ABCMdb

ABCC7 p.Val562Ile

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Publications

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

No. Sentence Comment

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

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
109 Studies in a CBAVD patient with the R334W/V562I and 5T/7T mutations. Login to comment
114 (a) CAVD patient with mutation V562I (heterozygote); (b) a normal individual. Login to comment

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

No. Sentence Comment

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

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

No. Sentence Comment

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

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

No. Sentence Comment

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

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

No. Sentence Comment

76 Meconium peritonitis;pseudocyst; volvulus 6 p.W1282X/p.S492F 2 months M IRT positive 57, 78, 75, 80, 81 Dx of CF, symptomatic 7 DF508/p.F1099Lb 2 months M IRT positive 48, 52 Asymptomatic at this point 8 DF508/[p.R352W; pP750L]c 1.5 months M IRT positive 1 nl, 44 Followed in CF clinic, being treated prophylactically, neg. elastase 9 DF508/c.1154insTC 4 days M Meconium ileus at birth Not done CF, two affected sibs 10 DF508/c.2789+2insA 2 months F IRT positive 58,57,53 Dx of CF a Concentrations >60 mmol/l on repeated analysis are diagnostic for cystic fibrosis b Novel CFTR mutation c Complex CFTR allele with two different mutations Table 4 Complex CFTR alleles observed in a series of 157 patient samples after extensive sequencing Subject Genotype Phenotype Age Sweat chloride concentration (mmol/l) 1 [p.G576A;p.R668C]/wta Chronic cough, sinusitis, and recurrent pneumonia 3 years Normal 2 p.R1158X/[p.V562I;p.A1006E] Mild CF 40 years 115 3 DF508/[p.R352W;p.P750L] Abnormal newborn screen 49 days 44 4 [c.1198_1203delTGGGCT;c.1204G>A]/wt Mild CF (respiratory symptoms) 12 years 110, 115 a This complex allele has been previously described in a patient with disseminated bronchiectasis with L997F on the other allele (Pignatti et al. 1995) Table6NovelCFTRvariantsfoundinaseriesof157patientsamplesafterextensivesequencing SubjectMutation type LocationNucleotidechangeEffectonproteinCFTRdomaina Mutationonother allele Phenotype 1MissenseExon4c.605G>Cp.S158TL1Nonedetected4-month-oldmale,abnormalnewbornscreen; 3borderlinesweattestresults 2ComplexalleleExon7[c.1198_1203delTGGGCT; c.1204G>A] [p.W356_A357del; p.V358I] AfterTM6and beforeNBD1 Nonedetected12-year-oldmale,meconiumilleusatbirth, respiratorysymptomsofCF;positivesweatchlorides (110,115mmol/l).Motheralsocarriescomplexallele 3MissenseExon9c.1484G>Tp.G451VNBD1DF50819-year-oldmale,diagnosisofCF 4MissenseExon10c.1573A>Gp.K481ENBD1Nonedetected15-year-oldmale,atypicalCF,asthma,2borderline sweatchlorides(low60s) 5MissenseExon10c.1604G>Cp.C491SNBD1NonedetectedNoabnormalsymptoms;sisterofCFpatientthat carriesp.P67L/DF508.Probablebenign variantascertainedduring singleexonsequencingofexon10 6DeletionExon10c.1641AG>Tp.K503NfsX23NBD1p.H609R22-year-oldmale,classicCF,PI,positivesweat chloride(>100mmol/l) 7DeletionExon15c.2949_2953delTACTCp.H939fsX32L3DF5083-month-oldfemale,diagnosisofCF,positivesweat chloride(105mmol/l) 8MissenseExon15c.2978A>Tp.H949LL3Nonedetected, but5Tpositive 12-year-oldmale,atypicalCF,sinusproblems. Login to comment
53 Finally, one CF patient with mild symptoms carried a complex allele [p.V562I; p.A1006E] and a nonsense mutation (p.R1158X) on the other allele. Login to comment
74 DF508/c.546insCTA CF; lung symptoms; PS; 2 sibs with CF NG Pos p.R1066C/c.3272-26 A>G Mild CF 40 115 [p.V562I;p.A1006E]b /p.R1158X CF, FTT 6 Not done DF508/c.1716G>A Classic CF 21 Not done p.R785X/c.2732insA Classic CF, PI 4 Not done DF508/p.R117C Classic CF 2 Not done DF508/p.R75X CF 19 Pos DF508/p.G451Va Mild CF 23 Pos DF508/p.L206W Classic CF 9 150s DF508/p.G542Xc Classic CF 15 Pos p.T1036N/p.T1036Na CF, PS 9 Pos DF508/c.3272-26 A>G Classic CF 33 Not done DF508/p.R117Hc Classic CF 35 Not done DF508/p.A455Ec CF 3 Pos p.G551D/p.Y275X a Novel CFTR variant b Complex CFTR allele c Both mutations are on the ACMG/ACOG panel Table 5 Diagnosis of CF in infants/newborns with abnormal newborn screening results Patient number Genotype Age at sequencing Sex Newborn screen result Sweat chloride concentration (mmol/l)a Phenotype 1 DF508/c.2789+2insA 3 months F Positive sweat test 88,96,89,84 Dx of CF, being treated prophylactically 2 DF508/c.2949del5b 3 months F IRT positive 105 Dx of CF 3 p.G551D/c.1259insA 14 months M Positive sweat test ?

In reference to DF508 and 1716G>A. Does this mean these two mutation have resulted in "classic CF"? Does this mean 1716G>A is disease causing?
Gibson75 on 2013-08-12 07:00:25

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103 The last two samples were from affected siblings and were found to be positive for three previously described CFTR mutations: p.V562I, p.A1006E, and p.R1158X. 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: 17098864 [PubMed] Roxo-Rosa M et al: "Revertant mutants G550E and 4RK rescue cystic fibrosis mutants in the first nucleotide-binding domain of CFTR by different mechanisms."

