ABCC7 p.Ser118Pro
| Predicted by SNAP2: | A: N (72%), C: N (61%), D: D (59%), E: N (57%), F: D (53%), G: N (61%), H: N (61%), I: D (59%), K: D (53%), L: D (53%), M: D (53%), N: N (78%), P: D (63%), Q: N (66%), R: D (53%), T: N (66%), V: N (53%), W: D (63%), 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, T: N, V: N, W: N, Y: N, |
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[hide] Heterogeneous spectrum of mutations in CFTR gene f... Mol Hum Reprod. 2014 Sep;20(9):827-35. doi: 10.1093/molehr/gau047. Epub 2014 Jun 23. Sharma H, Mavuduru RS, Singh SK, Prasad R
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.
Mol Hum Reprod. 2014 Sep;20(9):827-35. doi: 10.1093/molehr/gau047. Epub 2014 Jun 23., [PMID:24958810]
Abstract [show]
Cystic fibrosis (CF) is usually considered a rare disease in the Indian population. Two studies have reported on the frequency of cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations in Indian males with congenital absence of the vas deferens (CAVD), however, data on the spectrum of CFTR gene mutations are still lacking. Therefore, the present study was designed to identify the spectrum of CFTR gene mutations as well as to investigate an association of CF genetic modifiers in the penetrance of CAVD in infertile Indian men. A total of 60 consecutive infertile males with a diagnosis of CAVD were subjected to CFTR gene analysis which revealed 13 different CFTR gene mutations and 1 intronic variant that led to aberrant splicing. p.Phe508del (n = 16) and p.Arg117His (n = 4) were among the most common severe forms of CFTR mutations identified. The IVS8-T5 allele, which is considered as a mild form of CFTR mutation, was found with an allelic frequency of 28.3%. Eight novel mutations were also identified in the CFTR gene from our patient cohort. It is noteworthy that the spectrum of CFTR gene mutation is heterogeneous, with exon 4 and exon 11 as hot spot regions. Moreover, we also found an association of the CF genetic modifiers, viz., transforming growth factor (TGF)-beta1 and endothelial receptor type-A (EDNRA) genes with the CAVD phenotype. The findings are of considerable clinical significance because men suffering from infertility due to CAVD can decide to use artificial reproduction technology. The children of men with CAVD are at risk of carrying CFTR mutations; therefore, genetic counseling is a crucial step for such patients. With special reference to developing countries, such as India, where whole gene sequencing is not feasible, the outcome of our study will make the screening procedure for CFTR gene simpler and more cost-effective as we have identified hot spot regions of the CFTR gene which are more prone to mutation in Indian males with CAVD. Moreover, this is the first study from the Indian population to investigate the association of CF genetic modifiers with penetrance of the CAVD phenotype. The observed association of the genetic modifiers TGF-beta1 and EDNRA in the penetrance of CAVD further supports their involvement in genesis of the vas deferens.
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82 SSCP analysis and subsequent DNA sequencing further revealed eleven mutations, viz., p.Gly480Ser, p.Ser549Asn, p.Arg518Lys, p.Gly126Cys, p.Ala141Gly, p.His139Gln, p.Ser118Pro, p.Arg170Cys, p.Glu585Gln, p.Met281Arg, p.Arg933Thr and two intronic variants c.1679+24G.T, c.1766+48G.C.
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ABCC7 p.Ser118Pro 24958810:82:165
status: NEW86 edu/pph2/)for p.Gly126Cys,p.Ser118Pro,p.Met281Arg,p.Arg933Thr were more than 0.5 (threshold for pathological mutation) and therefore categorized as deleterious mutations and may possibly affect CFTR structure and function (Table IV).
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ABCC7 p.Ser118Pro 24958810:86:28
status: NEW90 p.Ser118Pro, p.Met281Arg and p.Arg933Thr as pathological damaging CFTR mutations, whereas five other novel mutations were predicted as being neutral by this program (Supplementary data, Table SIII).
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ABCC7 p.Ser118Pro 24958810:90:2
status: NEW94 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.
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ABCC7 p.Ser118Pro 24958810:94:218
status: NEW100 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.
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ABCC7 p.Ser118Pro 24958810:100:630
status: NEW147 Among the eight novel mutations identified, p.Ser118Pro, p.Met281Arg, p.Gly126Cys, p.Arg933Thr were predicted to be damaging, whereas p.Arg518Lys, p.Ala141Gly, p.His139Gln, p.Glu585Gln were possibly neutral mutations (http://genetics.bwh.harvard.edu/ pph2/).
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ABCC7 p.Ser118Pro 24958810:147:46
status: NEW[hide] Function, pharmacological correction and maturatio... J Cyst Fibros. 2015 Jan;14(1):34-41. doi: 10.1016/j.jcf.2014.06.008. Epub 2014 Jul 16. Sharma H, Jollivet Souchet M, Callebaut I, Prasad R, Becq F
Function, pharmacological correction and maturation of new Indian CFTR gene mutations.
