ABCMdb

PMID: 7525450

Dork T, Mekus F, Schmidt K, Bosshammer J, Fislage R, Heuer T, Dziadek V, Neumann T, Kalin N, Wulbrand U, et al.
Detection of more than 50 different CFTR mutations in a large group of German cystic fibrosis patients.
Hum Genet. 1994 Nov;94(5):533-42., [PubMed]

Sentences

No. Mutations Sentence Comment

49 ABCC7 p.Gly551Asp ABCC7 p.Arg553* ABCC7 p.Gly542* A few other mutations known to be frequent (e.g. NI303K, R553X, G542X, G551D, 2789+5 G-+A and 3849+10 kB C--+T) were then screened by specific direct methods as previously described (D6rk et al. 1992 a). Login to comment 57 ABCC7 p.Arg75* In the case of novel missense or splice site mutations, a panel of 100 normal chromosomes from unaffected members of CF families was screened for the G C G A G C T A G C T Control R 75 X Figo2 Direct sequencing showing heterozygosity for the R75X nonsense mutation (arrow, right) in exon 3 T C G A T C G A Fig. 1a--d SSCP analysis of genomic PCR products from different regions of the CFTR gene. Login to comment 58 ABCC7 p.Trp1282* ABCC7 p.Ser1251Asn a Detection of mutations in exon 20 (HphI fragment): 3850-3 T-eG (lane 3), S1251N (lane 4), W1282X (lane 5), 4002 A---~G(lane 6). Login to comment 59 ABCC7 p.Leu619Ser b Detection of mutations in exon 13 (DdeI fragment): 2043delG (lane 3) (Fanen et al. 1992), L619S (lane 4). Login to comment 61 ABCC7 p.Arg1066Cys d Detection of mutations in exon 17b (RsaI fragment): 3272-26 A---~G (lane 2), R1066C (lane 3). Login to comment 66 ABCC7 p.Arg75* ABCC7 p.Arg75* (1) R75X is a C-+T transition at nucleotide 355 leading to the termination mutation R75X (Fig. 2). Login to comment 67 ABCC7 p.Arg75Gln It was identified in a 9-year-old patient. This mutation occurs at a CpG dinucleotide within exon 3 where a benign missense variant (R75Q) has previously been described (Zielenski et al. 1991 b). Login to comment 68 ABCC7 p.Asn1303Lys ABCC7 p.Arg75* The pancreas-insufficient patient inherited R75X from his father and the mutation N1303K (Osborne et al. 1991) from his mother. Login to comment 69 ABCC7 p.Arg75* The R75X nonsense mutation is associated with a rare sequence variant 125 G---~C (Cutting et al. 1992) in the promoter region of the CFTR gene. Login to comment 71 ABCC7 p.Gly673* ABCC7 p.Gly673* (2) G673X is a nonsense mutation found in j G A A G G A -~-G G 673X Control Fig.3 Identification of the nonsense mutation G673X (arrow, left) in exon 13 T C G A T C G A T C G A c\A A A A A !_f Control 2184 ins A 2184 del A Fig.4 Direct sequencing showing heterozygosity for the frameshift mutation 2184insA (middle) and 2184delA (right) within exon 13 exon 13 of the CFTR gene. Login to comment 73 ABCC7 p.Gly673* ABCC7 p.Gly673* G673X was present in a 25-year-old female who is compound heterozygous for AI507 (Kerem et al. 1990) and G673X; she is pancreatic insufficient. Login to comment 74 ABCC7 p.Leu719* ABCC7 p.Leu719* (3) L719X was detected in a 4-year-old female who is compound heterozygous for AF508 and L719X. Login to comment 76 ABCC7 p.Leu1059* (4) The L1059X mutation represents a novel T---~G transversion within exon 17b where it abolishes a recognition site for HindIII. Login to comment 77 ABCC7 p.Gly551Asp ABCC7 p.Arg117His ABCC7 p.Ala455Glu ABCC7 p.Arg553* ABCC7 p.Arg334Trp ABCC7 p.Arg347Pro ABCC7 p.Gly542* ABCC7 p.His199Tyr ABCC7 p.Gln552* ABCC7 p.Arg117Cys ABCC7 p.Arg75* ABCC7 p.Leu558Ser ABCC7 p.Glu60* ABCC7 p.Glu92* ABCC7 p.Gln414* ABCC7 p.Val456Phe Table 1 Frequency distribution