No. Sentence Comment

1 Here, we investigate their mechanism of action by using biochemical and functional assays to examine their effects on F508del and three CF mutations (R560T, A561E, and V562I) located within a conserved region of the first nucleotide-binding domain (NBD1) of CFTR. Like F508del, R560T and A561E disrupt CFTR trafficking. Login to comment
3 Of note, the processing and function of V562I were equivalent to that of wild-type (wt)-CFTR, suggesting that V562I is not a disease-causing mutation. Login to comment
4 Biochemical studies revealed that 4RK generates higher steady-state levels of mature CFTR (band C) for wtand V562I-CFTR than does G550E. Login to comment
37 47 ͉ 17891-17896 and 4RK act by different mechanisms. To explore this possibility, we tested the effects of G550E and 4RK on three additional CF mutations within NBD1: R560T, A561E, and V562I.ʈ We selected for study these CF mutants because (i) these residues constitute a hot spot for disease-causing mutations (seven mutations are associated with these three residues࿣ ); (ii) A561E and R560T are the second and fourth most frequent mutations among Portuguese and Irish CF patients, respectively (28); (iii) like G550E and R555K (one of the 4RK mutants), these mutations affect residues located between the LSGGQ and Walker B motifs of NBD1, which are highly conserved across species; and (iv) they all lie within the same ␣-helix (H5; G550-Y563) within the ATP-binding cassette ␣-subdomain of NBD1 (29, 30). Login to comment
38 To test the hypothesis that G550E and 4RK act by different mechanisms, we used biochemical and functional assays to investigate how these revertants rescue F508del-, R560T-, A561E-, and V562I-CFTR. Login to comment
39 Results R560T, but Not V562I, Disrupts the Processing of CFTR. Like F508del-CFTR, many CF mutations disrupt the processing of CFTR and its delivery to the cell surface. Login to comment
41 For the reasons outlined in the Introduction, we chose to analyze the CF mutations R560T, A561E, and V562I. Login to comment
43 Therefore, we first investigated the processing of R560T and V562I by using Western blot (WB). Login to comment
45 In contrast, band B and a diffuse Ϸ180 kDa band (band C) were observed for both V562I-CFTR and wt-CFTR (Fig. 1A). Login to comment
46 These data suggest that R560T, disrupts the trafficking of CFTR, whereas V562I-CFTR is delivered to the cell surface. Login to comment
58 Fig. 1A demonstrates that steady-state levels of band C for both wtand V562I-CFTR were increased by 4RK but not by G550E, most strikingly for V562I-CFTR. Login to comment
61 To investigate this, we examined the turnover rate of band B and the efficiency of its processing into band C for wt-, F508del- and V562I-CFTR alone or in cis with the revertants by pulse-chase analysis, followed by IP (Fig. 2 A-C). Login to comment
65 For V562I-CFTR, the turnover rate of V562I-G550E was slightly, but not significantly (P Ͼ 0.05), reduced compared with those of V562I- and V562I-4RK-CFTR (Fig. 2F). Login to comment
66 Furthermore, the efficiency of processing of V562I-4RK (dotted line, Fig. 2I) was slightly increased relative to those of V562I and V562I-G550E (solid and dashed lines, Fig. 2I, respectively). Login to comment
67 Finally, Fig. 2 shows that the turnover rates of V562I- and wt-CFTR were equivalent (slope of solid lines in D and F; P Ͼ 0.05), whereas the processing of V562I- was slightly faster than that of wt-CFTR (solid lines in G and I).࿣The CFTR Mutation Database: http://www.sickkids.on.ca/cftr. Login to comment
70 (A) WB of total protein (30 ␮g) from BHK cells stably expressing wt-, F508del-, R560T-, A561E-, or V562I-CFTR, alone or in cis with 4RK and G550E. Login to comment
75 (D) BHK cells expressing F508del-, R560T-, or A561E-CFTR alone or in cis with the revertants 4RK and G550E were analyzed by CFTR IP after pulse-labeling for 3 h. Labeled arrows indicate the positions of bands A, B, and C. Thus, the higher steady-state levels of band C for 4RK variants of both wtand V562I-CFTR (Fig. 1A) are explained only in part by a slight (but not significant) increase in the efficiency of processing band B to band C. Surprised that the revertants did not exert stronger effects on the processing of CFTR, we wondered how they might influence CFTR Cl-channel function. Login to comment
76 WTand V562I-CFTR Have Equivalent Functions. Login to comment
79 Consistent with the biochemical data (Fig. 1), these agonists had no effect on F508del-, R560T-, or A561E-CFTR (Fig. 3 B-D) but evoked a striking efflux of I- from V562I-CFTR (Fig. 3E), which has a time course equivalent to that of wt-CFTR and 1.3-fold greater (Fig. 3F). Login to comment
80 A likely explanation for this enhanced efflux of I- from V562I-CFTR-expressing cells is their greater membrane abundance of CFTR (Fig. 1A). Login to comment
85 Interestingly, V562I-G550E generated an efflux of I- equivalent in magnitude and time-course to that of V562I-CFTR (Fig. 3 E and F) despite its lower steady-state levels of band C. However, 4RK, which generated higher steady-state levels of band Fig. 2. Login to comment
86 Turnover and processing of wt-, F508del-, and V562I-CFTR alone or in cis with 4RK and G550E. Login to comment
87 (A-C) BHK cells expressing wt-, G550E- and 4RK-CFTR (A); F508del-, F508del-4RK-, and F508del-G550E-CFTR (B); and V562I-, V562I-4RK-, and V562I-G550E-CFTR (C) were pulse-labeled for 20 min with 100 ␮Ci͞ml [35S]methionine and then chased for 0, 0.5, 1, 3, and 5 h. Login to comment
88 (D-F) Turnover of band B for wt- (D), F508del- (E), and V562I-CFTR (F) in the absence and presence of revertant mutations. Login to comment
91 (G and I) Efficiency of processing into band C for wt-CFTR (G) and V562I-CFTR (I) in the absence and presence of revertant mutations and for revertants of F508del-CFTR (H). Login to comment
96 (A-E) Time courses of I-efflux from BHK cells stably expressing wt- (A), F508del- (B), R560T- (C), A561E- (D), and V562I- (E) CFTR in the absence and presence of the 4RK and G550E mutations. Login to comment
102 C (Fig. 1A), decreased the magnitude of the V562I-evoked I-efflux to a level equivalent to that of wt-CFTR (Fig. 3 E and F). Login to comment
103 Taken together, our iodide efflux data strongly suggest that the increased steady-state levels of band C (and the slight increase in CFTR processing efficiency) observed for the 4RK variants of wtand V562I-CFTR (Figs. 1 and 2) do not result in increased CFTR channel activity. Login to comment
104 In contrast, the data suggest that G550E compensates for a decreased steady-state level of band C by enhancing the channel activity of wtand V562I-CFTR. Login to comment
107 To test the idea that the revertant G550E enhances the Cl-channel function of wt and CF mutants, we used the patch-clamp technique to study the single-channel behavior of wt-, V562I-, and F508del-CFTR in the absence and presence of the revertants. Login to comment
108 Fig. 4 demonstrates that the single-channel properties of V562I-CFTR were identical to those of wt-CFTR. Login to comment
109 Like wt-CFTR (2), the gating behavior of V562I-CFTR was characterized by bursts of channel openings interrupted by brief flickery closures and separated by longer closures between bursts (Fig. 4A). Login to comment
110 Strikingly, V562I-CFTR had the same open probability (Po), mean burst duration (MBD), interburst interval (IBI), and ATP-dependence [V562I, ATP concentration for half maximal activation (Km) ϭ 252 ␮M; wt, Km ϭ 210 ␮M] as wt-CFTR (Fig. 4 B-D and data not shown). Login to comment
111 Together with our observation that V562I-CFTR does not affect the efficiency of CFTR processing (Figs. 1 and 2), these data raise the possibility that V562I is not a disease-causing mutation. Login to comment
118 Like their effects on wt-CFTR, 4RK and G550E enhanced V562I-CFTR channel gating and rescued that of F508del-CFTR with different efficacies (Fig. 4). Login to comment
127 Like F508del, R560T and A561E disrupt CFTR processing, whereas V562I traffics normally to the cell surface, forming a Cl-channel with properties indistinguishable from those of wt-CFTR. Login to comment
136 Single-channel activity of wt-, V562I-, and F508del-CFTR alone and in cis with 4RK and G550E. Login to comment
140 Columns and error bars are means Ϯ SEM (wt: n ϭ 6 for all data; 4RK: Po, n ϭ 2; MBD and IBI, n ϭ 1; G550E: Po, n ϭ 3; MBD and IBI, n ϭ 1; V562I: Po, n ϭ 5; MBD and IBI, n ϭ 2; V562I-4RK: Po, n ϭ 4; MBD and IBI, n ϭ 3; V562I-G550E: Po, n ϭ 8; MBD and IBI, n ϭ 3; F508del: n ϭ 10 for all data; F508del-4RK: Po, n ϭ 13; MBD and IBI, n ϭ 10; F508del-G550E: Po, n ϭ 5; MBD and IBI, n ϭ 4). Login to comment
144 Surprisingly, our data demonstrate that V562I-CFTR is processed as efficiently as wt-CFTR (Fig. 2) and forms a Cl-channel functionally equivalent to wt-CFTR (Fig. 4). Login to comment
145 Indeed, our structural model predicts that V562I is without effect on the tertiary structure of NBD1. Login to comment
146 Based on these data, we do not consider V562I-CFTR to be a CF-causing variant. Login to comment
182 However, the opposite effect was observed for both wtand V562I-CFTR when in cis with 4RK; therefore, the effects observed with the R31 mutants must result from the loss of a stabilizing role played by the N terminus rather than from interference with an AFT. Login to comment
205 When compared with both wtand F508del-CFTR, clones expressing V562I- and R560T-CFTR expressed higher and lower levels of protein, respectively, precluding studies on cell lines with equivalent amounts of CFTR protein. 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

