ABCMdb

PMID: 15070876

Dayangac D, Erdem H, Yilmaz E, Sahin A, Sohn C, Ozguc M, Dork T
Mutations of the CFTR gene in Turkish patients with congenital bilateral absence of the vas deferens.
Hum Reprod. 2004 May;19(5):1094-100. Epub 2004 Apr 7., [PubMed]

Sentences

No. Mutations Sentence Comment

5 ABCC7 p.Asp1152His Two predominant mutations, IVS8-5T and D1152H, accounted for more than one-third of the alleles. Login to comment 35 ABCC7 p.Arg347His ABCC7 p.Asn1303Lys ABCC7 p.Gly85Glu ABCC7 p.Asp1152His ABCC7 p.Asp110His We next screened for six further CFTR gene mutations of the coding region and ¯anking intron sequences by previously described restriction-enzyme based methods: G85E, D110H, R347H, 2789+5G®A, D1152H, N1303K (DoÈrk et al., 1994a, 1997). Login to comment 40 ABCC7 p.Arg347His ABCC7 p.Glu831* ABCC7 p.Asp1152His ABCC7 p.Leu997Phe ABCC7 p.Asp110His Finally, the 5'-UTR and minimum promoter region were Table I. CFTR gene mutations identi®ed in 51 CBAVD patients Mutation Location Nucleotide alteration Predicted effect Allele frequency (%) Reference IVS8-5T Intron 8 Deletion of 2T between 1342±12 and 1342±6 Aberrant splicing 20 (19.6)a Chu et al. 1993 D1152H Exon 18 G®C at 3586 Amino acid substitution 15 (14.7)a Highsmith et al. 1992* D110H Exon 4 G®C at 460 Amino acid substitution 3 (2.9) Dean et al. 1990 DF508 Exon 10 Deletion of 3 nt at 1652±1655 Amino acid deletion 3 (2.9) Kerem et al. 1989 2789+5G®A Intron 14b G®A at 2789+5 Aberrant splicing 3 (2.9) Highsmith et al. 1997 L997F Exon 17a G®C at 3123 Amino acid substitution 3 (2.9) Fanen et al. 1992b CFTRdele2 (ins186) Introns 1±2 Deletion of 8.1 kb and insertion of 186 bp In-frame-deletion 2 (2.0) DoÈrk et al. 2000b R347H Exon 7 G®A at 1172 Amino acid substitution 2 (2.0) Cremonesi et al. 1992 E831X Exon 14a G®T at 2623 Truncation 2 (2.0) Ferec et al. 1992* 1767del6 Exon 11 Deletion of 6 nt at 1767±1773 In-frame-deletion 2 (2.0) (a) This study 3041-15T®G Intron 15 T®G at 3041±15 Aberrant splicing? Login to comment 42 ABCC7 p.Arg74Trp ABCC7 p.Ala349Val ABCC7 p.Arg334Gln ABCC7 p.Thr388Met 2 (2.0)a This study R74W Exon 3 C®T at 352 Amino acid substitution 1 (1.0) Claustres et al. 1993b 359insT Exon 3 Insertion of T within 360±365 Truncation 1 (1.0) Claustres et al. 1995* A349V Exon 7 C®T at 1178 Amino acid substitution 1 (1.0) Audrezet et al. 1993 R334Q Exon 7 G®A at 1133 Amino acid substitution 1 (1.0) Ferec et al. 1994* T388M Exon 8 C®T at 1295 Amino acid substitution 1 (1.0) Zielenski et al. 1996 IVS8-6T Intron 8 Deletion of T between 1342±12 and 1342±6 Aberrant splicing? Login to comment 43 ABCC7 p.Glu585* ABCC7 p.Ile853Phe 1 (1.0) DoÈrk et al. 2001 1677delTA Exon 10 Deletion of 2 nt at 1674±1678 Truncation 1 (1.0) Ivaschenko et al. 1991 E585X Exon 12 G®T at 1885 Truncation 1 (1.0) Cremonesi et al. 1992 I853F Exon 14a A®T at 2689 Amino acid substitution 1 (1.0) This study 2752-15C®G Intron 14a C®G at 2752±15 Aberrant splicing? Login to comment 44 ABCC7 p.Met952Ile ABCC7 p.Arg1070Trp ABCC7 p.Gly1130Ala 1 (1.0) DoÈrk et al. 1997b M952I Exon 15 G®C at 2988 Amino acid substitution 1 (1.0) Girodon et al. 1995 3120+1G®A Intron 16 G®A at 3120+1 Aberrant splicing 1 (1.0) Macek et al. 1997 3272-26A®G Intron 17a A®G at 3272±26 Aberrant splicing 1 (1.0) Fanen et al. 1992 R1070W Exon 17b C®T at 3340 Amino acid substitution 1 (1.0) Macek et al. 1993* G1130A Exon 18 G®C at 3521 Amino acid