) G551D (25), N1303K (7), R560T (8), I148T (1), G85E (3), A559T (1), L1077P (2), T1234V (1), (47 PI, 1 PS) R117H (10), R347H (3), R347P (1), D614G (1), S1251N (2), (all PS) P574H (2), A455E (2), (all PS) 3272-26A-+G (4), 3849+10KbC---~T (2), 3120G-+A (1), (all PS) analysis, we further grouped the patients according to the molecular consequences conferred by the CFTR alleles. Login to comment
106 Variation in the level of normal RNA splicing affects the clinical consequence of at least one common CFFR mutation (R117H).I8 Although the level of normal CFrR expression dictates the encoded chloride channel activity, the exocrine pancreatic function appears to be a good indicator of any residual activity. Login to comment
109 More recently, a multicenter study reported no significant differences in sweat chloride levels in 79 compound heterozygotes carrying the mutations G55ID with AF508 (class III), in comparison with those homozygous for AF508.21 In addition, no significantdifferences in sweat chloride values could be detected between those who were homozygous for AF508 and those who had other common "severe" mutations, including the nonsense mutations (G542X, R553X, and W1282X), missense mutation (N1303K), and splice site mutations (621 + 1G--->Tand 1717 - 1G--~A).22 In the latter study there was a significant difference in sweat chloride concentration between a group heterozygous for the mild missense mutation (AF508/R117H) and the reference group (AF508/AF508).22 These data were limited by the range of mutations and were defined by genotype rather than functional class, but the results are in complete agreement with the findings of the present study. Login to comment
12 Abnormal function of the channel results in aber- cAMP CF CFTR NBF PI PS RT-PCR Cyclicadenosinemonophosphate Cysticfibrosis Cysticfibrosistransmembraneconductance regulator Nucleotidebindingfold Pancreaticinsufficiency Pancreaticsufficiency Restrictiontransferasepolymerasechainreaction rant chloride conductance across the apical membrane of epithelial cells in a variety of organs.l-5 Approximately 70% of the CF chromosomes harbor a three base-pair deletionre- 705 0 Wilschanski et al. The Journal of Pediatrics November 1995 I II Ill IV V Normal Nonsense Missense G542X Missense Missense Missense A455E Frameshift AA deletion G551D R117H Alternative 394delTT AF508 splicing Splice junction 3849+10kbC~T 1717-1G~A (a) (b) (c) (d) (e) (f) Figure. Login to comment

PMID: 7573058 [PubMed] Zielenski J et al: "CFTR gene variant for patients with congenital absence of vas deferens."

No. Sentence Comment

20 The effect of this T-tract polymorphism in CFTR gene expression is also documented by its relationship with a known CF mutation R117H (Dean et al. 1990): While R117H(5T) is found in typical CF patients with pancreatic sufficiency, R117H(7T) is associated with CBAVD (Kiesewetter et al. 1993). 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
52 Lancet 336:512 Gervais R. Dumur V, Rigot J-M, Lafitte J-J, Roussel P, Claustres M, Demaille J (1993) High frequency of the R117H cystic fibrosis mutation in patients with congenital absence of vas deferens. N Engl J Med 328:446-447 Holsclaw DS, Perlmutter AD, Jockin H, Schwachman H (1971) Genital abnormalities in male patients with cystic fibrosis. 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

90 Moreover, some classical mild mutations, which have been frequently detected in other PS sample populations, are absent (R117H) (Dean et al. 1990) or infrequent (R347P) in our patients. Login to comment

PMID: 7541969 [PubMed] Tizzano EF et al: "CFTR expression and organ damage in cystic fibrosis."

No. Sentence Comment

36 For example, a missense mutation (R117H), observed in persons with one of three phenotypes (asymptomatic persons, patients with pancreatic-sufficient cystic fibrosis, and patients with congenital bilateral absence of the vas deferens), occurs on two chromosome backgrounds that lead to the three different phenotypes (14). Login to comment
78 In the case of pancreatic disease, a clear correlation has been shown between genotype and phenotype, with a specific set of mutations (for example, R117H) leading to pancreatic sufficiency and the rest, including DF508, to pancreatic insufficiency. Login to comment

PMID: 7581390 [PubMed] Varon R et al: "Recurrent nasal polyps as a monosymptomatic form of cystic fibrosis associated with a novel in-frame deletion (591del18) in the CFTR gene."

No. Sentence Comment

45 Further, CFTR mutations AF508 and R117H have been reported in another disease, congenital bilateral absence of vas deferens (CBAVD), with normal to moderately elevated sweat electrolyte levels but without other CF symptoms (20,21). Login to comment

PMID: 7539891 [PubMed] Gan KH et al: "A cystic fibrosis mutation associated with mild lung disease."

No. Sentence Comment

29 Since the gene for cystic fibrosis was cloned, there have been several studies on associations between the genotype and the phenotype in cystic fibrosis.5-8 A number of mutations (R117H, R334W, R347P, A455E, and P574H) appear to be associated with pancreatic sufficiency9 and residual transmembrane transport of chloride.10,11 The most common mutation, ⌬F508, is associated with pancreatic insufficiency and severe pulmonary disease.5,6 There is great variation in the severity of lung disease, but until now no mutation associated with mild pulmonary disease has been found. Login to comment
91 R117H, a mutation associated with residual transmembrane chloride transport,10 was also associated with an older age at diagnosis and with pancreatic sufficiency, but not with better lung function. Login to comment
92 The severity of disease in cystic fibrosis is determined by the mutation resulting in the least severe disease.9 All the A455E compound heterozygotes included in our study had a mutation on their other allele that was associated with severe disease. Login to comment
108 Because of the relatively high frequency of the A455E mutation among our patients, we were able to include 33 patients, as compared with the 23 patients with the R117H mutation included in the consortium`s report.8 When sufficient numbers of patients are studied, it should be possible to show that other mutations associated with the preservation of pancreatic function and residual transmembrane chloride transport are also associated with milder pulmonary disease. Login to comment
109 A455E is a missense mutation that leads to a change from alanine to glutamic acid in amino acid residue 455 of the CFTR protein.27 CFTR is a chloride transporter driven by cAMP, and the A455E mutation is situated in the first nucleotide-binding fold, two residues removed from the so-called Walker-A motif, the proposed site of interaction with the phosphoryl moiety of the bound cAMP.28 The A455E mutation may interfere with the binding of cAMP to the CFTR protein. Login to comment
28 Since the gene for cystic fibrosis was cloned, there have been several studies on associations between the genotype and the phenotype in cystic fibrosis.5-8 A number of mutations (R117H, R334W, R347P , A455E, and P574H) appear to be associated with pancreatic sufficiency9 and residual transmembrane transport of chloride.10,11 The most common mutation, F508, is associated with pancreatic insufficiency and severe pulmonary disease.5,6 There is great variation in the severity of lung disease, but until now no mutation associated with mild pulmonary disease has been found. Login to comment

PMID: 7540706 [PubMed] Jarvi K et al: "Cystic fibrosis transmembrane conductance regulator and obstructive azoospermia."

No. Sentence Comment

18 We screened for 6 CF mutations (AF508, G551D, G542X, W1283X, N1303K, R117H), representing the most common mutations detected previously in men with CBAVD, and determined the CFTR gene variants of R75Q and T tract length of intron 8. Login to comment

PMID: 7539210 [PubMed] Rave-Harel N et al: "CFTR haplotype analysis reveals genetic heterogeneity in the etiology of congenital bilateral aplasia of the vas deferens."

No. Sentence Comment

42 The R117H mutation (Dean et al. Login to comment
45 The PCR product with the R117H mutation has an HaeII site, while the normal allele does not. Login to comment
60 In addition, the mutations R117H and D1270H, previously found in CBAVD patients from other populations (Anguiano et al. 1992), were analyzed. 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
43 The R117H mutation (Dean et al. Login to comment
46 The PCR product with the R117H mutation has an HaeII site, while the normal allele does not. Login to comment
61 In addition, the mutations R117H and D1270H, previously found in CBAVD patients from other populations (Anguiano et al. 1992), were analyzed. 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
106 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 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 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 7 2 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

PMID: 7539342 [PubMed] Jezequel P et al: "Structural analysis of CFTR gene in congenital bilateral absence of vas deferens."

No. Sentence Comment

44 R117H/? Login to comment
45 F508I R117H F5O8/ R1O7OW F508/A1067V 621+1G-*T /? Login to 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
59 Detection of CFTR lntron-8 Polypyrimidine Tract Length Variants Samples bearing the R117H mutation were analyzed for the intron-8 splice variants 5T or 7T (6). Login to comment
63 Among the 50 chromosomes studied, 24 mutations (48%) were identified as follows: 13 patients were heterozygous for the SF508 deletion (52%), 6 of whom were compound heterozygous for the SF508 and missense mutations such as R117H (3 cases), R1O7OW (2 cases), and a rare mutation designated as A1067V (1 case) recently identified in a CBAVD patient (12); 5 patients had only one identified mutation: R117H (4 cases) and 621+1G-`T (1 case); and 7 patients had no mutation in the 13 studied exons. Login to comment
64 In the intron-8 splice acceptor site the 7T variant was found in all seven R117H carriers. Login to comment
69 In addition to iF508, we have characterized four mutations: R117H, R1O7OW, 621+1G-*T, and A1067V. Login to comment
74 Some authors have clearly shown that the R117H mutation found in typical CF was associated with a 5T variant in intron 8 of the CF gene. Login to comment
130 Male infertility as the only presenting sign of cystic fibrosis when homozygous for the mild mutation R117H. Login to comment
60 Detection of CFTR lntron-8 Polypyrimidine Tract Length Variants Samples bearing the R117H mutation were analyzed for the intron-8 splice variants 5T or 7T (6). Login to comment
65 In the intron-8 splice acceptor site the 7T variant was found in all seven R117H carriers. Login to comment
70 In addition to iF508, we have characterized four mutations: R117H, R1O7OW, 621+1G-*T, and A1067V. Login to comment
75 Some authors have clearly shown that the R117H mutation found in typical CF was associated with a 5T variant in intron 8 of the CF gene. Login to comment
131 Bienvenu T, Beldjord C, Adjiman M, Kaplan JC. Male infertility as the only presenting sign of cystic fibrosis when homozygous for the mild mutation R117H. 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 Ȳc;F508/R258G #2c;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: 7543317 [PubMed] Pignatti PF et al: "Increased incidence of cystic fibrosis gene mutations in adults with disseminated bronchiectasis."

No. Sentence 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
89 Among the 12 patients with obstructive pulmonary disease other than bronchiectasis, one chronic bronchitis patient had a mutation (R117H), and one a rare DNA polymorphism; one of the two emphysema patients had a DNA polymorphism. Login to comment

PMID: 7534226 [PubMed] Sheppard DN et al: "Mechanism of dysfunction of two nucleotide binding domain mutations in cystic fibrosis transmembrane conductance regulator that are associated with pancreatic sufficiency."

No. Sentence Comment

218 It is interesting to compare our present results with those from our study of mild CF mutations that occur in MSD1 (R117H, R334W and R347P). Login to comment

PMID: 7532150 [PubMed] Casals T et al: "Extensive analysis of 40 infertile patients with congenital absence of the vas deferens: in 50% of cases only one CFTR allele could be detected."

No. Sentence Comment

10 J. Gimrnez 9M. D. Ramos 9V. Nunes X. Estivill (Ig~l) Molecular Genetics Department, Cancer Research Institute, Hospital Duran i Reynals, Autovfa de Castelldefels Km. 2.7, L'Hospitalet de Llobregat, E-08907 Barcelona, Catalonia, Spain L. Bassas 9J. Ruiz-Romero 9H. Narwiez Andrology Department, I.U.N.A., Fundaci6 Puigvert, Barcelona, Catalonia, Spain G. Tapia Pediatrics Department, Hospital de Sant Pau, Barcelona, Catalonia, Spain D1270N, and R117H as benign CF mutations. Login to comment
59 Direct sequencing of these two abnormal fragments identified mutation R ll7H, a known Table 1 Semen analysis of patients with CAVD, given as the mean (range) CBAVD CUAVD (n = 27) (n = 10) Sperm (x 106/ml) 0 10.6 (0-90) Seminal volume (ml) 0.9 (0.2-3.1) 2.5 (0.4 5.4) pH 6.7 (6.0-8.0) 7.3 (6.4-7.7) Fructose (retool/l) 2.6 (0-9) 10.3 (3-) '~Citrate (mmol/l) 77.5 (11-188) 48.6 (36-88) ~Reference values: fructose, 8 28 retool/l; citrate, 10 35 retool/1 Table 2 CFTR mutation analysis in 30 CBAVD and 10 CUAVD patients (CBAVD congenital bilateral absence of the vas deferens, CUAVD congenital unilateral absence of the vas deferens, ND not determined, - absence of mutations, RRI recurrent respiratory infection, R rhinitis, RS rhino-sinusitis, BR.ASTH bronchitis asthmatic) Table 3 Congenital malformations associated with CAVD in 40 patients 207 Patient Age Phenotype Sweat test Mutation Other clinical (years) (mEq/l) features 1 37 CBAVD 108 1677delTA 2 28 CBAVD 50 G542X 3 28 CBAVD 118 - 4 33 CBAVD 90 AF508/L206W RRI, R 5 26 CBAVD 118 R117H/712-1G-+T 6 42 CBAVD 66 - RS 7 31 CBAVD 170 AF508 R 8 27 CBAVD 100 AF508/R74W + D1270N RRI, R 9 32 CBAVD 74 AE115 RS 10 35 CBAVD 90 - Nasal polyps 11 33 CBAVD 78 KI060T RI, family history 12 45 CBAVD 150 R334W RS 13 42 CBAVD 60 - 14 40 CBAVD 110 R 1070W RS 15 29 CBAVD 110 G542X 16 37 CBAVD 80 R117H RI, RS, BR.ASTH 17 37 CBAVD 85 - Asthma 18 46 CBAVD 15 R1162X 19 37 CBAVD 110 AF508 RS, diarrhoea 20 42 CBAVD 45 2789+5G--)A RI 21 49 CBAVD 95 AF508 22 36 CBAVD 70 AF508 RRI, RS 23 42 CBAVD 90 - 24 15 CBAVD 150 AF508 25 26 CBAVD 60 - 26 39 CBAVD 100 AF508 RRI, RS 27 33 CBAVD 57 AF508 RRI 28 33 CBAVD 80 G542X 29 34 CBAVD 78 - 30 32 CBAVD 113 G542X 31 33 CUAVD ND AF508 RS, pancreatitis 32 37 CUAVD ND - 33 31 CUAVD 77 - BR.ASTH 34 39 CUAVD ND - 35 40 CUAVD 40 - 36 33 CUAVD 59 - 37 40 CUAVD 90 - 38 47 CUAVD 40 - RRI 39 39 CUAVD 50 - 40 35 CUAVD 100 - No. Login to comment
70 Lane 2 corresponds to mutation R117H and lane 7to mutation zXE115 NORMAL AG G AG G A A1C00AC T C T A T CG It I II ii It I I I I I t i|t ~ tlo ktt I It I I I ! Login to comment
98 The second patient was heterozygous for mutations Rll7H/ 712-1G---)T, and had only a CBAVD phenotype, probably because of the benign mutation R117H (Dean et al. 1990). Login to comment

PMID: 7539448 [PubMed] Le Lannou D et al: "Obstructive azoospermia with agenesis of vas deferens or with bronchiectasia (Young's syndrome): a genetic approach."

No. Sentence Comment

4 The AF508 mutation occurred most frequently (54%), and the second most frequent mutation to occur was R117H (27%). Login to comment
42 The details of the genotype screening for these 20 patients as well as the other six CAVD patients are summarized in Table I. The AF508 mutation occurred the most frequently (54%), with R117H being the second most frequent (27%). Login to comment
43 Six patients were double heterozygotes: AF508/R117H (three cases), AF508/ R1070W (two cases), AF508/A1067V (one case). Login to comment
50 1 z 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 Details of cystic fibrosis (CF) mutations identified congenital agenesis of vas deferens CF mutation AF5O8/ AF508/ AF508/ AF508/ AF508/ AF5O8/A1067V AF5O8/ AF508/R1070W R117H/ AF508/R1070W - AF508/ R117H/ 621 + 1 G->T7 AF508/RU7H R117H/ AF508/R117H AF5O8/ - AF508/R117H G551D/ R117H/ Respiratory disease - - asthma bronchiectasia - - asthma - - - - rhinitis - - - - - asthma - - in all patients with Sweat tests (mmol/ml of chloride) 72a 42 31 64a 24 - 30 39 17 - 6 - 36 11 31 24 - - 7 52 - - Patients with two results >60 mmol/ml were considered positive. Login to comment
71 an incomplete clinical form of CF. However, if AF508 is excluded, the most frequent mutations in the CAVD group (R117H and R1070W) were not observed in a group of 108 CF patients in a separate study, and these mutations seemed to be specific to CAVD. 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

24 They also reported the frequent occurrence of a second mutation in theirgroup ofpatients, the mutation R117H (Gervais et al. 1993). Login to comment
65 In addition, we identified the following missense mutations: four R668C, one A800G, one (G628R + S1235R, borne on the same chromosome), one (R74W + D1270N, borne on the same chromosome), six R117H, one F1052V, one R117C, one S1235R, one G149R, one R258G, two R347H, one R1066H, one R75L, and one E193K. 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
135 Further, a second mutation, R117H, known to lead to a mild phenotype in CF patients, was also found to occur at high frequency in these men (Gervais et al. 1993). Login to comment
162 These genotypes could be considered extremely mild forms ofCF, the more frequent genotype forthis condition being AFS08/R117H. Login to comment
164 (1993) that R117H occurs on two chromosomal backgrounds, one carrying a ST variant with respect to a polypyrimidine tract in intron 8, which alters exon 9 splicing, and the other carrying a 7T variant associated with normal exon 9 splicing. Login to comment
165 The R117H mutations in this study are associated only with the 7T variant, indicating that the chromosomal background associated with CBAVD may be specific. Login to comment
166 These data show that the CBAVD phenotype is determined by the association ofthe R117H with a particular chromosomal background. Login to comment

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

No. Sentence Comment

574 On the other hand, many mutations (R117H, H199Y, R334W, R347P, R553X; L558S, 3272-26A�G, 3849+lOkbC�T, R1162X) are found associated with two or three haplotypes that cannot be possibly derived from each other by simple molecular mechanisms (58, 124). Login to comment
590 In another example, the clinical presentation of the missense mutation R117H can apparently be modulated by the length of a polythymidine tract upstream of the 3' splice site of intron 8 (101). Login to comment
628 This strategy may also be applied to patients with other Normal II III IV V No synthesis Block in Block in Altered Reduced processing regulation conductance synthesis Nonsense Missense G542X Missense Missense Missense A455E Frameshift N1303K G551D R117H 394deiTT AA deletion Alternative L1F508 R347P splicing Splice junction 1717-1G-->A 3849+1OkbC-->T Figure 3 Molecular consequence of different classes ofCF mutations. Login to comment
636 While R117H alone appears to have relatively high activity, the allele associated with CF patients also has the inefficient splice variant (see section on Complex Alleles). Login to comment
977 High frequency of the R117H cystic fibrosis mutation in patients with congenital absence of vas deferens. N. Engl. J. Med 328:446- 47 79. Login to comment

PMID: 7494407 [PubMed] Dorin JR et al: "Development of mouse models for cystic fibrosis."

No. Sentence Comment

81 Sheppard and colleagues (1993) report that the cAMP-mediated chloride conductance of R347P and R117H mutant constructs in the vaccinia virus T7 hybrid expression system are approximately 30% and 15% of wild type values, respectively. Login to comment

PMID: 7881429 [PubMed] Teng H et al: "Identification of seven rather infrequent and one novel CFTR mutation in the Belgian population."

No. Sentence Comment

6 Seven of these were described previously: R117H (2), G551D (3), R553X (3), 394delTT (4), L206W (4), G85E (5) and D1152H (6). 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

106 Slippage usually results in the addition or subtraction of one repeat unit either side Table 5 CpG Dinucleotides in CFTR Gene That Have More than One Mutational Event Position Change Mutation Reference 223 ......... CT R31C Ghanem et al. 1994 224 ......... GT R31L Zielenski et al., in press 355 ........ C- >T R75X Dork et al., in press 356 ......... G--*T R75L B. Costes, personal communication 356 ......... G-aA R75Q' Zielenski et al. 1991b 481 ......... CT R117C D6rk et al., in press 482 ......... G-oA R117H Dean etal. Login to comment
143 Mutation R117H has also been reported to have originated in two different genetic backgrounds, giving a different clinical status of CF in each (Kiesewetter et al. 1993). Login to comment
144 A collaborative study involving the analysis of 94 mutations in the CFTR gene has shown that mutations R117H, H199Y, R347H, R347P, L558S, 2184insA, R1162X, 3272-26A--G, and 3849+10kbC-)T have arisen more than once in different genetic backgrounds (authors' unpublished data). Login to comment
145 A collaborative study involving the analysis of 94 mutations in the CFTR gene has shown that mutations R117H, H199Y, R347H, R347P, L558S, 2184insA, R1162X, 3272-26A--G, and 3849+10kbC-)T have arisen more than once in different genetic backgrounds (authors' unpublished data). 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

77 Table 1 Frequency distribution and haplotypes of CFTR mutations in 700 German CF chromosomes Mutation~ Nucleotide changesb Locationc Frequencyd Haplotype~ Referencef Q39x C--~T at 247 Exon 2 1 (0.1%) D3 Cutting et al. (1992) E60X G-+T at 310 Exon 3 1 (0.1%) A2 Malone et al. (*) R75X C--+T at 355 Exon 3 1 (0.1%) C2 This study 405+1 G---~A G-+A at 405+1 Intron 3 1 (0.1%) C2 D6rk et al. (1993c) E92X G--~T at 406 Exon 4 2 (0.3%) B2 Will et al. (1994) R117C C---~Tat 481 Exon 4 1 (0.1%) C2 This study R117H G--+A at 482 Exon 4 2 (0.3%) B6 Dean et al. (1990) 621+1 G--+T G--+T at 621+1 Intron 4 1 (0.1%) B1 Zielenski et al. (1991b) H199Y C--+T at 727 Exon 6a 1 (0.1%) A2 This study (*) 1078delT Deletion of T at 1078 Exon 7 4 (0.6%) C2 Claustres et al. (1992) R334W C-~T at 1132 Exon 7 2 (0.3%) BI Gasparini et al. (1991) 1336K T-->A at 1139 Exon 7 3 (0.4%) A2 Cuppens et al. (1993) R347P G--+C at 1172 Exon 7 11 (1.6%) A2, C2 Dean et al. (1990) 1342-2 A--+C A--+C at 1342-2 Intron 8 3 (0.4%) A4 D/3rk et al. (1993b) Q414X C--+T at 1372 Exon 9 1 (0.1%) D3 D6rk et al. (1994a) A455E C-+A at 1496 Exon 9 1 (0.1%) BI Kerem et al. (1990) V456F G--~T at 1498 Exon 9 1 (0.1%) B3 D6rk et al. (1994a) A1507 Deletion of 3 bp between 1648-1653 Exon 10 1 (0.1%) D5 Kerem et al. (1990) AF508 Deletion of 3 bp between 1652-1655 Exon 10 504 (72.0%) B1, DI, B7 Kerem et al. (1989) 1717-1 G--+A G--+A at 1717-1 lntron 10 6 (0.9%) B3 Kerem et al. (1990) G542X G--+T at 1756 Exon 11 10 (1.4%) B1 Kerem et al. (1990) G551D G--+A at 1784 Exon 11 7 (l.0%) B3 Cutting et al. (1990) Q552X C-+T at 1786 Exon 11 1 (0.1%) A4 Devoto et al. (1991) R553X C--+T at 1789 Exon 11 16 (2.3%) A4, B4, D3 Cutting et al. (1990) L558S T--+C at 1805 Exon 11 1 (0.1%) C2 Maggio et al. (*) 1811+I.6kBA-+G A--+Gat 1811+l.6kB lntron 11 1 (0.1%) A2 Chillonetal. Login to comment
95 (1) In the first transmembrane domain, the mutation R117C was initially identified in a 12-year-old pancreatic sufficient German CF patient. This mutation occurs at the same CpG dinucleotide as the previously described and extensively characterized mutation Rll7H (Dean et al. 1990; Kiesewetter et al. 1993; Sheppard et al. 1993; The CF Genotype-Phenotype Consortium 1993) A G C T A G C T A G C T C G C T Control R 117 H R 117 C Fig. 5 Direct sequencing of the two mild missense mutations (arrows) R117H (middle) and R117C (right) in exon 4 in heterozygous patients A G C T A G C T G T T T_~- T Control L 619 S Fig.6 Direct sequencing of the missense substitution L619S (arrow, right) in exon 13 (Fig. 5). Login to comment

PMID: 7522998 [PubMed] Tsongalis GJ et al: "Association of pancreatic adenocarcinoma, mild lung disease, and delta F508 mutation in a cystic fibrosis patient."

No. Sentence Comment

22 For example, iF508 is associated with severe lung disease and early death, whereas the R117H mutation, even when heterozygous with F508, is associated with pancreatic sufficiency and longer survival (5). Login to comment
44 CorrelatIon of phenotype and genotype of CFTR mutations Key phenotypic Lung disease SweatC1 Exocnne pancreas function Vasdeferens Associated CFTR mutations Pancreatic InsuffIcIent Pancreatic sufficient Normalsweat C1 Severe Less severe Relatively mild Elevated Elevated Normal Insufficient Sufficient Sufficient Absent Absent Absent SF508, G542X, R553X, G5510, Ni 303K, Wi 282X, RI 17H, and others 2789 + 5G>A, R117H, R334W, R347P, A455E, P574H, S945L, G85E, and others G551S, R117H, 3849 + 10kb C>T, and others Congenitalabsence of the vas deferens None Normal or elevated Sufficient Absent F508C, Ri 17H, Di D1152H, and others FIg. 2. Login to comment
86 In patients who have the exon 4 missense mutation R117H in conjunction with a severe allele, the phenotype varies considerably, depending on a sequence variation in intron 8 that alters the efficiency of splicing of exon 9 (18). Login to comment

PMID: 7522329 [PubMed] Becq F et al: "Phosphatase inhibitors activate normal and defective CFTR chloride channels."

No. Sentence Comment

6 Most importantly, exposure ofmam- malian cells to phosphatase inhibitors alone activates CFTR channels that have disease-causing mutations, provided the mutant channels are present in the plasma membrane (R117H, G551D, and AF508 after cooling). Login to comment
106 We characterized the responses oftwo CFTR mutants that are processed similarly to wild type and are delivered to the plasma membrane; R117H, which causes a relatively mild (pancreatic-sufficient) form of CF (33, 34), and G551D, which does not respond to cAMP and causes severe disease (35, 36). Login to comment
107 Both R117H and G551D channels were activated on CHO cells by exposure to (-)-p-bromotetramisole (PO = 0.14 ± 0.1, n = 5, and 0.35 ± 0.07, n = 4, respectively) in the absence of cAMP agonists (Fig. 3 B-E), even thoughforskolin alone did not open G551D channels in 14 of 14 trials (Fig. 3 C and E). Login to comment
109 The mean number of mutant channels per patch that were activated in the presence of (-)-p-bromotetramisole (R117H, 2.0 ± 0.37,n = 7;G551D, 3.0 + 0.27, n = 31)was comparable to that determined for cells expressing wild-type CFTR (CHO, 4.0 ± 0.7, n = 11; airway; 3.2 ± 1.0, n = 5). Login to comment
110 Single-channel conductances of R117H (5.7 ± 0.15 pS, n = 7) and GS51D (5.3 ± 0.37 pS, n = 10) channels were decreased slightly (Fig. 3D) compared with wild-type channels (6.8 ± 0.21 pS, n = 6, P < 0.05). Login to comment
143 The activation of defective R117H and G551D channels by phosphatase inhib- I: I Physiology: Becq et aL A 71 I- - " Z '.1 L. 7r -I I.. i. Login to comment
151 (A and B) Wild-type or R117H channel activity on cells incubated with (-)-p- bromotetramisole (Br-t, 1 mM) or IBMX (1 mM), respectively. 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

PMID: 7949729 [PubMed] Dorin JR et al: "Long-term survival of the exon 10 insertional cystic fibrosis mutant mouse is a consequence of low level residual wild-type Cftr gene expression."

No. Sentence Comment

174 Sheppard and associates (1993) report that the chloride conductance of R347P and R117H mutant constructs in the vaccinia virus T7 hybrid expression system are approximately 30% and 15% of wild-type values respectively. Login to comment
175 Individuals who are R347P/AF508 or R117H/AF508 compound heterozygotes are therefore predicted to retain approximately 15% or 7.5% of normal CFTR function. Login to comment

PMID: 7525963 [PubMed] Chevalier-Porst F et al: "Mutation analysis in 600 French cystic fibrosis patients."

No. Sentence Comment

21 Among the 104 other CFTR mutations tested on the 373 non-AF508 CF chromosomes, none of the following 58 mutations were found: G91R, 435 insA, 444delA, D11OH, 556delA, 557delT, R297Q, 1154insTC, R347L, R352Q, Q359K/T360K, 1221delCT, G480C, Q493R, V520F, C524X, 1706dell7, S549R (A-C), S549N, S549I, G551S, 1784delG, Q552X, L558S, A559T, R560T, R560K, Y563N, P574H, 2307insA, 2522insC, 2556insAT, E827X, Q890X, Y913C, 2991de132 (Dork et al, personal communication), L967S, 3320ins5, 3359delCT, H1085R, R1158X, 3662delA, 3667del4, 3667ins4, 3732delA, 3737delA, W1204X, 3750delAG, I 1234V, Q1238X, 3850- 3T-+G, 3860ins31, S1255X, 3898insC, D1270N, R1283M, F1286S, 4005 + I G-A. Forty-six other mutations were found on at Distribution of CFTR mutations found in our sample ofpopulation (1200 CF chromosomes) Mutations tested No of CF chromosomes Haplotypes Method with the mutation XV2C-KM19 (% of total CF alleles) Exon 3: G85E 4 (033) 3C HinfI/ASO394delTT 2 2B PAGEExon 4: R117H 1 B ASOY122X 2 2C MseI/sequenceI148T 1 B ASO621+IG-J* 1 B MseIIASOExon 5: 711+1G--T 8(07) 8A ASOExon 7: AF311 1 C PAGE/sequencelO78delT 5 (0-42) 5C PAGE/ASOR334W 5 (0-42) 2A,2C,ID MspIlASOR347P 5 (042) 5A CfoI/NcoIR347H 1 Cfol/sequenceExon 9: A455E 1 B ASOExon 10: S492F I C DdeI/sequenceQ493X 1 D ASOl609deICA 1 C PAGE/Ddel/sequenceA1507 3 (025) 3D PAGE/ASOAF508 827 (69) 794B,30D,2C,IA PAGEl677delTA 1 A PAGE/sequenceExon I11: 1717-IG--.A 16(1-3) 14B Modified primers + AvaIIG542X 40 (3-3) 29B,5D,2A Modified primers + BstNiS549R(T--*G) 2 2B ASOG551D 3 (025) 3B HincII/Sau3AR553X 10(0-8) 6A,1B,2C,ID Hincll/sequenceExon 12: 1898+IG--A 1 C ASO1898+ IG-C 2 IC ASOExon 13: l9l8deIGC 1 A PAGE/sequence1949de184 I C PAGE/sequenceG628R(G-+A) 2 2A Sequence2118de14 I c PAGE/sequence2143de1T 1 B PAGE/modified primers2184de1A+2183A--*G 11 (0-9) lIB PAGE/ASO2184de1A 1 ASOK710X 3 (025) IC XmnI2372de18 1 B PAGE/sequenceExon 15: S945L 1 C TaqlExon 17b:L1065P I MnlIL1077P 1 A ASOY1092X 3 (025) 2C,IA Rsal/ASOExon 19: RI1162X 6 (0-5) 5C,IA DdeI/ASO3659delC 3 (025) 3C ASOExon 20: G1244E 2 2A MboIIS1251N 2 2C RsaI3905insT 4 (0-33) 4C PAGE/ASOW1282X 18 (105) 15B,1D MnlI/ASOR1283K 1 C Mnll/sequenceExon 21: N1303K 22 (1-8) 18B,lA,ID Modified primers+BstNI 47 mutations 1031 (85 9) least one CF chromosome (table): 21 of them are very rare as they were found on only one CF chromosome in our population. Login to comment

PMID: 7524909 [PubMed] Schaedel C et al: "A novel cystic fibrosis mutation, Y109C, in the first transmembrane domain of CFTR."

No. Sentence Comment

27 Two other substitution mutations, D110H and R117H, have been reported in the same sequence (3). Login to comment
28 At least R117H has been implicated in pancreatic sufficient cystic fibrosis. Login to comment

PMID: 7515047 [PubMed] Akabas MH et al: "Amino acid residues lining the chloride channel of the cystic fibrosis transmembrane conductance regulator."

No. Sentence Comment

16 Three mutationsassociated with mild clinical disease, R117H, R334W, and R347P,displayed altered single-channel properties (ll), but the structural basisof the functional changes is unknown. Login to comment

PMID: 7513963 [PubMed] Sheppard DN et al: "Expression of cystic fibrosis transmembrane conductance regulator in a model epithelium."

No. Sentence Comment

267 We have recently exploited FRT epithelia to characterize the dysfunction of CFTR Cl- channels caused by three mutations that are associated with a milder clinical CF phenotype 1O ` (R117H, R334W, and R347P) (31). 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

84 In particular, the R117H molecule encodes a protein that functions as a correctly regulated chloride channel. Login to comment

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

No. Sentence Comment

155 The R117H mutation can result in either a CF or a CBAVD (congenital bilateral absence of the vas deferens) mutant CFTR gene, depending on the allele present at the Tn locus. 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
54 COther = A1507, 621+1G- T, R117H, N1303K, 711+1G-*.T, 1717-1G-.A, R560T, Y122X, 1148T, G314E, 1078AT, R347P, Q493X, V520F, and 3659AC. Login to comment
56 The G542X mutation was found in 5.4% of Hispanic CF chromosomes, similar to the 3% frequency in the general population. Login to comment
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

PMID: 7516233 [PubMed] Culard JF et al: "A novel splice site mutation in the first exon of the cystic fibrosis transmembrane regulator (CFTR) gene identified in a CBAVD patient."

No. Sentence Comment

3 Some of these are compound heterozygotes for AF508 and missense mutations such as R117H or R347H (2-4), which are known to be associated with mild forms of CF. Login to comment

PMID: 7516232 [PubMed] Bienvenu T et al: "A new missense mutation (G27E) in exon 2 of the CFTR gene in a mildly affected cystic fibrosis patient."

No. Sentence Comment

36 Other missense mutations (i.e. E92K, R117H, R334W, R347P, R347L) especially located in the first transmembrane domain are associated with pancreatic sufficiency (15-17). Login to comment

PMID: 7505767 [PubMed] Dork T et al: "Exon 9 of the CFTR gene: splice site haplotypes and cystic fibrosis mutations."