53 In five out of the 14 patients carrying the (TG)11(T)5 allele, V562I was also identified, probably in cis as documented in two of these cases and in other patients who do not have CBAVD (Girodon et al., unpublished data). Login to comment
69 Frequent cystic fibrosis transmembrane conductance regulator (CFTR) defects found in congenital bilateral absence of the vas deferens (CBAVD) patients (above 1% among the identified alleles) Mutation No. of alleles % of the 390 identified alleles F508dela 119 30.5 IVS8(T)5a,b 107 27.4 (TG)12(T)5 82 (TG)13(T)5 16 (TG)11(T)5b 9 R117Ha 25 6.4 R668C 9 2.3 [D443Y;G576A;R668C] 6 [G576A;R668C] 2 R668C 1 L206W 7 1.8 D1152H 6 1.5 W1282Xa 5 1.3 [V562I;(TG)11(T)5] 5 1.3 [R74W;D1270 N] 4 1.0 [R74W;D1270 N] 3 [R74W;V201M;D1270 N] 1 Q1352H(G . Login to comment
71 b Do not include the [V562I;(TG)11(T)5] complex alleles that are indicated below. Login to comment
142 (TG)11(T)5 penetrance reaching only 11% (Groman et al., 2004), we systematically investigated the whole CFTR gene to look for other cis mutations in the 14 patients carrying this variant and we found V562I in five of them. Login to comment
144 Although V562I has been considered a severe CF mutation, a series of arguments question its severe deleterious effect: its presence in trans of the severe W1282X mutation, the case of a V562I homozygous CF patient who carried in cis the frameshift 2347delG (Girodon et al., unpublished data), and the fact that residue V562 is not conserved in other proteins containing the ATP-binding cassette motif. Login to comment
145 We suggest reconsidering V562I as a mild and CBAVD-associated mutation. Login to comment

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

No. Sentence Comment

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

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

No. Sentence Comment

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

PMID: 18716917 [PubMed] George Priya Doss C et al: "A novel computational and structural analysis of nsSNPs in CFTR gene."

