ABCC7 p.Val1475Met
| Predicted by SNAP2: | A: N (57%), C: N (61%), D: N (53%), E: N (53%), F: N (57%), G: N (53%), H: N (61%), I: N (87%), K: N (53%), L: N (87%), M: N (66%), N: N (57%), P: N (53%), Q: N (72%), R: D (53%), S: N (66%), T: N (82%), W: D (53%), Y: N (53%), |
| Predicted by PROVEAN: | A: N, C: N, D: N, E: N, F: N, G: N, H: N, I: N, K: N, L: N, M: N, N: N, P: N, Q: N, R: N, S: N, T: N, W: N, Y: N, |
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[hide] Missense mutation (G480C) in the CFTR gene associa... Hum Mol Genet. 1995 Feb;4(2):269-73. Smit LS, Strong TV, Wilkinson DJ, Macek M Jr, Mansoura MK, Wood DL, Cole JL, Cutting GR, Cohn JA, Dawson DC, et al.
Missense mutation (G480C) in the CFTR gene associated with protein mislocalization but normal chloride channel activity.
Hum Mol Genet. 1995 Feb;4(2):269-73., [PMID:7757078]
Abstract [show]
We have identified a novel CFTR missense mutation associated with a protein trafficking defect in mammalian cells but normal chloride channel properties in a Xenopus oocyte assay. The mutation, a cysteine for glycine substitution at residue 480 (G480C), was detected in a pancreatic insufficient, African-American, cystic fibrosis (CF) patient. G480C was found on one additional CF chromosome and on none of 220 normal chromosomes, including 160 chromosomes from normal African-American individuals. Western blot analysis and immunofluorescence studies revealed that, in 293T cells, the encoded mutant protein was not fully glycosylated and failed to reach the plasma membrane, suggesting that the G480C protein was subject to defective intracellular processing. However, in Xenopus oocytes, a system in which mutant CFTR proteins are less likely to experience an intracellular processing/trafficking deficit, expression of G480C CFTR was associated with a chloride conductance that exhibited a sensitivity to activation by forskolin and 3-isobutyl-1-methylxanthine (IBMX) that was similar to that of wild-type CFTR. This appears to be the first identification of a CFTR mutant with a single amino acid substitution in which the sole basis for disease is mislocalization of the protein.
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No. Sentence Comment
109 The full length constructs contain a methionine for valine substitution at amino acid 1475 (V1475M).
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ABCC7 p.Val1475Met 7757078:109:37
status: NEWX
ABCC7 p.Val1475Met 7757078:109:92
status: NEW110 V1475M CFTR is associated with wild-type activity in a Xenopus cocyte assay (12).
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ABCC7 p.Val1475Met 7757078:110:0
status: NEW[hide] Functional roles of the nucleotide-binding folds i... Proc Natl Acad Sci U S A. 1993 Nov 1;90(21):9963-7. Smit LS, Wilkinson DJ, Mansoura MK, Collins FS, Dawson DC
Functional roles of the nucleotide-binding folds in the activation of the cystic fibrosis transmembrane conductance regulator.
Proc Natl Acad Sci U S A. 1993 Nov 1;90(21):9963-7., [PMID:7694298]
Abstract [show]
The cystic fibrosis transmembrane conductance regulator (CFTR), a member of the traffic ATPase superfamily, possesses two putative nucleotide-binding folds (NBFs). The NBFs are sufficiently similar that sequence alignment of highly conserved regions can be used to identify analogous residues in the two domains. To determine whether this structural homology is paralleled in function, we compared the activation of chloride conductance by forskolin and 3-isobutyl-1-methylxanthine in Xenopus oocytes expressing CFTRs bearing mutations in NBF1 or NBF2. Mutation of a conserved glycine in the putative linker domain in either NBF produced virtually identical changes in the sensitivity of chloride conductance to activating conditions, and mutation of this site in both NBFs produced additive effects, suggesting that in the two NBFs this region plays a similar and critical role in the activation process. In contrast, amino acid substitutions in the Walker A and B motifs, thought to form an integral part of the nucleotide-binding pockets, produced strikingly different effects in NBF1 and NBF2. Substitutions for the conserved lysine (Walker A) or aspartate (Walker B) in NBF1 resulted in a marked decrease in sensitivity to activation, whereas the same changes in NBF2 produced an increase in sensitivity. These results are consistent with a model for the activation of CFTR in which both NBF1 and NBF2 are required for normal function but in which either the nature or the exact consequences of nucleotide binding differ for the two domains.