substitution 1 (1.0) This study Mutations were designated following the recommended nomenclature (Beaudet and Tsui, 1993) except for the IVS8-(T)n alleles which are named according to the number of their residual thymidines (Chu et al., 1993). Login to comment 47 ABCC7 p.Glu831* ABCC7 p.Asp1152His ABCC7 p.Met952Ile ABCC7 p.Arg1070Trp ABCC7 p.Arg334Gln ABCC7 p.Thr388Met *The following mutations were previously reported as personal communications to the CF Genetic Analysis Consortium (http://www.genet.sickkids.on.ca): 359insT by Claustres M, Desgeorges M, Romey M-C; R334Q by FeÂrec C, Quere I, Verlingue C, Raguenes O, AudreÂzet M-P, Mercier B; T388M by Zielenski J, Markiewicz D, Tsui L-C, Rawashdeh M, Khateeb M; E831X by FeÂrec C, Quere I, Audrezet MP, Verlingue C, Guillermit H, Mercier B; M952I by Girodon E, Costes B, Cazeneuve C, Ghanem N, Goossens M; R1070W by Macek M Jr, Sedriks S, Kiesewetter S, Cutting GR; D1152H by Highsmith WE Jr, Burch L, Friedman KJ, Wood BM, Spock A, Silverman LM, Knowles MR. Login to comment 51 ABCC7 p.Asp1152His Secondly, the D1152H mutation in exon 18 was uncovered on 15 chromosomes, thereby revealing an unexpected high frequency of this missense substitution in Turkish CBAVD patients. Login to comment 52 ABCC7 p.Asp1152His Screening for the IVS8-5T and D1152H mutations together led to the identi®cation of more than one-third of alleles. Login to comment 53 ABCC7 p.Asp1152His The D1152H mutation was found in the homozygous state in ®ve patients and the IVS8-5T allele was found homozygous in four patients (Table II). Login to comment 55 ABCC7 p.Glu831* There was one patient compound heterozygous for two truncating mutations (1677delTA/E831X), but all other patients with completely resolved mutation genotype carried a missense or splicing mutation on at least one allele. Login to comment 56 ABCC7 p.Arg347His ABCC7 p.Asp110His Several mutations were already known as `mild' alleles in cystic ®brosis, e.g. D110H, R347H or 2789+5G®A, and have been described previously in studies of patients with CBAVD. Login to comment 57 ABCC7 p.Arg74Trp ABCC7 p.Leu997Phe ABCC7 p.Leu997Phe A few other substitutions, e.g. R74W, 2751-15C®G, L997F, are not classic cystic ®brosis mutations but we cannot exclude the possibility that they may contribute to a CBAVD phenotype, and the L997F substitution was reported to be associated with mild forms of cystic ®brosis such as pancreatitis (Gomez Lira et al., 2000). Login to comment 59 ABCC7 p.Ile853Phe ABCC7 p.Gly1130Ala Five mutations are described here for the ®rst time: 1767del6, 3041-13del7, 3041-15T®G, I853F and G1130A. Login to comment 63 ABCC7 p.Ile853Phe ABCC7 p.Gly1130Ala The missense mutations I853F and G1130A lead to subtle amino acid alterations in less conserved portions of the CFTR protein. Login to comment 67 ABCC7 p.Arg347His One mutant allele was identi®ed in six patients (11.7%), of whom two carried clearly pathogenic mutations (DF508 and R347H, respectively) and four harboured unclassi®ed variants. Login to comment 72 ABCC7 p.Arg347His ABCC7 p.Glu831* ABCC7 p.Glu831* ABCC7 p.Glu585* ABCC7 p.Asp1152His ABCC7 p.Asp1152His ABCC7 p.Asp1152His ABCC7 p.Asp1152His ABCC7 p.Asp1152His ABCC7 p.Asp1152His ABCC7 p.Met952Ile ABCC7 p.Leu997Phe ABCC7 p.Leu997Phe ABCC7 p.Arg1070Trp ABCC7 p.Ala349Val ABCC7 p.Asp110His ABCC7 p.Asp110His ABCC7 p.Asp110His ABCC7 p.Arg334Gln ABCC7 p.Ile853Phe