No. Sentence Comment

125 The nsSNPs which were predicted to be Table 1 List of nsSNPs that were predicted to be deleterious by SIFT and PolyPhen SNPs ID Alleles AA change Tolerance index PSIC rs1800072 G/A V11C 1.00 0.150 rs1800073 C/T R31C 0.18 2.288 rs1800074 A/T D44V 0.01 2.532 rs1800076 G/A R75Q 0.03 1.754 rs1800078 T/C L138P 0.01 2.192 rs35516286 T/C I148T 0.41 1.743 rs1800079 G/A R170H 0.05 1.968 rs1800080 A/G S182G 0.03 1.699 rs1800086 C/G T351S 0.30 1.600 rs1800087 A/C Q353H 0.03 2.093 rs4727853 C/A N417K 1.00 0.015 rs11531593 C/A F433L 0.65 0.694 rs1800089 C/T L467F 0.15 1.568 rs213950 G/A V470M 0.17 1.432 rs1800092 C/A/G I506M 0.00 1.574 rs1801178 A/G I507V 0.38 0.314 rs1800093 T/G F508C 0.00 3.031 rs35032490 A/G K532E 1.00 1.525 rs1800097 G/A V562I 0.13 0.345 rs41290377 G/C G576A 0.33 1.262 rs766874 C/T S605F 0.03 2.147 rs1800099 A/G S654G 0.03 1.611 rs1800100 C/T R668C 0.01 2.654 rs1800101 T/C F693L 0.61 0.895 rs1800103 A/G I807M 0.01 1.554 rs1800106 T/C Y903H 0.52 0.183 rs1800107 G/T S909I 0.10 1.624 rs1800110 T/C L967S 0.07 1.683 rs1800111 G/C L997F 0.24 1.000 rs1800112 T/C I1027T 0.03 1.860 rs1800114 C/T A1067V 0.04 1.542 rs36210737 T/A M1101K 0.05 2.637 rs35813506 G/A R1102K 0.52 1.589 rs1800120 G/T R1162L 0.00 2.038 rs1800123 C/T T1220I 0.22 0.059 rs34911792 T/G S1235R 0.45 1.483 rs11971167 G/A D1270N 0.12 1.739 rs4148725 C/T R1453W 0.00 2.513 Highly deleterious by SIFT and damaging by PolyPhen are indicated as bold deleterious in causing an effect in the structure and function of the protein by SIFT, PolyPhen and Pupasuite correlated well with experimental studies (Tsui 1992; Ghanem et al. 1994; Bienvenu et al. 1998) (Table 3). Login to comment

PMID: 19812525 [PubMed] de Cid R et al: "Independent contribution of common CFTR variants to chronic pancreatitis."

No. Sentence Comment

81 CFTR Genotypes in Chronic Pancreatitis Patients and General Population Pt/Phenotype CFTR Genotype Pt/Phenotype CFTR Genotype 1/ACP F508del† , I1027T/j 19/ACP* R668C/j 2/ACP* F508del† /j 20/ACP D836Y/j 3/ACP F508del† , I1027T/Y1014C 21/ACP* L997F† /j 4/ACP F508del† /1716G9A 22/ACP* R1162L/j 5/ACP* F508del† /1716G9A 23/ACP 5T-11TG/j 6/ACP* F508del† /S1235R 24/ACP 5T-11TG/j 7/ACP G542X† /j 25/ACP 5T-11TG/j 8/ACP* W1282X† /j 26/ACP* 5T-11TG/j 9/ACP 5T-12TG† /5T-11TG 27/ACP* 5T-11TG/j 10/ACP* 5T-12TG† /j 28/ACP 1716G9A/4374+13A9G 11/ACP R75Q/j 29/ACP 1716G9A/j 12/ACP R75Q/j 30/ACP 1716G9A/j 13/ACP Y122C/Y122C 31/ACP 1716G9A/j 14/ACP* R170C/j 32/ACP 1716G9A/j 15/ACP* R258G/j 33/ACP* 1716G9A/j 16/ACP* M281T/j 34/ACP 2377C9T/j 17/ACP* R297Q† /- 35/ACP* 2377C9T/j 18/ACP T351S/- 36/ACP 3499+37G9A/j 1/ICP F508del† /- 10/ICP* 1716G9A/j 2/ICP D443Y,G576A,R668C† /j 11/ICP* 1716G9A/j 3/ICP* D443Y,G576A,R668C† /j 12/ICP 1716G9A/j 4/ICP* P205S† /j 13/ICP* 1716G9A/j 5/ICP* L997F† /j 14/ICP* 1716G9A/j 6/ICP* R170H/1716G9A 15/ICP* 1716G9A/j 7/ICP 109A9G/j 16/ICP* 1716G9A/j 8/ICP* 5T-11TG/j 17/ICP 1716G9A/j 9/ICP* 5T-11TG/j 1/GP 5T-12TG† /j 8/GP 1716G9A/j 2/GP 5T-12TG† /j 9/GP 1716G9A/j 3/GP A534E† /j 10/GP 1716G/A/j 4/GP 5T-11TG/V562I 11/GP 1716G9A/j 5/GP 5T-11TG/j 12/GP 1716G9A/j 6/GP 5T-11TG/j 13/GP 3690A9G/j 7/GP 1716G9A/j 14/GP 3690A9G/j Corresponding mutation nomenclature (Human Genome Variation Society and Cystic Fibrosis Mutation Data Base): c.1584G9A (1716G9A), c.1210-7_1210-6delTT (5T), 1210-34_1210-13TG (11TG), g.-23A9G (109A9G), c.4242+13A9G (4374+13A9G), c.2245C9T (2377C9T), c.3367+ 37G9A (3499+37G9A), and c.3558A9G (3690A9G). Login to comment

PMID: 20012660 [PubMed] Demmers KJ et al: "Molecular and functional characterization of the cystic fibrosis transmembrane conductance regulator from the Australian common brushtail possum, Trichosurus vulpecula."