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No. Sentence Comment
39 The full-length constructs contained a valine-for-methionine substitution at amino acid 1475 (V1475M).
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ABCC7 p.Val1475Met 7694298:39:94
status: NEW[hide] The silent codon change I507-ATC->ATT contributes ... FASEB J. 2013 Nov;27(11):4630-45. doi: 10.1096/fj.13-227330. Epub 2013 Aug 1. Lazrak A, Fu L, Bali V, Bartoszewski R, Rab A, Havasi V, Keiles S, Kappes J, Kumar R, Lefkowitz E, Sorscher EJ, Matalon S, Collawn JF, Bebok Z
The silent codon change I507-ATC->ATT contributes to the severity of the DeltaF508 CFTR channel dysfunction.
FASEB J. 2013 Nov;27(11):4630-45. doi: 10.1096/fj.13-227330. Epub 2013 Aug 1., [PMID:23907436]
Abstract [show]
The most common disease-causing mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene is the out-of-frame deletion of 3 nucleotides (CTT). This mutation leads to the loss of phenylalanine-508 (DeltaF508) and a silent codon change (SCC) for isoleucine-507 (I507-ATC-->ATT). DeltaF508 CFTR is misfolded and degraded by endoplasmic reticulum-associated degradation (ERAD). We have demonstrated that the I507-ATC-->ATT SCC alters DeltaF508 CFTR mRNA structure and translation dynamics. By comparing the biochemical and functional properties of the I507-ATT and I507-ATC DeltaF508 CFTR, we establish that the I507-ATC-->ATT SCC contributes to the cotranslational misfolding, ERAD, and to the functional defects associated with DeltaF508 CFTR. We demonstrate that the I507-ATC DeltaF508 CFTR is less susceptible to the ER quality-control machinery during translation than the I507-ATT, although 27 degrees C correction is necessary for sufficient cell-surface expression. Whole-cell patch-clamp recordings indicate sustained, thermally stable cAMP-activated Cl(-) transport through I507-ATC and unstable function of the I507-ATT DeltaF508 CFTR. Single-channel recordings reveal improved gating properties of the I507-ATC compared to I507-ATT DeltaF508 CFTR (NPo=0.45+/-0.037 vs. NPo=0.09+/-0.002; P<0.001). Our results signify the role of the I507-ATC-->ATT SCC in the DeltaF508 CFTR defects and support the importance of synonymous codon choices in determining the function of gene products.
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No. Sentence Comment
111 In addition to the 3-nt deletion in èc;F508 CFTR and the T&#a1;C alteration in the I507-ATC èc;F508 CFTR (Fig. 1), we identified 2 G&#a1;A nonsynonymous codon alterations compared to the GenBank sequences (nt 2490; V470M and nt 4423; V1475M).
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ABCC7 p.Val1475Met 23907436:111:242
status: NEW114 The nt 4423 V1475M polymorphism has not been reported previously and was found originally in the pcDNA3.1 wild-type CFTR expression vector constructed by Moyer et al. (40).
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ABCC7 p.Val1475Met 23907436:114:12
status: NEW[hide] Defining the disease liability of variants in the ... Nat Genet. 2013 Oct;45(10):1160-7. doi: 10.1038/ng.2745. Epub 2013 Aug 25. Sosnay PR, Siklosi KR, Van Goor F, Kaniecki K, Yu H, Sharma N, Ramalho AS, Amaral MD, Dorfman R, Zielenski J, Masica DL, Karchin R, Millen L, Thomas PJ, Patrinos GP, Corey M, Lewis MH, Rommens JM, Castellani C, Penland CM, Cutting GR
Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene.
Nat Genet. 2013 Oct;45(10):1160-7. doi: 10.1038/ng.2745. Epub 2013 Aug 25., [PMID:23974870]
Abstract [show]
Allelic heterogeneity in disease-causing genes presents a substantial challenge to the translation of genomic variation into clinical practice. Few of the almost 2,000 variants in the cystic fibrosis transmembrane conductance regulator gene CFTR have empirical evidence that they cause cystic fibrosis. To address this gap, we collected both genotype and phenotype data for 39,696 individuals with cystic fibrosis in registries and clinics in North America and Europe. In these individuals, 159 CFTR variants had an allele frequency of l0.01%. These variants were evaluated for both clinical severity and functional consequence, with 127 (80%) meeting both clinical and functional criteria consistent with disease. Assessment of disease penetrance in 2,188 fathers of individuals with cystic fibrosis enabled assignment of 12 of the remaining 32 variants as neutral, whereas the other 20 variants remained of indeterminate effect. This study illustrates that sourcing data directly from well-phenotyped subjects can address the gap in our ability to interpret clinically relevant genomic variation.
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No. Sentence Comment
509 The wild-type CFTR clone was obtained from an individual who did not have cystic fibrosis and encoded the known neutral variant p.Val1475Met.
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ABCC7 p.Val1475Met 23974870:509:130
status: NEW