No. Sentence Comment

61 Association of (TG),Tm alleles with CFTR mutations (TG),Tm CFTR mutationsa (TG)llT7 E60X, E92X, R117C, 1078delT, R347P, R553X, 2184delA, 2184insA, I1005R, 3272-26A--~G, L1059X, Y1092X, R1162X, 3659delC, 3850-3T-oG, S1251N Q39X, R117H, Q414X, V456F, AI507, 1717-1G--~A, G551D, 2043delG, 2183AA---~G, 2184insA, 2789 + 5 G---~A,3272-26A---~G, R1066C, L1077P, 3849 + l0 kB C---~T,4374 + 1 G---~T 621 + 1 G---~T,R334W, A455E, AF508, G542X, 2143delT, 3849 + 10 kB C---~T,NI303K 405 + 1 G----~A,1342-2 A---~C,R553X (TG)IoT7 (TG)10T9 (TG)12T7 a References are compiled in Tsui (1992), except for 2143delT (Dtrk et al. 1992b), 3850-3 T---~G,4374 + 1 G---~T,1342-2 A---~C (Dtrk et al. 1993a, b), Q414X, V456F (this work), 405 + 1 G---~A, E92X, R117C, 2184delA, 2184insA, I1005R, L1059X (T. Login to comment

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

40 The W1310X mutation and one 2184delA (plus A --~ G at 2183) allele were found in a patient from Turkish descent. Login to comment
41 The R117H mutation (8) was found in the non CF individual with the positive trypsin test. Login to comment
43 TABLE 1 Mutations (and Their Frequencies) Identified in This Study Predicted amino Mutation Nucleotide change~ acid change Location Frequencyb Reference E60X G --~ T at 310 (TAGATAGCT) Glu --~ Stop at 60 Malone et al. in (21); this study G --~ A at 482 (GAACACTCT) (8) A --~ C at 622-2 (TTTTCGACT) This study T --~ A at 1139 (AAAAAATTC) This study G --~ A at 1335 (TCTGAGAGG) This study C --~ A at 1496 (TTGGAGGTT) (14) G -~ T at 1505 (GCTGTATCC) (6) Deletion of ATC from 1651 (14); Schwarz et al. (TATC_TTTG) in (21) Deletion of CTT from 1653 145 (13) (TCAT_TGGT) G --~ A at 1717-1 (AATAAGACA) G --~ T at 1756 (TCTTTGAGA) G --~ C at 1898 + 1 (AAAGCTATG) G --~ C at 2014 (TTATCGGAC Deletion of A at 2184; A --~ G at 2183 (AAAAG CAAT) G --~ T at 2320 (TGATTAGCC Deletion of 11 nucleotides from 2721 (TGCT_TAGT) G --~ C at 3040 (AGCACGTAC A --~ G at 3272-26 (TGCAGTGTT) C --~ A at 3408 (TGTAACTGT) Deletion of C at 3659 (CCTA_CAAG) T --~ G at 3837 (TAAGGCCTG G --* A at 3884 (AAGAATACT G --~ A at 3978 (AGTGAAGGA' C --~ G at 4041 (AAAAGTTGG G -~ A at 4061 (CAGTAGAGT Insertion of T after 4218 (CAGTTAAGG) R117H 622-2A --~ C I336K W401X A455E G458V AI507 AF508 1717-1G -~ A G542X 1898+ 1G-~C G628R(G -~ C) 2184delA plus A -~ G at 2183 E730X 2721de111 G970R 3272-26A --~ G Y1092X 3659delc $1235R $1251N W1282X N1303K W1310X 4218insT Exon 3 2 (1.0%) Arg --~ His at 117 Exon 4 c 3' splice signal Intron 4 1 (0.5%) Ile -~ Lys at 336 Exon 7 1 (0.5%) Trp --~ Stop at 401 Exon 8 2 (1.0%) Ala --~ Glu at 455 Exon 9 2 (1.0%) Gly --* Val at 458 Exon 9 1 (0.5%) Deletion of Ile 507 Exon 10 1 (0.5%) Deletion of Phe 508 Exon 10 (72.5%) 3' splice signal Intron 10 5 (2.5%) Gly --* Stop at 542 Exon 11 11 (5.5%) 5' splice signal Intron 12 1 (0.5%) Gly -~ Arg at 628 Exon 13 1 (0.5%) Frameshift Exon 13 2 (1.0%) Glu --~ Stop at 730 Exon 13 1 (0.5%) Frameshift Exon 14a I (0.5%) Gly --~ Arg at 970 Exon 15 1 (0.5%) 5' splice signal? Login to comment
52 c The R117H mutation was not found in a CF patient and is therefore not included. 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
51 c The R117H mutation was not found in a CF patient and is therefore not included. Login to comment

PMID: 7505692 [PubMed] Osborne LR et al: "Nasal epithelial ion transport and genetic analysis of infertile men with congenital bilateral absence of the vas deferens."

No. Sentence Comment

25 Nasal potential difference, sweat sodium concentration and CF genotype in subjects with CBAVD, CF patients and controls CF genotype Control cohort CBAVD cohort CF cohort N/N« AF5O8/R347H SM9N/R1070Q AF508/Other R553X/N*> Unknown/Unknowtf AF 5«/AF5O8 AFjQj/Other AF508/R347P AF50e/G542X AFjQg/RllTH AF5O8/G85E AF5Q8/R553X AFJO8/G551D AF5O8A^520F AFJO8/S549N AF^/DIjQ, N1303K/Other G542X/R117H AFJ08/R334W Other/Other Subjects 50 1 1 1 6 1 16 25 18 3 2 1 1 1 2 1 1 1 3 1 1 3 Mean (range) sweat Na+ concentration (mmol/1) 50 (27-78) 88 N/A 94 57 (47-70) 36 49 (32-76) 126(80-162) 99 (80-128) 108 (99-115) 128 (118-137) 95 107 130 122 (116-128) 90 80 118 96 (92-99) 84 123 108(83-130) Mean (range) nasal potential difference (-mV) 21 (8-30) 31 N/A 34 23 (13-29) -15 20 (-13-28) 45 (32-58) 41 (33-61) 50 (36-77) 43 (33-52) 51 42 39 60 (50-71) 32 37 41 38 (36-40) 32 34 44(31-57) N = non-CF chromosome Other = uncharacterised CF chromosome N/A not available • with CF carrier frequency of 1/20-1/25, it is likely that 2 or 3 of these individuals will be carriers. Login to comment

PMID: 7505690 [PubMed] Ferec C et al: "Genotype analysis of adult cystic fibrosis patients."

No. Sentence Comment

5 The other allele carried is: (i) a missense mutation located in exons coding for transmembrane region in five patients [R334W (1); I336K (2); R117H (1); H1054D (1)]; (ii) a splice mutation in two patients [2789 + 5G - A], (ill) an uncharacterised mutations In one patient. Login to comment
41 The R117H exchanges an Arginine for an Histidine and is a missense mutation in exon 4 coding for a transmembrane domain (18). Login to comment
57 '*'* < GENOTYPE * • • ;i^>"; ' ' FUJ34W/G542X Exon 7/ Exon 11 Arginine •-> Tryptophan AF508/I336K Exon 10/Exon 7 Isoleucine ••> Lysine AF5O8/H1054O Exon 10/Exon 17b Histidine --> Aspartc Acid AF508 Unknown AF508 / 2789+5 G->A Exon 10/ Exon 14b Splice mutation AF508/2789+5 G->A Exon 10/ Exon 14b Splice mutation AF5O8/R117H Exon 10/Exon 4 Arginine -->Histidine AF508/O36K Exon 10/Exon 7 Isoteucine ••> Lysine SEX 4 M F M M F F F M DIAGNOSiS 13 13 27 17 39 32 30 17 PROFESSIONAL; . Login to comment
85 One patient (7) (genotype AF508/R117H) has a deteriorated pulmonary function. As these diagnostic tests are being carried out for these patients of mature years (30 years), of whom many were previously misdiagnesed previously, and as a result given inappropriate treatment, this may account for degeneration of their pulmonary functions. Login to comment
92 The mutation R117H has been found to be associated with congenital bilateral absence of vas deferens (30) which is now considered as a genital phenotype of CF (31). Login to comment
93 However it is interesting to note that we described in this paper a fertile female bearing a DF508/R117H genotype. Login to comment
98 Recently Sheppard et al. (33) have shown that CFTR carrying either R117H or R334W are correctly processed and when expressed in heterologous cells are able to generate cyclic AMP regulated Cl~ current, although at a much lower level. 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

64 17b 18 19 20 21 22 23 24 M1V E60X O220X | R117H G85E 621*1G>T 977msA AF508 I AI607 1898*1G>A G642X 2184delA 1078delT I I 8549N 2184insA I I 1154insTC S549R G651D I R553X I R560T I 1717-1G>A W846X1 3272-26A>G L1077P R12B3U 3669delC 4 016in aT I N1303K 3849*10kbC>T Figure 2. Login to comment
74 Frequencies of mutations in 183 CF families m MUTATION delta FSOB 621«1<3>T 18aS«1Q>A Q661O Q642X Q85E R663X 1078delT R1283M 3669delC R117H delta I607 N1303K 1717-1Q>A R660T M1V E80X Q220X S77lnaA 1154inaTC 8S49N 8649R 2184dtlA 2184ineA W846X1 3272-26A>Q L1077P 3849>10kbC>T 4018ln«T Total Total TOTAL Welsh 131 12 10 4 5 2 4 3 1 1 2 1 2 1 1 1 1 182 183 71.8% 6.6% 5.5% 2.2% 2.7% 1.1% 2.2% 1.6% 0.5% 0.6% 1.1% 0.6% 1.1% 0.6% 0.6% 0.5% 0.5% 99.6% 0 6% Other 1 14 6 7 7 4 4 2 1 1 1 1 1 1 1 1 1 1 1 1 1 1 167 168 72.2% 3.2% 4.4% 4.4% 2.6% 2.6% 1.3% 0.6% 0.6% 0.8% 0.8% 0.8% 0.6% 0.6% 0.6% 0.6% 0.6% 0.8% 0.8% 0.6% 0.8% 99.4% 0 6% Undefined 22 2 1 1 28 26 84.6% 7.7% 3.8% 3.8% 100% Wales TOTAL 267 19 18 11 9 6 4 4 3 2 2 2 2 2 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 366 2 3 6 7 72.8% 5.2% 4.9% 3.0% 2.6% 1 4% 1.1% 1.1% 0.8% 0.6% 0.6% 0.6% 0.6% 0.6% 0.3% 0.3% 0.3% 0.3% 0.3% 0.3% 0.3% 0.3% 0.3% 0.3% 0.3% 0.3% 0.3% 0.3% 0.3% 09 6% 0 6% Table 5. 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: 7692051 [PubMed] Bienvenu T et al: "Male infertility as the only presenting sign of cystic fibrosis when homozygous for the mild mutation R117H."

No. Sentence Comment

0 Jf Med Genet 1993; 30: 797-800 LETTERS TO THE EDITOR Male infertility as the only presenting sign of cystic fibrosis when homozygous for the mild mutation R117H Since the identification of the cystic fibrosis gene (CFTR),' more than 265 mutations have been described (CF Genetic Analysis Consortium, 1992). Login to comment
5 He is homozygous for the R117H CFTR mutation, which was detected by DGGE screening and characterised by direct sequencing of PCR amplified DNA from exon 4 using the Sequenase USB kit. Login to comment
78 From our 797 group.bmj.comon October 25, 2012 - Published byjmg.bmj.comDownloaded from doi: 10.1136/jmg.30.9.797 1993 30: 797J Med Genet T Bienvenu, C Beldjord, M Adjiman, et al. mild mutation R117H. 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

11 Group II was formed by 18 patients with various other CF mutations, including four compound heterozygotes (three with Delta F508/R117H and one with R553X/R117H) and one homozygote (R117H/R117H). Login to 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
63 Cystic fibrosis mutations and male infertility Delta F508/R117H and in two patients testing negative no spermatozoa were found. Login to comment
71 The patient homozygote had a genotype R117H/R117H. Login to comment
72 The R117H is a missense mutation localized on exon 4. Login to comment
101 To further stress this point, three patients were found to be compound heterozygotes with Delta F508 opposite to R117H. Login to comment

PMID: 7686820 [PubMed] Welsh MJ et al: "Molecular mechanisms of CFTR chloride channel dysfunction in cystic fibrosis."

No. Sentence Comment

21 For example, AF506 causes defective processing but may also cause defective regulation, and R117H causes both defective conduction and decreases the time that the channel is open. Login to comment
66 Three mutations in the first membrane-spanning domain (R117H, R334W, and R347P) affect arginine residues located in putative membrane-spanning sequences. Login to comment
69 Nevertheless, the amount of current is reduced, with wild-type CFTR > R347P > R117H > R334W. Login to comment
72 In addition, at least for R117H, the amount of time that the channel is open is reduced to one-third that of wild-type CFTR. Login to comment
98 In class IV mutants in which channel regulation appears intact but ion flow through an open Cl-channel is reduced, the residual activity may be sufficient to confer a pancreatic-sufficient phenotype. In fact, some individuals with these mutations (e.g., R117H) do not exhibit classic CF symptoms at all and have only a single manifestation of disease: male infertility (Anguiano et al., 1992). Login to comment

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

No. Sentence Comment

13 R117P (CGC-CCQ was found in the patient with the G542X allele and confirmed by family analysis. This mutation is the only novel one we have found in the 5' part of the CFTR gene and replaces the same nucleotide as the former described mutation R117H (10). Login to comment

PMID: 7682984 [PubMed] Guillermit H et al: "A novel mutation in exon 3 of the CFTR gene."

No. Sentence Comment

63 Other missense mutations reported by Kristidis et al. (1991) as being located in the transmembrane domain, i.e. R117H (exon 4), R334W (exon 7), R347P (exon 7), A455E (exon 9) and P574H (exon 12), are associated with pancreatic sufficiency; these observations are consistent with the genetic hypothesis that pancreatic sufficiency is a 235 dominant phenotypic trait associated with about 10% of the CF alleles. Login to comment

PMID: 7684943 [PubMed] Costes B et al: "Psoralen-modified oligonucleotide primers improve detection of mutations by denaturing gradient gel electrophoresis and provide an alternative to GC-clamping."

No. Sentence Comment

34 B. Analysis of the exon 4 mutation R117H. Login to comment
35 Lanes 1, 3 and 4: a R117H heterozygote without a clamp (1), with Chemidamp but not irradiated (3), and with ChemiClamp after UV irradiation(4). Login to comment
44 Two nucleotide substitutions lying in a single melting domain within CFTR exon 10 (1648 A-G named I506V) or exon 4 (482 G-A or R117H) were analysed with or without the chemical clamp at one end of the gene fragment. 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

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
69 In addition, both samples in lanes 3 and 5, rows D and E, of Figure 3 were shown to carry the R117H mutation. Login to comment
72 Example of results obtained from hybridizing four identical filters with ASOs specific for N (the normal sequence at position 508), AF508 (a 3 bp deletion at position 508), pool 1 (G542X, G551D, R553X, W1282X, and N13O3K), and pool 2 (AI507, R117H, 621 + 1 G - T , S549N, R560T, 1717-1 G-A). Login to comment
73 Row A contains positive control samples with the following genotypes: 1A (AF508/AF508); 2A (AF508/G542X); 3A (AF5O8/G551D); 4A (N/R553X); 5A (NAV1282X); 6A (AF5O8/N13O3K); 7A (N/AI5O7); 8A (N/R117H); 9A (N/621 + 1 G-T); 10A (AF508/S549N); HA (AF508/R560T); and 12A (N/1717-1 G-A). Login to comment
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

5 Four patients were found to be compound heterozygotes, three with genotypes Delta F-508/R117H, one with R553X/R117H. Login to comment
46 Four of the 26 patients were found to be compound heterozygotes, three with genotypes Delta F508/R117H and one with R553X/R117H. Login to comment
47 The mutation R117H was a missense mutation localized on exon 4. 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
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
95 R553X/R117H NA NA 2. Login to comment
96 DF508/R117H3 DF508 R117H 3. Login to comment
97 DF508/R117H NA NA 4. Login to comment
98 DF508/R117Ha R117H DF508 NA Neg. (g) DF508 Normal NA (b) DF508 Normal (+ vas) R117H - ??? Login to comment
113 Of the 28 wives tested, only one (3.6%) was found to be a carrier for a CF mutation (R117H), while her husband was a compound heterozygote (Delta F508/R117H). Login to comment
123 Of these, four patients were found to be compound heterozygotes, three with genotype Rl 17H/Delta F5O8 and one with R117H/R553X. Login to comment
127 However in the present study, we extended the genetic screening to the parents and the offspring of men with CAVD and moreover, by testing for 12 CF mutations, we demonstrated other rare CF mutations (R117H, G542X and 1717G-A) in patients with CAVD. Login to comment
129 However, by analysing the results of genetic testing of fathers of patients with CAVD, we found four carriers for known CFTR mutations of which two carried Delta F508, one carried R117H and one 1717G-A. Login to comment
138 Sweat chloride tests were only performed on two of the genotypes Delta F508/R117H and both were normal (40 and 45 mmol/1). Login to comment
139 This is the first time that compound heterozygotes for Delta F508/R117H have been found to have normal sweat chloride tests and CAVD as the only phenotypical expression of CF disease. Login to comment
140 218 This finding is consistent with another report of mild CF cases involving Delta F508/R117H genotypes (Dean et al. Login to comment
141 1990) where it appears that the R117H mutation opposite Delta F508 may moderate the more severe phenotype of the homozygous Delta F508 genotype. 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

PMID: 7683954 [PubMed] Nunes V et al: "A new missense mutation (E92K) in the first transmembrane domain of the CFTR gene causes a benign cystic fibrosis phenotype."

No. Sentence Comment

8 SSCP conditions for exon 4 of the CFTR gene, which allow discrimination of mutant and wild type alleles, were developed for several control mutations at this exon: D110H, R117H, 556delA and 621+ 1G-T (8, 9). Login to comment
26 Lanes 1 and 2 were R117H and621 + l G - T mutations used as controls. Login to comment

PMID: 1283148 [PubMed] Lindner M et al: "The spectrum of CFTR mutations in south-west German cystic fibrosis patients."

No. Sentence Comment

4 Another 5 mutations accounted for a further 12.5% (4% G542X; 3% R553X; 3% N1303K; 2% 1717-1 G--~A; 0.5% G551D) whereas 6 mutations (R117H, A455E, AI507, $549I, $549N, and R1162X) were not found. Login to comment
25 Sequences derived from Dean et al. (1990); Kerem et al. (1990); Riordan et al. (1989); Guillermit et al. (1990); Cutting et al. (1990) Exon PCR primers Mutation Allele specific probes 4 5'-AGTCACCAAAGCAGTACAGC-3' R117H N: 5'-GCTATTCTCATCTGCATTCC-3' M: 9 5'-TAATGGATCATGGGCCATGT-3' A455 E N: 5'-ACAGTG~ITGAATGTGGTGCA-3' M: 5'-GTTTTCCTGGATTATGCCTGGCAC-3' N: 5'-GTTGGCATGCTTTGATGACGCTTC-3' M: t0 11 5'-CAACTGTGGTTAAAGCAATAGTGT-3' 5'-GCACAGATTCTGAGTAACCATAAT-3' 5'-GAGGAACGCTCTATC-3' 5'-GAGGAACACTCTATC-3' 5'-GTTGTTGGCG GTI'GCT-3' 5'-GTTGTTGGAG GTTGCT-3' zXF508 5'-CACCAAAGATGATATTTTC-3' 5'-AACACCAATGATATTTTCTT-3' AI507 1717-1G--+A N: 5'-TTGGTAATAGGACATCTCCA-3' M: 5'-TTGGTAATAAGACATCTCCA-3' G542X N: 5'-CCACCTTCTCCAAGAACTAT-3' M: 5'-CCACCTTCTCAAAGAACTAT-3 G551D N: 5'-CTCGTTGACCTCCACTCAGT-3' M: 5'-CTCGTTGATCTCCACTCAGT-3' 19 5'-GCCCGACAAATAACCAAGTGA-3' R 1162X 5'-GCTAACACATTGCTFCAGGCT-3' 21 5'-AATGTTCACAAGGGACTCCA-3' N1303K 5'-CAAAAGTACCTGTTGCTCCA-3' N: 5'-AGGGATCCAAGTTTTTTCTA-3 ' M: 5'-AGGGATCCAACTTTTTTCTA-3' Materials and methods Determination of the CFTR genotype All mutation analyses were performed on Taq-PCR (polymerase chain reaction) amplified DNA fragments (30 cycles at 92~176 72~ for 30/60/90 s) using primers as shown in Table 1 (Sambrook et al. 1989). Login to comment
26 The R117H, A455E, 1717-1G~A, AF508, G542X, G551D, and NI303K mutations were identified by allele specific oligonucleotide hybridisation (ASO, Sambrook et al. 1989) using 32p-labelled probes specific for the normal or the mutated sequence (Table 1). Login to comment
48 We are grateful to Professor Kubanek for his continuous support, to Professor Kaiser, Pforzheim for sending blood samples and providing clinical information on some of his patients, and to Dr.M. Schwarz, Royal Manchester Children's Hospital, for providing allele specific oligonucleotides for the R117H, A455E and 1717-1G--~A mutations together with the appropriate controls. Login to comment

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

No. Sentence Comment

114 Although no specific example can be cited for the third class, it is reasonable to believe that some of the amino acid substitutions in the transmembrane domains [such as R334W (Ref. 21) and R347P (Ref. 20)] and neighboring regions [such as R117H (Ref. 20)] will belong to this class. Login to comment

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

No. Sentence Comment

157 Only in the case of the mutation R117H is there evidence for this. Login to comment
160 Thus a protein conformational change in CFTR resulting in a signif- FIBROSIS Table 4 CF Mutations encountered in United Kingdom Mutation Delta F508 G551D R553 G542X R56OT N1303K DI507 R117H 621+1G-T G85E W1282X E60X R75Q V520F 1717-1 G-A CF chromosomes screened 1 Mutations encountered 1062 199 (non Delta F508) 199 199 199 199 199 199 199 199 199 30 15 199 199 CF chromosomes with mutation in North-West England 863 37 8 11 6 6 4 5 10 4 2 2 1 3 3 Percentage 81.2 3.48 0 75 1.03 0.58 0 58 038 0.47 0.98 0.38 0 19 ? Login to comment

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

77 In some cases primers complementary to the sense strand were used, and this is indicated by the replacement of the - symbol with a + symbol in ARMS and common primers codes; for example, RH-d-N indicates that this primer is used to analyze the R117H mutation (RH), that it has an A residue as the penultimate base which mismatches a C residue in the target sequence (code d), and that it is specific for the normal allele (N). Login to comment
94 R I 17H The R117H mutation of exon IV of the CF gene is a G-A substitution atposition 482 (Dean et al. 1990). Login to comment
97 An R117H homozygote was not available for us to confirm the specificity ofthe normal primer. Login to comment
98 Three approaches were used in order to design an ARMS test specific for the R117H mutation. Login to comment
105 When control primers AAT3 and AAT4 (product size 360 bp) were included in both R117H ARMS reactions at a concentration of 0.86 pM, it was noted that the faint mutant R117H band previously detected in normal individuals was no longer visible (fig. 2c). Login to comment
106 In ARMS tests of individuals heterozygous for the R117H mutation, the intensity of normal and mutant R117H ARMS product bands was equal. Login to comment
113 The use of the primers incorporating the C/C mismatch resulted in a specific R117H test (fig. 2d). Login to comment
138 R553X: CACCTTGCTAAAGAAATTCTTGCTAG ................. CACCTTGCTAAAGAAATTCTTGCTAA ................. GS51D: GCTAAAGAAATTCTTGCTCGTTGCC ................. AGCTAAAGAAATTCTTGCTCGTTGCT ................. G542X: ACTCAGTGTGATTCCACCTTCTAC ...................... CACTCAGTGTGATTCCACCTTCTCA .................... 1717-1G>A: GTCTTTCTCTGCAAACTTGGAGATGTGC ............ GTCTTTCTCTGCAAACTTGGAGATGTGT ............ R117H: CACATATGGTATGACCCTCTATATAAACTC. Login to comment
152 In the multiplex, the normal ARMS reactions for AF508 and 621 + 1G--T are combined with the mutant overARMS reactions for G551D and G542X in the "A" Figure 2 Development of a single ARMS test for R117H. Login to comment
154 The second pair of tracks in each panel are the products when DNA from an R117H heterozygote is used. Login to comment
155 Shown are the results a n m n m R560T 317bp c n m n m 0551 D 286bp obtained using primers RH-d-N and RH-d-M at 0.86 pM (a), at reduced primer concentration 0.10 ItM (b), at 0.86 FM with the inclusion of AAT1 /2 control primers (c), and using primers RHh-N and RH-h-M (which are identical to RH-d-N/M, except for C/C mismatch at position - 2). Login to comment
213 During the development of single ARMS tests, two other approaches were found to be useful in obtaining specificity; these were reducing the primer concentration (e.g., R117H; fig. 2b) and inclusion of a control PCR reaction (e.g., R117H; fig. 2c). Login to comment
78 In some cases primers complementary to the sense strand were used, and this is indicated by the replacement of the - symbol with a + symbol in ARMS and common primers codes; for example, RH-d-N indicates that this primer is used to analyze the R117H mutation (RH), that it has an A residue as the penultimate base which mismatches a C residue in the target sequence (code d), and that it is specific for the normal allele (N). Login to comment
95 R I 17H The R117H mutation of exon IV of the CF gene is a G-A substitution atposition 482 (Dean et al. 1990). Login to comment
99 Three approaches were used in order to design an ARMS test specific for the R117H mutation. Login to comment
107 In ARMS tests of individuals heterozygous for the R117H mutation, the intensity of normal and mutant R117H ARMS product bands was equal. Login to comment
114 The use of the primers incorporating the C/C mismatch resulted in a specific R117H test (fig. 2d). Login to comment
141 R553X: CACCTTGCTAAAGAAATTCTTGCTAG ................. CACCTTGCTAAAGAAATTCTTGCTAA ................. GS51D: GCTAAAGAAATTCTTGCTCGTTGCC ................. AGCTAAAGAAATTCTTGCTCGTTGCT ................. G542X: ACTCAGTGTGATTCCACCTTCTAC ...................... CACTCAGTGTGATTCCACCTTCTCA .................... 1717-1G>A: GTCTTTCTCTGCAAACTTGGAGATGTGC ............ GTCTTTCTCTGCAAACTTGGAGATGTGT ............ R117H: CACATATGGTATGACCCTCTATATAAACTC. Login to comment
157 The second pair of tracks in each panel are the products when DNA from an R117H heterozygote is used. Login to comment
217 During the development of single ARMS tests, two other approaches were found to be useful in obtaining specificity; these were reducing the primer concentration (e.g., R117H; fig. 2b) and inclusion of a control PCR reaction (e.g., R117H; fig. 2c). 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

49 Detection of Exons 4 and 7 Mutations Patients with one or more unknown mutations were screened for mutations R117H and 621 + 1G--T in exon 4, by using allele-specific oligonucleotide (ASO) hybridization, and mutations R334W and R347P in exon 7, by using restriction-enzyme digestion (Dean et al. 1990; Gasparini et al. 1991; Shrimpton et al. 1991). Login to comment
52 Mutations R117H and Table I Oligonucleotides Used for DNA Sequencing Exon Sequencing Primer (sequence) 1 ... le-5' (5'-AGGCACCCAGAGTAGT-3') liF (5'-TCGGCTTTTAACGTGG-3') 2 .... Ex2Seq (5'-GACCAAATCAAGTGAATATCTGT-3') 9 .... 9s-3' (5'-AGACATGGACACCAAATTAAG-3') CF 38 (5'-GAAATTAATATCTTTCAGGACAGG-3') 10 ... lOs-5' (5'-AAGTGAATCCTGAGCGTG-3') lOs-3' (5'-GTAGTGTGAAGGGTTCAT-3') 11 ... li-S' (5'-CAACTGTGGTTAAAGCAATAGTGT-3') 12 ... 12s-5' (5'-GACCAGGAAATAGAGAGG-3') 19 ... 19s-5' (M-AAATTGTCTGCCATTCTT-3') 19i-3' (5'-GCTAACACATTGCTTCAGGCT-3') 20 ...... 20s-5' (5'-TATTTATGGCATGGTACC-3') 20s-3' (5'-CGTACAAGTATCAAATAGCAGT-3') 21 ...... 21s-5' (5'-TTACAATACAATAAGGGA-3') 22 ...... 22i-5'a (5'-GAATGTCAACTGCTTGAGTG-3') 22i-3' (5'-CACCATGAAGCAGGCATAA-3') 23 ...... 23s-5' (5'-GTGATATTATGTGTGG-3') 621 + 1G-*T were detected by using oligonucleotides CF48 (5'-GAGGAACACTCTATC-3') (Dean et al. 1990) and 337J (5'-GGAAGTATTAACTTCTTA- TA-3'), respectively. Login to comment
112 Four mutations, R117H (Dean et al. 1990) and 621 + 1 G-'T (Zielinski et al. 1991a) in exon 4 and R334W (Gasparini et al. 1991) and R347P (Dean et al. 1990) in exon 7, occur with some frequency in these populations. Login to comment
114 Three CF chromosomes from three U.S. Caucasians and from two Northern Irish patients were found to carry the 621 + 1G--T mutation, and one chromosome from a Northern Irish patient carried the R117H mutation. 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
56 Table I Twenty-five CF Gene Mutations Location and Mutation DNA Change Amino Acid Change Reference Exon 4: D11OH .......... 444delA ........ R117H .......... 556delA ........ 1148T ........... 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
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

PMID: 1284468 [PubMed] Cheadle JP et al: "A new missense mutation (R1283M) in exon 20 of the cystic fibrosis transmembrane conductance regulator gene."

No. Sentence Comment

5 From a sample of 373 CF chromosomes, 318 proved to have one of the following mutations: delta F508, delta 1507, G551D, R553X, G542X, R117H, 1717-1G>A, R560T and 621 + 1G>T. Login to comment

PMID: 1371263 [PubMed] Dork T et al: "Intra- and extragenic marker haplotypes of CFTR mutations in cystic fibrosis families."

No. Sentence Comment

93 The other identified CFTR mutations either perturb acceptor (1717-1 G---~A) (Guillermit et al. 1990; Kerem et al. 1990) or donor splice sites (2789 + 5 G---~A) (Highsmith et al. 1990), or abolish positive charges in the transmembrane domains of CFTR (R117H, R334W, R347P) (Dean et al. 1990b; Gasparini et al. 1991b). 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
140 4) In addition, the two cases R117H in our pool may also represent an independent mutational event. 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

53 On the other hand homo- R117H 116* 4 0.65% zygotes for G551D have milder disease but are 621+1 159* 10 1.19% pancreatic insufficient. Login to comment
54 Compound heterozygotes for W1282X 159* 1 0.24% AF5N and R117H however do have milder disease. Login to comment
55 V520F 63* 3 0.90% This supports a crucial role for the nucleotide binding G85E 40* 2 0.48% folds in determining severity-R117H is in exon 3, Total 91.99% part ofthe intramural anchoringprotein presumably not playing a major role in ion transport. Login to comment

PMID: 2344617 [PubMed] Dean M et al: "Multiple mutations in highly conserved residues are found in mildly affected cystic fibrosis patients."

No. Sentence Comment

58 This mutation changes an arginine codon to histidine; it will be referred to as R117H. Login to comment
97 Both of the families that carry the CF R117H mutation contain individuals that are very mildly afA. Login to comment
98 406 GAAGTCACCAAAGCAGTACAGCCTCTC~ACTGGGAAGAATCATAGCTTCCTAT~CCCG EVTKAVQPLLLGR IIASYDP CF DIIOH CAC H 466 GATAACAAGGAGGAAC~TCTATCGCGAmATCTACGCATCTAGGCATAGGC~ATGCC~CTC~T DNKEERSIAIYLGIGLCLLF CF R117H CAC H 526 ATTGTGAGGACACTGCTCCTACACCCAGCCA~GGCC~CATCACA~GGAATGCAG IVRTLLLHPAI FGLHHIGMQ 566 ATGAGAATAGCTATGTTTAGTTTGATTTATAAGAAG MRIAMFSLIYKK 6. Login to comment
117 of Chromosomes Mutation CF DllOH Wild Type Mutated x2 Normal CF CF R117H 94 0 14 1 6.0a Normal CF CF R347P 94 0 13 2 12b Normal CF 96 0 14 1 6.0a Allele Diagnosis D7S399 Number Pancreatic insufficient (PI) 1 2 2 34 Pancreatic sufficient (PS) 1 4 2 4 Number refers to number of chromosomes with the corresponding genotype for the marker MPW (D7S399). Login to comment
128 Thus the two families with the same pair of mutations (AF508 and CF R117H) both contain at least one individual with exceptionally mild disease. Login to comment
130 Three observations support the proposition that these mutations are responsible for disease: the mutations have not been found on over 94 normal chromosomes of the same haplotype; the mutations cause the replacement of highly charged amino acids that are highly conserved in vertebrates; and two families that carry the same combination of mutations (AFSo8 and CF R117H) show mild clinical features. Login to comment
167 The two families with the R117H mutation provide a clear example that clinical characterization of each combination of compound heterozygote may be important in predicting the severity of individual patients. Login to comment
195 The R347P mutation was confirmed by Hhal and Ncol digestion of amplified DNA The DllOH and R117H mutations were confirmed by hybridization at 42% with CF-49 (5`TCCTATCACCCGGAT) and CF-48 (5`.GAGGAACACTCTATC). Login to comment

PMID: 10419835 [PubMed] Shen BQ et al: "Hepatocyte growth factor inhibits amiloride-sensitive Na(+) channel function in cystic fibrosis airway epithelium in vitro."

No. Sentence Comment

34 Amiloride, which has been shown to MATERIALS AND METHODS inhibit the transport of Na+ ions by ENaC, has been shown to inhibit the baseline absorption of Na+ and CF bronchial cells (DF508/R117H and DF508/DF508 genotype) were isolated by protease digestion from fluid by >80%.4,9,10 Further, ENaC activity appears to be overexpressed in CF airway epithelial cells, tissues obtained surgically from CF patients. Login to comment

PMID: 10470322 [PubMed] Cohn JA et al: "Are mutations in the cystic fibrosis gene important in chronic pancreatitis?"

No. Sentence Comment

40 Finally, 3 of the 27 patients had genotypes in which both copies of the CFTR gene were abnormal, representing an 80-fold increase in the frequency for these rare genotypes (P < 0.00001).The two genotypes found in these three patients (AF508/R117H;9T/T and AF508/ WT;9T/5T) are the most common CBAVD genotypes? Login to comment
44 D Class #1 M AF508/R117H 9T/7T 45 1 1 46 moderate #2 F AF508/wt 9T/5T 32 7 52 moderate #3 F AF508/wt 9T/5T 48 20 100+ moderate #4 F AF508/wt 9T/7T 40 25 100+ moderate #5 F AF508/wt 9T/7T 15 16 62 mild #6 F R117H/wt nm 32 6 60 moderate #7 M N1303K/wt 7T/9T 43 1 6 moderate MUTATIONS IN THE CF GENE IMPORTANT IN CHRONIC PANCREATITIS? Login to comment

PMID: 10762539 [PubMed] Mickle JE et al: "Effects of cystic fibrosis and congenital bilateral absence of the vas deferens-associated mutations on cystic fibrosis transmembrane conductance regulator-mediated regulation of separate channels."

No. Sentence Comment

47 DNA was assayed for 16 common CFTR mutations (R117H, 62111GrT, R334W, R349P, A455E, DI507, DF508, 1717-1GrA, G542X, S549N, G551D, R553X, R560T, 3849110 Kb CrT, W1282X, and N1303K), by reverse dot-blot hybridization (Mickle et al. 1998). Login to comment

PMID: 10866956 [PubMed] Zhang ZR et al: "Interaction between permeation and gating in a putative pore domain mutant in the cystic fibrosis transmembrane conductance regulator."