No. Sentence Comment

136 The only difference was seen in the Walker B motif of NBD1, where there was a valine to isoleucine substitution at amino acid 562. Login to comment
212 Although this is in a ''hot spot`` for mutations that affect CFTR function and result in CF in humans (Roxo-Rosa et al. 2006), this particular mutation (V562I) has no effect on either the trafficking or function of human CFTR (Roxo-Rosa et al. 2006). Login to comment

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

No. Sentence Comment

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

PMID: 20551307 [PubMed] Da Paula AC et al: "Folding and rescue of a cystic fibrosis transmembrane conductance regulator trafficking mutant identified using human-murine chimeric proteins."

No. Sentence Comment

287 This raises the interesting possibility that P1290T might be a sequence variation (polymorphism) like V562I (24). 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

57 Exon 10 was also analyzed in order to complete the haplotype feature: M470 was homozygous in each individual while the V562I sequence variation was present in all but one patient. Login to comment
61 A similar rate has been observed in the Spanish population, while, surprisingly, this mutation was not detected among the Hispanics of the Latin American populations.11 The same study identified its association with the V562I and the IVS8-5T in a complex allele that is now updated including the TG11 polymorphism reported from our investigations. Login to comment
68 Moreover, all but one case (Pt1) show the V562I revealing a weaker association between this sequence variation and the previously described haplotype. Login to comment
73 TABLE 1. Allelic genotyping of the patients with CFTR geneTABLE 1. Allelic genotyping of the patients with CFTR geneTABLE 1. Allelic genotyping of the patients with CFTR geneTABLE 1. Allelic genotyping of the patients with CFTR geneTABLE 1. Allelic genotyping of the patients with CFTR geneTABLE 1. Allelic genotyping of the patients with CFTR gene Patients Haplotype Mutations Tn-TGm Sequence variations Sequence variations Pt1 Strand 1 F508del 9T-TG10 M470V Strand 2 A1006E 5T-TG11 M470V - Pts2-3 Strand 1 Q220X 7T-TG11 M470V Strand 2 A1006E 5T-TG11 M470V V562I Pts4-7 Strand 1 F508del 9T-TG10 M470V Strand 2 A1006E 5T-TG11 M470V V562I TABLE 2. Phenotypic features of patients with CFTR geneTABLE 2. Phenotypic features of patients with CFTR geneTABLE 2. Phenotypic features of patients with CFTR geneTABLE 2. Phenotypic features of patients with CFTR geneTABLE 2. Phenotypic features of patients with CFTR geneTABLE 2. Phenotypic features of patients with CFTR geneTABLE 2. Phenotypic features of patients with CFTR geneTABLE 2. Phenotypic features of patients with CFTR gene Pts Age at diagnosis Sweat test Current clinical statusCurrent clinical statusCurrent clinical statusCurrent clinical statusCurrent clinical status (years) (mmol/L) Age (years) X-Ray Lung Assessment FEV1% PS ARP 1 35 Cl: 84 36 Bronchiectasis 61 - - 2 21 Cl: 74 36 Bronchiectasis 76 - + 3 14 Cl: 76 29 Bronchiectasis 73 + - 4 IRT + Na: 76 18 Bronchial thickening 110 + - 5 16 Na: 121 34 Initial bronchiectasis 86 + - 6 14 Na: 119 32 Bronchiectasis; lobe excision 74 - + 7 13 Na: 97 31 Bronchial thickening 91 + - IRT: Immunoreactive Trypsinogen Test FEV1: Forced Expiratory Volume in 1 second PS: Pancreatic Sufficiency ARP: Acute Recurrent Pancreatitis ` IRT: Immunoreactive Trypsinogen Test FEV1: Forced Expiratory Volume in 1 second PS: Pancreatic Sufficiency ARP: Acute Recurrent Pancreatitis ` IRT: Immunoreactive Trypsinogen Test FEV1: Forced Expiratory Volume in 1 second PS: Pancreatic Sufficiency ARP: Acute Recurrent Pancreatitis ` IRT: Immunoreactive Trypsinogen Test FEV1: Forced Expiratory Volume in 1 second PS: Pancreatic Sufficiency ARP: Acute Recurrent Pancreatitis ` IRT: Immunoreactive Trypsinogen Test FEV1: Forced Expiratory Volume in 1 second PS: Pancreatic Sufficiency ARP: Acute Recurrent Pancreatitis ` IRT: Immunoreactive Trypsinogen Test FEV1: Forced Expiratory Volume in 1 second PS: Pancreatic Sufficiency ARP: Acute Recurrent Pancreatitis ` IRT: Immunoreactive Trypsinogen Test FEV1: Forced Expiratory Volume in 1 second PS: Pancreatic Sufficiency ARP: Acute Recurrent Pancreatitis ` IRT: Immunoreactive Trypsinogen Test FEV1: Forced Expiratory Volume in 1 second PS: Pancreatic Sufficiency ARP: Acute Recurrent Pancreatitis ` agnosis of 16.2 ± 10.5 years, median age of 14 years) the course of the disease leads to a complete phenotypic expression. 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

PMID: 21708286 [PubMed] Fresquet F et al: "Orphan missense mutations in the cystic fibrosis transmembrane conductance regulator a three-step biological approach to establishing a correlation between genotype and phenotype."

