ABCMdb

PMID: 24958810

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., [PubMed]

Sentences

No. Mutations Sentence Comment

4 ABCC7 p.Arg117His 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 ABCC7 p.Arg117His 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 ABCC7 p.Gly551Asp ABCC7 p.Arg117His ABCC7 p.Asn1303Lys 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 73 ABCC7 p.Gly126Cys Among eight patients identified with novel variant, only one with p.Gly126Cys mutation was observed with a slight elevated sweat chloride level (64mEq/l); however, in the remaining seven patients, sweat chloride level was in the intermediate range. Login to comment 76 ABCC7 p.Arg117His 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 82 ABCC7 p.Ser549Asn ABCC7 p.Arg170Cys ABCC7 p.His139Gln ABCC7 p.Gly126Cys ABCC7 p.Gly480Ser ABCC7 p.Arg933Thr ABCC7 p.Ala141Gly ABCC7 p.Met281Arg ABCC7 p.Arg518Lys ABCC7 p.Ser118Pro ABCC7 p.Glu585Gln 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. Login to comment 83 ABCC7 p.Arg117His 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 86 ABCC7 p.Gly126Cys ABCC7 p.Arg933Thr ABCC7 p.Met281Arg ABCC7 p.Ser118Pro 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). Login to comment 90 ABCC7 p.Arg933Thr ABCC7 p.Met281Arg ABCC7 p.Ser118Pro 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). Login to comment 94 ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.His139Gln ABCC7 p.Arg933Thr ABCC7 p.Ser118Pro 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 95 ABCC7 p.Ser549Asn ABCC7 p.Arg170Cys ABCC7 p.Gly126Cys ABCC7 p.Gly480Ser ABCC7 p.Ala141Gly ABCC7 p.Arg518Lys ABCC7 p.Glu585Gln 1679+24G.T 1 ND p.Meth281Arg/U 1 ND p.Arg170Cys/U 1 ND p.Gly126Cys/U 1 ND p.Gly480Ser/U 1 ND p.Ser549Asn/5T 1 ND p.Arg518Lys/U 1 ND p.Ala141Gly/U 1 ND c.1766+48G.C/U 1 ND p.Glu585Gln/5T 1 ND In 11 CAVD patients, no mutation could be detected in either CFTR allele U-unidentified; ND, not detected. Login to comment 100 ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Ser549Asn ABCC7 p.Ser549Asn ABCC7 p.Arg170Cys ABCC7 p.Gly480Ser ABCC7 p.Gly480Ser ABCC7 p.Arg933Thr ABCC7 p.Ala141Gly ABCC7 p.Met281Arg ABCC7 p.Arg518Lys ABCC7 p.Ser118Pro ABCC7 p.Glu585Gln 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 ABCC7 p.Arg117His 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 121 ABCC7 p.Ser549Asn One patient with a T5/ p.Ser549Asn genotype presented with the symptoms of repeated respiratory infection since childhood. Login to comment 135 ABCC7 p.Arg117His 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 ABCC7 p.Arg117His 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 141 ABCC7 p.Ser549Asn ABCC7 p.Arg170Cys ABCC7 p.Gly480Ser Intriguingly, extensive screening of 27 exons of CFTR in Indian CAVD males leads to the identification of eight novel substitutions which are reported only in the Indian population and three mutations, viz., p.Gly480Ser, p.Ser549Asn and p.Arg170Cys, which havebeen reported previously (Curtis et al., 1993; Fere et al., 1994; Kawose et al., 2001). Login to comment 144 ABCC7 p.Arg117His 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 147 ABCC7 p.His139Gln ABCC7 p.Gly126Cys ABCC7 p.Arg933Thr ABCC7 p.Ala141Gly ABCC7 p.Met281Arg ABCC7 p.Arg518Lys ABCC7 p.Ser118Pro ABCC7 p.Glu585Gln 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/). Login to comment