No. Sentence Comment

367 The choppy bursts of S1118F-CFTR closely resemble the bursts of mutant R117H, a mutation that causes mild cystic fibrosis (Sheppard et al., 1993). 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

10 Results: Over a 24-month period we identified 122 ࢞F508 heterozygotes and recruited 57; 4 had borderline sweat chloride levels (40 to 60 mmol/L), 5 (8.8%, 95% CI 1.4, 16.2) had a second CF mutation (R117H), and 11 (20%, 95% CI 10, 30) had the intron 8 5T allele. Login to comment
14 Screened infants with borderline sweat chloride levels almost certainly have CF, but long-term follow-up of the infants with the genotype ࢞F508/R117H and ࢞F508/5T is required to determine their outcome. Login to 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
49 Subject Genotypes Details of the gene mutation analysis and polythymidine tract alleles are presented in Table I. Five (8.8%) infants (95% CI 1.4, 16.2) had an additional exonic mutation, R117H. Login to comment
50 This is significantly higher than the reported frequency of R117H in the Australian CF population (1%, P < .01)27 and the reported frequency of R117H in a community-based screen of a predominantly white population (0.6%, P < .01).28 The intron 8 polythymidine sequences of the ࢞F508/R117H infants were 9T/7T. Login to comment
53 We divided the subjects into groups on the basis of genotype and initial sweat Cl values: initial borderline (40 to 60 mmol/L) sweat Cl levels (borderline, n = 4), subjects with a second mutation (࢞F508/R117H, n = 5), subjects with the 5T allele (࢞F508/5T, n = 11), and subjects with no other mutation and initial sweat Cl level <40 mmol/L (࢞F508/-, n = 37). Login to comment
54 Pancreatic Stimulation Tests Fifty-one infants underwent pancreatic stimulation testing including 3 of 4 infants with an initial borderline sweat Cl level, 4 of 5 infants with the R117H mutation, 10 of 11 infants with the 5T allele, and 34 with no additional mutation and sweat Cl levels <40 mmol/L (Table II). Login to comment
56 Male, female Intron 8 polythymidine sequences ࢞F508/R117H 5 2, 3 9T/7T ࢞I507/- 2 1, 1 7T/7T ࢞I507/- 1 0, 1 7T/5T ࢞F508/- 10 4, 6 9T/5T ࢞F508/- 37 18, 19 9T/7T ࢞F508/- 2 1, 1 9T/9T Total 57 Table I. Results of the extended CF gene mutation analysis HCO3 - + Cl- H2O Colipase activity Genotype group (mmol/kg/h) (mL/kg/h) (%) Control group (n = 43) 1.24 (0.6-1.88) 9.02 (4.97-14.5) 94 (20-200) ࢞F508/R117H (n = 4) 0.71* (0.62-0.89) 7.0 (5.8-9.4) 53* (48-59) ࢞F508/5T (n = 10) 0.81* (0.67-0.97) 7.9 (6.5-9.0) 32* (24-49) ࢞F508/- (n = 34) 0.84* (0.68-0.96) 7.5 (5.8-8.9) 30* (21-42) Borderline (n = 3) 0.44ߤ (0.37-0.52) 6 (5.9-6.2) 33* (23-50) Cystic fibrosis 0.32 (0.22-0.45) 2.9 (1.9-5.2) 35 (8-68) (PS, n = 22) Cystic fibrosis 0.18 (0.10-0.25) 2.2 (1.0-2.9) 0 (0-0) (PI, n = 20) Results are presented as median values with interquartile ranges presented in parentheses. Login to comment
62 In those subjects with an initial sweat Cl level <40 mmol/L, including those with R117H or the 5T allele, the median pancreatic electrolyte secretion, water flow, and colipase activity were midway between values for members of the control group and pancreatic insufficient patients with CF (Figure). Login to comment
63 Three of the 4 R117H subjects and 4 of the 11 5T subjects who had pancreatic stimulation testing had pancreatic electrolyte secretion <0.7 mmol/kg/h (CF range). Login to comment
68 None of the R117H infants had symptoms, nor did those with the 5T allele. Login to comment
74 This is supported by other groups who have directly measured transepithelial Cl transport from rectal suction biopsy specimens and have demonstrated reduced Cl transport through CFTR in patients with sweat Cl levels of 30 to 60 mmol/L.32,33 We found more ࢞F508/R117H compound heterozygotes than expected. Login to comment
75 For patients with R117H, the length of the intron 8 polythymidine sequences determined the proportion of CFTR messenger RNA transcripts containing exon 9, which is critical in determining 217 an initial sweat Cl level between 30 and 40 mmol/L, and repeat sweat Cl level was in the same range (n = 2) or lower (n = 1) at 12 months; all were well on clinical evaluation. Login to comment
80 Boxplot comparison of pancreatic electrolyte secretion (summed HCO3 - + Cl-) for control group, infants with no additional mutation and initial sweat Cl- levels <40 mmol/L (࢞F508/-), infants with 5T allele (࢞F508/5T), infants with second mutation (࢞F508/R117H), infants with borderline initial sweat test results (Borderline), patients with PS CF (CF:PS), and pancreatic insufficient patients with CF (CF:PI). Login to comment
83 the clinical outcome.34 The ࢞F508/ R117H genotype may cause PS CF, usually when R117H is in cis with the 5T allele,21 and congenital absence of the vas deferens when in cis with the 7T allele.20,35 The ࢞F508/R117H subjects in this study had the 9T/7T alleles and could be expected to have ~5% CFTR activity, an amount sufficient to prevent serious respiratory and pancreatic disease.36 However, variable splicing is common,15 and patients with R117H in cis with 7T have been described with PS CF,21 recurrent pancreatitis,37 and allergic bronchopulmonary aspergillosis.38 Therefore it is possible that the R117H subjects from this study may have variants of CF and represent infants missed by screening. Login to comment
86 The subjects with R117H or 5T meet some of the criteria for a diagnosis of CF according to the criteria of the Cystic Fibrosis Foundation,42 namely a positive newborn screening result (elevated IRT level), mutations in each CFTR gene known to cause CF, and for some R117H subjects (n = 3) and 5T subjects (n = 4), evidence of in vivo abnormalities of ion transport. Login to comment
89 We are unable to assess the state of the vas deferens either on clinical evaluation or ultrasonography in the male infants with R117H (n = 2) or the 5T allele (n = 5) to provide evidence of disease expression. Login to comment
96 Reduced pancreatic function in some carriers of CFTR mutations may be the explanation for the association with chronic panceatitis,37,43,44 and there are reports of other disease manifestations in apparently true carriers, such as disseminated bronchiectasis45 and allergic bronchopulmonary aspergillosis38 and perhaps asthma.46 We conclude that the excess of apparent carriers from the IRT/࢞F508 screening program is partly explained by the presence of a second mutation (R117H) and the 5T allele in some infants and that pancreatic duct function is reduced in ࢞F508 heterozygotes with neonatal hypertrypsinogenemia. Login to comment

PMID: 10989979 [PubMed] Arduino C et al: "Genetics of chronic pancreatitis."

No. Sentence Comment

24 Mutation R117H is found on the external face of the trypsin molecule, opposite the bond site for the pancreatic secretory trypsin inhibitor (PSTI) and far from the lateral chain of the trypsinogen activation peptide (TAP). Login to comment
29 It would seem, then, that mutation R117H in the cationic trypsinogen leads to this autosomal dominant disease through a 'gain of function`, which eliminates a decisive inhibitory mechanism. Login to comment
30 The mechanism with which mutation R117H causes pancreatitis seems clear, while it is only possible to hypothesize how mutation N2 1I acts. Login to comment

PMID: 11001491 [PubMed] Kleizen B et al: "Regulated trafficking of the CFTR chloride channel."

No. Sentence Comment

99 Syntaxin binding is observed also with CFTR mutant proteins (e.g. the processing mutant DF508; the regulation mutant G551D; the conduction mutant R117H) and, unlike typical t-SNARE/v-SNARE interactions, is specific for the syntaxin 1A isoform: CFTR is not physically complexed with other epithelial syntaxins (i.e. syntaxin 2 &#b1; 4; with the possible exception of syntaxin 8; see later (Thoreau et al., 1999)), and the cytosolic syntaxin 1A peptide did not augment CFTR Cl currents in syntaxin 1A-deficient but syntaxin 3-containing mouse fibroblasts (L cells) (Naren et al., 2000). Login to comment

PMID: 11113843 [PubMed] Callen A et al: "A simplified cyclic adenosine monophosphate-mediated sweat rate test for quantitative measure of cystic fibrosis transmembrane regulator (CFTR) function."

No. Sentence Comment

60 Among the females with CF, 7 had homozygous ࢞F508 genotypes; 2 had ࢞F508/unknown genotypes; and one each had a genotype of ࢞F508/G551D, ࢞F508/R117H, ࢞F508/3489 + 10 kb C to T, ࢞F508/G542X, ࢞F508/R347P, and R117H/unknown. Login to comment
108 Similarly, some CF homozygotes with so-called "mild mutations" (partially functional CFTR proteins) may be able to produce sweat with a normal or borderline chloride concentration (eg, R117H or 3849 + 10 kb C ࢐ T),4 making the sweat chloride test non-diagnostic in these subjects, although their cAMP-stimulated sweat rate may be decreased. Login to comment
113 Although it is possible that the single CFTR mutation might still retain some partial degree of CFTR function, as would be predicted for the R117H allele, very few of the heterozygote volunteers had such genotypes. Login to comment

PMID: 11231624 [PubMed] Quinton PM et al: "The neglected ion: HCO3-."

No. Sentence Comment

69 Some CFTR mutations (E193K) may support apparently normal, or even much larger than normal (A800G), Cl-transport whereas others (R117H) do not. Login to comment

PMID: 11270251 [PubMed] Barthellemy S et al: "[Evaluation of 47,213 infants in neonatal screening for cystic fibrosis, using pancreatitis-associated protein and immunoreactive trypsinogen assays]."

No. Sentence Comment

101 (n = 12), R117H (n = 3), N1303K (n = 1). Login to comment

PMID: 11448786 [PubMed] Wine JJ et al: "Cystic fibrosis: the 'bicarbonate before chloride' hypothesis."

No. Sentence Comment

49 The value given for R117H is based on repeated measures of an individual homozygous for that mutation (our unpublished data). Login to comment
52 Ion transport (% WT) 42 41 69 75 >100 >100 98 + 103 100 + + 120 Pancreatic sufficient Pancreatic insufficient Bicarbonate Chloride - intermediate Chloride - high Unknown WT D648V R117H R1070Q H949Y G551S H620Q I148T A1067T G178R G970R S1255P G1244E G551D G1349D 0 0.5 1 1.5 2 2.5 Current Biology ࢞F508 Dispatch R absence of the vas deferens [16]. Login to comment
76 Critical information was provided by Thilo D&#f6;rk (H620Q); R. Moss (R117H & G551D homozygotes); David Kessler, Theresa Grebe and Elizabeth Perkett (D648V); Monica Brooks and contributors to the Cystic Fibrosis Foundation Registry (G178R and G1244E); Aleksey Savov and Luba Kalaydjieva (R1070Q); and Christiane De Boeck and Harry Cuppens (G970R). Login to comment

PMID: 11530206 [PubMed] Glick MC et al: "Activity of fucosyltransferases and altered glycosylation in cystic fibrosis airway epithelial cells."

No. Sentence Comment

103 Some mutations (e.g., G542X) produce a truncated transcript and no protein, while other mutations (e.g., R117H) produce a protein that has impaired conduction properties. Login to comment

PMID: 11597137 [PubMed] Manson A et al: "Skipping of exon 9 of human CFTR in YAC-transgenic mice."

No. Sentence Comment

30 Thus the mild R117H missense mutation occurs on both 7T and 5T haplotypes [22] and the phenotype of R117H mutations (as a compound heterozygote with a severe mutation such as èc;F508) is more severe when combined with the 5T allele (mostly pancreatic sufficient CF) than when combined with the 7T allele (mostly CBAVD) [22]. Login to comment
73 Another, 7T44, was generated with a YAC carrying the original TG10T7 splice site with the R117H and T94I mutations. Login to comment
79 However, we cannot determine whether this is due to the T94I mutation, the R117H mutation, and/or low splicing efficiency. Login to comment
80 As further controls, two cell lines (F7T.2 and F7T.5) were made with the YAC carrying the R117H and T94I mutations and the 7T splice site. Login to comment
94 mRNA (n)a of transgeneb TgN(yCFTR)T30Clh T30 TG10T7 2 0.108 (2) 11% TgN(yCFTR)T57Clh T57 TG10T7 1 0.109 (2) 22% TgN(yCFTR)A10Clh A10 TG12T5, R117H, T94I 6 0.205 (2) 7% TgN(yCFTR)7T44Clh 7T44 TG10T7, R117H, T94I nd nd nd Cell line name F7T.2 TG10T7, R117H, T94I 2 0.178 (2) 18% F7T.5 TG10T7, R117H, T94I 8 0.825 (3) 21% a Number of independent cDNA and RT-PCR reactions. Login to comment
125 The level of skipping of exon 9 in the lung, trachea, gall bladder, duodenum, colon, uterus, and epididymis of A10 mice (5Ts, R117H, and T94I) was quite uniform at about 91%. Login to comment
127 A10 differs from T30 not only at the splice site of exon 9, but also in having the R117H and T94I mutations in exon 4. Login to comment
128 To determine whether the R117H and T94I mutations were affecting splicing of exon 9, we also determined the level of skipping of exon 9 in the duodenum and testis of a 7T44 mouse. Login to comment
130 Although slightly higher than the values obtained for T30 mice, the R117H and T94I mutations do not account for the much higher levels of skipping in the A10 line than the T30 line. Login to comment
139 Our original intention was to also study the R117H missense mutation that was introduced into exon 4, but another missense mutation, T94I, was inadvertently introduced into exon 4 at the same time so the effect of the R117H mutation could not be studied. Login to comment
141 In this case, the presence of the R117H and T94I mutations in exon 4 has little effect on the level of skipping of exon 9 as indicated by the similar splicing in the lines T30 and 7T44, which differ only by the two mutations in exon 4 (Fig. 5). Login to comment
176 This may be true for otherwise normal alleles and mild mutations such as R117H in which the CFTR-related phenotype has been shown to be more severe when there is less full-length mRNA. Login to comment
198 The YAC y37AB12 was then modified by homologous recombination in the yeast host to change the splice acceptor to the 5T allele and to introduce the R117H mutation. Login to comment
200 This YAC was then modified to carry the R117H mutation in exon 4 and the 5T splicing variant in intron 8 using the "pop-in pop-out" procedure as described [44]. Login to comment
201 Patient DNAs with the R117H mutation and the 5T splice acceptor allele were kindly provided by Liz Kay (North West Thames Regional Genetic Service). Login to comment
202 The exon 4 region carrying the R117H mutation was amplified using the primers 5b18;-TCACATATGGTATGACCCTC-3b18; and 5b18;-TTGTACCAGCTCACTACCTA-3b18; [45]. Login to comment
210 PCR and sequencing was used to confirm the clones which had been modified with the R117H mutation. Login to comment
212 On later analysis it transpired that a point mutation (nt 413, C to T), in addition to the desired R117H mutation, had been cloned and introduced. 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
29 A I.10 R117H E.4 G542X E.11 Y122X E.4 G551D E.11 711 + 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: 11755605 [PubMed] Hamilton JW et al: "Gentamicin in pharmacogenetic approach to treatment of cystic fibrosis."

No. Sentence Comment

75 THE LANCET ߦ Vol 358 ߦ December 15, 2001 2015 COMMENTARY Effect of CFTR mutations in epithelial cells Lumen Cytoplasm Nucleus Class 4 (eg, R117H) Class 3 (eg, G551D) Class 2 (eg, èc;F508) Class 1 (eg, G542X) Class 5 (eg, A455E) Apical surface Basolateral surface ATP CFTR MSD NBD NBD RD Golgi ER CFTR gene Collectively, the five mutant classes result in little or no functional CFTR expression at the apical surface of epithelial cells, but through different mechanisms. Login to comment
80 Class 4 mutations (such as R117H) result in proteins that have altered chloride conductance, mainly due to mutations within or near one of the transmembrane segments. Login to comment

PMID: 12531063 [PubMed] Lim M et al: "Therapeutic strategies to correct malfunction of CFTR."

No. Sentence Comment

60 Type Genotype Phenotypea Defect Potential therapeutics Class I G542X PI No CFTR synthesis, aminoglycosides 621 + 1 G ࢐T No cell surface Cl- 3905insT transport W1282X R553X 1717-1 G ࢐ A Class II F508b PI Defective CFTR 4-PBA, flavonoids, N1303K trafficking and chemical chaperones, P574Hb processing xanthines A455Eb Class III G551D PI Defective channel flavonoids, milrinone G551S regulation, reduced or absent Cl-transport Class IV R117H PS Reduced Cl-transport 4-PBA, xanthines, R334W flavonoids G314E R347P F508b P574Hb ClassV 3849 + 10 kb C࢐T PS Reduced number of flavonoids, milrinone, 2789 + 5 G ࢐A normal CFTR proteins 4-PBA 3272 - 26 A ࢐ G Reduced Cl-transport A455Eb 3120+1 G࢐A 1811 + 1.6 kb A ࢐ G a PI indicates pancreatic insufficiency; PS indicates pancreatic sufficiency. Login to comment

PMID: 12531100 [PubMed] McAuley DF et al: "Cystic fibrosis: basic science."

No. Sentence Comment

26 The most common of these is the R117H mutation, which is associated with mild disease and late diagnosis.2 Mutations can be divided into five classes, as illustrated in Figure 1.2 Class 1 and class 2 mutations result in no CFTR trafficking to the cell membrane. Login to comment
28 Some of these mutations (e.g. class 3 mutation G551D and class 4 mutation R117H) have residual chloride channel activity. Login to comment
37 These splicing mutations may occur on the same allele (for example, ࢞F508/R117H (5T)) and be associated with the cystic fibrosis phenotype or on the opposite allele (R117H/IVS8-5T or IVS8-5T/IVS8-5T), resulting in congenital bilateral absence of the vas deferens (CBAVD). Login to comment
39 III Severe nucleotide 1784 Substitution of aspartic acid for glycine at AA551 R > H Substitution on exon 4 R117H Missence mutation at IV Mild (5T) AA117 Variable (7T) Insertion of aT after 3905 insT Frame shift due to one II Severe nucleotide 3905 base insertion G to A at nucleotide 5 from 5' 2789 + 5G > A Splice junction mutation V Mild junction of intron starting after nucleotide 2789 Splicing mutation of intron 8 IVS8-5T Frequent out-splicing of V Variable exon 9 AA = amino acid; G = glycine;A = alinine; R = Arginine; H = histidine;T = thymidine; IVS = intravening sequence; > = substitution; Ins = insertion. Login to comment
43 Defective Processing Gogli E.R. R Domain Figure 1 Classification of cystic fibrosis mutations (taken from Knowles et al.2 ) does not cause disease, but R117H with 7T on the same allele has been associated with mild CF disease and CBAVD. Login to comment
48 Approximately 50% of males with CBAVD have two disease-associated mutations of the CF gene.3 The majority of affected individuals have either the 5T splicing mutation (IVS8-5T) or R117H alleles. Login to comment
52 In one study, 10% of patients with CBAVD had mild CF-associated symptoms, but it is possible over time that more may develop lung disease.3 Idiopathic chronic pancreatitis Idiopathic chronic pancreatitis, particularly in the absence of a chronic alcohol history, is associated with mutations of the CF gene.4 ࢞F508, R117H, N1303K and IVS8-5T splicing mutation have all been associated with chronic pancreatitis. Login to comment
54 The most common combination is a severe mutation such as ࢞F508 associated with a splicing mutation such as IVS8-5T, or a mild mutation such as R117H. Login to comment
59 The situation for patients with obstructive azoospermia is clear, and mutations of the CF gene, particularly R117H and IVS8-5T, should be sought, a clinical assessment undertaken and appropriate investigations arranged.6 Genes which modify the CF phenotype There have been some interesting studies investigating the possible effect of other gene mutations and polymorphisms on the CF phenotype. 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

8 In the analysis of the 11 most common genotypes, èc;F508/R117H, èc;F508/èc;I507, èc;F508/3849+10 kbC࢐T, and èc;F508/2789+5G࢐A had a significantly lower mortality rate (4&#b7;7, 8&#b7;0, 11&#b7;9, and 4&#b7;4, respectively) than the genotype homozygous for èc;F508 (21&#b7;8, p=0&#b7;0060). Login to comment
9 èc;F508/R117H, èc;F508/èc;I507, èc;F508/ 3849+10 kbC࢐T, èc;F508/2789+5G࢐A, and èc;F508/A455E have a milder clinical phenotype. Login to 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
62 Patients with genotypes èc;F508/ èc;I507, èc;F508/R117H, èc;F508/3849+10 kbC࢐T, or èc;F508/2789+5G࢐A alleles had significantly lower standardised mortality rates than those homozygous for èc;F508 (table 2). 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
73 Patients with the èc;F508/ R117H, èc;F508/èc;I507, and èc;F508/3849+10 kbC࢐T genotypes had a significantly later age at diagnosis, lower sweat chloride, better nutritional measures, and less pancreatic insufficiency than did èc;F508 homozygotes. Login to comment
74 Patients with genotypes èc;F508/ R117H, èc;F508/A455E, èc;F508/èc;I507 and èc;F508/ 2789+5G࢐A had significantly better lung function and lower rates of P aeruginosa colonisation than èc;F508 homozygotes. Login to comment
93 The investigators showed that, with the exception of èc;F508/R117H, measures of pulmonary function, pancreatic insufficiency, and nutritional status did not differ between the genotypes. Login to comment
94 èc;F508/R117H was associated with lower sweat chloride and less pancreatic insufficiency than èc;F508 homozygotes matched for age and sex. Login to comment
106 Our work confirms previous findings that èc;F508/R117H,9 èc;F508/A455E,12 èc;F508/3849+10 kbC࢐T,13,25 and èc;F508/2789+5G࢐A13,25 are associated with mild clinical manifestations. Login to comment
107 We have also shown that the èc;F508/R117H, èc;F508/èc;I507, èc;F508/3849+10 kbC࢐T, and èc;F508/ 2789+5G࢐A genotypes have a reduced mortality. Login to comment
111 In patients with the èc;F508/R117H genotype, this phenotypic variability could be partly accounted for by different polythymidine sequences in intron 8 of CFTR that have been associated with different clinical features.26,27 Information about polythymidine sequences was not recorded in the registry, so we could not estimate the effect of these variants on outcomes, but this variable should be considered in future interpretation of our results. Login to comment
123 The frequency of èc;F508 homozygotes and heterozygotes is similar to that of Kerem and co-workers.6 Rates of pancreatic insufficiency in the cohorts with èc;F508/R117H and èc;F508/A455E genotypes are higher than that recorded by others.9,12,27 This finding is probably related to an overestimation of pancreatic insufficiency from use of a surrogate marker- pancreatic enzyme supplementation. Login to comment

PMID: 12828958 [PubMed] Hanck C et al: "Genetic polymorphisms in alcoholic pancreatitis."

No. Sentence Comment

48 Two missense mutations within the cationic trypsinogen gene, R122H and N29I (older nomenclature R117H and N21I) cause the majority of cases of HP.2022 Therefore, it had been hypothesized that an inappropriate activation of pancreatic zymogens (either by the prevention of trypsin inactivation, or by an enhanced activation of trypsinogen or by both mechanisms) might also play a role in alcoholic pancreatitis and that alcoholic pancreatitis might have the same genetic background as HP. 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

19 Frequency of 31 mutations in the CFTR gene in 194 Belgian CF chromosomes The 51255X, W1316X ;5 S549N, G551D, R553X, A559T;6 D110H, R117H, R347P;' Q493X, S5491, S549R(T-+G), R560T, Y563N, P574H ;9 W846X, Y913C;10 2556insAT;" R334W;" S549R(A-+C);'6 444delA, 3821deIT;" 621 +1G-*T18 mutations were not present in this random sample of the Belgian CF population . Login to comment

PMID: 14569807 [PubMed] Wang L et al: "Laboratory tests for the diagnosis of cystic fibrosis."

No. Sentence Comment

59 Some mutations (eg, R117H) are reported to be associated with widely variable clinical manifestations, from entirely healthy individuals to the typical multiorgan manifestations of CF. Therefore, the diagnosis of CF cannot be based solely on the identification of CFTR mutations. 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: 15463804 [PubMed] Dodge JA et al: "CF or not CF? That is the question."

No. Sentence Comment

15 However, the question remains whether a given young adult with mild clinical features, an equivocal sweat test and a single 'severe` mutation (such as F508del), either alone or in combination with a 'mild` mutation (such as R117H, in its 7T or 9T version), or with 5T variant, should be diagnosed as having CF. Login to comment

PMID: 15463806 [PubMed] Vankeerberghen A et al: "The cystic fibrosis transmembrane conductance regulator: an intriguing protein with pleiotropic functions."

No. Sentence Comment

383 R117H, R334W and R234P all give rise to a chloride channel with a normal phosphorylation and ATP-dependent regulation, but with reduced single channel currents. Login to comment

PMID: 15463882 [PubMed] Hubert D et al: "Diagnosis of cystic fibrosis in adults with diffuse bronchiectasis."

No. Sentence Comment

47 We used an oligonucleotide ligation assay using a commercially available kit (Cystic Fibrosis Assay, Applied Biosystems, Foster City, CA, USA) to seek 31 mutations in the CFTR gene (F508del, I507del, Q943X, V520F, 1717y1GࡊA, G542X, G551D, R553X, R560T, S549R, S549 N, 3849q10kbCࡊT, 3849q4AࡊG, R1162X, 3659delC, W1282X, 3905insT, 621q1GࡊT, R117H, Y122X, 711q1GࡊT, 1078delT, R347P, R347H, R334 W, A455E, N1303K, G85E, 1898q1GࡊA, 2183AAࡊG, 2789q5GࡊA) which allowed to detect 82% of the CF alleles in France. Login to comment
128 The consensus opinion is Table 3 Sensitivity of the sweat test and genotyping for the diagnosis of cystic fibrosis Positive diagnosis of CF Number of patients (percentage) Sweat test (sweat chloride)60 mmol l ) y1 37 (80%) Molecular analysis: -screening for 31 mutations 18 (39%) -complete screening 36 (78%) Combination of sweat test and molecular analysis: -sweat testqscreening for 31 mutations 42 (91%) -sweat testqcomplete screening 45 (98%) Table 4 Efficacy of the CFTR genetic analysis according to the screening method used Identified mutations Two mutations At least one mutation No mutations Screening for F508del Number of patients (%) 3 (7%) 31 (67%) 15 (33%) Screening for nine mutations* Number of patients (%) 6 (13%) 36 (78%) 10 (22%) Screening for 31 mutations** Number of patients (%) 18 (39%) 43 (93%) 3 (7%) Complete screening Number of patients (%) 36 (78%) 46 (100%) 0 Nine mutations: F508del, I507del, G542X, G551D, R553X, 621q1GࡊT, G85E, R117H, N1303K. Login to comment
129 * 31 mutations: F508del, I507del, Q493X, V520F, 1717y1GࡊA, G542X, G551D, R553X, R560T, S549R, S549 N, 3849q10kbCࡊT, 3849q ** 4AࡊG, R1162X, 3659delC, W1282X, 3905insT, 621q1GࡊT, R117H, Y122X, 711q1GࡊT, 1078delT, R347P, R347H, R334 W, A455E, N1303K, G85E, 1898q1GࡊA, 2183AAࡊG, 2789q5GࡊA. that the laboratory criteria for the diagnosis of CF should be expanded to include identification of CFTR mutations and abnormal bioelectrical properties of the nasal epithelium, in addition to the sweat test w7x. Login to comment

PMID: 16426904 [PubMed] Lording A et al: "Pulmonary infection in mild variant cystic fibrosis: implications for care."

No. Sentence Comment

4 Methods: A retrospective cohort study was carried out comparing frequency of bacterial isolates and clinical outcomes in eleven compound heterozygotes for DF508 and a second mild mutation, mainly R117H, with a matched group of DF508 homozygotes. Login to comment
17 For example, Chmiel et al. expressed their doubts over diagnosing CF in an asymptomatic infant with a DF508/R117H genotype [2]. Login to comment
28 Methods A retrospective cohort study was carried out assessing frequency of bacterial isolates and clinical outcomes in a group of eleven patients (4 male) who were compound heterozygotes for the DF508 mutation and a second mild mutation, mainly R117H (Table 1a). Login to comment
54 There was also a small but significant difference in chest radiograph (Chrispin-Norman) scores (median+range), (mild 5.1, 4-9 vs. severe 5.8, 3-10; p 0.04), although all eleven patients with mild phenotype showed some abnormality on chest X-ray Table 1a Patient details for mild variant cohort Age (years) Sex Genotype Splice site marker Sweat Na+ /Cl (mmol/l) Average Shwachman score/100 Average Chrispin-Norman score/38 Total positive sputum culturesa Positive sputum cultures/year (mean)a 3 Male dF508/R117H 7T/9T 91 5 0 0 5 Male dF508/R117H 7T/9T 93 6 15 2.8 7 Female dF508/R117H 7T/9T 51/49 91.7 7 13 3.3 11 Female dF508/3849+10 kb C>T Unknown 30/36 74.3 9 7 1.8 7 Female dF508/R117H 7T/9T 74/75 93.2 5.3 23 4.6 1 Male dF508/R117H 7T/9T 8 8 4 Female dF508/R117H 7T/9T 95 4 0 0 5 Female dF508/R117H 7T/9T 31/28 95 5.3 14 2.3 6 Female dF508/R117H 7T/9T 42/38 95 4.6 25 3.6 7 Male dF508/R117H 7T/9T 42/28 97 4 5 2.5 7 Female dF508/R117H 7T/7T 50/40 95.7 4.5 41 5.9 a Culture samples based on naso-pharyngeal aspirates/cough swabs/sputum cultures (age dependent). 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: 16678395 [PubMed] Munthe-Kaas MC et al: "CFTR gene mutations and asthma in the Norwegian Environment and Childhood Asthma study."

No. Sentence Comment

5 Possible associations between asthma, reduced lung function, bronchial hyperresponsiveness (BHR), and increased or decreased nitrogen oxide (NO) levels (based on structural parental interview, spirometry, PD20 methacholine challenge test and exhaled NO measurements), and the five most common CFTR mutations in Norway (DF508, R117H, R117C, 4005+2T-C, 394delTT), the modulating polymorphisms IVS8(TG)mTn and the IVS8-5T were investigated. Login to comment
45 The CFTR mutations DF508, R117H, 4005+2T-C, 394delTT, IVS8 Tn(TG)m were analyzed by different PCR-based methods, as described in details below. Login to comment
52 In order to correlate the IVS8 Tn(TG)m haplotype to the fragment lengths, a couple of samples were sequenced and used as standards.30 R117C was analyzed by PCR with the forward primer 50 -M13-TTCACATATGGTATGACCCTC and reverse primer 50 - TTGTACCAGCTCACTACCTA followed by restriction digestion by BsmI and visualized on agarose gel. The fragment sizes from normal samples were 330 and 126 bp, while heterozygote samples got additional bands of 228 and 102 bp.31 R117H was analyzed in two separate PCR`s with a common forward primer C: 50 TCACATATGGTATGACCCTC, and with normal specific arms reverse primer in one tube 50 -CTTATGCCTAGATAAATCGCGA- TAGAAC and mutated specific arms reverse primer 50 -CTTATGCCTAGATAAATCGCGATAGACT in the other tube. Login to comment
53 A R117H heterozygote sample would produce a 237 bp long fragment in both reactions. 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: 16828872 [PubMed] Marcet B et al: "Relationships between cystic fibrosis transmembrane conductance regulator, extracellular nucleotides and cystic fibrosis."

No. Sentence Comment

555 Increased ADO is not expected to improve mucociliary clearance in CF lungs because A2B receptor-mediated stimulation of CFTR channel activity is defective (Boucher, 1994a, 1994b), although an A2B receptor-mediated activation of R117H-CFTR has been demonstrated (Clancy et al., 1999). Login to comment

PMID: 16912456 [PubMed] Okazaki K et al: "[Genetic abnormality and pancreatitis]."