No. Sentence Comment

40 The exception was p.[Val562Ile] (V562I), which we encountered in two unrelated families with distinct genotypes. Login to comment
66 [274-6TϾC(ϩ)1210-12T(5)(ϩ)1684GϾ A] (equaling V562I). Login to comment
97 Sequences of Site-Directed Mutagenesis Primers Mutation Sense oligonucleotide sequences L102P 5=-GTACAGCCTCTCTTACCGGGAAGAATCATAGCTTCC-3= L167R 5=-AAGAAGACTTTAAAGCGGTCAAGCCGTGTTCTAG-3= P574S 5=-GCTGATTTGTATTTATTAGACTCTTCTTTTGGATACCTAGATG-3= V562I 5=-AGAATTTCTTTAGCAAGAGCAATATACAAAGATGCTGATTTG-3= K696R 5=-CAGACTGGAGAGTTTGGGGAAAGAAGGAAGAATTCTATTCTC-3= P841R 5=-GATATGGAGAGCATACGAGCAGTGACTACATGG-3= CFTR Missense Mutation Biological Assay 3 JMD Month 2011, Vol. xx, No. Login to comment
116 The lowered maturation of P574S suggests an attenuated class II mutation. Login to comment
124 [274-6TϾC(ϩ)1210-12T(5) (ϩ)1684GϾA (ϭp.[Val562Ile])] Infertility, no CBAVD, previously treated bilateral cryptorchidism Ø Ø Ø In the genotype column, the amino acid substitutions that we investigated are boldfaced. Login to comment
137 Normal Phenotype for the V562I CFTR Variant The controversial V562I substitution lies inside nucleotide-binding domain 1. Login to comment
139 By using Western blot analysis, the maturation process of V562I-CFTR appears similar to the one visualized for WT-CFTR (Figure 4B). Login to comment
142 In our cell model, according to the three techniques that we used, V562I substitution behaves like a polymorphism with no evidence for cellular or functional impact. Login to comment
145 This confirms that V562I substitution should be a polymorphism with no structural or functional impact on the CFTR protein. Login to comment
173 This finding is in accordance with the dramatically reduced activity that we found for L102P-CFTR protein in cell culture. Login to comment
199 A B C V562I actin mergeV562I actin merge % of maximal activation ns 0 50 100 WT V562I % of maximal activation ns 0 50 100 WT V562I % of maximal activation ns 0 50 100 WT V562I B CFTR NaKATPase C WT F508del V562I B CFTR NaKATPase C WT F508del V562I Figure 4. Login to comment
200 The V562I amino acid substitution does not alter CFTR phenotype. Login to comment
214 His genotype was p.[Pro841Arg] ϩ [Arg74Trp;Val201Met; Asp1270Asn]. Login to comment
218 We found the V562I missense variation in a case of male infertility (genotype previously given). Login to comment
224 Our results are concordant with those previously obtained in baby hamster kidney cells overexpressing CFTR23 (by using Western blot analysis, iodide effluxes, and inside-out patch-clamp experiments in which the V562I mutant behaves like WT CFTR). Login to comment
225 However, V562I, which was first reported as a polymorphism,24 has been reassigned as a non-CF-causing mutation, notably implicated in the CBAVD phenotype.20 Because the V562I-CFTR protein appears unaffected, the mutation could only elicit dysfunction at the RNA level. Login to comment
60 Sequences of Site-Directed Mutagenesis Primers Mutation Sense oligonucleotide sequences L102P 5=-GTACAGCCTCTCTTACCGGGAAGAATCATAGCTTCC-3= L167R 5=-AAGAAGACTTTAAAGCGGTCAAGCCGTGTTCTAG-3= P574S 5=-GCTGATTTGTATTTATTAGACTCTTCTTTTGGATACCTAGATG-3= V562I 5=-AGAATTTCTTTAGCAAGAGCAATATACAAAGATGCTGATTTG-3= K696R 5=-CAGACTGGAGAGTTTGGGGAAAGAAGGAAGAATTCTATTCTC-3= P841R 5=-GATATGGAGAGCATACGAGCAGTGACTACATGG-3= was presented. Login to comment
67 [274-6TϾC(ϩ)1210-12T(5)(ϩ)1684GϾ A] [c.1684GϾA equaling p.Val562Ile (V562I)]. Login to comment
83 [274-6TϾC(ϩ)1210-12T(5) (ϩ)1684GϾA (ϭp.[Val562Ile])] Infertility, no CBAVD, previously treated bilateral cryptorchidism Ø Ø Ø In the genotype column, the amino acid substitutions that we investigated are boldfaced. Login to comment
117 The V562I amino acid substitution does not alter CFTR phenotype. Login to comment
165 Normal Phenotype for the V562I CFTR Variant The controversial V562I substitution lies inside nucleotide-binding domain 1. Login to comment
167 By using Western blot analysis, the maturation process of V562I-CFTR appears similar to the one visualized for WT-CFTR (Figure 4B). Login to comment
170 In our cell model, according to the three techniques that we used, V562I substitution behaves like a polymorphism with no evidence for cellular or functional impact. Login to comment
220 Our results are concordant with those previously obtained in baby hamster kidney cells overexpressing CFTR23 (by using Western blot analysis, iodide effluxes, and inside-out patch-clamp experiments in which the V562I mutant behaves like WT-CFTR). Login to comment
221 However, V562I, which was first reported as a polymorphism,24 has been reassigned as a non-CF-causing mutation, notably implicated in the CBAVD phenotype.20 Because the V562I-CFTR protein appears unaffected, the mutation could only elicit dysfunction at the RNA level. Login to comment