ABCC7 p.Gly1130Ala CFTR genotypes in 51 patients with congenital bilateral absence of the vas deferens Mutation genotypes IVS8-(TG)mTn M470V n (%) Two mutations detected: D1152H/D1152H (TG)11 7T/ (TG)11 7T V/V 5 (9.8) IVS8-5T/IVS8-5T (TG)13 5T/ (TG)13 5T M/M 2 (3.9) (TG)12 5T/ (TG)13 5T M/V 1 (1.9) (TG)12 5T/ (TG)12 5T V/V 1 (1.9) IVS8-5T/D1152H (TG)12 5T/ (TG)11 7T V/V 2 (3.9) IVS8-5T/DF508 (TG)12 5T/ (TG)10 9T M/V 2 (3.9) IVS8-5T/2789+5G®A (TG)12 5T/ (TG)10 7T M/V 2 (3.9) IVS8-5T/365insT (TG)13 5T/ (TG)11 7T M/V 1 (1.9) IVS8-5T/D110H (TG)12 5T/ (TG)11 7T M/V 1 (1.9) IVS8-5T/E585X (TG)12 5T/ (TG)10 7T M/V 1 (1.9) IVS8-5T/2752-15C®G (TG)12 5T/ (TG)11 7T V/V 1 (1.9) IVS8-5T/M952I (TG)12 5T/ (TG)10 7T M/V 1 (1.9) IVS8-5T/3120+1G®A (TG)12 5T/ (TG)11 7T V/V 1 (1.9) D1152H/A349V (TG)10 7T/ (TG)11 7T M/V 1 (1.9) D1152H/2789+5G®A (TG)10 7T/ (TG)11 7T M/V 1 (1.9) D1152H/G1130A (TG)10 7T/ (TG)11 7T M/V 1 (1.9) CFTRdele2(ins186)/ IVS8-6T (TG)13 6T/ (TG)11 7T M/V 1 (1.9) CFTRdele2(ins186)/D110H (TG)11 7T/ (TG)11 7T V/V 1 (1.9) E831X/D110H (TG)11 7T/ (TG)11 7T V/V 1 (1.9) E831X/1677delTA (TG)11 7T/ (TG)11 7T V/V 1 (1.9) R334Q/R347H (TG)11 7T/ (TG)11 7T V/V 1 (1.9) 1767del6/1767del6 (TG)11 7T/ (TG)11 7T V/V 1 (1.9) 3041-15T®G/3041-15T®G (TG)12 7T/ (TG)12 7T M/M 1 (1.9) 3041-13del7/3041-13del7 (TG)10 7T/ (TG)10 7T M/M 1 (1.9) R1070W/3272-26A®G (TG)10 7T/ (TG)11 7T M/V 1 (1.9) I853F/L997F (TG)11 7T/ (TG)10 9T V/V 1 (1.9) One mutation detected: L997F/? Login to comment 73 ABCC7 p.Arg74Trp (TG)11 7T/ (TG)10 9T M/V 1 (1.9) (TG)11 7T/ (TG)11 7T V/V 1 (1.9) R74W/? Login to comment 74 ABCC7 p.Arg347His (TG)12 5T/ (TG)10 7T M/V 1 (1.9) R347H/? Login to comment 75 ABCC7 p.Thr388Met (TG)11 7T/ (TG)10 9T M/V 1 (1.9) T388M/? Login to comment 93 ABCC7 p.Asp1152His The results of this study re¯ect the high allelic heterogeneity of CFTR gene mutations, although two mutations, IVS8-5T and D1152H, were found to be very common in Turkish CBAVD patients. Login to comment 97 ABCC7 p.Asp1152His Secondly, the D1152H missense substi- Figure 1. Login to comment 112 ABCC7 p.Asp1152His In vitro studies have shown that the D1152H substitution does not interfere with the maturation of the CFTR protein but strongly reduces its cAMP-activated chloride conductance (Vankeerberghen et al., 1998) which may provide the basis for a mild expression of disease. Login to comment 113 ABCC7 p.Arg117His ABCC7 p.Asp1152His 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 114 ABCC7 p.Asp1152His All D1152H alleles appeared to be linked with the same haplotype comprising the IVS8-7T(TG)11 and Val470 alleles (Table II). Login to comment 115 ABCC7 p.Asp1152His Screening for the IVS8-5T and D1152H mutations together led to the identi®- cation of more than one-third of alleles in Turkish CBAVD males. Login to comment 123 ABCC7 p.Glu831* The ®rst exception is one patient in our study who is a compound heterozygote for the two truncating mutations 1677delTA and E831X. Login to comment 126 ABCC7 p.Glu831* Exon 14a is the subject of alternative splicing (Hull et al., 1994; Bienvenu et al., 1996) and the mutation E831X at the ®rst base of this exon may increase its in-frame skipping. Login to comment 141 ABCC7 p.Asp1152His In this regard, a population-speci®c mutation panel including the D1152H mutation and the IVS8-5T allele should be highly recommended for Turkish CBAVD patients. Login to comment