No. Sentence Comment

11 3 ௻db;e2;᜕ᶒఔa8d;ఉĴb;İc;,d8;c6;ed;᜕ᶒKc7;f8b;௼Qe8; e8a;ᡠ΂b;௻dee;ᶒĲf;Ĳa;௤&#ff0e; N34S ᜕ᶒĲb;ఐĴa;, ea;b8;f3;fc; a4;bd;ed;a4;b7;f3;Ze8;f4d; (K42-142) Ĳe;5cd;fdc;ឋİc;᜕ᓄ௱, Vcb;˿d;ᑖYe3;σb;bb3;4b9;ʧc;İc;e1b;f31;௳Ĵb;5ef;Pfd;ឋİc;ὃ௨఑Ĵc;௺ ௤Ĵb;&#ff0e; ᱯ˿a;ឋ᠒ឋQb5;˄e;௻Ĳf; 25~40% Ĳe; ad8;᳛Ĳb;a8d;ఉ ఑Ĵc;Ĵb; N34S d8;c6;ed;᜕ᶒĲf;,eba;5e3;Ĳe;d04; 1% Ĳb;e00;̶c; Ĳb;a8d;ఉ఑Ĵc;Ĵb;&#ff13; &#ff10;) &#ff0e; ௱İb;௱Ĳa;İc;఑, b9f;ωb;Ĳb;Ĳf;d8;c6;ed;᜕ ᶒఔᨵ௳Ĵb;eba;İc;fc5;ıa;௱ఊ᠒ឋQb5;˄e;Ĳb;Ĳa;Ĵb;Ĵf;௫௻Ĳf; Ĳa;௤ıf;ఉ,İa;ıd;఑İf;,ed6;Ĳe;΋a;f1d;b50;ᶒe38;ఌJb0;᛻8e0;b50; Ĳa;௽İc;4a0;Ĵf;௷௺Qb5;˄e;ఔ˿a;Kc7;௳Ĵb;ఊĲe;௼ὃ௨఑Ĵc; Ĵb;&#ff0e;ĳe;ıf;,b27;c73;eba;Ĳe;ᛊᔠ,db;e2;᜕ᶒĲf;ᱯ˿a;ឋ᠒ឋ Qb5;˄e;Ĳe;d04; 10% a0b;ea6;Ĳb;a8d;ఉ఑Ĵc;, d8;c6;ed;᜕ᶒĲe;fdd;ᨵ 914 ᳛İb;఑?a8;bdf;௳Ĵb;௼db;e2;᜕ᶒĲf;eba;5e3; 4 e07;eba;Ĳb; 1 eba;Ĳe; ϗb;ea6;İc;<f3;b9a;௯Ĵc;Ĵb;&#ff0e;ᱯ˿a;ឋQb5;˄e;İc; 16000 eba;Ĳb; 1 eba; ௻௢Ĵb;௭௼ఐĴa;&#ff13; &#ff10;) ,N34S db;e2;᜕ᶒĲe; penetration Ĳf; 25% ee5;e0a;௼ὃ௨఑Ĵc;Ĵb;&#ff0e;ıd;Ĳe;ed6;Ĳe; SPINK1 ᜕ ᶒĲb;Ĳf;, ATG Ze8;ᑖĲe;ξb;;cb;b3;c9;f3;Ĳb;d8;c6;ed;᜕ᶒఔİd; ıf;௳ M1T ᜕ᶒఔᨵ௳Ĵb; 1 bb6;cfb;Ĳe;ᛇȠa;İc;௢Ĵb;&#ff12; &#ff19;) &#ff0e; ௭ Ĳe;΋a;f1d;f62;f0f;Ĳf;Ȁa;ឋ΋a;f1d;௼əd;Ĵf;Ĵc;Ĵb;İc;,N34S ௻Ĳf; SPINK1 [cf;ఔe1b;c11;௯ıb;, 4a3;ឋ΋a;f1d;f62;f0f;ఔ௼Ĵb;&#ff0e; ௭Ĳe; ఐ௦Ĳb; SPINK1 ΋a;f1d;b50;Ĳe;ᛊᔠ,ᑩĲe;᜕ᶒఔᩭıf;௱ ௺ఊ,ᶒĲa;Ĵb;΋a;f1d;f62;f0f;Ĳb;ఐĴa;d50;ʧc;ḄĲb;Ȝc;௲Qe8;e8a;2cf; ఔ௼Ĵb;௼ὃ௨఑Ĵc;Ĵb;&#ff13; &#ff11;) &#ff0e; 3&#ff0e;Cystic fibrosis transmembrane conductance regulator(CFTR)΋a;f1d;b50;Ĳe;᜕ᶒ௼Qb5;˄e; Ĳe;௦Pde;ឋdda;dad;Kc7;(CF)௻Ĳf;b8c;ᐰĲa;Qb5;a5f;Pfd;e0d;ᐰİb; ఑ĳb;ĳc;b63;e38;a5f;Pfd;ĳe;௻e45;e83;௤Qb5;Kc5;᜕ఔᕈ௳Ĵb;௭௼İc; Me5;఑Ĵc;௺௤Ĵb;&#ff0e;Kc7;faf;ឋQb5;˄e;Ĳf; CF ఌQb5;a5f;Pfd;e0d;ᐰ<a3; ὅĲe; 1~2% Ĳb;ĳf;఑Ĵc;Ĵb;&#ff13; &#ff12;) &#ff0e;CFTR ΋a;f1d;b50;Ĳf;b2c; 7 Cd3;⁐f53;(7q31)e0a;Ĳb;b58;ᙠ௱,d04; 250kb,27 a8;af;bd; f3;İb;఑Ĳa;Ĵb;ᜧİd;Ĳa;΋a;f1d;b50;௻௢Ĵa;,af;ed;e9;a4;c9;c1;e3; f3;cd;eb;ఔb3;fc;c9;௳Ĵb;İc;,Qb5;௻Ĳf;Qb5;ba1;e0a;Lae;d30;Pde;Ĳb;˿a; Ife;௱௺[cd;Fad;⏚a4;aa;f3;ᑖccc;Ĳb;[cd;⌕Ĳa;2cd;İd;ఔ௱,CF Ĳb;İa;௤௺Ĳf; CFTR ΋a;f1d;b50;᜕ᶒİc;[cd;⌕௻௢Ĵb;௭௼ İc;Ae2;Ĳb;ᛇȠa;௯Ĵc;௺௤Ĵb;&#ff0e; Sharer ఑Ĳf; 134 f8b;Ĳe;Qb5;˄e; <a3;ὅĲe;௦௵ 18 f8b; (13.4%) Ĳb; CFTR ΋a;f1d;b50;Ĳe;d8;c6; ed;᜕ᶒఔa8d;ఉ௺İa;Ĵa;,bb6;Acf;b74;Ĳe;Ĳa;௤᠒ឋQb5;˄e;<a3;ὅ 60 f8b;e2d; 12 f8b;௻ఊ௭Ĳe;᜕ᶒఔa8d;ఉ௺௤Ĵb;&#ff13; &#ff13;) &#ff0e;ĳe;ıf;, Cohn ఑Ĳf; 27 f8b;e2d; 17 f8b;௻ CFTR ΋a;f1d;b50;᜕ᶒఔa8d; ఉ ௺ ௤ Ĵb;&#ff13; &#ff14;) &#ff0e;CFTR ᶒ e38; Ĳb; 9fa; ௹ İf; ᠒ ឋ Qb5; ˄e; Ĳf; CFTR d8;c6;ed;᜕ᶒ௢Ĵb;௤Ĳf;ed6;Ĳe;΋a;f1d;b50;ᶒe38;ఊ௼ ఊĲa;௦⋋ᔠɂb;ᶒe38;Ĳb;ఐĴb;e38;Cd3;⁐f53;4a3;ឋ΋a;f1d;f62;f0f;௼ ὃ௨఑Ĵc;௺௤Ĵb;&#ff12; &#ff19;) &#ff0e; CF ௻Ĳf;ĳb;௼క௽İc;db;e2;᜕ᶒ௻ ௢Ĵb;İc;,Qb5;˄e;௻Ĳf;d8;c6;ed;᜕ᶒ௻௢Ĵb;௭௼İc;ɏa;İf;, Ĵf;İc;8fd;௻Ĳf;d77;᜜Ĳe;᜕ᶒ௼Ĳf;ĳe;௷ıf;İf;ᶒĲa;Ĵb;௭௼İc; ʔe;఑İb;Ĳb;௯Ĵc;௺௤Ĵb;&#ff0e;Kimura ఑Ĳf;,᠒ឋQb5;˄e; 47 f8b;(a2;eb;b3;fc;eb;ឋ 31 f8b;,ᱯ˿a;ឋ 14 f8b;,bb6;Acf;ឋ 2 f8b;)Ĳe; CFTR ΋a;f1d;b50;ఔʳc;d22;௱,࢞F508 ௼ R117H ᜕ᶒĲf;a8d;ఉĲa;௤ఊĲe;Ĳe;,a4;f3;c8;ed;f3; 8 Ĳe;΋a;f1d;b50;ɏa; ɂb;Ĳe;ϗb;ea6;İc;ʔe;఑İb;Ĳb; ad8;௤௭௼ఐĴa;,Ae5;ʠc;eba;Ĳe;᠒ឋ Qb5;˄e;Ĳb;_a2;Ĵf;Ĵb;5ef;Pfd;ឋఔ̙a;ᖂ௱ıf;&#ff13; &#ff15;) &#ff0e; 4&#ff0e;b1;1-antitrypsin ΋a;f1d;b50;᜕ᶒ௼Qb5;˄e; b1;1-antitrypsin Ĳf;⊈e2d;Ĳb;b58;ᙠ௳Ĵb;˯f;ᳮḄĲa;c8;ea; d7;b7;f3;σb;bb3;ᱥcea;௻௢Ĵa;,ıd;Ĳe;b20;ʀd;Ĳf;ᳮad6;ḄĲb;Ĳf;᠒ ឋQb5;˄e;Ĳe;țf;8e0;Ĳb;Ĳa;Ĵb;5ef;Pfd;ឋİc;௢Ĵa;,b9f;ωb;ıd;Ĳe;5ef;Pfd; ឋఔ̙a;ᖂ௳Ĵb;Kc7;f8b;ఊᛇȠa;௯Ĵc;௺Ĳf;௤Ĵb;İc;&#ff13; &#ff16;) ,ᔲb9a; ḄĲa;ᛇȠa;ఊ௢Ĵb;&#ff0e;b2c; 14 Cd3;⁐f53;e0a;Ĳb;b58;ᙠ௱ 12.2kb ╩௻ 7 ௸Ĳe;a8;af;bd;f3;ఐĴa;Ĳa;Ĵb;΋a;f1d;b50;௻௢Ĵb;&#ff0e;Witt ఑Ĳf; 96 f8b;Ĳe;᠒ឋQb5;˄e;ఔYe3;᪆௱,PiS ௼ PiZ ௼௤௦ 2 ௸Ĳe; b1;1-antitrypsin ΋a;f1d;b50;b20;ʀd;ఔa8d;ఉıf;İc;, ᠒ឋ Qb5;˄e;௼Ĳe;_a2;⌿ឋĲf;ĳf;௤௴ıb;Ĳa;İb;௷ıf;&#ff13; &#ff11;) &#ff0e;Ife;᧲Fb9;௻ Ĳf; b1;1-antitrypsin İc;᠒ឋQb5;˄e;Ĳe;țf;8e0;Ĳb;_a2;e0e;௳Ĵb;5ef; Pfd;ឋĲf;e0d;ʔe;௻௢Ĵa;,eca;f8c;Ĳe;ʳc;a0e;İc;fc5;⌕௼ὃ௨఑Ĵc; Ĵb;&#ff0e; İa;Ĵf;Ĵa;Ĳb; f93;ᩭ,᠒ឋQb5;˄e;Ĳe;a73;d30;Ĳa;˿a;Kc7;a5f;e8f;Ĳf;ʔe;఑İb;௻Ĳa; İb;௷ıf;İc;,΋a;f1d;ឋQb5;˄e;Ĳe;Kc5;8e0;΋a;f1d;b50;᜕ᶒĲe;Ȝc;b9a;Ĳb; ఐĴa;,Qb5;˄e;˿a;Kc7;Ĳe;a5f;e8f;İc;ᑖb50;ec;d9;eb;௻Ye3;᪆௯Ĵc;Ĵb; ఐ௦Ĳb;Ĳa;௷ıf;&#ff0e;ᛇȠa;௯Ĵc;௺௤Ĵb;΋a;f1d;b50;ᶒe38;Ĳe;௳ఇ ௺İc;Qb5;˄e;˿a;Kc7;Ĳe;țf;8e0;Ĳb;Ĳa;௷௺௤Ĵb;İb;Ĳf;eca;Ĳe;௼௭Ĵd; e0d;ʔe;௻eca;f8c;Ĳe;ʳc;a0e;ఔ⌕௳Ĵb;İc;, Qb5;˄e;௼c8;ea;d7;b7;f3;, c8;ea;d7;b7;f3;a4;f3;d2;d3;bf;fc;௼Ĳe;_a2;⌿ឋĲb;௸௤௺d7;ed; bb;c3;b7;f3;b0;ωc;bb3;,d3b;ឋᓄea2;⍈,e0d;d3b;ᓄea2;⍈Ĳa;௽Ĳe; a5f;e8f;İc;ὃ௨఑Ĵc;௺İa;Ĵa;,ıd;Ĵc;఑ఔe2d;fc3;Ĳb;ff0;ఇıf;&#ff0e; ᦻ ˜e; 1)ca1;d0e;Ȥc;e00;:᠒ឋQb5;˄e;Ĳe;Kc5;ɦb;௼cbb;ᷚ&#ff0e;Ae5;ʠc;ᑁOd1;b66;f1a; b66;f1a;`d1;a8c; 94 ; 71ߟ76 : 2005 2)Comfort MW, Steinberg AG : Pedigree of a family with hereditary chronic relapsing pancreatitis . 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
74 p.R117H, a frequent mutation in the British patients, was investigated in the patients from Argentina [[18], Varela and Targovnik, personal communication], Brazil [15,28,29], Colombia [14], Costa Rica [35] and Mexico [13], and was found only in one CF patient from Mexico. Login to comment
98 As an example, in the case of Argentina and Uruguay, the p.F508del mutation shows the highest frequencies (59% and Table 5 Mutations with frequencies less than 0.1% Panel A Mutation Number of chromosomes % Country p.R75X 3 0.07 Mexico c.W1089X 3 0.07 Argentina, Brazil c.406-1GNA 3 0.07 Mexico c.1898+1GNA 3 0.07 Argentina, Brazil c.2686_2687insTÌe; 3 0.07 Argentina, Brazil p.L206W 2 0.05 Brazil p.I506T 2 0.05 Mexico p.S589I 2 0.05 Argentina c.711+1GNT 2 0.05 Argentina c.935delA 2 0.05 Mexico c.2055_2063del 2 0.05 Mexico c.2347delG 2 0.05 Brazil c.2566_2567insTÌe; 2 0.05 Argentina c.2789+2_2789+3insA 2 0.05 Argentina c.3199_3204del 2 0.05 Mexico c.3272-26ANG 2 0.05 Argentina c.4016_4017insT 2 0.05 Argentina Panel B Mutation N % each Country p.L6VÌe;, p.W57X, p.Q220X, p.Y362XÌe;, p.I1027T, p.G1061R, p.R1283M, c.297-2ANG, c.1353_1354insTÌe;, c.1460_1461delATÌe;, c.1782delA, c.1898+3ANG, c.2184delA, c.2594_2595delGTÌe;, c.2869_2870insG, c.4005Ìe;1GNA, c.4005-1GNA# 17 0.02 Argentina p.R117H, p.H199Y, p.G551S, p.L558S, p.P750L, p.V754M, p.W1069X#, p.W1098CÌe;, p.W1204X, c.297-1GNAÌe;, c.846delTÌe;, c.1078delT, c.1716GNA, c.1924_1930del, c.4160_4161insGGGGÌe; 15 0.02 Mexico p.V201M, p.V232D, p.Y275XÌe;, p.R347P, p.R851L, p.Q1238X, c.3171delC, c.3617_3618delGAÌe;# 8 0.02 Brazil p.A559T, p.H609RÌe;, c.1215delG, c.1323_1324insAÌe;, c.2185_2186insC, c.3500-2ANGÌe;, c.3849+1GNA, 7 0.02 Colombia c.-834GNT 1 0.02 Uruguay The upper part (Panel A) shows the mutations found in more than one patient, whereas the lower part (Panel B) of the table shows all the mutations that are present only once in each country. 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

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

PMID: 18291560 [PubMed] Durieu I et al: "[Cystic fibrosis in 2008]."

No. Sentence Comment

61 En fonction des cons&#e9;quences des mutations du g&#e8;ne CFTR sur la structure et la fonction de la prot&#e9;ine CFTR, un regroupement par classe a &#e9;t&#e9; propos&#e9; [12] : le groupe 1 correspond aux mutations responsables d`absence de production prot&#e9;ique ; les mutations du groupe 2 (auquel appartient la mutation F508) sont &#e0; l`origine d`un d&#e9;faut de transfert intracellulaire avec d&#e9;gradation pr&#e9;matur&#e9;e de la prot&#e9;ine dans le cytoplasme et une absence d`expression &#e0; la membrane ; les mutations des groupes 3 et 4 sont responsables d`une prot&#e9;ine pr&#e9;sente &#e0; la membrane mais non fonctionnelle, soit par d&#e9;faut de r&#e9;gulation par l`ATP (groupe 3), soit par diminution de la conductance (groupe 4) comme la mutation R117H ; enfin les mutations du groupe 5 sont responsables d`une quantit&#e9; r&#e9;duite de prot&#e9;ine fonctionnelle. Login to comment

PMID: 18801689 [PubMed] Robin G et al: "[Why and how to assess hypospermia?]."

No. Sentence Comment

157 Les mutations DF508 et R117H sont retrouv&#e9;es relativement fr&#e9;quemment dans les formes g&#e9;nitales de mucoviscidose mineure avec absence uni- ou bilat&#e9;rale des canaux d&#e9;f&#e9;rents [53,54]. Login to comment
324 BMC Med Genet 2004;5:p.8. [53] Gervais R., et al. High frequency of the R117H cystic fibrosis mutation in patients with congenital absence of the vas deferens. N Engl J Med 1993;328(6):446-7. Login to comment

PMID: 18822253 [PubMed] Munck A et al: "[The French nationwide cystic fibrosis newborn screening program: strategy and results]."

No. Sentence Comment

50 L`organigramme du DNN (fig. 1) pr&#e9;voit une valeur seuil de TIR &#e0; J3 d&#e9;termin&#e9;e sur les donn&#e9;es des r&#e9;gions fran&#e7;aises ayant d&#e9;but&#e9; ce d&#e9;pistage il y a plus de 10 ans afin de s&#e9;lec- Mutations recherch&#e9;es par le Kit Elucigen dans le cadre du d&#e9;pistage n&#e9;onatal de la mucoviscidose (Kit CF30) : F508del ; I 507del ; 1078delT, 1717-1 G>A ; 2183AA>G ; 3659delC ; 3849+10kbC>T ; 621+1G>T ; A455E ; E60X ; G542X ; G551D ; N1303K ; R1162X ; R117H ; R334W ; R347P ; R553X ; S1251N ;W1282X ; 1811+1.6kbA>G ; 2789+5G>A ; 3120+1G>A ; 3272-26A>G ; 394delT ; 711+1G>T ; G85E ; Y1092X ; Y122X ;W846X. Login to comment
148 Immunoreactive trypsin/DNA newborn screening for cystic fibrosis: should the R117H variant be included in CFTR mutation panels? Login to comment
150 O`Sullivan BP, Zwerdling RG, Dorkin HL, et al. Early pulmonary manifestation of cystic fibrosis in children with the DeltaF508/ R117H-7T genotype. Login to comment

PMID: 19181498 [PubMed] Gaillard D et al: "[Mild cystic fibrosis: genetics - extending follow-up is necessary]."

No. Sentence Comment

15 &#df; 2009 Elsevier Masson SAS. All rights reserved. Mots cl&#e9;s : CFTR ; Test de la sueur ; Mucoviscidose ; R117H 1. Login to comment
43 Parmi les variations de s&#e9;quence identifi&#e9;es en p&#e9;riode n&#e9;onatale par le kit &#c9;lucig&#e8;ne1 CF30, plusieurs sont reconnues comme ayant un effet mod&#e9;r&#e9;, comme R117H, R334W, R2789 + 5G > A, 3272-26A > G, 3849 + 10kbC > T [7,9,10], voire variable, notamment G85E, A455E [3] ; les 23 autres mutations sont reconnues comme s&#e9;v&#e8;res. Login to comment
82 La mutation R117H est la deuxi&#e8;me mutation d&#e9;tect&#e9;e lors du d&#e9;pistage n&#e9;onatal et repr&#e9;sente 7 % des cas en France. Login to comment
84 Les enfants h&#e9;t&#e9;rozygotes composites F508del/R117H-7T pr&#e9;sentent une forme att&#e9;nu&#e9;e de mucoviscidose &#e0; de tr&#e8;s rares exceptions pr&#e8;s. Login to comment
114 [11] Thauvin-Robinet C, Munck A, Huet F, et al. A French collaborative study indicative of a very low classical-CF penetrance of R117H; implication for genetic counselling. 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

103 [33,36,37] With a class IV mutation (e.g. R117H, R334W, R234P), CFTR processing to the apical membrane and regulation by cAMP and cAMP-dependent protein kinase (PKA) are not affected. Login to comment

PMID: 20619026 [PubMed] Ras JE et al: "[Cystic fibrosis in a woman aged seventy]."

No. Sentence Comment

16 Wegens het vermoeden van cystische fibrose (CF) werd het 'cystic fibrosis transmembrane conductance regulator`(CFTR)-gen geanalyseerd, waarbij de mutaties F508del en R117H -7T werden aangetoond. Login to comment
35 Genetisch onderzoek toonde een F508del- en een R117H-7T-mutatie. Login to comment
44 bronchi&#eb;ctasie&#eb;n NEDTIJDSCHR GENEESKD. 2010;154:A1342 K L I NI SCH E PR AK TI JK bepalend voor de ernst van de symptomen.1-3 In de kaukasische populatie is de prevalentie van de R117H-7T-mutatie uit klasse IV slechts 0,3%. Login to comment
45 Het fenotype bij de F508del/R117H-7T-mutatie is zeer variabel. Login to comment
49 Als een pati&#eb;nt de R117H-mutatie heeft, bepaalt de lengte van de sequentie de ernst van de symptomen. Login to comment
51 Het 7T-allel zit hier tussenin.6 Onze pati&#eb;nte had de F508del/R117H-7T-mutatie, die zich uitte met ge&#ef;so- leerde bronchi&#eb;ctasie&#eb;n. Login to comment
56 Bij een pati&#eb;nt met niet-klassieke CF en een milder ziektebeeld kan de chlorideconcentratie echter normaal (< 30 mmol/l) of licht verhoogd (30-60 mmol/l) zijn; de F508del/R117H-7T-mutatie leidt doorgaans tot waarden boven de 30 mmol/l.7 Als de zweettest geen duidelijkheid geeft over de diagnose, kan disfunctie van CFTR aangetoond worden met een neuspotentiaalmeting of door het aanto- nen van twee mutaties in het CFTR-gen (tabel 2).3,4,9 Conclusie Onze pati&#eb;nte presenteerde zich met recidiverende luchtweginfecties door S. aureus bij perifere bronchi&#eb;ctasie&#eb;n, vooral in de bovenkwabben; daarnaast had zij een ABPA. Login to comment
58 De mutaties F508del en R117H-7T die bij de mutatie-analyse werden gevonden toonden echter aan dat onze pati&#eb;nte een niet eerder onderkende vorm van CF had. Login to 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
84 6 Massie RJH, Poplawski N, Wilcken B, Goldblattz J, Byrnes C, Robertson C. Intron-8 polythymidine sequence in Australasian individuals with CF mutations R117H and R117C. Login to comment
87 7 Thauvin-Robinet C, Munck A, Huet F, G&#e9;nin E, Bellis G, Gautier E, et al. The very low penetrance of cystic fibrosis for the R117H mutation: a reappraisal for genetic counselling and newborn screening. Login to comment

PMID: 22043142 [PubMed] Lilley M et al: "Newborn screening for cystic fibrosis in Alberta: Two years of experience."

No. Sentence Comment

22 A relatively high frequency of the R117H mutation and the M1101K mutation was noted. Login to comment
24 The presence of the R117H mutation has created both counselling and management dilemmas. Login to comment
29 Les d&#e9;pistages positifs sont suivis d`un test &#e0; la sueur et d`une &#e9;valuation par un sp&#e9;cialiste de la FK. Des 99 408 nouveau-n&#e9;s ayant fait l`objet d`un test de d&#e9;pistage en Alberta pendant les deux premi&#e8;res ann&#e9;es du programme, 221 ont obtenu des r&#e9;sultats positifs au d&#e9;pistage n&#e9;onatal de la FK. Le programme a ensuite permis de rep&#e9;rer et d`amorcer un traitement chez 31 nouveau-n&#e9;s atteints de FK. On a remarqu&#e9; une fr&#e9;quence relativement &#e9;lev&#e9;e des mutations R117H et M1101K. Login to comment
31 La pr&#e9;sence de la mutation R117H a cr&#e9;&#e9; &#e0; la fois des dilemmes de counseling et de prise en charge. Login to 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
48 Molecular analysis of parents is recommended when R117H and 5 thymine (5T) are identified to assess phase. Login to comment
52 Newborns are reported to have an inconclusive screen if they fall into one of the following three categories: an elevated IRT and one mutation; a markedly elevated IRT and no mutations; or an elevated IRT and two mutations, in which the second mutation is R117H without 5T. Login to comment
53 Newborns with an elevated IRT and two mutations (excluding R117H without 5T) are reported as having probable CF. Login to comment
58 Sweat chloride testing is generally performed when infants are between four and six weeks of Immunoreactive Trypsinogen (IRT) measurement Elevated IRT Normal IRT= Negative newborn screen for CF CFTR mutation screening (39 mutation panel) Probable Screen (2 mutations, excluding R117H without 5T) Inconclusive Screen (1 mutation, IRT >99.9% or mut/ R117H) Negative screen (no mutations and IRT is not markedly elevated) Lab Genetic Counsellor contacts physician regarding results Lab Genetic Counsellor contacts physician regarding results Referral to CF Clinic for sweat test and clinical assessment Referral to CF Clinic for sweat test and clinical assessment Sweat Test Positive Clinical diagnosis of CF Sweat Test Borderline/ Negative Further follow-up required Sweat Test Positive Full CFTR sequencing Sweat Test Borderline Repeat sweat test and/or CFTR full sequencing Sweat Test Negative CF carrier, unlikely to have classic CF Figure 1) Alberta cystic fibrosis (CF) newborn screening protocol. Login to comment
75 During the first two years of the program, 198 newborns had an inconclusive screen including 191 newborns with one mutation, two newborns with markedly elevated IRTs and five newborns with R117H/delF508 genotypes (Table 2). Login to comment
79 Six newborns had R117H in conjunction with a second CF mutation. Login to comment
81 Five of the newborns had delF508/R117H without 5T and, therefore, were reported as having an inconclusive screen for CF. Login to comment
84 TAbLe 1 Mutation frequency Mutation name Number of times detected (247 total mutations) Frequency, % expected, % (reference) delF508* 156 63.2 68.6 (1) R117H* 36 14.6 0.7 (1) G551D* 11 4.5 2.1 (1) 3849+10kbC࢐T* 6 2.4 0.7 (1) M1101K 5 2.0 Undetermined (1) G542X* 4 1.6 2.4 (1) 1717-1G࢐A* 4 1.6 0.7 (1) 621+1G࢐T* 3 1.2 0.9 (1) 3120+1G࢐A* 3 1.2 1.5 (1) G85E* 2 0.8 0.3 (1) A455E* 2 0.8 0.2 (1) R553X* 2 0.8 0.9 (1) 2789+5G࢐A* 2 0.8 0.3 (1) ƊI507* 1 0.4 0.3 (1) 711+1G࢐T* 1 0.4 0.1 (1) R334W* 1 0.4 0.2 (1) N1303K* 1 0.4 1.3 (1) 1898+1G࢐A* 1 0.4 Undetermined (1) 2184delA* 1 0.4 0.1 (1) 394delTT 1 0.4 Undetermined (1) R347H 1 0.4 0.2 (4) V520F 1 0.4 0.2 (4) S549N 1 0.4 0.1 (1) 2307insA 1 0.4 0.2 (1) R347P* 0 0 0.2 (1) R560T* 0 0 0.2 (1) R1162X* 0 0 0.2 (1) 3659delC* 0 0 0.2 (1) W1282X* 0 0 1.4 (1) 1078delT 0 0 0.03 (2) Y122X 0 0 Undetermined (3) A559T 0 0 0.2 (1) S549R 0 0 Undetermined (1) 1898+5G࢐T 0 0 Undetermined (1) 2183AA࢐G 0 0 0.1 (1) Y1092X 0 0 Undetermined (1) S1255X 0 0 0.2 (1) 3876delA 0 0 Undetermined (4) 3905insT 0 0 0.12 (1) *American College of Medical Genetics-recommended mutations TAbLe 2 Positive cystic fibrosis newborn screen summary Screen result Unaffected Affected Further follow-up required Lost to follow-up Total Probable screen 0 23 0 0 23 Inconclusive screen One mutation 179 8 2 2 191 Markedly elevated IRT 2 0 0 0 2 R117H/F508del 0 0 5 0 5 Total 181 31 7 2 221 Data presented as n. IRT Immunoreactive trypsinogen TAbLe 3 F508del/R117H cases ID number Mutation status Sweat test result(s), &#b5;mol/L Other clinical information 24827 F508del/R117H 28 None 23726 F508del/R117H 36/insufficient/20 Fecal elastase normal 22578 F508del/R117H 10 None 24500 F508del/R117H 34/insufficient None 18527 F508del/R117H 29 None 23317 F508del/R117H+5T 47/62 Affected sibling 5T 5 thymine There were 23 newborns with probable screens. Login to comment
109 The individual frequency of those mutations was as expected, apart from R117H, which was more common in our study population. Login to comment
114 The overall frequency of the R117H mutation in our sample population appears to be higher than previously reported in the literature. Login to comment
115 The R117H mutation is known to be modified by the length of the polythymine tract in intron 8. Login to comment
117 Whereas, when R117H is in cis with 7T or 9T, it is believed to act as a mild mutation and is associated primarily with congenital absence of the vas deferens or atypical adult-onset CF. Login to comment
118 The frequency of R117H in the literature varies from 0.5% to 0.7% of CF mutations (3,7-9). Login to comment
119 In our population of screen-positive newborns, the frequency of R117H was 36 of 247 mutations (14.6%). Login to comment
120 In six of 36 cases, a second CFTR mutation was detected and in 30 of 36 cases, the baby carried only the R117H mutation, with or without 5T. Login to comment
121 Other newborn screening programs also report a high frequency of R117H in newborns with two CFTR mutations. Login to comment
122 The frequency of an R117H mutation in newborns with two CFTR mutations ranges from 7.2% in France, to 8% in Massachusetts (USA), to 26.7% in Wisconsin (USA) (2,10,11). Login to comment
125 Predicted splice site mutation 14780 35 69 F508del R352W Rare, no clinical data published 17316 53/35 74 F508del L206W Variable, ranging from classic CF to isolated CBAVD (8) 16053 26/62 72 F508del 5T Associated with atypical CF and CBAVD (9) 21739 N/A 98 F508del G458V Associated with classic CF (17) 16229 31/32 62 F508del - N/A 16369 38/48 79 711+G࢐T - N/A 12468 NSQ/30 103 F508del - N/A 5T 5 thymine; CBAVD Congenital bilateral absence of the vas deferens; CF Cystic fibrosis; IRT Immunoreactive trypsinogen; N/A Not available; NSQ Not sufficient quantity or absent phenotype, individuals with the R117H mutation may be underdiagnosed and the mutation frequency may be under-represented. Login to comment
126 Newborns with a genotype involving a known disease-causing mutation and R117H create counselling and management dilemmas. Login to comment
127 We identified five newborns with a F508del/R117H genotype in the absence of 5T. Login to comment
131 Congenital bilateral absence of the vas deferens is also associated with the combination of a severe mutation and R117H. Login to comment
133 Currently, there is no consensus on how to manage children with a F508del/R117H genotype. Login to comment
136 There has been debate in the literature regarding the inclusion of R117H in newborn screen. Login to comment
189 Massie RJ, Poplawski N, Wilcken B, Goldblatt J, Byrnes C, Robertson C. Intron-8 polythymidine sequence in Australasian individuals with CF mutations R117H and R117C. Login to comment
196 Scotet V, Audrezet MP, Roussey M, et al. Immunoreactive trypsin/ DNA newborn screening for cystic fibrosis: Should the R117H variant be included in CFTR mutation panels? Login to comment

PMID: 22527665 [PubMed] Smaczny C et al: "[Emergencies in adult mucoviscidosis patients]."

No. Sentence Comment

19 Bei Neugeborenen kommt es typischerweise zu einem Tab. 1ߓ Typische Mutationen bei der Mukoviszidose Mutationsklasse Defektbeschreibung Beispiele (alte Nomenklatur) I Vollst&#e4;ndigerVerlust der CFTR-Protein- synthese R553X, G542X, N1303K, Êf; 1717-1 G &#e1;ߙ A II St&#f6;rung der Reifung und des intrazellul&#e4;- renTransports des CFTR-Proteins DF508 III Regulationsst&#f6;rung des Ionenkanals G551D IV St&#f6;rung der Ionenleitf&#e4;higkeit des CFTR-Kanals R347H, R117H V Verminderte CFTR-Konzentration in der Zelle 3849+10kBÊf;C &#e1;ߙ T VI Beschleunigter CFTR-Abbau ߕ CFTRÉe;Cystic fibrosis transmembrane conductance regulator". Login to comment

PMID: 23164641 [PubMed] Kelly C et al: "Expression of the inflammatory regulator A20 correlates with lung function in patients with cystic fibrosis."

No. Sentence Comment

4 Methods: Primary nasal epithelial cells (NECs) from CF patients (F508del/F508del, n=7, R117H/F508del, n=6) and controls (age-matched, n=8), and 16HBE14o-cells were investigated. Login to comment
7 Following LPS stimulation A20 and TAX1BP1 expression was induced in control NECs and reduced in CF NECs, broadly reflecting the CF genotype: F508del/F508del had lower expression than R117H/F508del. Login to comment
27 Here we further investigate the relationship between A20, TAX1BP1 and CFTR as well as any association with lung function (FEV1) in patients homozygous for F508del and heterozygous for R117H/F508del. Login to comment
29 Materials and methods Primary nasal epithelial cells (NEC) were obtained from CF patients (F508del/F508del {n=7}, R117H/F508del {n=6}) and age matched controls {n=8} as previously described [11] and were fully differentiated at air-liquid interface (ALI). Login to comment
42 The effect of different CF genotypes (R117H/F508del and F508del/F508del) on basal A20 (C) and TAX1BP1 (D) mRNA expression was determined by qPCR. Login to comment
58 F508del homozygotes showed a more pronounced reduction in A20 expression than R117H/F508del heterozygotes (pb0.05, Fig. 1E). Login to comment
60 To provide a basic indication of how reduced A20 expression may relate to NF-ba;B and the inflammatory response we assessed the expression of p65 (NF-ba;B subunit) by qPCR Following LPS stimulation, p65 expression was higher in F508del homozygotes than R117H/F508del heterozygotes (pb0.05, Fig. 2A). Login to comment
65 The median FEV1 for the R117H/F508del Fig. 2. Login to comment
67 The effect of different CF genotypes (R117H/F508del and F508del/ F508del) on LPS-induced p65 (A) expression was determined by qPCR. Login to comment
82 Basally and following LPS stimulation, A20 expression was reduced in CF cells in a manner that largely reflected genotype; the F508del/F508del group had a lower expression than the R117H/F508del group. Login to comment

PMID: 23209179 [PubMed] Ferec C et al: "Assessing the Disease-Liability of Mutations in CFTR."

No. Sentence Comment

94 Other C. Ferec and G.R. Cutting 4 Cite this article as Cold Spring Harb Perspect Med 2012;2:a009480 www.perspectivesinmedicine.org by Cold Spring Harbor Laboratory Press at SEMMELWEIS UNIV OF MEDICINE on December , mutations that alter residual CFTR function such as R117H (p.Arg117His) and R347P (p.Arg347Pro) have been associated with the pancreatic sufficiency (Kristidis et al. 1992). Login to comment
107 As residual CFTR function is increased, such as in the case of the R117H mutation bearing the 7T variant, lung function is improved sufficiently such that a CF diagnosis may not be evident. Login to comment
108 Males bearing the combination of F508del mutation panel with R117H-7T are generally discovered because of infertility caused by absence of the vas deferens (see below). Login to comment
128 A role for CFTR in male infertility was extended by Anguiano et al. who provided evidence of compound heterozygosity for CFTR mutations (i.e., F508del and R117H) inCBA VDpatients(Anguianoetal.1992).Other groups confirmed the presence of two CFTR mutations in a subset of males with CBA VD (De Braekeleer and Ferec 1996; Wilschanski et al. 1996). Login to comment
132 The second one is a complex haplotype with the R117H missense mutation in exon 7 associated in cis with the IVS8-7T (Kiesewetter et al. 1993; Mercier et al. 1995; Cuppens et al. 1998). Login to comment
144 The two most common CFTR-RD alleles are the IVS8-5T, a poly T tract in intron 8 of the CFTR, and the R117H associatedwiththe 7Ttract (Chillo &#b4;net al.1995). Login to comment
148 The IVS8 poly tract of T is also a genetic modifier of the R117H when associated in cis. Login to comment
149 The combination of R117H-7T is found in CBA VD, but R117H associated in cis with a 5T is a complex CFallele generally associated with a mild phenotype of CF (Kiesewetter et al. 1993). 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

77 Similarly, all cases with the R117H-IVS8 T(7) in cis, which did not meet the diagnostic criteria were also excluded from this study. Login to comment

PMID: 23317763 [PubMed] van Meegen MA et al: "CFTR-mutation specific applications of CFTR-directed monoclonal antibodies."

No. Sentence Comment

3 Mutant CFTR was detected in HEK293 cells transiently expressing the mutations; G542X, R1162X, F508del, N1303K, G551D, R117H, A455E. Login to comment
17 Class III (G551D) and IV (R117H) mutations affect gating and chloride conductivity, respectively, but display normal trafficking [6,10,11]. Login to comment
76 We selected wt-CFTR, F508del (class II), G542X (I), R1162X (I), G551D (III), R117H (IV), A455E (V), and N1303K (II) that were ectopically expressed in HEK293 cells. Login to comment
82 Expression of G551D (class III) and R117H (class IV) was comparable to wt-CFTR. Login to comment
95 CFTR Mutants F508del R1162X G551D R117H A455E N1303K 596, 769, 24.1 , 570, 432,450 570, 432, 450 570, 432, 450, 24.1, 769, 596 570, 570, 596, 769, 24.1, 432, 450 596, 769, 24.1, 432, 450 769, 596, 570, 24.1, 432, 450 is likely still preserved and bound to interacting proteins that may affect the binding to specific mAbs. Login to comment
111 G551D was expressed at levels comparable to wt-CFTR, expression of R117H, N1303K, A455E and R1162X was intermediate, and low levels were observed for F508del and G542X. Login to comment
112 Expression of R117H and N1303K by mAb 570 was higher compared to the other R-domain mAbs. Login to comment
145 Western blots containing 25 bc;g of total protein of HEK293 cells transiently transfected with pcDNA3 containing; CFTR-wt, F508del, G542X, R1162X, G551D, R117H, A455E, N1303K or empty vector. Login to comment
151 Monoclonal antibody 450 detected wt-CFTR, G551D, R117H and N1303K (Fig. 4C). Login to comment
154 The NBD2-selective mAb 596 could recognize wt-CFTR, G551D, R117H and N1303K equally (Fig. 4C). Login to comment
216 Furthermore, we confirmed [31,32] and expanded data on mutant G551D and R117H by demonstrating with Western blot and flow cytometry that expression and trafficking were not affected. Login to comment
220 Furthermore, we provide more insight on the impact of CFTR mutations N1303K, A455E, G551D and R117H on CFTR expression. Login to comment

PMID: 23361109 [PubMed] Sorio C et al: "Impaired CFTR function in mild cystic fibrosis associated with the S977F/T5TG12complex allele in trans with F508del mutation."

No. Sentence Comment

60 Furthermore, where genetic variants arise, the complete scanning of the gene is required since synergies in different variants/polymorphisms can affect the CFTR function and lead to manifestation of the disease, as in the case of R117H [16]. Login to comment

PMID: 23378595 [PubMed] Tsui LC et al: "The cystic fibrosis gene: a molecular genetic perspective."