J Cyst Fibros. 2015 Jan;14(1):34-41. doi: 10.1016/j.jcf.2014.06.008. Epub 2014 Jul 16., [PMID:25042876]
Abstract [show]
BACKGROUND: Cystic fibrosis (CF) is rare in India. Most CF mutations identified are not yet functionally characterized. Hence, genetic counseling and adoption of therapeutic approach are particularly difficult. Our aim was to study the function and maturation of a spectrum of eleven Indian CFTR mutations from classical CF and infertile male patients with CBAVD. METHODS: We used Western blot, pharmacology and iodide efflux to study CFTR maturation and chloride transport in BHK cells expressing pEGFP-CFTR constructs for L69H, F87I, S118P, G126S, H139Q, F157C, F494L, E543A, S549N, Y852F and D1270E. RESULTS: Among these CFTR mutants, only L69H is not processed as a c-band and not functional at 37 degrees C. However, the functions of L69H and S549N and the maturation of L69H are corrected at 27 degrees C and by the investigational drug VX809. CONCLUSION: These data should help in developing counseling and therapeutic approaches in India. We identified L69H as a novel class II CF mutation.
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4 Methods: We used Western blot, pharmacology and iodide efflux to study CFTR maturation and chloride transport in BHK cells expressing pEGFP-CFTR constructs for L69H, F87I, S118P, G126S, H139Q, F157C, F494L, E543A, S549N, Y852F and D1270E.
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ABCC7 p.Ser118Pro 25042876:4:172
status: NEW33 Because the cellular and functional data on these mutations can improve CF genetic counseling, we examined here the functional and cellular consequences of eleven rare missense mutations, L69H, F87I, S118P, G126S, H139Q, F157C, F494L, E543A, S549N, Y852F and D1270E present in CFTR gene from both classical CF patients and CBAVD patients, which have been detected during molecular diagnosis of Indian CF patients (Fig. 1).
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ABCC7 p.Ser118Pro 25042876:33:200
status: NEW44 The activation of nine CFTR mutants F87I, S118P, G126S, H139Q, F157C, F494L, E543A, Y852F and D1270E was not significantly different from WT-CFTR (Fig. 3A for example of traces and Fig. 3B for a summary).
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ABCC7 p.Ser118Pro 25042876:44:42
status: NEW49 Mutation Nucleotide change Location in CFTR Patient phenotype CFTR dysfunction L69H T to A at 338 N-terminal Patient 1: Pancreatic insufficient, sweat chloride N 60 mEq/L, S. aureus positive; Patient 2: CBAVD Defective CFTR maturation and channel activity, class-II CF mutation F87I T to A at 391 MSD1 CBAVD No dysfunction S118P T to C at 484 MSD1 CBAVD No dysfunction G126S G to A at 508 MSD1 CBAVD No dysfunction H139Q C to G at 549 MSD1 CBAVD No dysfunction F157C T to G at 602 MSD1 CBAVD No dysfunction F494L T to C at 1612 NBD1 CBAVD No dysfunction E543A A to C at 1760 NBD1 CBAVD No dysfunction S549N G to A at 1778 NBD1 Patient 1: Frequent respiratory infection.
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ABCC7 p.Ser118Pro 25042876:49:323
status: NEW70 Discussion The present study investigated the potential deleterious functional consequence of novel rare missense mutations 0 2 4 6 8 0.0 0.1 0.2 0.3 WT F87I S118P H139Q F157C NT Time (min) k (min -1 ) 0 2 4 6 8 0.0 0.1 0.2 0.3 G126S S549N Y852F WT F508del L69H Time (min) k (min -1 ) 0 2 4 6 8 0.0 0.1 0.2 0.3 WT F508del F494L D1270E NT E543A Time (min) k (min -1 ) W T F 8 7 I S 1 1 8 P G 1 2 6 S H 1 3 9 Q F 1 5 7 C F 4 9 4 L E 5 4 3 A Y 8 5 2 F D 1 2 7 0 E S 5 4 9 N L 6 9 H F 5 0 8 d e l 0.0 0.5 1.0 1.5 2.0 ns *** *** *** *** ns (k peak - k basal) mutant / (k peak - k basal) WT A B Fig. 3.
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ABCC7 p.Ser118Pro 25042876:70:158
status: NEW72 Iodide efflux experiments in transfected BHK-21 cells, WT-CFTR, L69H, F87I, S118P, G126S, H139Q, F157C, F494L, E543A, S549N, Y852F and D1270E.
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ABCC7 p.Ser118Pro 25042876:72:76
status: NEW100 In our study, the eleven CFTR mutants i.e. L69H, F87I, S118P, G126S, H139Q, F157C, F494L, E543A, S549N, Y852F and D1270E produced different results.
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ABCC7 p.Ser118Pro 25042876:100:55
status: NEW121 The functional characterization of nine other novel mutations associated with CBAVD viz., F87I, S118P, G126S, H139Q, F157C, F494L, E543A, Y852F and D1270E revealed that these mutants did not cause any effect on normal CFTR maturation process and Cl-channel activity.
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ABCC7 p.Ser118Pro 25042876:121:96
status: NEW129 Patients profile Eleven rare missense mutations i.e. L69H, F87I, S118P, G126S, H139Q, F157C, F494L, E543A, S549N, Y852F, and D1270E were characterized by using single stranded conformation polymorphism and subsequently by DNA sequencing in Indian infertile CBAVD male patients [7,8].
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ABCC7 p.Ser118Pro 25042876:129:65
status: NEW138 The remaining all nine mutations viz., G126S, Y852F, F87I, S118P, H139Q, F157C, F494L, E543A, and D1270E were identified in Indian infertile males diagnosed with only CBAVD.
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ABCC7 p.Ser118Pro 25042876:138:59
status: NEW