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

No. Sentence Comment

45 (%) p.F508del # E.10 1009 (51.74) p.G542X # E.11 150 (7.69) p.N1303K # E.21 57 (2.92) c.1811 + 1.6kbA > G I.11 36 (1.84) p.R334W # E.7 35 (1.79) p.L206W E.6a 32 (1.64) c.711 + 1G > T # I.5 31 (1.58) p.Q890X E.15 28 (1.43) p.R1162X # E.19 25 (1.28) c.2789 + 5G > A # I.14b 24 (1.23) p.R1066C E.17b 23 (1.18) p.I507del # E.10 21 (1.07) c.1609delCA E.10 18 (0.92) c.712-1G > T I.5 18 (0.92) c.3272-26A > G I.17a 18 (0.92) c.2183AA > G # E.13 16 (0.82) p.G85E # E.3 15 (0.77) c.2869insG E.15 15 (0.77) p.W1282X # E.20 15 (0.77) p.V232D E.6a 14 (0.71) p.A1006E * E.17a 12 (0.61) c.2184insA E.13 11 (0.56) p.K710X E.13 11 (0.56) TOTAL (n = 23) 1,634 (83.72) * , the complex allele [p.A1006E; p.V562I; IVS8-6(5T)] #, CF mutations identified with the Celera Diagnosis Cystic Fibrosis v2 genotyping assay and the Inno-Lipa CFTR12, CFTR17 + Tn Samples with microsatellite haplotypes 16/45-46-47 (IVS8CA/IVS17bTA) were submitted to direct analysis of the c.1811 + 1.6kbA > G mutation, which was found mainly associated with the 16-46 haplotype. Login to comment
70 The major complexity detected is attributable to the polyvariant [p.A1006E; p.V562I; IVS8-6(5T)], which was observed in all patients with the p.A1006E mutation (Table 1). Login to comment

PMID: 23082198 [PubMed] Sousa M et al: "Measurements of CFTR-Mediated Cl(-) Secretion in Human Rectal Biopsies Constitute a Robust Biomarker for Cystic Fibrosis Diagnosis and Prognosis."

No. Sentence Comment

103 As to the 5 individuals showing inconclusive Ussing chamber measurements, one individual had one CF-disease causing mutation (G542X) and two individuals had RD- related mutations (V562I and G576A). Login to comment

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

No. Sentence Comment

90 Table 1 CFTR mutations detected in 36 Algerian patients (N=72 CF chromosomes) Mutations Substitution nucleotide Substitution amino acid Localisation N % Cum. fr. hF508del del CTT Del phe 507/508 Exon 10 12 16.7 16.7 N1303K C→G 4041 Asn→Lys 1303 Exon 21 6 8.3 25.0 711+1G→T G→T711+1 MRNA splicing defect Intron 5 6 8.3 33.3 2183AA/G del A2184 Frameshift Exon 13 3 4.2 37.5 A→G 2183 1609delCA delCA Frameshift Exon 10 2 2.8 40.3 1812-1G→A G→A 1812-1 mRNA splicing defect Intron 11 2 2.8 43.1 V562I G→A 1816 Val→Ile 562 Exon 12 2 2.8 45.9 V754M G→A 2392 Val→Met 754 Exon 13 1 1.4 47.3 W1282X G→A 3978 Trp→Stop 1282 Exon 20 3 4.2 51.5 621+3A/Ga A→G 621+3 mRNA splicing defect Intron 4 1 1.4 52.9 4332delTGa delTG4332 Frameshift Exon 23 G542X G→T 1756 Gly→Stop 542 Exon 11 1 1.4 54.3 4271delC del A 4271 Frameshift Exon 23 1 1.4 55.7 S977F C→T 3062 Ser→Phe 97 Exon 16 1 1.4 57.1 21Kb del 21-kb del Del AA E2-E3 1 1.4 58.5 R74W C→T 352 Arg→Trp 74 Exon 3 0 0 D1270N G→A 3940 Asp→Asn 1270 Exon 20 0 0 Total 43 58.5 N=number of chromosomes; Cum. fr.=cumulative frequency. Login to comment
94 The duplication of 11 bases [1716+(51→61)] was only found in the father of a compound heterozygote V562I/S997F CF patient. 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

108 g D44G, 300delA, W57X, 405+1G>A, D110H, E116K, 541del4, 542del7, L137R, 621+2T>G, I175V, H199R, H199Y, C225X, V232D, Q290X, E292X, G314V, T338I, 1221delCT, W401X, Q452P, I502T, 1716+2T>C, G544S, R560S, A561E, V562I, Y569D, 1898+3A>G, 1898+5G>A, G628R(G>A), 2143delT, G673X, R851X, Q890X, S977F, 3129del4, 3154delG, 3271+1G>A, G1061R, R1066L, R1070W, 3601-17T>C, S1196X, 3732delA, G1249R, 3898insC, 4374+1G>A, del25kb. Login to comment
140 Non-F508del Mutations Found as Homozygous in a Sample of 3,710 Patients With Cystic Fibrosis Mutation n 711+1G>T 8 G542X 7 N1303K 7 2183delAA>G 5 W1282X 4 G551D 3 3905insT 3 R334W 2 R347P 2 1078delT 2 1811+1.6kbA>G 2 2113delA 2 Y1092X 2 R1162X 2 306insA 1 E92K 1 G178R 1 L227R 1 1677delTA 1 1717-1G>A 1 1717-8G>A 1 R553X 1 S549R(T>G) 1 R560S 1 V562I 1 Y569D 1 2711delT 1 S945L 1 R1158X 1 I1234V 1 3849+10kbC>T 1 Q1313X 1 del25kb 1 E831X 1 I175V 1 G314V 1 L1077P 1 produce a small quantity of functional protein as a result of a variable proportion of normal CFTR mRNA transcripts in addition to the abnormal ones (class V); 3) they are located in sites known to generate less severe mutants (external loops, residues lining the pore); and/or 4) they have been observed in CF with pancreatic sufficiency, CBAVD, and/or CF-related attenuated phenotypes only. Login to comment

PMID: 10445602 [PubMed] Puechal X et al: "Increased frequency of cystic fibrosis deltaF508 mutation in bronchiectasis associated with rheumatoid arthritis."