No. Sentence Comment

104 However, if the 5T allele is present in combination with another mild mutation, p.Arg117His (R117H) (Gervais et al. 1993), the combined effect of R117H-5T (reduced protein function and lower abundance of correctly spliced transcript) is ap- parentlysufficient to cause CF, albeit the pancreatic sufficient form (Chu et al. 1993; Massie et al. 2001; Zuccato et al. 2004). 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

0 ORIGINAL ARTICLE CFTR p.Arg117His associated with CBAVD and other CFTR-related disorders Christel Thauvin-Robinet,1,2 Anne Munck,3,4 Fr&#e9;d&#e9;ric Huet,2,3,5 Alix de Becdeli&#e8;vre,6 Cl&#e9;ment Jimenez,7 Guy Lalau,8 Elodie Gautier,9,10 Jacques Rollet,11 Jean Flori,12 Rapha&#eb;lle Nov&#e9;-Josserand,13 Jean-Claude Soufir,14 Alain Haloun,15 Dominique Hubert,16 Elise Houssin,3 Gil Bellis,17 Gilles Rault,18 Albert David,19 Laurent Janny,20 Rapha&#eb;l Chiron,21 Nathalie Rives,22 Dominique Hairion,23 Patrick Collignon,24 Antoine Valeri,25 Gilles Karsenty,26 Annick Rossi,27 Marie-Pierre Audr&#e9;zet,28 Claude F&#e9;rec,28 Julie Leclerc,8 Marie des Georges,29 Mireille Claustres,29 Thierry Bienvenu,30 B&#e9;n&#e9;dicte G&#e9;rard,31 Pierre Boisseau,32 Fa&#ef;za Cabet-Bey,33 David Cheillan,3,34 Delphine Feldmann,35 Christine Clavel,36 Eric Bieth,37 Albert Iron,38 Brigitte Simon-Bouy,39 Vincent Izard,40 Julie Steffann,41 St&#e9;phane Viville,42 Catherine Costa,6 V&#e9;ronique Drouineaud,7 Patricia Fauque,2,7 Christine Binquet,9 Claire Bonithon-Kopp,9 Mike A Morris,43 Laurence Faivre,1,2 Michel Goossens,6 Michel Roussey,3,44 Emmanuelle Girodon,6 the collaborating working group on p.Arg117His b8; Additional material is published online only. Login to comment
4 ABSTRACT Background The high frequency of the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) gene mutation p.Arg117His in patients with congenital bilateral absence of the vas deferens (CBAVD) and in newborns screened for CF has created a dilemma. Login to comment
5 Methods Phenotypic and genotypic data were retrospectively collected in 179 non-newborn French individuals carrying p.Arg117His and a second CFTR mutation referred for symptoms or family history, by all French molecular genetics laboratories, referring physicians, CF care centres and infertility clinics. Login to comment
6 Results 97% of the patients had the intronic T7 normal variant in cis with p.Arg117His. Login to comment
12 Eight children were born, including four who were compound heterozygous for p.Arg117His and one with a severe CF mutation. Login to comment
13 Conclusions Patients with CBAVD carrying p.Arg117His and a severe CF mutation should benefit from a clinical evaluation and follow-up. Login to comment
20 The c.350G>A (p.Arg117His, R117H) mutation, though initially described in CF patients,5 has been considered predominantly associated with CBAVD.6-9 Phenotypic variability was mostly attributed to the presence of a polymorphic intronic polyT variant, c.1210-12T(5) or T(7) in cis with p.Arg117His (ie, T5 or T7 on the same chromosome as p.Arg117His). Login to comment
21 While the T7 variant is considered neutral, the T5 variant in cis 220 with p.Arg117His has been associated with a more severe outcome. Login to comment
22 11 The recent observation of a high frequency of p. Arg117His in newborns screened for CF has reinforced diagnostic and genetic counselling dilemmas,12 even for CBAVD couples because of reproductive concerns. Login to comment
23 Epidemiological data from a large collaborative French survey on this mutation have already identified very low penetrance of classical CF in individuals carrying p.Arg117His in cis with T7 and the most frequent CF mutation, c.1521_1523del (p.Phe508del, F508del), with penetrance estimated at 0.03%.13 The aim of the present study was to focus on and detail phenotype and genotype data in CBAVD patients who carried two CFTR mutations with p.Arg117His on at least one allele, and to document the outcomes of assisted reproduction techniques (ART), and prenatal and preimplantation diagnoses (PND and PGD) for the couples, with a view to improving practices for follow-up and genetic counselling. Login to comment
24 SUBJECTS AND METHODS Clinical and genotype-phenotype correlation studies A retrospective cohort study was initiated by the French CF laboratory network to collect phenotype and genotype data of all individuals with two CFTR mutations including p.Arg117His on at least one allele, identified from 1990 until 1 January 2008. Login to comment
25 CFTR mutations in trans of p.Arg117His (ie, on the other chromosome) were classified by their potential for causing disease (A: CF-causing; B: associated with CFTR-RD; C: no clinical consequences; D: unknown or uncertain clinical relevance).2 4 Genotype data also included the polyT variant at c.1210-12T(5_9). Login to comment
39 RESULTS A total of 278 individuals with two CFTR mutations including at least one p.Arg117His were collected. Login to comment
42 The overall cohort Genotype description In the 278 individuals, 44 different mutations were associated with p.Arg117His. Login to comment
43 CF mutations (class A) were present in trans of p.Arg117His in nearly 90% of individuals, including c.1521_1523del (p.Phe508del, F508del) in 121 individuals (67%). Login to comment
45 One individual was p.Arg117His homozygous. Login to comment
46 No significant clinical difference was noticed between patients according to the mutation in trans of p.Arg117His. Login to comment
47 Among the 172 patients with a documented polyT variant, only five carried T5 in cis with p.Arg117His, two males and three females, including one sibship (see online supplementary data table A). Login to comment
62 By contrast, four other men without CBAVD spontaneously fathered children: three carried a severe CF mutation and one had a mild, CFTR-RD mutation in trans of p. Arg117His. Login to comment
69 No significant clinical difference was noticed between CBA VD patients according to the mutation in trans of p.Arg117His. Login to comment
70 No significant difference related to classification of the mutation in trans of p.Arg117His was noticed between patients with isolated CBAVD and other patients. Login to comment
84 Table 1 Probability of the occurrence of clinical features at a specific age in 166 compound heterozygous individuals carrying p.Arg117His Total cohort n=166 CBAVD patients n=125 No. Login to comment
96 Eight children were born, including four who were compound heterozygous for p.Arg117His and one severe CF mutation. Login to comment
97 They are healthy so far. DISCUSSION We have recently shown that the penetrance of classical CF in individuals carrying p.Arg117His on a T7 background and p. Phe508del is very low, at 0.03%, and that only 3.1% of individuals expected to carry this genotype have come to clinical attention and been tested for CFTR mutations.13 The objective of the present study was to describe the overall phenotype Table 2 Fertility data in the 40 couples followed in assisted medical reproduction centres with available data n Per puncture Per fresh transfer Mean Std Mean Std Injected ovocytes 738 8.4 4.7 Fertilised ovocytes 426 4.5 4.5 Embryos 361 4.2 4.2 Fertilisation rate* - 51% 29% Fresh cycle outcomes Punctures with fresh transfers 78 85% 36% Transferred embryos 143 1.6 1.0 Clinical pregnancy rate 26 29% 45% 34% 48% Miscarriage rateߤ 5 6% 25% Delivery rate 19 22% 42% 26% 44% Frozen embryos 82 0.9 1.9 *Fertilisation rate=number of embryos/number of ovocytes injected. Login to comment
103 Thauvin-Robinet C, et al. J Med Genet 2013;50:220-227. doi:10.1136/jmedgenet-2012-101427 223 Genotype-phenotype correlations associated with p.Arg117His plus a second CFTR mutation, in order to improve practices for the diagnosis and follow-up of patients and improve genetic counselling, in particular, for couples requiring assisted reproduction. Login to comment
104 Indeed, p.Arg117His was shown to be the third most frequent mutation found in French CBAVD patients.8 9 The frequency of the T5 variant in cis with p.Arg117His was much lower in France than that reported in Australian and UK populations,10 11 thus preventing any correlation between phenotype and polyT variation in the present study. Login to comment
105 Our conclusions can thus be drawn only for populations in whom p. Arg117His on a T7 background is predominant. Login to comment
107 As nearly 90% of patients carried a CF mutation in trans of p.Arg117His, it is hypothesized that compound heterozygosity for p.Arg117His on a T7 background and another mild mutation would predominantly be associated with no obvious CFTR disease.13 An overall mild phenotype with predominant CBAVD in males and a low penetrance in females We present the genotypes and phenotypes of 166/179 individuals carrying two CFTR mutations with p.Arg117His on at least one allele, which is the largest cohort described to date. Login to comment
113 Late presentation of CF has previously been reported in the literature, in two males at 61 and 64 years of age, carrying p.Arg117His in cis with T7 and presenting with infertility and severe bronchiectasis.16 Thus, a complete initial evaluation and regular follow-up should be proposed in CBAVD patients, who might develop pulmonary symptoms a long time after the genetic analysis requested for assisted reproduction purposes. Login to comment
116 All the patients with pancreatic symptoms had the T7 allele in cis with p.Arg117His. Login to comment
119 These observations question the positive diagnostic value of sweat testing in individuals carrying p.Arg117His in cis with T7, as previously reported.20 Males and fertility CFTR-RD is not the rule in individuals carrying p.Arg117His plus a CF mutation, as previously demonstrated13 and exemplified by the four healthy men of the study who fathered spontaneously. Login to comment
121 (Phe508del);(Arg117His) p.Phe508del 1998 Offer of sperm donor na CF or CFTR-RD p. Login to comment
122 (Phe508del);(Arg117His) p.Phe508del 2000 2001: PND leading to twin pregnancy 2005: PGD leading to twin pregnancy 2 2* CF or CFTR-RD p. Login to comment
123 (Phe508del);(Arg117His) p.Phe508del 2004 2005: PGD, no pregnancy - CF or CFTR-RD c. Login to comment
125 (Ala455Glu);( Arg117His) p.Gly551Asp 1995 No spontaneous pregnancy and no in vitro fertilisation - CF or CFTR-RD p. Login to comment
126 (Leu206Trp);( Arg117His) p.Ser1235Arg 2000 2 ICSI cycles, no pregnancy Offer of donor sperm - CFTR-RD p. Login to comment
127 (Phe508del);(Arg117His) c.3528del 2001 2001-2006: 6 preimplantation cycles, 7 transferred embryos, 3 pregnancies (including 1 triple) 2 CF or CFTR-RD Genotypes are written according to HGVS Human Genome Variation Society (HGVS) recommendations. Login to comment
128 Notably, c.350G>A corresponds to p.Arg117His and c.3705T>G to p.Ser1235Arg. Login to comment
129 All CBAVD patients carried the T7 variant in cis with p.Arg117His. Login to comment
131 (Phe508del);(Arg117His) genotype. Login to comment
136 Nevertheless, given that CBAVD is the most frequent symptom observed in our cohort, we suggest that male individuals carrying p.Arg117His in combination with another CFTR mutation and referred for a family study, or respiratory or pancreatic symptoms be offered fertility investigations in an ART clinic, according to the clinical context and the patients` wishes. Login to comment
139 Based on the recent reclassification of p. Arg117His in cis with T7 as a CFTR-RD mutation, it should not be considered for either cascade testing in relatives, or for a risk of classical CF in offspring. Login to comment
143 On the other hand, once CBAVD patients are found to carry a CF-causing mutation in trans of p.Arg117His (90% of cases in our series), their partner should be offered testing for frequent CF mutations. Login to comment
147 Because of the increased risk of obtaining embryos carrying two CF-causing mutations, it could be discussed to implant embryos with a CFTR-RD genotype in a PGD process, as was the case for two couples in our series who associated p. Arg117His and a CF mutation. Login to comment
149 In conclusion, our results indicate the need for a complete initial clinical evaluation in patients with at least one p. Arg117His mutation, especially in CBAVD patients who may be free of respiratory symptoms at the time of the genetic analysis requested for assisted reproduction purposes, and for appropriate genetic counselling. Login to comment
152 Thauvin-Robinet C, et al. J Med Genet 2013;50:220-227. doi:10.1136/jmedgenet-2012-101427 225 Genotype-phenotype correlations 20 Laboratoire de Biologie de la Reproduction et CECOS, CHU Estaing, Clermont-Ferrand, France 21 CRCM-Service de P&#e9;diatrie, CHU Montpellier, Montpellier, France 22 EA 4308 &#ab; Spermatog&#e9;n&#e8;se et qualit&#e9; du sperme m&#e2;le &#bb;, IFRMP23-IHU Rouen Normandie, Laboratoire de Biologie de la Reproduction-CECOS, CHU Rouen, Rouen, France 23 Laboratoire d`analyses m&#e9;dicales Giorgetti, Marseille, France 24 G&#e9;n&#e9;tique M&#e9;dicale, CH Toulon, Toulon, France 25 Service d`Urologie, CHU Brest, Brest, France 26 Chirurgie Urologique, H&#f4;pital Sainte-Marguerite, APHM, Marseille, France 27 EFS-Normandie, Bois-Guillaume, France 28 Laboratoire de G&#e9;n&#e9;tique Mol&#e9;culaire et d`Histocompatibilit&#e9;, CHU de Brest, Brest, France 29 Laboratoire de G&#e9;n&#e9;tique Mol&#e9;culaire, IURC, CHU de Montpellier, Montpellier, France 30 Laboratoire de Biochimie-G&#e9;n&#e9;tique, H&#f4;pital Cochin, APHP, Paris, France 31 Laboratoire de Biochimie G&#e9;n&#e9;tique, H&#f4;pital Robert Debr&#e9;, APHP, Paris, France 32 Service de G&#e9;n&#e9;tique M&#e9;dicale, Laboratoire de G&#e9;n&#e9;tique Mol&#e9;culaire, CHU H&#f4;tel Dieu, Nantes, France 33 Service d`Endocrinologie Mol&#e9;culaire et Maladies rares, Centre de Biologie et Pathologie Est, CHU de Lyon, Bron, France 34 Service des Maladies H&#e9;r&#e9;ditaires du M&#e9;tabolisme et D&#e9;pistage N&#e9;onatal, Centre de Biologie et de Pathologie Est, Hospices Civils de Lyon, Bron, France 35 Laboratoire de Biochimie et Biologie Mol&#e9;culaire, H&#f4;pital d`Enfants Armand Trousseau, APHP, Paris, France 36 CHU Reims, Inserm UMRS 903, Laboratoire Pol Bouin, UF Biologie Cellulaire, H&#f4;pital de la Maison Blanche, Reims, France 37 Service de G&#e9;n&#e9;tique M&#e9;dicale, H&#f4;pital Purpan, Toulouse, France 38 Laboratoire de G&#e9;n&#e9;tique Mol&#e9;culaire, Service de G&#e9;n&#e9;tique M&#e9;dicale, Groupe Hospitalier Pellegrin, CHU de Bordeaux, Bordeaux, France 39 Laboratoire SESEP, Centre hospitalier de Versailles, Le Chesnay, France 40 Service d`Urologie, CHU Bic&#ea;tre, APHP, France 41 Unit&#e9; INSERM U781, Universit&#e9; Paris-Descartes, Facult&#e9; de M&#e9;decine, Service de G&#e9;n&#e9;tique M&#e9;dicale, AP-HP, Paris, France 42 Unit&#e9; de diagnostic pr&#e9;-implantatoire, Centre M&#e9;dico-Chirurgical et Obst&#e9;trical (SIHCUS-CMCO), Schiltigheim, France 43 Laboratoire de Diagnostic mol&#e9;culaire, Service de M&#e9;decine G&#e9;n&#e9;tique, H&#f4;pitaux Universitaires de Gen&#e8;ve, Gen&#e8;ve, Switzerland 44 CRCM-D&#e9;partement de m&#e9;decine de l`enfant et de l`adolescent, CHU de Rennes -H&#f4;pital Sud, Rennes, France Collaborators working group on p.Arg117His Referring molecular geneticists of the French CF laboratory network (34 molecular genetics laboratories): Dr A Bazin (Saint-Ouen l`Aum&#f4;ne), Dr M Blayau (Rennes), Dr JP Bonnefont (Paris), Dr J Bouligand (Le Kremlin Bic&#ea;tre), Dr M Ch&#e9;ry (Nancy), Dr F Chevalier-Porst (Lyon), Dr JM Costa (Saint-Ouen l`Aum&#f4;ne), Dr M Coude (Le Mans), Dr I Creveaux (Clermont-Ferrand), Dr V Dalstein (Reims), Dr F Gerson (Nantes), Dr S Gobin-Limballe (Paris), Dr AM Gouget (Besan&#e7;on), Pr A Kitzis (Poitiers), Dr C Lagier-Tourenne (Strasbourg), Dr C Magdelaine (Limoges), Dr MC Malinge (Angers), Dr P Malzac (Marseille), Dr H Mittre (Caen), Dr V Petit (Epinal), Dr C Philippe (Vandoeuvre-les-Nancy), Dr P Ray (Grenoble), Dr M Raynaud (Tours), Dr C Ronsin (Ivry-sur-Seine), Dr S Schmitt (Nantes). Login to comment

PMID: 23454013 [PubMed] Denny RA et al: "Recent developments in targeting protein misfolding diseases."

No. Sentence Comment

60 Mutations of class IV cause abnormalities in the structure of the transmembrane protein and therefore reduce the conduction of the chloride channel (i.e., mutations R117H, R334W). 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

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: 23457168 [PubMed] Elborn JS et al: "The impact of personalised therapies on respiratory medicine."

No. Sentence Comment

53 IV Channel conductance R117H Sufficient Potentiator?" 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

41 Mutation Region Legacy name cDNA name Protein name # of Patient Number of cycles Number of transfers Number of embryos transferred Pregnancy Birth 125G/C c.-8G>C NA Promoter 1 2 2 2 1 (1) 0 E60X c.178G>T p.Glu60X Exon 3 1 1 1 1 0 0 G85E c.254G>A p.Gly85Glu Exon 3 1 1 1 2 1 1 R75Q c.224G>A p.Arg75Gln Exon 3 1 1 1 1 1 1 R75X c.223C>T p.Arg75X Exon 3 1 1 1 2 1 2 A120T c.358G>A p.Ala120Thr Exon 4 1 1 1 1 0 0 R117C c.349C>T p.Arg117Cys Exon 4 2 6 3 5 1 1 R117H c.350G>A p.Arg117His Exon 4 14 22 19 38 8 6 621+1G-T c.489 &#b1; 1G>T - Intron 4 4 7 4 6 2 1 852del22 c.720_741 p.Gly241GlufsX13 Exon 6 1 1 0 0 0 0 L206W c.617T>G p.Leu206Trp Exon 6 1 2 1 2 0 0 A349V c.1046C>T p.Ala349Val Exon 8 1 2 2 4 2 4 1078delT c.948delT p.Phe316LeufsX12 Exon 8 1 1 1 1 1 0 1154ins-TC c.1022_1023insTC p.Phe342HisfsX28 Exon 8 1 2 1 2 0 0 Q359K/T360K c. Login to comment
53 Almost half of these (195/404 cycles) were performed for DF508 mutation, one-quarter (103/404 cycles)forsixotherfrequentmutations(W1282X,R117H,G551D, G542X, N1303K, 1717-1G>A), and only a few for each of the remaining 45 CFTR mutations (Table 2). Login to comment
56 (CA)n EXON 4 (GATT)n Intron 4 Poly T tract Intron 10 R117H G--A R75XH C--T A120T G--A I148T T--C A349V C--T 1259 Ins A 621+1 G--T EXON 3 EXON 7 EXON 8 Delta I 507 EXON 10 Delta F 508 EXON 11 1717-1 G--A G542X G--T G550X G--T G551D G--A R553X C--T R560T G--C EXON 19 EXON 20 EXON 21 R1162X C--T W1282X G--A N1303K C--G IVS 1 Mutations in CFTR gene (PGD PERFORMED FOR 52 MUTATIONS) IVS 6 a IVS 8 (CA)n (CA)n IVS 17b (TA)n (CA)n D7S486 D7S522 D7S633 D7S677 D7S2847 D7S655 115,89 116.07 117.01 117.13 117.19 117.20 118.6 118.81 Mb IVS8-1 IVS8-2 Figure 1 Mutations (above) and linked markers (below) in CFTR that were used in multiplex PCR. Login to comment
67 PGD for this case seemed to be the only choice, as the male partner was double heterozygous for DF508 and R117H and the female partner was a carrier of the DF508 mutation. Login to comment
81 Because the female partner was double heterozygous, involving two different mutations (R117H and G542X), and the male partner was a carrier of R117H mutation, PGD was based on blastomere biopsy. Login to comment
92 1.1 1.2 PGD PGD MARKERS ORDER D7S486 D7S522 D7S633 D7S677 INTRON 1 INTRON 6 INTRON 8-1 CFTR D7S847 1 2 3 4 5 9 10 11 Oocyte # Predicted Genotype: Sequential Polar Body Analysis 117 135 150 131 212 100 126 F508 161 122 131 148 125 217 104 124 N 149 117 137 150 135 208 104 124 R117h 161 124 131 150 131 212 100 139 F508 161 117 135 150 131 212 100 126 F508 161 122 131 148 125 217 104 124 N 149 117 135 150 131 212 100 126 F508 161 122 131 148 125 217 104 124 N 149 122 131 148 125 217 104 124 N 149 117 135 150 131 212 100 126 F508 161 122 131 148 125 217 104 124 N 149 122 131 148 125 217 104 124 N 149 117 135 150 131 212 100 126 F508 161 117 135 150 131 212 100 126 F508 161 117 135 150 131 212 100 126 F508 161 122 131 148 125 217 104 124 N 149 122 131 148 125 217 104 124 N 149 122 131 148 125 217 104 124 N 149 117 135 150 131 212 100 126 F508 161 117 135 150 131 212 100 126 F508 161 117 135 150 131 212 100 126 F508 161 122 131 148 125 217 104 124 N 149 122 131 148 125 217 104 124 N 149 122 131 148 125 217 104 124 N 149 PB1 PB2 AFFECTED AFFECTED NORMAL NORMAL AFFECTED NORMAL NORMAL AFFECTED ET ET 2.1 2.2 R117H/N R117H/N 117 135 150 131 212 100 126 F508 161 Figure 3 PGD for a double-heterozygous CF-affected male patient by sequential polar body analysis. Login to comment
93 (Upper panel) Pedigree showing that the paternal partner is a double-heterozygous CF-affected patient, with two different CFTR mutations, DF508 and R117H, while the maternal partner is a carrier of DF508. Login to comment
95 Two embryos resulting from oocytes 3 and 4 were transferred (ET), resulting in an unaffected twin pregnancy and birth of two healthy baby girls carrying the paternal R117H mutation. Login to comment
109 (Upper panel) Pedigree, showing that the maternal partner is a double-heterozygous CF-affected patient, with two different CFTR mutations, R117H and G542X, while the paternal partner is a carrier of the 1717 mutation. Login to comment

PMID: 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
63 Class IV or V: R117H, 2789+5G.A, TG12T5, R347P, D1152H, R117C. Login to comment

PMID: 23637307 [PubMed] Wilschanski M et al: "The cystic fibrosis of exocrine pancreas."

No. Sentence Comment

128 Another study on HEK293 cells expression system showed that CFTR mutants associated with PI (e.g., I1489T) did not support HCO3 2 transport, whereas those associated with PS (e.g., R117H) show reduced transport (Choi et al. 2001). 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: 23768522 [PubMed] Chiang HS et al: "Advantages of magnetic resonance imaging (MRI) of the seminal vesicles and intra-abdominal vas deferens in patients with congenital absence of the vas deferens."

No. Sentence Comment

94 We previously reported genetic analyses of CFTR gene mutations in our collected cases of CBAVD.16,17 As Taiwan is an area with very low incidence of CF, none of the patients with CBAVD had major CFTR gene mutations, such as DF508 or R117H, except for IVS8-5T with the presence of (TG)12/13. Login to comment

PMID: 23775370 [PubMed] Abou Tayoun AN et al: "A comprehensive assay for CFTR mutational analysis using next-generation sequencing."

No. Sentence Comment

53 of cases af9;/af9; c.1521_1523delCTT; c.1521_1523delCTT èc;F508; èc;F508 CF Yes 97 Dartmouth 1 af9;/af9; c.1521_1523delCTT; c.350Gb0e;A èc;F508; R117H CF Yes 53; 50 Dartmouth 1 af9;/af9; c.350Gb0e;A; c.1477Cb0e;T R117H; Q493*b CF Yes 52; 49 Dartmouth 1 af9;/af9; c.1521_1523delCTT; c.1000Cb0e;T èc;F508; R334W CF Yes 49; 54 Dartmouth 1 af9;/af9; c.1521_1523delCTT; c.489af9;1Gb0e;T èc;F508; 621af9;1Gb0e;T CF Yes 48; 47 Dartmouth 1 af9;/af9; c.1521_1523delCTT; c.1364Cb0e;A èc;F508; A455E CF Yes 51; 46 Dartmouth 1 af9;/af9; c.489af9;1Gb0e;T; c.2988af9;1Gb0e;A 621af9;1Gb0e;T; 3120af9;1Gb0e;A CF Yes 48; 49 Coriell 1 af9;/af9; c.1521_1523delCTT; c.1657Cb0e;T èc;F508; R553* CF Yes 44; 49c Coriell 2 af9;/af9; c.1521_1523delCTT; c.3528delC èc;F508; 3659delC CF Yes 46; 46 Coriell 1 af9;/af9; c.489af9;1Gb0e;T; c.579af9;1Gb0e;T 621af9;1Gb0e;T; 711af9;1Gb0e;T CF Yes 50; 51 Coriell 1 af9;/af9; c.489af9;1Gb0e;T; c.254Gb0e;A 621af9;1Gb0e;T; G85E CF Yes 50; 45 Coriell 1 af9;/af9; c.1521_1523delCTT; c.1679Gb0e;C èc;F508; R560T CF Yes 44; 52 Coriell 1 af9;/af9; c.489af9;1Gb0e;T; c.1364Cb0e;A 621af9;1Gb0e;T; A455E CF Yes 50; 49 Coriell 1 af9;/af9; c.3909Cb0e;G; c.4046Gb0e;A N1303K; G1349D CF Yes 47; 52 Coriell 1 af9;/af9; c.2657af9;5Gb0e;A; c.2657af9;5Gb0e;A 2789af9;5Gb0e;A; 2789af9;5Gb0e;A CF Yes 100 Coriell 1 af9;/af9; c.1040Gb0e;C; c.1652Gb0e;A R347P; G551D CF Yes 51; 49 Coriell 1 af9;/af9; c.1000Cb0e;T; c.3368-2Ab0e;T R334W; 3500-2Ab0e;G CF Yes 53; 45 Coriell 1 af9;/af9; c.254Gb0e;A; c.3454Gb0e;C G85E; D1152H CF Yes 44; 47 Coriell 1 af9;/af9; c.1521_1523delCTT; c.350Gb0e;A èc;F508; R117H CF Yes 49; 50 Coriell 1 af9;/af9; c.1521_1523delCTT; c.54-5940_273af9;10250del21kb èc;F508; CFTRdel2,3 CF Yes 47; N/Ad Coriell 1 af9;/af9; c.1521_1523delCTT; c.1766af9;1Gb0e;A èc;F508; 1898af9;1Gb0e;A CF Yes 47; 50 Coriell 1 af9;/af9; c.1521_1523delCTT; c.2051_2052delAAinsG èc;F508; K684Sfs CF Yes 47; 50 Coriell 1 af9;/af9; c.1521_1523delCTT; c.2052del èc;F508; K684Nfs*38 CF Yes 51; 55 Coriell 1 af9;/afa; c.1521_1523delCTT èc;F508 Carrier Yes 50c Dartmouth 16 af9;/afa; c.1652Gb0e;A G551D Carrier Yes 50c Dartmouth 5 af9;/afa; c.1519_1521delATC èc;I507 Carrier Yes 46 Dartmouth 1 af9;/afa; c.3454Gb0e;C D1152H Carrier Yes 50 Dartmouth 1 af9;/afa; c.1657Cb0e;T R553* Carrier Yes 51 Dartmouth 1 af9;/afa; c.178Gb0e;T E60* Carrier Yes 51 Dartmouth 1 af9;/afa; c.3846Gb0e;A W1282* Carrier Yes 45c Dartmouth 3 af9;/afa; c.1000Cb0e;T R334W Carrier Yes 51 Dartmouth 1 af9;/afa; c.1624Gb0e;T G542* Carrier Yes 47c Dartmouth 4 af9;/afa; c.3484Cb0e;T R1162* Carrier Yes 43 Dartmouth 1 af9;/afa; c.1766af9;1Gb0e;A 1898af9;1Gb0e;A Carrier Yes 57 Dartmouth 1 af9;/afa; c.3773_3774insT 3905insT (L1258Ffs*7) Carrier Yes 37 Dartmouth 1 af9;/afa; c.350Gb0e;A R117H Carrier Yes 50c Dartmouth 3 af9;/afa; c.1645Ab0e;C S549R Ab0e;C Carrier No N/A Dartmouth 1 af9;/afa; c.1040Gb0e;A R347H Carrier Yes 47 Dartmouth 1 af9;/afa; c.3909Cb0e;G N1303K Carrier Yes 46 Dartmouth 1 af9;/afa; c.3718-2477Cb0e;T 3849af9;10kbCb0e;T Carrier Yes 51 Coriell 1 af9;/afa; c.2988af9;1Gb0e;A 3120af9;1Gb0e;A Carrier Yes 49 Coriell 1 af9;/afa; c.489af9;1Gb0e;T 621af9;1Gb0e;T Carrier Yes 50 Coriell 1 af9;/afa; c.1585-1Gb0e;A 1717-1Gb0e;A Carrier Yes 51 Coriell 1 afa;/afa;e N/Af N/A Normal N/A N/A Dartmouth 9 a af9;/af9;, 2 pathogenic mutations; af9;/afa;, carrier of a single pathogenic mutation; afa;/afa;, absence of any pathogenic mutations. Login to comment
115 Mutation cDNA position Mutation class Sensitivity (TPa ) Specificity (TN) Accuracyb G85E c.254Gb0e;A Missense Detected (2/2) 100% (77/77) 100% R117H c.350Gb0e;A Missense Detected (6/6) 100% (73/73) 100% 621af9;1Gb0e;T c.489af9;1Gb0e;T Splice site Detected (6/6) 100% (73/73) 100% 711af9;1Gb0e;T c.579af9;1Gb0e;T Splice site Detected (1/1) 100% (78/78) 100% R334W c.1000Cb0e;T Missense Detected (3/3) 100% (76/76) 100% R347P c.1040Gb0e;C Missense Detected (1/1) 100% (78/78) 100% A455E c.1364Cb0e;A Missense Detected (2/2) 100% (77/77) 100% èc;I507 c.1519_1521delATC In-frame deletion Detected (1/1) 100% (78/78) 100% èc;F508 c.1521_1523delCTT In-frame deletion Detected (30/30) 100% (49/49) 100% G542* c.1624Gb0e;T Nonsense Detected (4/4) 100% (75/75) 100% G551D c.1652Gb0e;A Missense Detected (6/6) 100% (73/73) 100% R553* c.1657Cb0e;T Nonsense Detected (3/3) 100% (76/76) 100% R560T c.1679Gb0e;C Missense Detected (1/1) 100% (78/78) 100% 1898af9;1Gb0e;A c.1766af9;1Gb0e;A Splice site Detected (2/2) 100% (77/77) 100% 2789af9;5Gb0e;A c.2657af9;5Gb0e;A Splice site Detected (1/1) 100% (78/78) 100% 3120af9;1Gb0e;A c.2988af9;1Gb0e;A Splice site Detected (2/2) 100% (77/77) 100% R1162* c.3484Cb0e;T Nonsense Detected (1/1) 100% (78/78) 100% 3659delC c.3528del Frameshift deletion Detected (1/1) 100% (78/78) 100% 3849af9;10kbCb0e;T c.3718-2477Cb0e;T Splice site Detected (1/1) 100% (78/78) 100% W1282* c.3846Gb0e;A Nonsense Detected (3/3) 100% (75/75) 100% N1303K c.3909Cb0e;G Missense Detected (1/1) 100% (78/78) 100% 2184delA c.2052del Frameshift deletion Detected (1/1) 97% (76/78) 97% 1717-1Gb0e;A c.1585-1Gb0e;A Splice site Detected (1/1) 100% (78/78) 100% a TP, true-positive rate; TN, true-negative rate. Login to comment

PMID: 23818513 [PubMed] Rowe SM et al: "Cystic fibrosis transmembrane regulator correctors and potentiators."

No. Sentence Comment

9 The F508del mutation, which is present in at least one allele in 90% ofCFpatients,impairsCFTRfolding,stabilityat the endoplasmic reticulum and plasma membrane, and chloride channel gating (Dalemans etal.1991;Denningetal.1992;Lukacsetal.1993; Duetal.2005a).Othermutationsprimarilyalter channelgating(e.g.,G551D),conductance(e.g., R117H),ortranslation(e.g.,G542X)(Welshand Smith1993).ThefundamentalpremiseofCFTR corrector and potentiator therapy for CF is that Editors: John R. Riordan, Richard C. Boucher, and Paul M. Quinton Additional Perspectives on Cystic Fibrosis available at www.perspectivesinmedicine.org Copyright # 2013 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/cshperspect.a009761 Cite this article as Cold Spring Harb Perspect Med 2013;3:a009761 1 correction of the underlying defects in the cellular processing and chloride channel function of CF-causing mutant CFTR alleles will be of clinical benefit. Login to comment

PMID: 23866907 [PubMed] Landaburu I et al: "Genetic testing of sperm donors for cystic fibrosis and spinal muscular atrophy: evaluation of clinical utility."

No. Sentence Comment

51 The panel of mutations studied was: S549N, S549R, R553X, G551D, V520F, I507del, F508del, 3876delA, 1717-1G->A, G542X, R560T, 3120+1G->A, A455E, R117H, 394delTT, 2183AA- >G, 2184delA, 2789+5G->A, 1898+1G->A, 621+1G->T, 711+1G- >T, G85E, R347P, R347H, W1282X, R334W, 1078delT, 3849+10kbC->T, R1162X, N1303K, 3659delC, 3905insT. Login to comment

PMID: 23891278 [PubMed] Sommerburg O et al: "Comparison of different IRT-PAP protocols to screen newborns for cystic fibrosis in three central European populations."

No. Sentence Comment

154 mutations (i.e. R117H;7T) and low PAP concentrations in some patients with PI mutations (i.e. F508del). 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

44 None M1V A46D E56K P67L R74W G85E E92K D110E D110H R117C R117H E193K L206W R334W I336K T338I S341P R347H R347P R352Q A455E L467P S492F F508del V520F A559T R560S R560T A561E Y569D D579G R668C L927P S945L S977F L997F F1052V H1054D K1060T L1065P R1066C R1066H R1066M A1067T R1070Q R1070W F1074L L1077P H1085R M1101K D1152H S1235R D1270N N1303K 0 100 200 300 400 500 600 * * * CFTR Mutation mRNA (% Normal CFTR) Fig. 1. Login to comment
64 Mutant CFTR form CFTR processing Mature/total % Normal CFTR Normal 0.89 &#b1; 0.01 100.0 &#b1; 18.5 G85E -0.05 &#b1; 0.04 -1.0 &#b1; 0.9 R560S 0.00 &#b1; 0.00 0.0 &#b1; 0.0 R1066C 0.02 &#b1; 0.01 0.0 &#b1; 0.0 S492F 0.00 &#b1; 0.00 0.1 &#b1; 0.1 R560T 0.01 &#b1; 0.01 0.2 &#b1; 0.1 V520F 0.05 &#b1; 0.03 0.3 &#b1; 0.2 M1101K 0.05 &#b1; 0.03 0.3 &#b1; 0.1 A561E 0.08 &#b1; 0.04 0.5 &#b1; 0.2 R1066M 0.02 &#b1; 0.02 0.5 &#b1; 0.4 N1303K 0.02 &#b1; 0.02 0.5 &#b1; 0.3 A559T 0.16 &#b1; 0.09 0.6 &#b1; 0.2 M1V 0.06 &#b1; 0.06 0.7 &#b1; 0.6 Y569D 0.11 &#b1; 0.04 0.6 &#b1; 0.2 R1066H 0.08 &#b1; 0.02a 0.7 &#b1; 0.2a L1065P 0.05 &#b1; 0.05 1.0 &#b1; 0.8 L467P 0.10 &#b1; 0.07 1.2 &#b1; 0.8 L1077P 0.08 &#b1; 0.04 1.5 &#b1; 0.6 A46D 0.21 &#b1; 0.08 1.9 &#b1; 0.5a E92K 0.06 &#b1; 0.05 1.9 &#b1; 1.3 H1054D 0.09 &#b1; 0.04 1.9 &#b1; 0.8 F508del 0.09 &#b1; 0.02a 2.3 &#b1; 0.5a H1085R 0.06 &#b1; 0.01a 3.0 &#b1; 0.7a I336K 0.42 &#b1; 0.05a 6.5 &#b1; 0.7a L206W 0.35 &#b1; 0.10a 6.8 &#b1; 1.7a F1074L 0.52 &#b1; 0.03a 10.9 &#b1; 0.6a A455E 0.26 &#b1; 0.10a 11.5 &#b1; 2.5a E56K 0.29 &#b1; 0.04a 12.2 &#b1; 1.5a R347P 0.48 &#b1; 0.04a 14.6 &#b1; 1.8a R1070W 0.61 &#b1; 0.04a 16.3 &#b1; 0.6a P67L 0.36 &#b1; 0.04a 28.4 &#b1; 6.8a R1070Q 0.90 &#b1; 0.01a 29.5 &#b1; 1.4a S977F 0.97 &#b1; 0.01a 37.3 &#b1; 2.4a A1067T 0.78 &#b1; 0.03a 38.6 &#b1; 6.1a D579G 0.72 &#b1; 0.02a 39.3 &#b1; 3.1a D1270N 1.00 &#b1; 0.00a,c 40.7 &#b1; 1.2a S945L 0.65 &#b1; 0.04a 42.4 &#b1; 8.9a L927P 0.89 &#b1; 0.01a,b 43.5 &#b1; 2.5a,b R117C 0.87 &#b1; 0.02a,b 49.1 &#b1; 2.9a,b T338I 0.93 &#b1; 0.03a,b 54.2 &#b1; 3.7a,b L997F 0.90 &#b1; 0.04a,b 59.8 &#b1; 10.4a,b D110H 0.97 &#b1; 0.01a,b 60.6 &#b1; 1.5a,b S341P 0.79 &#b1; 0.02a 65.0 &#b1; 4.9a,b R668C 0.94 &#b1; 0.03a,b 68.5 &#b1; 1.9a,b R74W 0.78 &#b1; 0.01a 69.0 &#b1; 2.7a,b D110E 0.92 &#b1; 0.05a,b 87.5 &#b1; 9.5a,b R334W 0.91 &#b1; 0.05a,b 97.6 &#b1; 10.0a,b K1060T 0.87 &#b1; 0.02a,b 109.9 &#b1; 28.0a,b R347H 0.96 &#b1; 0.02a,c 120.7 &#b1; 2.8a,b S1235R 0.96 &#b1; 0.00a,c 139.0 &#b1; 9.0a,b E193K 0.84 &#b1; 0.02a,b 143.0 &#b1; 17.1a,b R117H 0.86 &#b1; 0.01a,b 164.5 &#b1; 34.2a,b R352Q 0.98 &#b1; 0.01a,b 179.9 &#b1; 8.0a,c F1052V 0.90 &#b1; 0.01a,b 189.9 &#b1; 33.1a,b D1152H 0.96 &#b1; 0.02a,c 312.0 &#b1; 45.5a,b Notes to Table 1: Quantification of steady-state CFTR maturation expressed as the mean (&#b1;SEM; n = 5-9) ratio of mature CFTR to total CFTR (immature plus mature) or level of mature mutant CFTR relative to mature normal-CFTR (% normal CFTR) in FRT cells individually expressing CFTR mutations. Login to comment
74 Because the level of CFTR mRNA was similar across the panel of cell lines tested, the range in baseline activity and ivacaftor response likely reflects the severity of the functional defect and/or the 0 50 100 150 200 S341P R347P L467P S492F A559T A561E Y569D L1065P R1066C R1066M L1077P M1101K N1303K R560S L927P R560T H1085R V520F E92K M1V F508del H1054D I336K A46D G85E R334W T338I R1066H R352Q R117C L206W R347H S977F S945L A455E F1074L E56K P67L R1070W D110H D579G D110E R1070Q L997F A1067T E193K R117H R74W K1060T R668C D1270N D1152H S1235R F1052V Baseline With ivacaftor * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * Chloride transport (% Normal) Mutant CFTR form 0 100 200 300 400 S341P R347P L467P S492F A559T A561E Y569D L1065P R1066C R1066M L1077P M1101K N1303K R560S L927P R560T H1085R V520F E92K M1V F508del H1054D I336K A46D G85E R334W T338I R1066H R352Q R117C L206W R347H S977F S945L A455E F1074L P67L E56K R1070W D110H D579G D110E R1070Q L997F A1067T E193K R117H R74W K1060T R668C D1270N D1152H S1235R F1052V * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * Mature CFTR (% Normal) Mutant CFTR form A B Fig. 2. Login to comment
82 Mutation Patientsa Chloride transport (bc;A/cm2 ) Chloride transport (% normal) EC50 Baseline With ivacaftor Baseline With ivacaftor Fold increase over baselineb Normal 204.5 &#b1; 33.3 301.3 &#b1; 33.8c 100.0 &#b1; 16.3 147.3 &#b1; 16.5c 1.5 266 &#b1; 42 G551D 1282 1.5 &#b1; 0.7 113.2 &#b1; 13.0c 1.0 &#b1; 0.5 55.3 &#b1; 6.3c 55.3 312 &#b1; 73 F1052V 12 177.3 &#b1; 13.7 410.2 &#b1; 11.3c 86.7 &#b1; 6.7 200.7 &#b1; 5.6c 2.3 177 &#b1; 14 S1235R ND 160.6 &#b1; 25.7 352.1 &#b1; 43.4c 78.5 &#b1; 12.6 172.2 &#b1; 21.2c 2.2 282 &#b1; 104 D1152H 185 117.3 &#b1; 23.0 282.7 &#b1; 46.9c 57.4 &#b1; 11.2 138.2 &#b1; 22.9c 2.4 178 &#b1; 67 D1270N 32 109.5 &#b1; 20.5 209.5 &#b1; 27.4c 53.6 &#b1; 10.0 102.4 &#b1; 13.4c 1.9 254 &#b1; 56 R668C 45 99.0 &#b1; 9.4 217.6 &#b1; 11.7c 48.4 &#b1; 4.6 106.4 &#b1; 5.7c 2.2 517 &#b1; 105 K1060T ND 89.0 &#b1; 9.8 236.4 &#b1; 20.3c 43.5 &#b1; 4.8 115.6 &#b1; 9.9c 2.7 131 &#b1; 73 R74W 25 86.8 &#b1; 26.9 199.1 &#b1; 16.8c 42.5 &#b1; 13.2 97.3 &#b1; 8.2c 2.3 162 &#b1; 17 R117H 739 67.2 &#b1; 13.3 274.1 &#b1; 32.2c 32.9 &#b1; 6.5 134.0 &#b1; 15.7c 4.1 151 &#b1; 14 E193K ND 62.2 &#b1; 9.8 379.1 &#b1; 1.1c 30.4 &#b1; 4.8 185.4 &#b1; 1.0c 6.1 240 &#b1; 20 A1067T ND 55.9 &#b1; 3.2 164.0 &#b1; 9.7c 27.3 &#b1; 1.6 80.2 &#b1; 4.7c 2.9 317 &#b1; 214 L997F 27 43.7 &#b1; 3.2 145.5 &#b1; 4.0c 21.4 &#b1; 1.6 71.2 &#b1; 2.0c 3.3 162 &#b1; 12 R1070Q 15 42.0 &#b1; 0.8 67.3 &#b1; 2.9c 20.6 &#b1; 0.4 32.9 &#b1; 1.4c 1.6 164 &#b1; 20 D110E ND 23.3 &#b1; 4.7 96.4 &#b1; 15.6c 11.4 &#b1; 2.3 47.1 &#b1; 7.6c 4.1 213 &#b1; 51 D579G 21 21.5 &#b1; 4.1 192.0 &#b1; 18.5c 10.5 &#b1; 2.0 93.9 &#b1; 9.0c 8.9 239 &#b1; 48 D110H 30 18.5 &#b1; 2.2 116.7 &#b1; 11.3c 9.1 &#b1; 1.1 57.1 &#b1; 5.5c 6.2 249 &#b1; 59 R1070W 13 16.6 &#b1; 2.6 102.1 &#b1; 3.1c 8.1 &#b1; 1.3 49.9 &#b1; 1.5c 6.2 158 &#b1; 48 P67L 53 16.0 &#b1; 6.7 88.7 &#b1; 15.7c 7.8 &#b1; 3.3 43.4 &#b1; 7.7c 5.6 195 &#b1; 40 E56K ND 15.8 &#b1; 3.1 63.6 &#b1; 4.4c 7.7 &#b1; 1.5 31.1 &#b1; 2.2c 4.0 123 &#b1; 33 F1074L ND 14.0 &#b1; 3.4 43.5 &#b1; 5.4c 6.9 &#b1; 1.6 21.3 &#b1; 2.6c 3.1 141 &#b1; 19 A455E 120 12.9 &#b1; 2.6 36.4 &#b1; 2.5c 6.3 &#b1; 1.2 17.8 &#b1; 1.2c 2.8 170 &#b1; 44 S945L 63 12.3 &#b1; 3.9 154.9 &#b1; 47.6c 6.0 &#b1; 1.9 75.8 &#b1; 23.3c 12.6 181 &#b1; 36 S977F 9 11.3 &#b1; 6.2 42.5 &#b1; 19.1c 5.5 &#b1; 3.0 20.8 &#b1; 9.3c 3.8 283 &#b1; 36 R347H 65 10.9 &#b1; 3.3 106.3 &#b1; 7.6c 5.3 &#b1; 1.6 52.0 &#b1; 3.7c 9.8 280 &#b1; 35 L206W 81 10.3 &#b1; 1.7 36.4 &#b1; 2.8c 5.0 &#b1; 0.8 17.8 &#b1; 1.4c 3.6 101 &#b1; 13 R117C 61 5.8 &#b1; 1.5 33.7 &#b1; 7.8c 2.9 &#b1; 0.7 16.5 &#b1; 3.8c 5.7 380 &#b1; 136 R352Q 46 5.5 &#b1; 1.0 84.5 &#b1; 7.8c 2.7 &#b1; 0.5 41.3 &#b1; 3.8c 15.2 287 &#b1; 75 R1066H 29 3.0 &#b1; 0.3 8.0 &#b1; 0.8c 1.5 &#b1; 0.1 3.9 &#b1; 0.4c 2.6 390 &#b1; 179 T338I 54 2.9 &#b1; 0.8 16.1 &#b1; 2.4c 1.4 &#b1; 0.4 7.9 &#b1; 1.2c 5.6 334 &#b1; 38 R334W 150 2.6 &#b1; 0.5 10.0 &#b1; 1.4c 1.3 &#b1; 0.2 4.9 &#b1; 0.7c 3.8 259 &#b1; 103 G85E 262 1.6 &#b1; 1.0 1.5 &#b1; 1.2 0.8 &#b1; 0.5 0.7 &#b1; 0.6 NS NS A46D ND 2.0 &#b1; 0.6 1.1 &#b1; 1.1 1.0 &#b1; 0.3 0.5 &#b1; 0.6 NS NS I336K 29 1.8 &#b1; 0.2 7.4 &#b1; 0.1c 0.9 &#b1; 0.1 3.6 &#b1; 0.1c 4 735 &#b1; 204 H1054D ND 1.7 &#b1; 0.3 8.7 &#b1; 0.3c 0.8 &#b1; 0.1 4.2 &#b1; 0.1c 5.3 187 &#b1; 20 F508del 29,018 0.8 &#b1; 0.6 12.1 &#b1; 1.7c 0.4 &#b1; 0.3 5.9 &#b1; 0.8c 14.8 129 &#b1; 38 M1V 9 0.7 &#b1; 1.4 6.5 &#b1; 1.9c 0.4 &#b1; 0.7 3.2 &#b1; 0.9c 8.0 183 &#b1; 85 E92K 14 0.6 &#b1; 0.2 4.3 &#b1; 0.8c 0.3 &#b1; 0.1 2.1 &#b1; 0.4c 7.0 198 &#b1; 46 V520F 58 0.4 &#b1; 0.2 0.5 &#b1; 0.2 0.2 &#b1; 0.1 0.2 &#b1; 0.1 NS NS H1085R ND 0.3 &#b1; 0.2 2.1 &#b1; 0.4 0.2 &#b1; 0.1 1.0 &#b1; 0.2 NS NS R560T 180 0.3 &#b1; 0.3 0.5 &#b1; 0.5 0.1 &#b1; 0.1 0.2 &#b1; 0.2 NS NS L927P 15 0.2 &#b1; 0.1 10.7 &#b1; 1.7c 0.1 &#b1; 0.1 5.2 &#b1; 0.8c 52.0 313 &#b1; 66 R560S ND 0.0 &#b1; 0.1 -0.2 &#b1; 0.2 0.0 &#b1; 0.0 -0.1 &#b1; 0.1 NS NS N1303K 1161 0.0 &#b1; 0.0 1.7 &#b1; 0.3 0.0 &#b1; 0.0 0.8 &#b1; 0.2 NS NS M1101K 79 0.0 &#b1; 0.0 0.0 &#b1; 0.0 0.0 &#b1; 0.0 0.0 &#b1; 0.0 NS NS L1077P 42 0.0 &#b1; 0.0 0.0 &#b1; 0.0 0.0 &#b1; 0.0 0.0 &#b1; 0.0 NS NS R1066M ND 0.0 &#b1; 0.0 0.0 &#b1; 0.0 0.0 &#b1; 0.0 0.0 &#b1; 0.0 NS NS R1066C 100 0.0 &#b1; 0.0 0.0 &#b1; 0.0 0.0 &#b1; 0.0 0.0 &#b1; 0.0 NS NS L1065P 25 0.0 &#b1; 0.0 0.0 &#b1; 0.0 0.0 &#b1; 0.0 0.0 &#b1; 0.0 NS NS Y569D 9 0.0 &#b1; 0.0 0.0 &#b1; 0.0 0.0 &#b1; 0.0 0.0 &#b1; 0.0 NS NS A561E ND 0.0 &#b1; 0.1 0.0 &#b1; 0.1 0.0 &#b1; 0.0 0.0 &#b1; 0.1 NS NS A559T 43 0.0 &#b1; 0.0 0.0 &#b1; 0.0 0.0 &#b1; 0.0 0.0 &#b1; 0.0 NS NS S492F 16 0.0 &#b1; 0.0 1.7 &#b1; 1.2 0.0 &#b1; 0.0 0.8 &#b1; 0.6 NS NS L467P 16 0.0 &#b1; 0.0 0.0 &#b1; 0.0 0.0 &#b1; 0.0 0.0 &#b1; 0.0 NS NS R347P 214 0.0 &#b1; 0.0 0.0 &#b1; 0.0 0.0 &#b1; 0.0 0.0 &#b1; 0.0 NS NS S341P 9 0.0 &#b1; 0.0 0.2 &#b1; 0.2 0.0 &#b1; 0.0 0.1 &#b1; 0.1 NS NS a Number of individuals with the individual mutation in the CFTR-2 database (www.CFTR2.org). Login to comment
89 For mutant CFTR forms that have multiple defects (e.g., R117H, F508del, S945L, R1070Q, A1067T, R1070W, and R347P), the relative impact of each defect is likely to affect the magnitude of the baseline chloride transport and ivacaftor response in vitro and in a clinical setting. Login to comment
90 For example, the channel open probability and conductance of R117H-CFTR were reported to be 28% and 86% of normal CFTR, respectively [9]. Login to comment
91 This suggests that the R117H mutation may be associated with defective channel gating, as well as conductance defects, and may explain why the ivacaftor response was larger than for CFTR mutations that result in defects in conductance alone (e.g., R347H, R352Q). Login to comment
92 Mutant CFTR forms that did not significantly respond to ivacaftor under the experimental conditions used in this study were generally associated with severe defects in CFTR processing A B C D E F 0 100 200 300 400 -9 -8 -7 -6 -5 -4 0 S1235R D1152H F1052V D1270N ivacaftor [Log M] 0 100 200 300 400 -9 -8 -7 -6 -5 -4 0 R668C K1060T R74W R117H ivacaftor [Log M] 0 100 200 300 400 -9 -8 -7 -6 -5 -4 0 E193K A1067T L997F R1070Q ivacaftor [Log M] Chloride Transport ( &#b5;A/cm 2 ) Chloride Transport ( &#b5;A/cm 2 ) Chloride Transport ( &#b5;A/cm 2 ) Chloride Transport ( &#b5;A/cm 2 ) Chloride Transport ( &#b5;A/cm 2 ) Chloride Transport ( &#b5;A/cm 2 ) Chloride Transport ( &#b5;A/cm 2 ) Chloride Transport ( &#b5;A/cm 2 ) Chloride Transport ( &#b5;A/cm 2 ) 0 100 200 300 400 -9 -8 -7 -6 -5 -4 0 D110E D579G D110H R1070W ivacaftor [Log M] 0 100 200 300 400 -9 -8 -7 -6 -5 -4 0 F1074L E56K P67L A455E ivacaftor [Log M] 0 100 200 300 400 -9 -8 -7 -6 -5 -4 0 R347H S945L L206W S977F ivacaftor [Log M] 0 100 200 300 400 -8 -6 -4 0 T338I R1066H R117C R352Q ivacaftor [Log M] 0 100 200 300 400 -9 -8 -7 -6 -5 -4 0 F508del R334W H1054D E92K ivacaftor [Log M] 0 5 10 15 20 -9 -8 -7 -6 -5 -4 0 F508del R334W H1054D E92K R1066H T338I ivacaftor [Log M] G H I Fig. 3. Login to comment
107 Similarly, patients with CF who have the most common class IV mutation, R117H, typically have a lower sweat chloride concentration than those with R347P (60 mmol/L vs. 99 mmol/L, respectively) [22]. Login to comment
113 For example, the R117H CFTR mutation is relatively common among people heterozygous for the F508del CFTR mutation and is frequently identified in newborn screening programs [8,16]. Login to comment
114 When the R117H CFTR mutation is found on the same CFTR gene (in cis) with the 5T mutation (5 thymidine repeats in intron 8) a milder form of CF characterized by pancreatic sufficiency may be present, whereas when the 7T mutation in cis with R117H is found, CFTR-related disorders or no disease may be present. Login to comment

PMID: 23951356 [PubMed] Masson E et al: "A conservative assessment of the major genetic causes of idiopathic chronic pancreatitis: data from a comprehensive analysis of PRSS1, SPINK1, CTRC and CFTR genes in 253 young French patients."

No. Sentence Comment

25 Whereas the presence of two highly deleterious ('severe`) CFTR alleles (as in p.F508del homozygotes) is necessary to give rise to classic cystic fibrosis, heterozygosity for such an allele is sufficient to confer an increased risk of ICP, whilst compound heterozygosity, involving a severe CFTR allele plus a less deleterious ('mild`) allele (e.g. p. F508del/p.R117H), confers a further increase in risk [7,8]. 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: 24002981 [PubMed] Wang W et al: "Comprehensive screening for PRSS1, SPINK1, CFTR, CTRC and CLDN2 gene mutations in Chinese paediatric patients with idiopathic chronic pancreatitis: a cohort study."

No. Sentence Comment

86 The rate of pancreatic pseudocyst was Table 2 PRSS1, SPINK1, CFTR and CTRC gene mutations in the patients with ICP Gene mutations Region Functional class Positive, n (%) PRSS1 A16V Exon 2 Missense 0 N29I Exon 2 Missense 1 (1.3) E79K Exon 3 Missense 0 R116C Exon 3 Missense 0 A121T Exon 3 Missense 0 R122H or R122C Exon 3 Missense 6 (8.0)* SPINK1 N34S Exon 3 Missense 0 IVS3+2T>C IVS 3 Splicing 43 (57.3)ߤ CFTR R117H Exon 4 Missense 0ߥ F508del Exon 11 Del 0 c.2562T>G Exon 15 Nonsense 51 (68.0)&#a7; c.4389G>A Exon 27 Nonsense 1 (1.3) CTRC c.143A>G Exon 3 Missense 0 c.180C>T Exon 3 Nonsense 0 c.217G>A Exon 3 Missense 0 c.703G>A Exon 7 Missense 0 c.760C>T Exon 7 Missense 0 p.K247_R254del Exon 7 Del 0 CLDN2 c.22G>A Exon 1 Nonsense 2 c.327A>T Exon 2 Nonsense 1 c.592A>C Exon 2 Missense 1 c.768T>C Exon 2 Nonsense 22 *One was c.364 C>T and other five were c.365 G>A. ߤThirty-three were heterozygous and 10 were homozygous. 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

136 Table 4 Online information for patients and providers Genetics Home Reference ghr.nlm.nih.gov/condition/ cystic-fibrosis Cystic-L - Cystic Fibrosis Information and Support www.cystic-l.org CysticFibrosis.com www.cysticfibrosis.com CFvoice (by Novartis) www.cfvoice.com Cystic Fibrosis Foundation www.cff.org Canadian Cystic Fibrosis Foundation www.cysticfibrosis.ca European Cystic Fibrosis Society www.ecfs.eu Cystic Fibrosis Trust www.cftrust.org.uk CFTR2 www.cftr2.org For providers only GeneTests/GeneReviews www.genetests.org Cystic Fibrosis Mutation Database www.genet.sickkids.on.ca R117H/PolyT The disease-causing potential of the R117H mutation is influenced by the cis status of a haplotype that includes a polymorphic tract of thymidines (5T, 7T and 9T) and a variable length TG repeat tract (see below) in intron 8 of CFTR near the splice site for exon 9 (Kiesewetter et al. 1993). Login to comment
140 Individuals with a disease-causing CFTR mutation in trans to R117H/5T typically have PS cystic fibrosis, whereas individuals with a CFTR mutation in trans to R117H/7T are more likely to be asymptomatic (possibly CRMS if an elevated IRT was detected on the CF NBS) or have a phenotype consistent with a CFTR-related disorder (Massie et al. 2001; Kiesewetter et al. 1993). Login to comment
141 R117H/9T is highly unlikely to act as a disease-causing mutation (CFTR2, 2013). Login to comment
142 Infants with a positive CF NBS diagnosed with CRMS are commonly found to have a genotype consisting of one disease causing mutation and either R117H-7T or 5T in trans to that mutation (Borowitz et al. 2009). Login to comment
143 Current laboratory guidelines state that intron 8 polyT status should be assessed as a reflex test when R117H is detected, since clarifying the polyT status in individuals with R117H can help delineate the range of potential phenotype (Grody et al. 2001; Watson et al. 2004). Login to comment
145 Because the 5T variant is associated with a significant reduction in functional CFTR protein, it has the potential to be clinically significant not only in cis with another variant (like R117H) but also as a stand-alone mutation. Login to comment
153 RECOMMENDATION 8: THE R117H/POLY T and 5T/TG TRACT ALLELES If a client is found to carry an R117H mutation, it is important to ensure the testing laboratory performs reflex testing for poly T status along with studies to determine the cis/trans orientation of the poly T alleles. Login to comment
154 In the absence of an R117H mutation, assessment of the intron 8 poly T or TG tracts is not recommended for routine CF carrier testing. Login to comment

PMID: 24030637 [PubMed] Deeks ED et al: "Ivacaftor: a review of its use in patients with cystic fibrosis."

No. Sentence Comment

17 Mutations can be classified on the basis of their functional consequences, which include CFTR protein that is truncated and fails to reach the cell surface (class I) [e.g. R1162X]; is misfolded, improperly processed and defective, little of which reaches the cell surface (class II) [e.g. F508del]; is unable to open and transport chloride properly (class III) [e.g. G551D] or has reduced chloride conductance due to channel narrowing (class IV) [e.g. R117H] but reaches the cell surface; or transports chloride effectively but reaches the cell surface in reduced amounts due to defective transcript splicing (class V) [e.g. 3120?1G?A] [1, 3]. Login to comment
36 Further in vitro data suggest that other CFTR proteins with residual function may also be potentiated by ivacaftor, including those with mutations that affect conductance (e.g. R117H, D110H), mildly affect CFTR processing (e.g. E56K, P67L) or have uncharacterized effects (e.g. D110E, S1235R) [5, 16]. Login to comment
176 A phase III ivacaftor trial in patients with the class IV CFTR mutation, R117H, is also recruiting participants [33]. Login to comment

PMID: 24204751 [PubMed] Wine JJ et al: "In vivo readout of CFTR function: ratiometric measurement of CFTR-dependent secretion by individual, identifiable human sweat glands."

No. Sentence Comment

102 PS2 M F508del/R117H, 5T 92.5 2 38 0 0% 2.16 0.000 0.000 0.00% - - PS4 F F508del/3849+10 kb CRT 90 2 59 2 3% 2.42 0.000 0.000 0.00% 51% MRSA, Pa (muc, non-m) PS5 M F508del/R117H 83 3 51 0 0% 4.20 0.000 0.000 0.00% 66% Pa(muc and non), SA PS6 F F508del/3849+10 kb CRT 70 3 37 0 0% 1.23 0.000 0.000 0.00% 38% Pa (m) CFPS Mean 6 SD or sumsR 80612 12 228 2 1% 2.261.3 0.000 0.000 0.00% 49% CFTR-Related R1 M F508del/F1052V, nv 7T/9T 69 2 40 40 100% 6.76 0.265 0.038 14.16% - - R2 F M470V 44 3 57 57 100% 2.88 0.620 0.211 79.65% 81% A. xylosoxidans R3 F M470V, 7T/7T 71 3 34 13 38% 1.87 0.010 0.004 1.52% - - R4 M F508del/Unk 52 2 69 44 64% 4.03 0.021 0.005 1.98% 44% Pa (mucoid) positioned 1.7 cm above the skin to produce more diffuse light that worked well with the stained sweat droplets. Login to comment

PMID: 24210900 [PubMed] Berkhout MC et al: "Sinonasal manifestations of cystic fibrosis: a correlation between genotype and phenotype?"

No. Sentence Comment

163 Genotype Frequency; N (%) Class of mutation F508del/F508del 61 (58.7) I-III F508del/3849 + 10kbC 2 (1.9) IV-V F508del/N1303K 2 (1.9) I-III F508del/R1162X 2 (1.9) I-III F508del/A455E 12 (11.5) IV-V F508del/3272-26A N G 5 (4.8) IV-V F508del/E528X 1 (1.0) I-III F508del/S1251N 3 (2.9) IV-V F508del/R75Q 1 (1.0) IV-V F508del/G542X 2 (1.9) I-III F508del/1717-1G N A 1 (1.0) I-III F508del/Ser489X 1 (1.0) I-III F508del/4382delA 1 (1.0) -a F508del/L1077 1 (1.0) I-III F508del/1813insC 1 (1.0) -b A455E/S1251N 1 (1.0) IV-V A455E/E60X 1 (1.0) IV-V 3272-26A N G/G970R 1 (1.0) IV-V 3272-26A N G/R1162X 1 (1.0) IV-V F508del/UNK 2 (1.9) -c R117H-7T/UNK 1 (1.0) -d UNK/UNK 1 (1.0) -e Total 104 (100.4) One patient with pancreatic sufficiency and diagnosed at 46 years of age (class IV-V). Login to comment

PMID: 24274930 [PubMed] Thomas M et al: "Is there evidence for correct diagnosis in cystic fibrosis registries?"

No. Sentence Comment

112 Allowing a more liberal interpretation of which mutation can be considered disease causing might allow inclusion of more patients, possibly also patients with mild phenotype or even doubtful diagnosis, as described in France for the R117H mutation [15]. Login to comment

PMID: 24309546 [PubMed] Durupt S et al: "[Therapeutic update in cystic fibrosis]."

No. Sentence Comment

71 Une quantit&#e9; normale de prot&#e9;ine arrive &#e0; la surface cellulaire, mais reste non fonctionnelle par d&#e9;faut de r&#e9;gulation par l`ATP (exemple : G551D) IV Mutations donnant naissance &#e0; une prot&#e9;ine &#e0; la conformation anormale avec une diminution de la conductance (exemple : R117H) V Mutations responsables d`une quantit&#e9; diminu&#e9;e de prot&#e9;ine fonctionnelle VI Mutations responsables d`une prot&#e9;ine fonctionnelle mais &#e0; la demi-vie diminu&#e9;e &#e0; la surface cellulaire Les mutations de classe 4, 5 et 6 sont responsables g&#e9;n&#e9;ralement de formes plus mod&#e9;r&#e9;es de la maladie car associ&#e9;es &#e0; la pr&#e9;sence d`une prot&#e9;ine partiellement fonctionnelle [12]. Login to comment
113 Par ailleurs, au-del&#e0; de son utilisation en combinaison avec un correcteur (compos&#e9; VX-809 et VX-661) vis-&#e0;-vis de la mutation F508del, son int&#e9;r&#ea;t chez des patients porteurs de mutations d`autres groupes en particulier R117H (classe 4) va faire l`objet d`&#e9;tudes. Login to comment

PMID: 24357848 [PubMed] Zvereff VV et al: "Cystic fibrosis carrier screening in a North American population."

No. Sentence Comment

54 The R117H variant was the second most common variant identified by both panels (Tables 1 and 2). Login to comment
55 Among 5,198 carriers of the R117H variant detected by the 32-mutation panel, two copies of 5T alleles were detected in only 23 cases (0.44%). Login to comment
57 The 5T status of the R117H variant could not be determined in 468 cases (9%) for carriers of 5T/7T or 5T/9T alleles. Login to comment
58 The 69-mutation panel identified two cases with two copies of the 5T allele (0.73%) among 274 R117H carriers, whereas the majority of carriers (89.41%) did not carry a 5T allele (Table 4). Login to comment
59 In 27 occurrences (9.86%) the 5T background of the R117H variant could not be identified. Login to 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
80 The Table 3ߒ Frequency of 5T/7T/9T genotypes as a result of R117H reflex testing Poly-T alleles Number of detected alleles (%) CF32 panel CF69 panel 5T/5T 23 (0.44) 2 (0.73) 5T/7T 430 (8.27) 26 (9.49) 5T/9T 38 (0.73) 1 (0.37) 7T/7T 4,103 (78.93) 219 (79.92) 7T/9T 604 (11.61) 26 (9.49) 9T/9T 1 (0.02) 0 Total 5,198 (100) 274 (100) 394delTTd c.262_263delTT 3 0.10 G178Rd p.G178R 3 0.10 V520Fd p.V520F 3 0.10 2143delTd c.2012delT 2 0.06 935delAe c.803delA 2 0.06 A455Eb p.A455E 2 0.06 Q890Xd p.Q890X 2 0.06 S549Rd p.S549R 2 0.06 2869insGd c.2737insG 1 0.03 405ߙ+ߙ3A>Ce c.273ߙ+ߙ3A>C 1 0.03 G480Ce p.G480C 1 0.03 M1101Kd p.M1101K 1 0.03 Y122Xd p.Y122X 1 0.03 Total 3,088 100 a 1898ߙ+ߙ5G>Te , 444delA, G330X, S364Pe , K710X, and S1196X mutations were not detected in the target population. Login to comment

PMID: 24416359 [PubMed] Cebotaru L et al: "Correcting the cystic fibrosis disease mutant, A455E CFTR."

No. Sentence Comment

29 Unlike other mild missense mutations such as R117H that have altered channel conductance [10] and are considered class IV mutations, the single-channel characteristics of A445E resemble those of wild-type CFTR [11,12] . Login to comment

PMID: 24440181 [PubMed] De Boeck K et al: "The relative frequency of CFTR mutation classes in European patients with cystic fibrosis."

No. Sentence Comment

34 Other mutation class specific treatments are in the pipeline [18]: stop codon read through drugs for patients with premature stop codon mutations, combination therapy with correctors and potentiators in subjects with class II mutations, evaluation of the efficacy of the CFTR potentiator ivacaftor in subjects with R117H class IV mutation or residual CFTR function. Login to comment
56 Class Type of defect List of mutations attributed to this class Class I Defective protein production Nonsense mutations Large deletions and insertions 1078delT; 1717-1G࢐A; 3659delC; 621+1G࢐T Class II Defective protein processing G85E, F508del, I507del, R560T, N1303K Class III Defective protein regulation ('gating`) G178R, S549N, S549R, G551D, G551S, G970R, G1244E, S1251N, S1255P, G1349D Class IV Defective protein conductance R117H, R334W, R347P Class V Reduced amount of functioning protein 2789+5G࢐A, 3849+10KbC࢐T, A455E Unclassified All other mutations, including those unknown. Login to comment

PMID: 24440239 [PubMed] Muthuswamy S et al: "Spectrum and distribution of CFTR gene mutations in asthma and chronic pancreatitis cases of North Indian population."

No. Sentence Comment

3 Methods: A total of 800 subjects including 400 controls, 250 asthma cases and150 chronic pancreatitis cases were analyzed for 6 mutations (F508del, G542X, G551D, R117H, W1282X, and S549N) and IVS8 Tn polymorphism. Login to comment
6 The carrier frequency of F508del, G542X, G551D, R117H, S549N and T5 was 0.015, 0.025, 0.02, 0.005, 0.005, and 0.022 respectively. Login to comment
44 ARMS PCR Identification of F508del, G551D, G542X, R117H and W1282X mutations were carried out by ARMS PCR (Ferrie et al., 1992). Login to comment
63 Mutation Primer Method Amplicon (size in bp) Reference DF508 C GACTTCACTTCTAATGATGATTATGGGAG ARMS Ferrie et al. (1992) N GTATCTATATTCATCATAGGAAACACCAC 160 M GTATCTATATTCATCATAGGAAACACCAT 157 G551D C TAAAATTTCAGCAATGTTGTTTTTGACC N GCTAAAGAAATTCTTGCTCGTTGCC 285 M AGCTAAAGAAATTCTTGCTCGTTGCT 286 G542X C TAAAATTTCAGCAATGTTGTTTTTGACC N ACTCAGTGTGATTCCACCTTCTAC 256 M CACTCAGTGTGATTCCACCTTCTCA 257 R117H C CACATATGGTATGACCCTCTATATAAACT N CCTATGCCTAGATAAATCGCGATAGAAC 237 M CCTATGCCTAGATAAATCGCGATAGAAT 237 S549N For TTCAGCAATGTTGTTTTGACCAAC RFLP (DdeI) N: 13 + 238 + 174 H: 13 + 238 + 174 + 412 M: 13 + 412 Kerem et al. (1990) Rev CACAGATTCTGAGTAACCATAATC IVS8 Tn For1 TAATGGATCATGGGCCATGT Nested PCR (Xmn1) 5T - 84 7T - 86 9T - 88 Chillon et al. (1995) Rev1 ACAGTGTTGAATGTGGTGCA For2 CCGCCGCTGTGTGTGTGTGTGTGTTTTT Rev2 GGATCCAGCAACCGCCAACA 3. Login to comment
71 Controls (n = 400) Minor allele frequency of F508del, G542X, G551D, R117H and S549N observed to be 0.0075, 0.0125, 0.01, 0.0025 and 0.0025 respectively (Table 2). Login to comment
73 We further stratified data as per their prevalence and found G542X to be the most common mutation with the frequency of 2.49%, followed by G551D, F508del, R117H and S549N with 2.00%, 1.50%, 0.50% and 0.50% respectively and 2.24% for 5T allele (Fig. 1A). Login to comment
75 Asthma cases (n = 250) We observed a minor allele frequency of 0.008, 0.022, 0.028, 0.002, 0.01 and 0.058 for F508del, G452X, G551D, R117H, S549N and IVS8 T5 respectively (Table 2). Login to comment
76 The frequency of individuals falling in different mutations were 10%, 5.6%, 4.4%, 2.0%, 1.6% and 0.4% with respect to IVS8 T5, G551D, G542X, S549N, F508del and R117H (Fig. 1B). Login to comment
78 CP cases (n = 150) 300 chromosomes belonging to this subgroup found to have the minor allele frequency of 0.04, 0.03, 0.03, 0.006, 0.013 and 0.02 for F508del, G452X, G551D, R117H, S549N and IVS8 T5 respectively (Table 2). Login to comment
79 The frequency of heterozygous individuals were 8.67%, 6.67%, 6.00%, 2.67%, 1.33% and 4.00% for F508del, G452X, G551D, R117H, S549N and IVS8 T5 respectively (Fig. 1C). Login to comment
98 R117H and S549N mutations The mutation falls in class IV and class III categories respectively. Login to comment
100 The frequency for R117H mutation among the CP patients was 1.3%/150, which was statically different compared to neither the group of asthma patients (0.4%/250) nor the controls (0.5%/400). Login to comment
112 Serial no. Mutation General population (400) Asthma (250) Chronic pancreatitis (150) 1 DF508 0.0075 0.0080 0.0433 2 G542X 0.0125 0.0220 0.0333 3 G551D 0.01 0.0280 0.03 4 R117H 0.0025 0.0020 0.0066 5 S549N 0.0025 0.0100 0.0133 6 IVS8-5T 0.01125 0.0580 0.02 thrive, pancreatic insufficiency, elevated sweat electrolytes, late-stage diabetes and cardiac failure, besides male infertility due to congenital bilateral absence of the vas deferens (CBAVD) (Schrijver et al., 2005). Login to comment
119 B) In asthma patients IVS8-T5 polymorphism is the common one accounting for 42% (25 out of 60) and the least one is R117H mutation of 2%(1 out of 60). Login to comment
120 C) In chronic pancreatitis cases the most common mutation is F508del account for 30% (13 out of 44) and the least one is R117H mutation of 4% (2 out of 44). Login to comment
134 Serial No. Mutation General population (n = 400)% Asthma (n = 250)% Chronic pancreatitis (n = 150)% Chi square-testÌe; P value Asth vs ctrl Cp vs ctrl Asth vs CP 1 DF508 1.5 1.6 8.7 NS 0.0002 0.0013 2 G542X 2.5 4.4 6.7 NS 0.03 NS 3 G551D 2.0 5.6 6.0 0.02 0.02 NS 4 R117H 0.5 0.4 1.3 NS NS NS 5 S549N 0.5 2 2.7 NS NS NS 6 IVS8-5T 2.2 10 4.0 b0.0001 NS 0.03 7 Total 9.3 24 29.3 b0.0001 b0.0001 NS Ìe; P b 0.05 is considered significant (Bold values). Login to comment
145 Based on our data G551D, G542X, F508del, T5, R117H and S549N mutations may be considered for Indian subjects. Login to comment

PMID: 24513262 [PubMed] Sarles J et al: "Neonatal screening for cystic fibrosis: comparing the performances of IRT/DNA and IRT/PAP."

No. Sentence Comment

20 http://dx.doi.org/10.1016/j.jcf.2014.01.004 including R117H in the mutation panel, implies their management, which goes beyond the goal of newborn screening and iii/the panel of mutations is based on frequencies observed in the general population, which is unfair for ethnic minorities. 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: 24520399 [PubMed] Char JE et al: "A little CFTR goes a long way: CFTR-dependent sweat secretion from G551D and R117H-5T cystic fibrosis subjects taking ivacaftor."