No. Sentence Comment

83 mmol.L-1 mV gene mutation 1 F 67 51 Yes II II 0401/1401 51 20 P. aeruginosa 48 -24 DF508/- 2{ F 52 29 Yes IV IV 0406/0416 35 50 P. aeruginosa ND -31 DF508/- 3 F 35 16 II II 0311/1302 4 82 H. influenzae 18 -21 DF508/- 4 F 52 42 II II 03011/1001 4 79 ND 55 -21.0 DF508/- 5 F 56 48 II III 0101/0401 12 90 Normal flora 40 -15.3 R668C/- 6 F 59 49 III III 0401/0405 4 14 P. aeruginosa 57 ND S1235R/- 7 F 55 53 II I 0101/1001 2 92 Normal flora 42 -17.3 -/- 8 F 55 46 III III 0101/1302 3 83 Normal flora 60 -18.7 -/- 9{ F 66 20 III IV 0101/0401 4 78 P. mirabilis 35 -15.8 -/- 10 M 71 61 II III 0701/1001 67 60 Normal flora 34 -19.2 V562I/- 11 M 59 34 II III 0101/0408 53 94 H. influenzae 62 -20.8 -/- 12 F 56 30 Yes III III 0101/0311 10 89 Normal flora 53 -11.1 -/- 13 F 46 43 Yes II III 0101/0405 9 73 H. influenzae 29 -21.3 -/- 14 F 47 41 II III 03011/0401 9 80 Normal flora 86 -16.5 -/- 15 F 54 44 II II 0401/0401 1 67 Normal flora 50 -13 -/- 16 F 59 37 III III 0101/0401 3 53 H. influenzae 70 -16.8 -/- 17 F 49 47 I I 03011/1401 10 58 H. parainfluenzae 79 -18.5 -/- 18{ F 65 37 Yes III III 03011/1501 56 43 Normal flora 35 -33.8 -/- 19 F 65 54 Yes II III 0101/1101 10 91 ND 64 -9.6 -/- 20 F 70 55 III III 0101/0401 4 80 Normal flora 38 -13.5 -/- 21 F 69 53 IV IV 0101/1501 4 35 P. aeruginosa 35 ND -/- 22 M 66 63 II II 0401/1104 63 97 Normal flora 36 -20.2 -/- 23 F 61 56 I I 03011/0701 4 76 Flavobacterium spp. Login to comment
164 Although the V562I and S1235R mutations have been described in CF patients, the putative detrimental effect of these mutations is disputable. Login to comment
163 Although the V562I and S1235R mutations have been described in CF patients, the putative detrimental effect of these mutations is disputable. Login to comment

PMID: 10447267 [PubMed] Telleria JJ et al: "Spectrum of CFTR mutations in the Middle North of Spain and identification of a novel mutation (1341G-->A). Mutation in brief no. 252. Online."

No. Sentence Comment

33 Spectrum of CFTR Mutations Table 1 Spectrum of CFTR mutations identified in the present study compared with data published by Casals et al. (Casals et al. 1997) This study Casals et al. Mutation Exon/Intron n % n % ∆F508 E 10 51 65.4 681 53.2 711+1G→T I 5 3 3.8 22 1.7 G542X E 11 3 3.8 108 8.43 1213delT E 7 2 2.6 0 0 1341G→A E 8 2 2.6 0 0 R1066C E 17b 2 2.6 14 1.09 1717-1G→A I 10 1 1.3 1 0.08 S549R E 11 1 1.3 0 0 V562I E 12 1 1.3 0 0 G576A E 12 1 1.3 0 0 2183AA→G E13 1 1.3 5 0.39 2789+5G→A I 14b 1 1.3 11 0.86 Q890X E 15 1 1.3 13 1.01 3849+1G→A I 19 1 1.3 0 0 N1303K E 21 1 1.3 34 2.65 Other 0 0 391 30.5 Known mutations 72 92.3 1155 90.23 Unknown mutations 6 7.7 125 9.7 DISCUSSION The knowledge of the spectrum of mutations causing CF in any specific geographic region provide useful information to design the best approach in pre and postnatal diagnosis of CF; for the screening of mutations in the population at risk; to stimate the genetic risk etc. Moreover, the response to different therapeutic approaches could vary depending on the CF mutations in any case. Login to comment

PMID: 23810505 [PubMed] Prach L et al: "Novel CFTR variants identified during the first 3 years of cystic fibrosis newborn screening in California."

No. Sentence Comment

165 Participant 3 was identified with novel variant c.-837T>C (found to be in cis with p.V562I after parent testing) and p.F508del on the opposite chromosome. 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

215 The Q779X (p.Gln779*) mutation was found in a CF-PS brother and sister with a [(TG)11T5; V562I; A1006E]/Q779X (c. Login to comment
288 The V562I (p.Val562Ile) and the A1006E (p.Ala1006Glu) were only found within the complex allele. Login to comment
377 [1210-14TG[11];1210-12T[5];1684G>A;3017C>A] CF-PS,CFTR-RD T5 varying clinical consequence; V562I nd; A1006E nd K442X c.1324A>T CF-PI nd p.Lys442* T465N c.1394C>A CF-PI nd p.Thr465Asn [S466X(TGA);R1070Q] c. Login to comment