No. Sentence Comment

0 A Little CFTR Goes a Long Way: CFTR-Dependent Sweat Secretion from G551D and R117H-5T Cystic Fibrosis Subjects Taking Ivacaftor Jessica E. Char1 , Marlene H. Wolfe1 , Hyung-ju Cho1 , Il-Ho Park1 , Jin Hyeok Jeong1 , Eric Frisbee1 , Colleen Dunn2 , Zoe Davies2 , Carlos Milla2 , Richard B. Moss2 , Ewart A. Login to comment
1 C. Thomas3 , Jeffrey J. Wine1,2,3 * 1 Cystic Fibrosis Research Laboratory, Stanford University, Stanford, California, United States of America, 2 Department of Pediatrics, Stanford University School of Medicine, Stanford, California, United States of America, 3 Department of Psychology, Stanford University, Stanford, California, United States of America Abstract To determine if oral dosing with the CFTR-potentiator ivacaftor (VX-770, Kalydeco) improves CFTR-dependent sweating in CF subjects carrying G551D or R117H-5T mutations, we optically measured sweat secretion from 32-143 individually identified glands in each of 8 CF subjects; 6 F508del/G551D, one G551D/R117H-5T, and one I507del/R117H-5T. Login to comment
12 Citation: Char JE, Wolfe MH, Cho H-j, Park I-H, Jeong JH, et al. (2014) A Little CFTR Goes a Long Way: CFTR-Dependent Sweat Secretion from G551D and R117H-5T Cystic Fibrosis Subjects Taking Ivacaftor. Login to comment
25 Recently, ivacaftor was shown to improve CFTR-dependent ion transport in human airway epithelial cells carrying an R117H mutation [6], and trials are now underway to determine if ivacaftor will be clinically beneficial for patients with R117H-5T mutations. Login to comment
38 Therefore, we also used the assay to measure the efficacy of ivacaftor in two CF subjects with R117H-5T mutations. Login to comment
40 After written informed consent, six adults with genotypes G551D/F508del, one with G551D/R117H-5T and one with I507del/R117H-5T were enrolled, along with a healthy control. Login to comment
78 doi:10.1371/journal.pone.0088564.g001 measures of PO and c for R117H [12] and mRNA transcript measurements of n [13] to provide an independent estimate of unpotentiated R117H-5T channel function. Login to comment
218 Summary of results for R117H-5T CF subjects and the healthy control. Login to comment
220 (nl/gland) MCh Rate Estimate nl/gl/min Cktl Avg Final Vol (pl/gl) Cktl Rate (pl/gl/min) C mean/ M mean % WT % WT (Highest 12 M-sweat) % WT (Hi-12, Loss-Corrected) S4 G551D/R117H-5T (+) ivacaftor data S4 F 8/22/ 2012 37 8 22% 16.05 1.07 100 3.33 0.31% 1.22% - - S4 F 11/6/ 2012 32 6 19% 10.66 0.69 30 1.00 0.14% 0.55% - - S4 F 4/30/ 2013 37 11 30% 13.57 0.57 150 5.00 0.55% 2.16% - - S4 (+) Averages 35.33 8.33 23% 13.43 0.78 93 3.11 0.35% 1.31% 2.13% 7.83% S8 R117H/I508del (2) ivacaftor S8 M 1/31/ 2013 52 1 2% 46.76 3.12 6 0.19 0.01% 0.02% - - S8 M 2/8/2013 54 1 2% 49.88 3.33 12 0.39 0.01% 0.04% - - S8 M 2/15/ 2013 50 1 2% 59.51 3.97 4 0.14 0.00% 0.01% - - S8 (2) Averages 52 1 0% 52 3 7 0.24 0.01% 0.03% 0.06% 1.50% S8 R117H/I508del (+) ivacaftor S8 M 3/15/ 2013 53 28 53% 41.40 2.76 531 17.70 0.64% 2.42% - - S8 M 3/22/ 2013 53 45 84% 54.35 3.62 766 25.55 0.71% 2.66% - - S8 M 3/29/ 2013 49 42 86% 53.88 3.59 1146 38.20 1.06% 4.01% - - S8 M 6/17/ 2013 53 43 81% 57.84 3.86 645 21.49 0.56% 2.10% - - S8 M 6/24/ 2013 53 40 75% 53.85 3.59 474 15.80 0.44% 1.66% - - S8 (+) Averages 52.2 39.6 76% 52.26 3.48 712 23.75 0.68% 2.57% 4.51% 5.89% Healthy Control WT F 3/14/ 2013 51 50 98% 35.94 2.40 9687 323 13% 51% - - WT F 3/25/ 2013 51 51 100% 36.98 2.47 9371 312 13% 48% - - WT F 3/28/ 2013 51 51 100% 28.81 1.92 11519 384 20% 75% - - WT F 5/2/2013 51 50 98% 36.48 2.43 10540 351 14% 54% - - WT Averages 51 50.5 99% 34.55 2.30 10279 343 15% 57% 60.65% 62.97% Table is arranged using same format as Table 1 and shows data for S8, S4 and the healthy control. Login to comment
221 doi:10.1371/journal.pone.0088564.t002 Within-subject study of an R117H-5T subject (2) and (+) ivacaftor Subject 8 has genotype I507del/R117H-5T. Login to comment
222 The I507del mutation does not traffic [18,19] and so is predicted to be unresponsive to ivacaftor, allowing us to assess the in vivo effect of ivacaftor on the R117H-5T mutation in isolation. Login to comment
239 Study of a CF subject with two responsive mutations: G551D/R117H-5T Subject 4 (S4, female, G551D/R117H-5T) has two mutations that are each expected to respond to ivacaftor. Login to comment
259 Images of C-sweat responses for CF subject 8: male, I507del/R117H-5T (&#b1;) ivacaftor (N of 1 trial). Login to comment
272 Summary data for S8, R117H-5T, (&#b1;) ivacaftor. Login to comment
295 Even so, the differences within G551D subjects are overshadowed by the much higher C/M ratio seen in R117H-5T subject 8, and in S4, who, with two responsive mutations, had the highest C/M ratio after partially correcting for M-sweat rate. Login to comment
304 Discussion Our first goal in this study was to determine if this bioassay could detect improved CFTR function in CF subjects with G551D or R117H-5T mutations who were taking ivacaftor. Login to comment
307 But no clinical data were available on ivacaftor treated R117H-5T subjects, so our finding of a strong ivacaftor effect for subjects with this compound allele provides in vivo support for the prediction that ivacaftor will be therapeutic in such patients [2]. Login to comment
314 Summary data for S4, a female CF subject having two potentially responsive mutations: G551D & R117H-5T who was tested 3 times (+) ivacaftor. Login to comment
322 doi:10.1371/journal.pone.0088564.g009 R117H-5T CFTR. Login to comment
341 With this background, we first consider results for the R117H-5T subject. Login to comment
351 doi:10.1371/journal.pone.0088564.g010 Quantifying R117H-5T CFTR function in vivo and in vitro R117H-5T CFTR retains partial function and confers pancreatic sufficiency when trans to a severe allele. Login to comment
352 Studies of heterologously expressed CFTR channels by Sheppard and colleagues [12] found that the whole-cell Cl2 conductance of R117H was reduced to 15% of WT, while single channel analysis found that both PO and c were reduced predicting ,24% WT CFTR channel function. Login to comment
353 In a male and a female each having R117H/R117H on a 7T/7T background, all clinical indices were normal except for CBAVD in the male, electrophysiological measurements of nasal and intestinal epithelia were also normal, and sweat chloride values were 34 mM for the male and 42 mM for the female [23]. Login to comment
354 However, when R117H-CFTR is in cis with a 5T allele, n = 0.1/0.7 = 14% WT, reducing R117H-5T function to 2.1-3.7% of WT function. Login to comment
357 To estimate the amount of primary sweat in S8 that was lost in the (2) ivacaftor condition, we assigned a CFTR functional level = 1.5% WT to S8, based on the above analysis of R117H-5T function [12,13]. Login to comment
360 If ivacaftor restored normal PO to R117H and left n and c unchanged, it would increase R117H-5T CFTR function equivalent to 5T function on 1 allele, or 7% of WT. Login to comment
363 Thus, in this R117H-5T subject, functional estimates based on patch-clamp [12] and mRNA transcript analysis [13] converged with those of based on C/M-sweat bubble analysis. Login to comment
370 Based on all the data and on comparisons with the ivacaftor-treated R117H subject, we estimate ivacaftor-potentiated CFTR function in G551D/ F508del subjects to be ,5% WT. Login to comment
371 Subject S4 has mutations R117H-5T and G551D. Login to comment
372 In the (+) ivacaftor condition, the data from patch clamp and transcript analysis predicts CFTR function of 2.6-5% function for R117H-5T, and up to 5% for G551D, or up to 10% function for the combination. Login to comment
382 S1-S3 and S5 each has one G551D mutation, S8 has R117H-5T, and S4 has both. Login to comment
412 Conclusions Multiple measures of C-sweating and M-sweating from individual glands revealed that oral dosing with ivacaftor improved b-adrenergic cocktail-stimulated, CFTR-dependent sweating (C-sweating) in CF subjects with G551D or R117H-5T mutations. Login to comment
431 doi:10.1371/journal.pone.0088564.g014 function was 2.6661.06% of WT for the 4 G551D subjects, 6.1% for the R117H-5T subject, and 7.7% for the subject with both mutations. Login to comment
432 The finding that CFTR-dependent sweat secretion was greater in R117H-5T than in G551D subjects supports prior work suggesting that ivacaftor will be clinically useful for subjects with the R117H-5T mutation [6]. Login to comment
511 23. de Nooijer RA, Nobel JM, Arets HG, Bot AG, van Berkhout FT, et al. (2011) Assessment of CFTR function in homozygous R117H-7T subjects. Login to comment

PMID: 24532752 [PubMed] Lane MA et al: "A new era in the treatment of cystic fibrosis."

No. Sentence Comment

11 > Class IV defects (eg R117H) result in reduced conductance of CFTR at the cell surface. Login to comment
48 Class IV defects Ivacaftor is also being studied in patients with the class IV defect R117H. Login to comment

PMID: 24561283 [PubMed] Ikpa PT et al: "Cystic fibrosis: toward personalized therapies."

No. Sentence Comment

1646 This new gating model may explain why VX-770 increases the open probability of both WT CFTR and all 10 class III gating mutants tested (Yu et al., 2012), as well as numerous other CFTR forms with missense mutations or deletions, including F508del and R117H (Rowe and Verkman, 2013; Van Goor et al., 2014). Login to comment
1675 Such a strategy may be particularly important to identify corrector effects in biopsies carrying very mild mutations (e.g. R117H) that are associated with < 80% loss of CFTR function. 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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103 IL17 (INNOLiPA_CFTR17_TnUpdate): 621+1G.T; 3849+10kbC.T; 2183AA.G; 394delTT; 2789+5G.A; R1162X; 3659delC; R117H; R334W; R347P; G85E; 1078delT; A455E; 2143delT; E60X; 2184delA; 711+5G.A; polymorphism 5T/7T/9T. 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
152 The relatively high frequency (0.54%) of IVS9 T5_TG12-13 (without R117H in cis) in PL patients could not be compared with other populations. Login to comment
153 While TG12-13 in cis with T5 are known to contribute to less efficient splicing of exon 10 and to abnormal phenotype [31-32], most of the CF tests do not determine the length of the TG repeat, and reporting the T5 in intron 9 (l.n.IVS8-T5) as a pathogenic mutation has been recommended only if in cis with R117H [12]. Login to comment

PMID: 24621136 [PubMed] Caldrer S et al: "Challenging the diagnosis of cystic fibrosis in a patient carrying the 186-8T/C allelic variant in the CF transmembrane conductance regulator gene."

No. Sentence Comment

56 It is known that Normal and borderline sweat tests were obtained in CF patients in the presence of specific CFTR genotypes: the most representative includes mutations 3849 + 10 kb C > T, D1152H and R117H [12,13]. 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

70 Group A Group B Group C Group D Classic-CF CF-causing mutations Non-classic CF CFTR-related disorder associated mutations No clinical consequence Unknown clinical relevance All mutations in Table 2 and 711 + 3A > G*, R117H-T5*, D1152H*, L206W*, TG13-T5* TG13-T5a , R117H-T5a , D1152Ha , L206Wa , L997F, M952I, D565Ga , TG11-T5b , R117H-T7b , D443Y-G576A-R668C, R74W-D1270N, R75Qb TG11-T5b , R117H-T7b , R75Qb , 875 + 40A/G, M470V, T854T, P1290P, I807M, I521F, R74W, F508C, I506V, I148T All mutations (mostly missense) not yet analyzed or undergoing functional analysis a Mutations that may belong either to Group A or to Group B. b Mutations that may belong either to Group B or to Group C. Login to 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
81 These 23 mutations fall into Group A, as classic CF-causing mutations, with the exception of p.Arg117His, which is discussed later in a paragraph dedicated to complex alleles. Login to comment
122 The p.Arg117His mutation is the best-characterized class IV mutation. Login to comment
149 This can be illustrated by the class IV R117H mutation (c.350G > A, p.Arg117His) whose severity is modulated in cis by the 5/7/9T polypyrimidine tract (c.1210-12T(5 9)) in intron 9. Login to comment
150 While the R117H-T7 genotype is associated with milder forms of CF such as CBAVD, and most of the time even absence of symptoms, the R117H-T5 can be identified in patients having elevated sweat chloride and clinical cystic fibrosis, which in some cases is severe (Thauvin-Robinet et al., 2009). Login to comment
227 It also has the ability to increase the open probability of the wild-type channel and other mutants, namely p.Phe508del (Van Goor et al., 2009) and p.Arg117His (Van Goor et al., 2012). 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

1987 Encouragingly, the data suggest that ivacaftor potentiates multiple gating mutants located in different parts of CFTR structure including R117H (M2), R668C (RD) and A1067T (ICL4) (Yu et al., 2012; Van Goor et al., 2014). Login to comment
1988 3.4. Class IV mutations: defective channel conduction Analysis of three CF-PS mutations located in MSD1 (R117H [M2], R334W [M6] and R347P [M6]) provided the first evidence that some CF mutations perturb anion flow through the CFTR pore (Fig. 3). Login to comment
1991 For R117H, the reduction was Fig. 4. Login to comment
2012 Although the CF mutation R117H is classified as a class IV mutation, it is principally a gating mutation, reducing channel activity (measured by open probability [Po]) to ~30% wild-type levels, but single-channel conductance by only ~15% (Sheppard et al., 1993). Login to comment
2013 Further analyses of the impact of R117H on CFTR channel gating are required. Login to comment
2015 The data suggest that R117H destabilises the open-channel configuration with the result that the pattern of channel gating bears some resemblance to that of wild-type CFTR inhibited by intermediate speed open-channel blockers (e.g. glibenclamide; Sheppard and Robinson, 1997). Login to comment
2016 Of note, H&#e4;mmerle et al. (2001) systematically investigated the impact of ten CF mutations in extracellular loop 1 (ECL1), including R117H, on CFTR expression and function. Login to comment

PMID: 24925916 [PubMed] Mall MA et al: "CFTR: cystic fibrosis and beyond."

No. Sentence Comment

90 This hypothesis is currently being tested in a series of clinical trials in patients with non-G551D gating mutations and the pancreatic sufficient mutation R117H. Login to comment

PMID: 24932877 [PubMed] Bell SC et al: "New pharmacological approaches for cystic fibrosis: promises, progress, pitfalls."

No. Sentence Comment

506 In most CF newborn screening programmes a surplus of "patients" carrying the R117H mutation in trans with F508del were identified (Scotet et al., 2006; Thauvin-Robinet et al., 2009; Lilley et al., 2010) and many of these subjects did not develop phenotypic features of CF. Login to comment
507 Although R117H by itself somewhat reduces CFTR conductance and gating (Sheppard et al., 1993), it was found that the Table 1 Clinical features of cystic fibrosis. Login to comment
508 Sinopulmonary Gastrointestinal/hepatobiliary Reproductive and endocrine Salt loss syndromes Other Chronic bronchial infection leading to bronchiectasis Chronic infection with multi-resistant pathogens Haemoptysis Pneumothorax Respiratory failure Allergic bronchopulmonary aspergillosis Chronic rhinosinusitis and nasal polyposis Pancreatic exocrine insufficiency Recurrent acute pancreatitis in those with pancreatic sufficiency Fat soluble vitamin deficiency Distal intestinal obstruction syndrome Intussusception Appendiceal abscess Cirrhosis with portal hypertension Gastroesophageal reflux Constipation Bacterial overgrowth including pseudomembranous colitis Obstructive azoospermia in males Reduced fertility in women Delayed puberty Oligomenorrhea Cystic fibrosis-related diabetes Metabolic bone disease (reduced bone mineral density) Acute dehydration due to heat prostration Hyponatraemic, hypochloraemic metabolic alkalosis Pseudo-Bartter syndrome Difficult vascular access Hypersensitivity reaction to antibiotics CF arthropathy/hypertrophic pulmonary osteoarthropathy Chronic kidney disease Nephrolithiasis/oxalate nephropathy Depression Anxiety number of thymidine (T) repeats in intron 8 (IVS8) in cis with R117H explains the variability of the phenotype. Login to comment
547 Class Type of defect List of mutations attributed to this class Class I Defective protein production Nonsense mutations: G542X, R1162X, RW1282X Deletions and insertions: CFTRdele2,3; 1078delT; 1717-1G ࢐ A; 3659delC; 621+1G N T Class II Defective protein processing G85E, F508del, I507del, R560T, A561E, R1066C, N1303K Class III Defective protein regulation (gating) G178R, S549N, S549R, G551D, G551S, G970R, G1244E, S1251N, S1255P, G1349D Class IV Defective protein conductance R334W, R347P, R117H Class V Reduced amount of functioning protein 2789+5G ࢐ A, 3272-26ANG, 3849+10KbC ࢐ T, A455E Class VI Reduced cell surface stability Rescued F508del, c.120del23 Unclassified All other mutations, including those unknown a F508del-CFTR pocket (at NBD1:ICL4 interface) (Farinha et al., 2013). Login to comment
567 Another example is R117H which could be classified as class IV due to a slight decrease in channel conductance but is not a CF-causing mutation per se (Thauvin-Robinet et al., 2009; de Nooijer et al., 2011). Login to comment
569 So the "real CF-causing mutation" is the complex allele R117H-5 T which can be considered as a class IV/V mutation. Login to comment
640 In a randomized controlled trial including 69 children and adults with the R117H mutation (a class IV CFTR mutation), which is the most frequent mutation with residual function, the primary endpoint of improvement in FEV1 was not met (www.ccf.org, 2014). Login to comment

PMID: 24954874 [PubMed] Shelton CA et al: "Genetics and treatment options for recurrent acute and chronic pancreatitis."

No. Sentence Comment

44 Members of the CFTR bicarbonate-defective genetic variants (CFTRBD ) include R74Q, R75Q, R117H, R170H, L967S, L997F, D1152H, S1235R, and D1270N [23ߦߦ, 25]. Login to comment

PMID: 24958810 [PubMed] Sharma H et al: "Heterogeneous spectrum of mutations in CFTR gene from Indian patients with congenital absence of the vas deferens and their association with cystic fibrosis genetic modifiers."

No. Sentence Comment

4 p.Phe508del (n &#bc; 16) and p.Arg117His (n &#bc; 4) were among the most common severe forms of CFTR mutations identified.TheIVS8-T5 allele,which isconsideredas amild formofCFTR mutation,wasfound withan allelicfrequencyof28.3%. Login to comment
21 The p.Phe508del, p.Arg117His and T5 allele were identified as most common CFTR mutations in Caucasians associated with CAVD phenotype (Chillon et al., 1995; De Braekeller and Ferec, 1996). Login to comment
56 CFTR mutations, viz., p.Arg117His, p.Asn1303Lys and p.Arg553X were analyzed by single ARMS PCR, whereas mutations 621+1G.T, p.Gly542X, p.Gly551Asp and p.Trp1282X were screened by multiplex ARMS PCR. Login to comment
76 p.Phe508del (n &#bc; 16) and p.Arg117His (n &#bc; 4) are the most common severe form of CFTR mutations identified in the Indian CAVD males. Login to comment
83 Among them, eight mutations were novel and have been reported only in the Indian CAVD male population(TableII).Among50healthycontrolsscreenedforthecommonmuta- tions, viz., p.Phe508del, p.Arg117His and T5 allele, only seven of them were detected as a carrier of T5 allele (Table III and Supplementary data, Table SII). Login to comment
94 Genotype Number of CAVD subjects (n 5 60) Number of healthy controls (n 5 50) p.Phe508del/U 11 ND p.Phe508del/5T 5 ND 5T/5T 8 ND 5T/U 9 7 p.Arg117His/7T 2 ND p.Arg117His/5T 2 ND p.Arg933Thr/U 1 ND p.His139Gln/U 1 ND p.Ser118Pro/c. Login to comment
100 Mutations Nucleotide change Consequences Exon/Intron Number of alleles T5 Reduction of oligo T tract to 5T, c.1210-12T[5] Aberrant splicing Intron 8 34 p.Phe508del c.1521_1523delCTT or c.1522_1524delTTT Deletion of phenylalanine at amino acid 508 Exon 11 16 p.Gly480Ser c.1438G.A Glycine to Serine at 480 Exon 11 1 p.Arg518Lysa c.1553G.A Arginine to Lysine at 518 Exon 11 1 p.Arg117His c.350G.A Arginine to Histidine at 117 Exon 4 4 p.Gly126Cysa c.376G.T Glycine to Cystine at 126 Exon 4 1 p.Ala141Glya c.422C.G Alanine to Glycine at 141 Exon 4 1 p.His139Glna c.417C.G Histadine to Glutamine at 139 Exon 4 1 p.Ser118Proa c.352T.C Serine to Proline at 118 Exon 4 1 p.Arg170Cys c.508C.T Arginine to Cystine at 170 Exon 5 1 p.Glu585Glna c.1753G.C Glutamate to Glutamine at 585 Exon 13 1 p.Met281Arga c.842T.G Methionine to Arginine at 281 Exon 7 1 p.Arg933Thra c.2798G.C Arginine to Threonine at 933 Exon 17 1 p.Ser549Asn c.1646G.A Serine to Asparagine at 549 Exon 12 1 CTFR, cystic fibrosis transmembrane conductance regulator. Login to comment
105 However, no significant association was established between CF genetic modifiers (TGF-b1 and EDNRA) and the most common mutations identified in the Indian CAVD males, namely viz., p.Phe508del, p.Arg117His and IVS8-T5. Login to comment
135 The second most common mutation identified was p.Arg117His observed with an allelic frequency of 3.3%, and this frequency is similar to that of France (Grangeia et al., 2004) and Greece (Estivill et al., 1997) but lower than that of Germany (11%; Dork et al., 1997). Login to comment
136 Two of the patients with a p.Arg117His heterozygous mutation were associated with a T7 allele, which is considered a mild CFTR mutation in Europe and may lead to the CAVD phenotype (Thauvin et al., 2009). Login to comment
144 As the frequency of novel substitutions identified in the Indian CAVD male is very low, we can include only p.Phe508del, p.Arg117His and T5 in mutation screening panel. 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

52 CFTR gene analysis, for the presence F508del, R117H, N1303K and R553X mutations was performed by single ARMS PCR as described by Ferrie et al. (1992). Login to comment

PMID: 25024266 [PubMed] Cui G et al: "Three charged amino acids in extracellular loop 1 are involved in maintaining the outer pore architecture of CFTR."

No. Sentence Comment

15 Mutation R117H has been reported to reduce current amplitude, whereas D110H, E116K, and R117C/L/P may impair channel stability. Login to comment
29 Sheppard et al. (1993) demonstrated that R117H exhibits reduced single-channel conductance, altered sensitivity to external pH, and altered single-channel kinetics resulting in reduction of macroscopic current. Login to comment
31 H&#e4;mmerle et al. (2001) reported that mutations D110H, E116K, and R117H induce no trafficking defect when expressed in baby hamster kidney (BHK) cells but affect channel function significantly. Login to comment
32 When studied in planar lipid bilayers, R117H-CFTR had gating kinetics similar to WT-CFTR, but a reduced single-channel conductance, whereas D110H- and E116K- CFTR displayed unstable channel openings, leading the authors to propose that ECL1 might contribute to maintaining the open pore architecture of CFTR (H&#e4;mmerle et al., 2001). Login to comment
37 Mutations at each of these sites are associated with milder forms of CF; R117H in particular is associated with pancreatic sufficiency and is a common mutation related to mild CF (Kristidis et al., 1992; Sheppard et al., 1993). 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

5 Nine variants (CFTR R74Q, R75Q, R117H, R170H, L967S, L997F, D1152H, S1235R, and D1270N) not associated with typical CF were associated with pancreatitis (OR 1.5, p = 0.002). Login to comment
62 Of 43 CFTR variants identified in the NAPS2 cohort (Table 1), nine not associated with typical CF but reported in patients with pancreatitis[25-29] were of particular interest: R74Q, R75Q, R117H (CFTRm-v only when in cis with IVS8-T5[30]; R117H*T5), R170H, L967S, L997F, D1152H, S1235R, and D1270N. Login to comment
73 Functional assays on CFTR variants For our functional studies, we cloned the nine CFTR variants and confirmed that they had normal folding, glycosylation (Figure 1a) and chloride channel activities, except for R117H (Figure 1b). Login to 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
119 Blank cells indicate undefined (e.g. x40) **IVS8 T5 is reported but causes CF only when in cis with either R117H or IVS8 TG12or13. Intronic mutations are reported in standard nomenclature ''####+/2##N.N`` except IVS8-T5 (1210-12T[5]). Login to comment
124 We identified the R75Q, R117H, L967S, L997F, D1152H, and S1235R CFTRBD variants as well as CFTRCF -associated variants (e.g., F508del, G542X) in cases with rhinosinusitis. Login to comment
129 We identified R75Q, R117H, and S1235R as well as the CFTRCF variants F508del, G542X and 2789+5G,A in male cases with infertility. Login to comment
212 The final variant (R117H) is located in an extracellular domain and has functional effects beyond the other CFTRBD variants. Login to comment
213 R117H is a complex variant that is associated with CF only when found in cis with a T5 tract in intron 8. Login to comment
214 The CFTR R117H variant was identified in 22 cases (2.3%) and 8 controls (0.7%) (p = 0.001), with only 3 cases and 1 control having the CF-associated R117H*T5 haplotype (p = ns), which links the CFTR variant R117H to pancreatitis regardless of the intron 8 T5 haplotype. Login to comment
216 The R117H variant was the only one with reduced chloride current density (Figure 1b). Login to comment
228 In addition, other possible mechanisms of CFTR channel dysfunction linked to altered bicarbonate conductance are possible, such as mechanisms linked to CFTR R117H. 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
356 *IVS8 T5 and R117H are reported but CF disease causing only when in cis with each other or IVS8 T5 with IVS8 TG12or13. Intronic mutations are reported in standard nomenclature ''####+/2##N.N`` except IVS8-T5, (1210-12T[5]). Login to comment

PMID: 25071991 [PubMed] Chen N et al: "Development of allele-specific multiplex PCR to determine the length of poly-T in intron 8 of CFTR."

No. Sentence Comment

1 Although poly-T allele analysis in intron 8 of CFTR is required when a patient is positive for R117H, it is not recommended for routine carrier screening. Login to comment
2 Therefore, commercial kits for CFTR mutation analysis were designed either to mask the poly-T allele results, unless a patient is R117H positive, or to have the poly-T analysis as a standalone reflex test using the same commercial platform. Login to comment
21 Additional testing of the poly-Thymidine (poly-T) tract in intron 8 of CFTR is indicated when a patient is positive for R117H, one of the 23 recommended mutations (Grody et al., 2001). Login to comment
25 Presence of both R117H and 5T allele on the same chromosome (i.e., R117H and 5T in cis-configuration) constitutes a disease-causing CF mutation (Bienvenu et al., 1993; Chmiel et al., 1999; Dean et al., 1990). Login to comment
27 Testing parents of patients is able to define whether R117H and 5T are from the one parent (i.e., in cis-configuration) or different parent (i.e., in trans-configuration), if 5T is detected in R117H positive samples. Login to comment
28 Because R117H and poly-T alleles are about 18 kb apart, long-range PCR has also been developed to determine the cis- or trans-relationship of R117H and 5T alleles to circumvent testing unaffected parents (Chen & Schrijver, 2011; Pont-Kingdon et al., 2004). Login to comment
30 For this reason, some commercial assays mask the results of the poly-T tract and only provide poly-T results when the samples are R117H positive. Login to comment
32 When a clinician wants to test the poly-T tract for a male patient with clinical indication of CBAVD, a standalone poly-T test (i.e., poly-T test in a separate tube) would be ordered, because it is impossible to obtain the poly-T tract results with R117H negative samples if laboratories only run commercial CFTR mutation analysis with masked poly-T results. Login to comment
208 Overall, we developed a simple, easy to implement standalone multiplex AS-PCR method to detect all three poly-T alleles in intron 8 of CFTR. Our assay can be implemented as a reflex test in patients with positive R117H, if another method for CFTR mutation analysis didn`t include poly-T analysis. 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

44 Also excluded were challenges for the IVS8 polyT polymorphism for samples that did not contain the R117H mutation. Login to comment
45 The ACOG/ACMG recommendations suggest testing for IVS8 5T only when the R117H mutation is discovered because the polyT modifies the clinical severity of this mutation.5,6,9 Three sample challenges included the R117H mutation and the associated IVS8 polyT polymorphism. Login to 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
120 The 5T variant in intron 8 was evaluated only for the three sample challenges that contained the R117H mutation. Login to comment
121 In three different surveys, a compound heterozygous sample (R117H/ F508del) was distributed. Login to comment
149 The IVS8 5T variant modifies the severity of the R117H mutation when on the same chromosome (in cis), but by itself it is considered a mild mutation not associated with classic CF.9 The R117H mutation and reflex testing for the IVS8 polyT were challenged in three surveys. Login to comment
153 Given the ACMG/ACOG recommendations to reflex R117H samples to test for the 5T variant, laboratories should perform this test for challenges in which the R117H mutation is detected. Login to comment
154 One possible explanation for not reporting intron 8 polyT status is that laboratories may send samples with the R117H mutation to a referral laboratory to detect the 5T variant; reporting of outside laboratory results is a practice that is prohibited in PT testing. Login to comment

PMID: 25083129 [PubMed] Pettit RS et al: "CFTR Modulators for the Treatment of Cystic Fibrosis."

No. Sentence Comment

14 V R117H Synthesis and surface expression of normal CFTR proteins are reduced because of promoter or splicing abnormalities. Login to comment
53 A phase 3 trial of ivacaftor monotherapy in CF patients with R117H showed a nonsignificant 2.1% increase in the mean absolute change from baseline in percent predicted FEV1 (P = 0.2).36 A subgroup analysis of patients at least 18 years old found a statistically significant 5% difference in the mean absolute change from baseline in percent predicted FEV1 (P = 0.01). Login to comment
54 Although ivacaftor did not meet its primary endpoint in patients with R117H, Vertex planned to discuss the finding with the FDA to determine future direction.36 Ivacaftor has shown efficacy in patients with a G551D mutation, one of the class III "gating" mutations, and initially received FDA approval for patients with this mutation. 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
78 p.Arg117His (R117H) was the second most frequent alteration in the cohort as a whole (7.8% of patients; n = 105). Login to comment
139 Whether these cases, representing up to 13.66% of our overall cohort, half of which carry a p.Arg117His mutation, might benefit from NBS is highly questionable. Login to comment
140 Recently, Thauvin et al.31 assessed individuals carrying a p.Arg117His mutation and a CF-causing mutation, showing classic CF penetrance of 0.03% and severe CF penetrance in adulthood of 0.06%. Login to comment
141 Considering that the aim of NBS is early diagnosis of classic forms of CF, their findings provide a strong argument for removing the p.Arg117His mutation from the CFTR NBS mutation panel. Login to comment

PMID: 25225552 [PubMed] Lin WY et al: "A single amino acid substitution in CFTR converts ATP to an inhibitory ligand."

No. Sentence Comment

230 A little CFTR goes a long way: CFTR-dependent sweat secretion from G551D and R117H-5T cystic fibrosis subjects taking ivacaftor. Login to comment

PMID: 25280757 [PubMed] Bagheri-Hanson A et al: "Intestinal current measurement versus nasal potential difference measurements for diagnosis of cystic fibrosis: a case-control study."

No. Sentence Comment

39 For sweat stimulation and collection, the Macroduct&#ae; system (Wescor, Table 1 Characteristics and CFTR response of pancreatic insufficient (CF-PI) and pancreatic sufficient (CF-PS) patients with CF and controls CF-PI (n = 12) CF-PS (n = 6) CF-all (n = 18) Controls (n = 13) Age, years 24.0 &#b1; 6.1 23.3 &#b1; 11.8 22.8 &#b1; 8.0 30.6 &#b1; 10.4 22.0 (19.0 - 26.0) 16.0 (14.5 - 30.5) 20.5 (18.3 - 25.3) 25.0 (23.5 - 35.5) Gender, females:males 3:9 5:1 8:10 7:6 Body mass index Z-score -1.18 &#b1; 0.80 -0.62 &#b1; 1,41 -0.99 &#b1; 1.03* 0.00 &#b1; 0.65* -1.05 (-2.40 - 0.00) 1.41 (-0.20 - 0.70) -0.90 (-2.60 - 0.70) 0.00 (-1.10 - 1.30) Sweat chloride (mmol/l) 110 &#b1; 13** 86 &#b1; 14** 102 &#b1; 17* 19 &#b1; 8* 106 (92 - 140) 90 (70 - 99) 104 (70 - 140) 19 (10 - 36) NPD CFTR response average Ɗ0Cl- + Iso (mV) 4.6 &#b1; 3.9 1.5 &#b1; 4.1 3.6 &#b1; 4.1* -13.6 &#b1; 8.5* 5.1 (-3.0 -11.9) 1.5 (-3.2 - 6.23) 4.5 (-3.2 - 11.9) -12.7 (-26.4 - -1.92) ICM CFTR response average ƊIsc (bc;A/cm2) ) (forskolin/IBMX + carbachol + histamine) -0.3 &#b1; 8.1 5.3 &#b1; 10.9 1.6 &#b1; 9.2* 77.8 &#b1; 34.8* -0.6 (-12.6 - 17.9) 5.0 (-9.7 - 19.0) 0.1 (-12.6 - 19.0) 65.3 (39.6 -140.9) Genotyping F508/F508 (6&#d7;) F508/R347P (2&#d7;) 148 T/R117H-7 T F508/G551D (2&#d7;) F508/3849 + 10 kb C- > T (2&#d7;) F508/- F508/G542X F508/R334W --/-- F508/N1303K F508/? Login to comment

PMID: 25287046 [PubMed] Mornon JP et al: "Full-open and closed CFTR channels, with lateral tunnels from the cytoplasm and an alternative position of the F508 region, as revealed by molecular dynamics."

No. Sentence Comment

352 Interestingly, amino acid R117, which is involved in the mutations R117C and R117H and is located in the first extracellular loop (ECL1) at the very beginning of TM2, can make a salt bridge with E1124 in ECL6 (distances of 5.5 and 5.8 A da; ) and might thus, among others, participate in the stabilization of the open form of the channel (Fig. 7b). Login to comment
353 The R117H mutation (varying clinical consequence) appears less severe than R117C (CF-causing), as histidine probably retains part of the attraction with the glutamate E1124 situated at 7.9 A da; . 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

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: 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
29 The three CFTR mutations most commonly associated with CBAVD are: c.1521_1523delCTT (F508del), c.1210-12T(5) (5T variant allele in intron 8) and c.350G.A (R117H) [10,11,12]. Login to comment
30 Most of the cases with CBAVD are usually compound heterozygous for two different alleles and the most frequent mutations involved are F508del with 5T or R117H [6,13,14]. Login to comment
31 The 5T allele is known to modify the expression of the R117H mutation when it is present on the same chromosome (in cis). Login to comment
32 R117H mutation can be found in cis with IVS8-5T or -7T underlying a mild CF-causing complex allele when in cis with IVS8-5T, or as a CFTR-RD mutation when in cis with IVS8-7T [15]. 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
101 [1624G.T];[1521_1523delCTT] 1 100% R117H/F508del c. Login to comment
145 CBAVD is the most common CFTR-RD, which is usually associated with the presence of one severe mutation (most commonly F508del) and one mild mutation (most commonly R117H or IVS8-5T) or two mild mutations. Login to comment

PMID: 25467948 [PubMed] Dekkers R et al: "A bioassay using intestinal organoids to measure CFTR modulators in human plasma."

No. Sentence Comment

26 CFTR function measurements in organoids Intestinal crypts were isolated from cystic fibrosis patients (R117H/F508del, S1251N/F508del and F508del/F508del), and CFTR function was quantified by measurement of forskolin-induced swelling of intestinal organoid cultures as previously described [9]. Login to comment
43 (D) Swelling of R117H organoids after stimulation with forskolin (0.05 bc;M) and serial dilution of plasma containing VX-770 (2 bc;M in 100% plasma). Login to comment
50 Stimulating CFTR-R117H organoids with forkolin (0.05 bc;M) and increasing amounts of plasma containing VX-770 (2 bc;M in 100% plasma) resulted in a dose-dependent increase in organoid swelling (Fig. 1D). Login to comment

PMID: 25630966 [PubMed] Munck A et al: "Cystic Fibrosis Screen Positive, Inconclusive Diagnosis (CFSPID): A new designation and management recommendations for infants with an inconclusive diagnosis following newborn screening."

No. Sentence Comment

222 [8] Scotet V, Audrezet MP, Roussey M, Rault G, Dirou-Prigent A, Journel H, et al. Immunoreactive trypsin/DNA newborn screening for cystic fibrosis: should the R117H variant be included in CFTR mutation panels? Login to comment
224 [9] Thauvin-Robinet C, Munck A, Huet F, Genin E, Bellis G, Gautier E, et al. The very low penetrance of cystic fibrosis for the R117H mutation: a reappraisal for genetic counselling and newborn screening. J Med Genet 2009;46(11):752-8. Login to comment
226 Delayed diagnosis of cystic fibrosis associated with R117H on a background of 7 T polythymidine tract at intron 8. 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

31 Both methods used 5 &#b5;l of isolated DNA for the NGS assay. NGS assay for detection of CFTR mutations/variants CFTR mutations are described using both the international nomenclature of the Human Genome Variation Society Mutations that have varying consequences c.3454G>C (D1152H) c.3154T>G (F1052V) c.3208C>T (R1070W) c.2930C>T (S977F) - c.3808G>A (D1270N) c.3205G>A (G1069R) c.350G>A (R117H) PolyTG/ polyT - c.1736A>G (D579G) c.3209G>A (R1070Q) c.220C>T (R74W) - - Mutations still under evaluation c.2657ߙ+ߙ2_2657ߙ+ߙ3insA (2789ߙ+ߙ2insA) c.680T>G (L227R) c.1705T>G (Y569D) - - c.1841A>G (D614G) c.1673T>C (L558S) - - - c.3700A>G (I1234V) c. Login to comment
74 However, the sensitivity of the IRT/NGS algorithm would have decreased as much as 50% for classic CF cases when a positive screen is defined as two CF-causing mutations because of uncommon mutations found in five patients Table 2ߒ Cases with a second mutation detected from the next-generation sequencing panel Case no. IRT (ng/ml) Second-tier DNA Additional mutation Sweat chloride (mmol/l) Clinical assessmenta Test 1 Test 2 1 64 F508del D110H 71.4 67.1 CF 2 327 F508del Q1313X N/A N/A CF 3 297 F508del Q1313X N/A N/A CF 4 71 R117H (7T) R347H 45.2 41.5 CRMSb 5 148 F508del R117C 40 38 CRMSb 6 66 F508del 5Tc 36.9 30.8 CRMSb 7 147 F508del D1152Hc 27.9 24.6 CRMSb 8 121 F508del D1152Hc 11 QNS Carrier 9 176 F508del D1152Hc 24 26 Carrier CF, cystic fibrosis; CRMS, CFTR-related metabolic syndrome; IRT, immunoreactive trypsinogen; QNS, quantity not sufficient. Login to comment

PMID: 25698453 [PubMed] Carter S et al: "Ivacaftor as salvage therapy in a patient with cystic fibrosis genotype F508del/R117H/IVS8-5T."

No. Sentence Comment

0 Case Report Ivacaftor as salvage therapy in a patient with cystic fibrosis genotype F508del/R117H/IVS8-5T S. Carter, S. Kelly, E. Caples, B. Grogan, J. Doyle, C.G. Gallagher, E.F. McKone Ìe; National Referral Centre for Adult Cystic Fibrosis, St. Vincent's University Hospital, Elm Park, Dublin 4, Ireland Received 12 January 2015; revised 23 January 2015; accepted 23 January 2015 Available online 16 February 2015 Abstract Ivacaftor is a novel CFTR potentiator that increases CFTR activity and improves clinical outcomes in cystic fibrosis (CF) patients with at least one copy of CFTR-G551D. Login to comment
3 R117H-CFTR is a relatively common CFTR mutation that demonstrates an in-vitro response to ivacaftor [2,3]. Login to comment
4 A clinical trial has suggested that there may be a role for ivacaftor in older patients with R117H-CFTR although this trial did not include patients with very severe CF lung disease [4]. Login to comment
5 In 2014, ivacaftor was approved in the United States as a treatment for CF subjects aged greater than 6 years old with a copy of R117H-CFTR. Login to comment
6 We present a case demonstrating a substantial therapeutic effect of ivacaftor in a CF patient with genotype F508del/R117H and advanced lung disease. Login to comment
9 Clinical Case MC, a 45 year old male with CF (F508del/R117H/IVS8-5T/ 9T), was diagnosed at the age of 16 years old. Login to comment
32 Discussion R117H-CFTR is a CFTR mutation that is found in between 2% and 14% of CF patients worldwide. Login to comment
34 R117H-CFTR results in impaired CFTR conductance with some preservation of CFTR function. Login to comment
35 As a result, R117H-CFTR, when occurring on the opposite chromosome (in-trans) to a severe CFTR mutation, is associated with a milder CF phenotype with later age at diagnosis, older onset of pancreatic insufficiency and less severe lung disease than those with 2 severe CFTR mutations [5,6]. Login to comment
36 The R117H-CFTR phenotype is quite variable with some of this variability explained by the presence of additional CFTR polymorphisms. Login to comment
38 An IVS8-5T repeat variant in-cis with R117H-CFTR is associated with a more reduced CFTR activity and a more severe phenotype compared to the patients who have R117H-CFTR in-cis with either the 7T or 9T variant [8,9]. Login to comment
39 The perception that R117H-CFTR only causes a mild phenotype has led to R117H-CFTR being reconsidered for inclusion in CF newborn screening programs [10]. Login to comment
40 In countries where R117H-CFTR occurs predominantly on a background of IVS8-5T, such as the UK [11] and Ireland (Dr David Barton, personal communication), CF patients can have very severe disease as seen in this case. Login to comment
41 These patients also may have a greater therapeutic benefit with drugs like ivacaftor as their CFTR expression is both reduced in function due to the impaired conductance seen with R117H-CFTR as well as reduced in quantity as a result of the IVS8-5T splicing variant. Login to comment
43 This is supported by the recent clinical trial results that show a benefit of ivacaftor in adult R117H patients with more severe disease who are more likely to have the R117H-IVS5T variants. Login to comment

PMID: 25732475 [PubMed] Yousef S et al: "Improved clinical and radiographic outcomes after treatment with ivacaftor in a young adult with cystic fibrosis with the P67L CFTR mutation."

No. Sentence Comment

2 Originally approved for the G511D CFTR mutation, ivacaftor is now approved for eight additional alleles exhibiting gating defects and has also been tested in R117H, a CFTR mutation with residual function that exhibits abnormal gating. Login to comment
44 Currently, evaluation of conductance mutations has been limited to the R117H mutation, which also exhibits abnormal gating.15 Although ivacaftor has been reported to reduce the stability of some CFTR forms in vitro, including P67L, any detrimental effect on cell surface levels was not apparent based on a robust and sustained clinical response in this individual.16,17 Our positive experience emphasizes the need for definitive studies to test the potential benefit of ivacaftor for patients with CF with nongating missense mutations. Login to comment

PMID: 25739099 [PubMed] Regan JF et al: "A rapid molecular approach for chromosomal phasing."

No. Sentence Comment

57 The cystic fibrosis cell lines derived from Epstein-Barr virus transformed B-lymphocytes included: GM11286 and GM11274, which were determined to have c.1652G>A (p.Gly551Asp) and c.1521_1523delCTT (p.Phe508del) variants [22]; GM11279, which was determined to have 129G>C (promoter), c.350G>A (p.Arg117His), and c.1521_1523delCTT (p.Phe508del) variants [23]; GM11472, which was characterized to have c.1210-12T[7], c.1210-12T[9], c.3909C>G (p. Asn1303Lys), and c.4046G>A (p.Gly1349Asp) variants [24,25] (c.4046G>A is also referred to as c.4178G>A in some dbSNP databases); and GM13591, which was characterized to have c.350G>A (p.Arg117His), c.1210-12T[5], c.1210-12T[9], and c.1521_1523delCTT (p.Phe508del) variants [26]. Login to comment
180 Variant 129G/C R117H 5T 7T 9T ƊF508 G551D N1303K G1349D Effect on cDNA promoter 350G>A intron intron intron 1521_1523 delCTT 1652G>A 3909C>G 4046G>A (4178G>A) GM11286 Hap 1 Hap 2 GM03465 Hap 1 Hap 2 GM11274 Hap 1 Hap 2 GM11279 Hap 1 Hap 1 Hap 1 Hap 2 Hap 2 GM11472 Hap 1 Hap 2 Hap 2 Hap 1 GM13591 Hap 1 Hap 1 Hap 2 Hap 2 Key: Hap 1 = Haplotype 1, Hap 2 = Haplotype 2 doi:10.1371/journal.pone.0118270.t001 Fig 4. Login to comment

PMID: 25797027 [PubMed] Bergougnoux A et al: "Should diffuse bronchiectasis still be considered a CFTR-related disorder?"

No. Sentence Comment

73 Sequence variation Allelic frequency Distribution cDNA name Protein name Legacy name rs number DB group (n = 94) Control group (n = 94) General populationa CF groupb Databasesc Our study c.-1043dupT - -912dupT no rs 0.01 0 NA 0 (n1) UV NNV c.-966 T N G - -834 T N G rs4148682 0.051 0.0319 0.043-0.562 (19 studies) 0.02 (n1) P P c.-812 T N G - -680 T N G rs181008242 0.01 0 NA 0.015 (n1) UV NNV c.137C N A p.Ala46Asp A46D rs151020603 0.01 0 NA 0.00015 (n2) CF CF c.224G N A p.Arg75Gln R75Q rs1800076 0.021 0.018 0-0.11 (7 studies) 0 (n1) P NNV c.350G N A p.Arg117His R117H rs78655421 0.01 0 0-0.002-0.004 (3 studies) 0.003 (n2) 0.005 (n3) M M c.489 + 23C N G p. Login to comment
89 The mild mutation p.Leu997Phe was found in two patients and one control, whereas p.Arg117His was associated with the c. Login to comment
153 Quantification of the blots indicated that the level of mature CFTR protein was decreased by 17%-26% in cells expressing the p.Arg75Gln, p.Arg117His, p.Gly576Ala, p.Arg668Cys (alone and together), p.Leu997Phe or p.Thr966Thr variant, and by 48% and 39% in cells expressing p.Glu528Glu and p.Val754Met, respectively (Fig. 2D, lower panel). Login to comment

PMID: 25824995 [PubMed] Salinas DB et al: "Benign outcome among positive cystic fibrosis newborn screen children with non-CF-causing variants."

No. Sentence Comment

86 An example of this is the poly-T repeat within intron 9 that influences the penetrance of R117H [22]. 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: 25866147 [PubMed] Sellers ZM et al: "Strain rate echocardiography uncovers subclinical left ventricular dysfunction in cystic fibrosis."

No. Sentence Comment

72 Characteristics CF Cohort (n = 8) Age (years) 35 &#b1; 13 (35) Gender (M:F) 6:2 BMI (kg/m2 ) 26.6 &#b1; 10.2 (24) CF genotypes ƊF508/ƊF508 5 ƊF508/R117H 1 ƊF508/D1152H 1 ƊF508/1898 + 1G- N A 1 FEV1 (%) 68 &#b1; 27 (61) Last CF exacerbation requiring hospitalization/ER visit (years) 6.2 &#b1; 5.1 (5.8) Subjects with CF-related diabetes 1 HR (beats/min) 75 &#b1; 17 (76) Systolic BP (mm Hg) 129 &#b1; 11 (128) Diastolic BP (mm Hg) 76 &#b1; 9 (74) BNP (pg/mL) 20 &#b1; 11 (20) Data are presented as means &#b1; SD. Login to comment

PMID: 25900089 [PubMed] Brennan ML et al: "Assessment of epithelial sodium channel variants in nonwhite cystic fibrosis patients with non-diagnostic CFTR genotypes."

No. Sentence Comment

124 Carrier status Number of patients CFTR variant Legacy name None 19 None Heterozygous 1 Complex rearrangement Heterozygous 4 p.Phe508del ƊF508 Heterozygous 1 p.Arg117His R117H Heterozygous 1 c.-288GNC N/A Heterozygous 1 c.-461ANG -329ANG Heterozygous 1 c.1393-42GNA 1525-42GNA Heterozygous 1 c.1327_1330dup 1461ins4 Heterozygous 1 c.2554dupT N/A Heterozygous 1 c.2620-15CNG 2752-15CNG Heterozygous 1 c.2988+1GNA 3120+1GNA Heterozygous 1 c.4243-5CNT 4375-5CNT CF patient DNA samples were screened at the CFTR genetic locus using sequencing with bidirectional confirmation and reflex to MLPA deletion/ duplication analysis. Login to comment
197 Other CFTR/ SCNN1 mutation combinations included one patient with CFTR p.Arg117His and p.Cys618Phe in SCNN1A and one patient with CFTR p.Phe508del and p.Gly183Ser in SCNN1G. 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

366 [227_228insT;1210-14TG[12];1210-12T[5]] uncertain: CF-PI and/or CF-PS and/or CFTR-RD 359insT nd; T5 varying clinical consequence G85E c.254G>A CF-PI,CF-PS CF-causing p.Gly85Glu D110H c.328G>C CF-PS CF-causing p.Asp110His R117C c.349C>T CF-PS CF-causing p.Arg117Cys R117H c.350G>A CFTR-RD varying clinical consequence p.Arg117His [R117L;L997F] c. Login to comment
422 A good level of agreement may also be recognized for mutations R117H (p.Arg117His) and S977F (p.Ser977Phe), classified in our study as CFTR-RD-causing, and the mutation D579G (p.Asp579Gly), classified in our study as CF-PS-causing, and both recognized in the CFTR2 study with varying clinical consequences, therefore also including our phenotypic findings. Login to comment

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

No. Sentence Comment

35 A/p.Arg117His (formerly R117H) mutation. Login to comment
50 A p.Arg117His (R117H) 1.14% c.265715G . Login to comment
156 A/p.Arg117His (formerly R117H) mutation, that is relatively common in the CF population, and leads to both defective channel regulation (sharing similarities with the class III mutations) and conduction. Login to comment
157 Thus, the FDA also approved ivacaftor as a treatment for CF subjects aged .6 years with at least 1 copy of R117H-CFTR.60 Additionally, ivacaftor is currently being tested in patients carrying non-R117H residual function mutations. Login to comment

PMID: 25963003 [PubMed] Ooi CY et al: "Inconclusive diagnosis of cystic fibrosis after newborn screening."

No. Sentence Comment

102 In contrast to previous reports, the vast majority of subjects with CFSPID carried 2 CFTR mutations.17-20 The majority of subjects were compound heterozygotes for 1 disease-causing mutation and 1 CFTR variant of variable or currently unknown consequence, with the F508del/ R117H-7T genotype being most common. Login to comment
103 In combination with a disease-causing mutation, R117H-7T has been associated with diagnostic uncertainties in CF, TABLE 2 Genotypes of Subjects With CFSPID According to Initial Sweat Chloride Measurements Sweat Chloride ,30 mmol/L Sweat Chloride 30-59 mmol/L Allele 1 Allele 2 n Allele 1 Allele 2 n F508dela R117H (7T)b 9 F508dela R117Cd 2c F508dela 5Tb 2 F508dela L206Wd 2c F508dela D1152Hb 2 F508dela P67Ld 1c F508dela R117Hb 1 F508dela 5Tb 8 F508dela D1270Nb 1 F508dela R117H (7T)b 3 F508dela L997F 3 F508dela R117Hb 3 F508dela 1716G.A 1 F508dela S1455X 1c F508dela 621+3G.A 1 F508dela R170H 1 F508dela I1328T 1 F508dela I148T 1 F508dela L967S 1 F508dela L997F 1 F508dela M1137T 1 F508dela Q1476X 1 F508dela Y301C 1 F508dela S1235R 1 1717-1G.Aa D1152Hb 1 F508dela T1299I 1 2183AA.Ga 5Tb 1 2183AA.Ga R117Cd 1 2183AA.Ga S431G 1 2789+5G.Aa R117H (7T)b 1 3849+10kbC.Ta 3041-15T.G 1 3849+10kbC.Ta 3041-15T.G 1 621+1G.Ta R117H (7T)b 1 621+1G.Ta G1069Rb 1 711+1G.Ta D1152Hb 1 G542Xa L206Wd 1c G542Xa R117H (7T)b 1 G542Xa C1410T 1 G542Xa D1152Hb 1 G551Da 5Tb 1 G551Da D1152Hb 1 N1303Ka 5Tb 1 N1303Ka D1152Hb 1 R1162Xa R117H (7T)b 1c N1303Ka E527G 1 R553Xa 5Tb 1 R117H (5T)a 5Tb 1 R553Xa L997F 1 R117H (7T)b R117H (7T)b 1 R560Ta G576A 1 R117H (7T)b 3041_71G.C 1 W1282Xa 5Tb 2 R117Hb Q1476X 1 F508dela - 2 R117H (5T)a - 1 -, no mutation identified on the second allele. Login to comment
108 TABLE 3 Characteristics of Subjects With CFSPID Who Later Met Diagnostic Criteria of CF Subject Number Allele 1 Allele 2 Ethnicity NBS IRT, mg/L Initial Sweat Chloride, mmol/L Highest Sweat Chloride, mmol/L Country 1 F508del R117C White 105.8 36 61 Canada 2 F508del S1455X White 66.6 46 74 Canada 3 F508del P67L White 151.2 38 38 Canada 4 F508del L206W White 83.8 58 64 Canada 5 G542X L206W White 67 49 66 Canada 6 F508del L206W White 59.9 45 45 Canada 7 R1162X R117H-7T White 126 36 70 Italy 8 2183AA.G R117C White 129 32 32 Italy 9 F508del R117C White 80.4 48 56 Canada e OOI et al including in newborn-screened infants with equivocal CF diagnosis and in older individuals with single-organ manifestations of CF.17,18,20-22 As in the case of the 7 subjects who were initially classified as CFSPID but who were subsequently recognized to carry 2 disease-causing mutations on the basis of the CFTR2 project, the diagnostic consequences (benign versus disease-causing) of the CFTR mutations identified in all of the other subjects with CFSPID may not be apparent until later on, when new genetic information becomes available and classification of CFTR mutations currently considered to be of "unknown" consequences is updated. Login to comment
129 Current comparisons between CFSPID࢐CFSPID and CFSPID࢐CF do not account for these potential changes over time. There are similarities in the genotypes of subjects with CFSPID and symptomatic adults who present later in life with single-organ manifestations of CF, including but not exclusive to mutations such as R117H-7T.21,22 A long-term prospective study may shed more light into the proportion and characteristics of individuals with CFSPID who develop CF. 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

35 In CBAVD men from European descent, the two most common genotypes are p.Phe508del in trans either with the '5T allele` in intron 8 (now designated as c.1210-12T[5] in intron 9) (30%) or with the variants R117H-7T (p. Arg117His associated with a 7T allele (c.1210-12T[7]) (6%). Login to comment
85 (Gly1323_Val1415del) 4209TGTT4AA c.4077_4080delTGTTinsAA 4382delA c.4251delA p.Glu1418Argfs*14 Examples of common variants with varying or indetermined clinical consequencesb R117H c.350G4A p.Arg117His L227R c.680 T4G p.Leu227Arg Q359K/T360K c. Login to comment
96 The most studied examples are R117H and the 5 T allele. Login to comment
97 When paired in trans with a severe CF variant, R117H is considered as causing CFTR-RD (or rarely mild CF-PS) if associated in cis with a 5 T allele (rare occurence), whereas it is considered as a neutral or CFTR-RD variant when associated in cis with the common 7 T allele.11 Owing to the extremely low penetrance of R117H for CF,18 in some countries this variant has been removed from the newborn CF screening panels, as its presence created both management and counseling dilemmas (many healthy carriers of R117H-7 T could be wrongly considered as CF carriers and prenatal diagnosis inappropriately proposed). Login to comment
104 I1027T is usually found in cis with F508del: Notes: (i) Some missense variants classified as either indeterminate or non CF-causing (R74Q, R75Q, R117H, R170H, L967S, L997F, D1152H, S1235R and D1270N) can selectively alter the bicarbonate permeation of the CFTR channel (but not the chloride channel), thus affecting primarily the organs that utilize CFTR for bicarbonate secretion (pancreas, nasal sinus, or vas deferens) and, consequently, they could be involved in the pathogenic mechanisms of CFTR-RDs.14 (ii) In Table 1, the traditional name of common CFTR variants is referenced alongside the HGVS version in order to ensure compatibility with clinical reports and understanding by clinicians and couples. Login to comment
115 [3718-2477C4T(;)3909C4G] Two heterozygote variants on one allele (in cis) R117H-T5/normal c. Login to comment
126 Prenatal diagnosis, Preimplantation genetic diagnosis, offered to Parents of a CF patient Carrier couples identified through carrier testing Carrier couples identified through investigations for fetal bowel anomalies Couples with one individual affected with CF and a carrier partner Couples with one individual affected with CBAVD and a carrier partner Table 4 Inclusion and exclusion criteria for CF-PGD according to countries France Italy Spain Belgium Greece UK USA Parents 1 affected+1 carrier S/LS A A A A A A A 1 affected+1 carrier M R A A A A A A 1 affected+1 carrier U A A A A R Aਭ A 2 carriers S/LS A A A A A A A 1 carrier S/LS+1 carrier M R A A A A A A 1 carrier S/LS+1 carrier U A A A A R Aਭ A Abbreviations: S, severe CF-causing variant (p.Phe508del, p.Gly542ਭߪ); LS, large spectrum variant (p.Leu206Trp, c.2657+5G4A ߪ); M, mild variant with variable disease penetrance (IVS8-5 T allele, p.Arg117His-7 T ߪ); U, variants of unproven or uncertain CF clinical relevance (p.Pro1013His, p.Arg1162Leu ߪ); A, accepted; R, refused. Login to comment
211 Nat Genet 2013; 45: 1160-1167. 18 Thauvin-Robinet C, Munck A, Huet F et al: The very low penetrance of cystic fibrosis for the R117H mutation: a reappraisal for genetic counselling and newborn screening. J Med Genet 2009; 46: 752-758. 19 Claustres M, Altieri JP, Guittard C, Templin C, Chevalier-Ports F, Des Georges M: Are p.148 T, p.R74W and p.D1270N CF causing mutations? Login to comment

PMID: 26021452 [PubMed] Corvol H et al: "[Challenges of personalized medicine for cystic fibrosis]."

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51 La mutation R117H appartient a ` cette classe ; classe V : mutations alte &#b4;rant la stabilite &#b4; de l`ARNm de CFTR. Login to comment

PMID: 26091951 [PubMed] Barry PJ et al: "New and Emerging Treatments for Cystic Fibrosis."

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68 Class IV mutations (e.g. R117H) represent mutations that lead to the production of CFTR protein, which demonstrate altered conductance, a qualitative defect. Login to comment
69 Part of this qualitative defect in the mutation R117H has been attributed to 'gating` problems similar to class III mutations, and highlighting the complexities of classifying individual mutations. Login to comment
70 KONDUCT was a randomised double-blind, placebo-controlled trial of ivacaftor therapy in patients expressing the R117H mutation [26]. Login to comment

PMID: 26160248 [PubMed] Krzyzanowska P et al: "Exogenous and endogenous determinants of vitamin K status in cystic fibrosis."

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122 The genotypes of the studied patients were as follows: F508del/F508del (nߙ=Èa;ߙ74); F508del/- (nߙ=Èa;ߙ23); F508del/3849ߙ+Èa;ߙ10ߙkbCߙ>Èa;ߙT (nߙ=Èa;ߙ6); F508del/2143delT (nߙ =Èa;ߙ 6); F508del/R553X (nߙ =Èa;ߙ4); F508del/2183AAߙ>Èa;ߙG (nߙ=Èa;ߙ3); F508del/1717-1G>Èa;A (nߙ=Èa;ߙ3); F508del/CFTRdele2,3(21ߙkb) (nߙ=Èa;ߙ3); F508del/3272-26Aߙ>Èa;ߙG (nߙ=Èa;ߙ 2); F508del/N1303K (nߙ =Èa;ߙ2); F508del/4374ߙ+Èa;ߙ1Gߙ>Èa;ߙT (nߙ=Èa;ߙ1); F508del/621ߙ+Èa;ߙ1Gߙ>Èa;ߙT (nߙ=Èa;ߙ 1); F508del/3659delC (nߙ =Èa;ߙ1); F508del/ G1244R (nߙ =Èa;ߙ 1); F508del/G542X (nߙ =Èa;ߙ 1); F508del/R117H (nߙ =Èa;ߙ 1); F508del/R334W (nߙ =Èa;ߙ1); G542X/- (nߙ=Èa;ߙ2); CFTRdele2,3(21ߙkb)/- (nߙ=Èa;ߙ2); CFTRdele2,3(21ߙkb)/CFTRdele2,3(21ߙkb) (nߙ=Èa;ߙ1); 1717-1-Gߙ>Èa;ߙA/ CFTRdele2,3(21ߙkb) (nߙ=Èa;ߙ1); 3849ߙ+Èa;ߙ10ߙkbCߙ>Èa;ߙT/- (nߙ=Èa;ߙ1); 3849ߙ+Èa;ߙ10ߙkbCߙ>Èa;ߙT/1717ߙ-Èa;ߙ1Aߙ>Èa;ߙG (nߙ=Èa;ߙ1); N1303K/- (nߙ=Èa;ߙ1); N1303K/3272-26Aߙ>Èa;ߙG (nߙ=Èa;ߙ1); G542X/R553X (nߙ=Èa;ߙ1); 1524ߙ+Èa;ߙ1Gߙ>Èa;ߙA/E585X (nߙ=Èa;ߙ1); 2183AAߙ>Èa;ߙG/- (nߙ=Èa;ߙ1); 2184insA/622-1Gߙ>Èa;ߙA (nߙ=Èa;ߙ1); 2143delT/R1102X (nߙ=Èa;ߙ1); 3272-26Aߙ>Èa;ߙG/- (nߙ=Èa;ߙ1); 3659delC/- (nߙ=Èa;ߙ1); R347P/R347P (nߙ=Èa;ߙ1); S1196X/Q1382X (nߙ=Èa;ߙ1). Login to comment

PMID: 26229102 [PubMed] Corradi V et al: "Cystic Fibrosis Transmembrane Conductance Regulator (CFTR): CLOSED AND OPEN STATE CHANNEL MODELS."

No. Sentence Comment

204 This observation might explain why mutations at Arg-117 in TM2 caused inward rectification and a decrease in single channel conductance, consistent with the R117H mutation causing mild forms of cystic fibrosis (76, 78). Login to comment

PMID: 26403534 [PubMed] Brodlie M et al: "Targeted therapies to improve CFTR function in cystic fibrosis."

No. Sentence Comment

36 Class IV mutations, such as Arg117His, often result in a milder phenotype owing to partial CFTR function. Login to comment
58 Table 1 Summary of different classes of CFTR mutations Mutation class Nature of defect Functional consequence Example Therapeutic strategy I CFTR protein synthesis Reduced CFTR protein expression Gly542X Production correctors (ataluren) II CFTR protein processing Misfolded CFTR not transported to cell surface Phe508del Corrector plus potentiator (lumacaftor plus ivacaftor, VX-661 plus ivacaftor) III CFTR channel gating Reduced/lack of CFTR channel opening Gly551Asp Potentiator (ivacaftor) IV CFTR channel conductance Misshaped CFTR pore restricts Cl- movement Arg117His Potentiator (ivacaftor) V Reduced CFTR protein production Very low levels of CFTR protein 3849 + 10 kb C ࢐ T No data available VI High CFTR protein turnover at cell surface Functional but unstable CFTR protein at cell surface 120del23 No data available kb kilobases CFTR dysfunction as the underlying defect and potential therapeutic target The relationship between the severity of disease in an individual and sweat chloride concentration as a readout of the level of CFTR function is complex. Login to comment
156 These mutations include the Arg117His CFTR missense mutation that causes mixed conductance (class IV) and gating (class III) abnormalities, which is responsible for around 2 % of CFTR mutations in northern European populations [49]. Login to comment
169 Arg117His CFTR mutation The phenotype associated with the Arg117His mutation is variable, depending on the other CFTR mutation present and the presence of a polypyrimidine variant in the intron 8 acceptor splice site; the mutation is often associated with less severe clinical problems [52]. Login to comment
170 The KONDUCT study was a phase III randomized controlled 24-week trial of ivacaftor versus placebo in people aged ࣙ6 years with an Arg117His CFTR mutation (Table 3) [53]. Login to comment
171 The primary outcome was change in percentage predicted FEV1, with secondary outcomes including changes in BMI, sweat chloride levels and the Table 3 Summary of clinical studies investigating the efficacy of ivacaftor in patients with cystic fibrosis mutations other than Gly551Asp Study name and reference Flume et al. 2012 [54] KONNECTION: De Boeck et al. 2014 [51] KONDUCT: Moss et al. 2015 [53] Type of study Phase II RCT with open label extension Phase III randomized crossover trial with open label extension Phase III RCT Number of participants n = 104 n = 39 n = 69 Ivacaftor 34; placebo 35 Duration 16 weeks (96-week extension) 24 weeks (total) 24 weeks 8 weeks placebo/ivacaftor 8 weeks ivacaftor/placebo 12 weeks ivacaftor Inclusion criteria ࣙ12 years ࣙ6 years ࣙ6 years Phe508del homozygous >1 non-Gly551Asp gating mutation >1 Arg117His mutation FEV1 > 40 % FEV1 > 40 % FEV1 > 40-90 % (>12 years) FEV1 > 40-105 % (6-11 years) Weight >15 kg Outcome measure Treatment effect Treatment effect after 8 weeks Treatment effect Mean FEV1 (percentage predicted) +1.7 (P = 0.15) +10.7 (P < 0.0001) All ages: +2.1 (P = 0.2) >18 years: +5 (P = 0.01) 6-11 years: -6.3 (P = 0.03) Sweat chloride levels (mmol/L) -2.9 (P = 0.04) -49.2 (P < 0.0001) -24 (P < 0.0001) CFQ-R score (points) No significant differences +9.6 (P = 0.0004) +8.4 (P = 0.009) Weight (kg) No significant differences - - BMI No significant differences BMI-for-age z-score 0.28 (P = 0.001) - BMI body mass index (the weight in kilograms divided by the square of the height in meters), CFQ-R revised Cystic Fibrosis Questionnaire, FEV1 percentage predicted forced expiratory volume in 1 second for age, sex and height, RCT randomized controlled trial respiratory domain of CFQ-R, as well as safety. Login to comment
181 Overall, these results suggest a potential benefit of ivacaftor in patients with the Arg117His CFTR mutation and more advanced lung disease. Login to comment
194 In December 2014 the US FDA also approved the use of ivacaftor in patients with the Arg117His CFTR mutation. Login to comment

PMID: 26410289 [PubMed] Nwokoro CE et al: "Highlights of the 28(th) North American Cystic Fibrosis Conference 2014."

No. Sentence Comment

23 Data was also presented regarding the potential of Ivacaftor in R117H patients and of the class 1 corrector Ataluren, both of which have shown promise, while the failure of the Ivacaftor/Lumacaftor combination in F508del heterozygotes was also discussed. Login to comment

PMID: 26474553 [PubMed] Lenherr N et al: "Ivacaftor in a young boy with the rare gating mutation S549R--use of lung clearance index to track progress: a case report."

No. Sentence Comment

5 Keywords: Cystic fibrosis, Ivacaftor, S549R, Gating mutation, N2MBW, LCI Background Ivacaftor acts as a potentiator of the cystic fibrosis transmembrane conductance regulator (CFTR) and increases the transepithelial chloride (Cl- ) transport of CFTR in 9 of 10 known gating mutations and in R117H mutation (class IV) causing cystic fibrosis. Login to comment

PMID: 26517912 [PubMed] Bose SJ et al: "Exploiting species differences to understand the CFTR Cl- channel."

No. Sentence Comment

111 Recognizing that the gating pattern of hX1-6 resembled the CF mutant R117H-CFTR [53], Price et al. [39] focused on sequence differences in the ECLs. Login to comment

PMID: 26526359 [PubMed] Amaral MD et al: "Hallmarks of therapeutic management of the cystic fibrosis functional landscape."

No. Sentence Comment

657 Yet, we are left with many challenges in terms of disease management given, for example, the modest impact of Lumacaftor-Ivacaftor combination on mitigating F508del disease phenotype [156] or Ivacaftor improving lung function in patients over 18 years with Arg117His variant but not in children [163]. 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
112 In clinical trials, some benefit is also proven in patients with the class IV mutation R117H [30] and likely but still to be firmly proven in subjects with mutations associated with residual CFTR function [41]. Login to comment
216 Moss RB, Flume PA, Elborn JS, Cooke J, Rowe SM, McColley SA, Rubenstein RC, Higgins M, VX11-770-110 (KONDUCT) Study Group (2015) Efficacy and safety of ivacaftor in patients with cystic fibrosis who have an Arg117His-CFTR mutation: a double-blind, randomised controlled trial. Lancet Respir Med 3(7):524-33 31. Login to comment

PMID: 26574590 [PubMed] Kharrazi M et al: "Newborn Screening for Cystic Fibrosis in California."

No. Sentence Comment

30 For example, the common yet variable R117H mutation was not included on the panel.7 After testing, IRT levels and mutation panel results (when IRT is positive) are reported at the same time as analyte results for other screened disorders. Login to comment
106 [1210-12[5]];[1210-34TG[13]] (IVS8 (TG)13-5T)c 5 1 (n = 2) 3 (n = 1) 4 (n = 2) c.1521_1523delCTT (F508del) / c.3454G.C (D1152H)c 2 0.5d (n = 1) 2 (n = 1) c.1521_1523delCTT (F508del) / c.350G.A (R117H)c 2 1 (n = 1) 2 d (n = 1) c.223C.T (R753) / c. Login to comment

PMID: 7505422 [PubMed] Lester LA et al: "Delta F508 genotype does not predict disease severity in an ethnically diverse cystic fibrosis population."

No. Sentence Comment

41 CFTR Mutation Analysis All persons were tested for the following mutations: SF508, G542X, G551D, G553X, W1282X, N1303K, 621 +IG-*T, R117H, S549N, 3849+lOkbC-T, l6O9delCA, and R1162X. Login to comment

PMID: 8697849 [PubMed] Colin AA et al: "Pulmonary function and clinical observations in men with congenital bilateral absence of the vas deferens."

No. Sentence Comment

38 His stool description Table 1.Age, Sweat Sodium and Chloride Concentration and Ratio, and Genotype Subject/Age, yr Symptoms Sweat Na+: mEq/L Sweat Cl mEq/L Na:Cl Ratio CFTR Genotype Polythymidine Splice Variant l*/32 2*/27 3f/30 4/23 5*/22 6*/31 7*/37 8/30 9/41 10/31 11/31 12/38 13/40 14/32 15/31 16/43 17/40 18/27 Asthma Malabsorption Bronchitis Asthma 100 39 53 37 36 36 26 46 42 35 83 74 44 44 44 28 21 106 80 37 51 35 34 34 24 45 43 32 79 75 46 44 40 32 22 0.94 1.05 1.03 1.06 1.05 1.05 1.08 1.00 0.98 1.09 1.05 0.99 0.96 1.00 1.10 0.90 0.95 AF508/R117H AF508/R117H AF508/- AF508/- AF508/- AF508/- AF508/- R117H/- Q493X/- AF508/- AF508/- AF508/R117H G551D/R117H G551D/D1152H AF508/- G542X/- R117H/- -/- 7/9 7/9 5/9 5/9 7/7 7/9 7/9 NT$ 7/7 NT NT 7/9 7/7 7/7 5/9 5/9 7/7 5/9 * Subject 1 and 2 are brothers. Login to comment
82 The low frequency and absence of homozygosity in this cohort probably reflects the severe phenotypicnature, with respect to the pancreas of this mutation.20 The R117H mutation accounted for 16% of the alleles found in this cohort. Login to comment
84 The milder phenotype associ&#ac; ated with R117H can be understood by the paradigm suggested by Welsh and Smith.23 According to this schema, R117H belongs to the class 4 mutations in which mutant CFTRs are correctly expressed, are present in the apical membrane, and generate cyclic adenosine monophosphate-regulated apical mem&#ac; brane currents, but there is defective conduction as a result of mutations in the membrane-spanning do&#ac; main. Login to comment
86 However, such specula&#ac; tion is not supported by Osborne et al15 who did not describe a higher than expected frequency of the R117H mutation in their study population. 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
54 Quatre sujetsetaientdoubles hedrozygotes pourlesmutationsAP508iR117H(trois) etR347H/R117H (un). Login to comment
73 A F508/ - - - A F508/- - - AF508/--- A F508 I- - - AF508/R117H ---,--- G542W - - - AF508i--- ---/--- ---,--- A F508&117H A F508/R117H A F508 I- - R347HlR117H A F508 I- - - A F508 /- - - A F508 /- - - A F508 /- - - A F508 f- - . Login to comment
74 ../.-- A F508 I- - - D 1270N/-- + 0 + N+D* 0 + + 0 i 0 0 + 0 0 + 0 + + ; 100 87 99 100 ND* 125 91 111 98 106 87 100 86 94 100 77 79 80 61 87 87 80 DISCUSSION Dix-huit sujetssurles22sontporteursd`au moinsune des22mutationsrecherchees (86 %) ; parmieux, quatre sontheterozygotescomposites(porteursd`unemu- tation surchacundesalleles),tousporteursdelamuta- tion R117H. Login to comment
82 p = 0,0O32 ; r` = 0.374. une mutation est de 54 B 65 % dans les skies de la littkature [lo-131,parmi lesquels 10 B 17 % sont h&k- rozygotes composites ; parmi ces demiers, la plupart sont porteurs de la mutation R117H. Login to comment
86 Soixante-treize sont porteurs d`au moins une mutation : 54 sont h&C- rozygotes (54 %) et 19 hktkrozygotes composites dont trois seulement porteurs de la mutation R117H. Login to comment
87 La mutation R117H est retrouvke frtquemment chez les h&- tkrozygotes composites, sauf dans la sCriede Chillon et al. Login to comment
89 L`existence de phknotypes diffkrents pour un m&me ginotype AF508/R117H - mucoviscidose ou ABCD - est peut-&tre expliqde par l`association gla mutation d`haplotypes diffkrents (I et II ou alkles 5T et 7T) modifiant le niveau de production de 1`ARNm de CFTR, c`est-&dire le niveau de transcription du gkne [231. Login to comment