and haplotypes of CFTR mutations in 700 German CF chromosomes Mutation~ Nucleotide changesb Locationc Frequencyd Haplotype~ Referencef Q39x C--~T at 247 Exon 2 1 (0.1%) D3 Cutting et al. (1992) E60X G-+T at 310 Exon 3 1 (0.1%) A2 Malone et al. (*) R75X C--+T at 355 Exon 3 1 (0.1%) C2 This study 405+1 G---~A G-+A at 405+1 Intron 3 1 (0.1%) C2 D6rk et al. (1993c) E92X G--~T at 406 Exon 4 2 (0.3%) B2 Will et al. (1994) R117C C---~Tat 481 Exon 4 1 (0.1%) C2 This study R117H G--+A at 482 Exon 4 2 (0.3%) B6 Dean et al. (1990) 621+1 G--+T G--+T at 621+1 Intron 4 1 (0.1%) B1 Zielenski et al. (1991b) H199Y C--+T at 727 Exon 6a 1 (0.1%) A2 This study (*) 1078delT Deletion of T at 1078 Exon 7 4 (0.6%) C2 Claustres et al. (1992) R334W C-~T at 1132 Exon 7 2 (0.3%) BI Gasparini et al. (1991) 1336K T-->A at 1139 Exon 7 3 (0.4%) A2 Cuppens et al. (1993) R347P G--+C at 1172 Exon 7 11 (1.6%) A2, C2 Dean et al. (1990) 1342-2 A--+C A--+C at 1342-2 Intron 8 3 (0.4%) A4 D/3rk et al. (1993b) Q414X C--+T at 1372 Exon 9 1 (0.1%) D3 D6rk et al. (1994a) A455E C-+A at 1496 Exon 9 1 (0.1%) BI Kerem et al. (1990) V456F G--~T at 1498 Exon 9 1 (0.1%) B3 D6rk et al. (1994a) A1507 Deletion of 3 bp between 1648-1653 Exon 10 1 (0.1%) D5 Kerem et al. (1990) AF508 Deletion of 3 bp between 1652-1655 Exon 10 504 (72.0%) B1, DI, B7 Kerem et al. (1989) 1717-1 G--+A G--+A at 1717-1 lntron 10 6 (0.9%) B3 Kerem et al. (1990) G542X G--+T at 1756 Exon 11 10 (1.4%) B1 Kerem et al. (1990) G551D G--+A at 1784 Exon 11 7 (l.0%) B3 Cutting et al. (1990) Q552X C-+T at 1786 Exon 11 1 (0.1%) A4 Devoto et al. (1991) R553X C--+T at 1789 Exon 11 16 (2.3%) A4, B4, D3 Cutting et al. (1990) L558S T--+C at 1805 Exon 11 1 (0.1%) C2 Maggio et al. (*) 1811+I.6kBA-+G A--+Gat 1811+l.6kB lntron 11 1 (0.1%) A2 Chillonetal. Login to comment 78 ABCC7 p.Asn1303Lys ABCC7 p.Arg1162* ABCC7 p.Arg1066Cys ABCC7 p.Ile1005Arg ABCC7 p.Leu719* ABCC7 p.Gly673* ABCC7 p.Gln1291Arg ABCC7 p.Leu619Ser (*) 1833delT Deletion of T at 1833 Exon 12 1 (0.1%) C2 Schwartz et al. (*) L619S T-+C at 1988 Exon 13 1 (0.1%) D3 This study 2143delT Deletion ofT at 2143/2144 Exon 13 5 (0.7%) BI DOrk et al. (1992b) G673X G-->T at 2149 Exon 13 l (0.1%) C2 This study 2183AA---)G Deletion of A at 2184 and A--~G at 2183 Exon 13 4 (0.6%) D5, B5 Bozon et al. (1994) 2184delA Deletion of A at 2184 Exon 13 2 (0.3%) A2 Chevalier-Porst et al. 1994, this study 2184insA Insertion of A at 2184 Exon 13 4 (0.6%) C2, B3, D3 This study L719X T-->A at 2288 Exon 13 1 (0.1%) B3 This study 2789+5 G--+A G--+A at 2789+5 lntron 14b 6 (0.9%) D3, B3 Highsmith et al. (*) 2991de132 Deletion of 32 bp from 2991-3022 Exon 15 2 (0.3%) D3 D6rk et al. (1994b) 3100insA Insertion of A at 3100 Exon 16 1 (0.1%) C2 This study I1005R T--+G at 3146 Exon 17a 3 (0.4%) A2 This study 3272-26 A--~G A--+G at 3272-26 Intron 17a 6 (0.9%) D3, A2 Fanen et al. (1992) LI059X T-~G at 3308 Exon 17b 1 (0.1%) C2 This study R1066C C-->T at 3328 Exon 17b 2 (0.3%) B3 Fanen et al. (1992) LI077P T---~Cat 3362 Exon 17b 1 (0.1%) A3 Bozon et al. (1994) YI092X C--+A at 3408 Exon 17b 2 (0.3%) C2 Bozcm et al. (1994) R1162X C--~T at 3616 Exon 19 2 (0.3%) C2 Gasparini et al. (1991) 3659de1C Deletion of C at 3659 Exon 19 4 (0.6%) C2 Kerem et al. (1990) 3849+10 kB C---)T C--+T at 3839+10 kB lntron 19 7 (1.0%) B l, D3 Highsmith et al. (*) 3850-3 T--+G T-->G at 3850 3 lntron 19 1 (0.1%) A2 D6rk et al. (1993a) S 1251N G---~Aat 3884 Exon 20 2 (0.3 %) C2 Kfilin et al. (1992a), Mercier et al. (1993) 3905insT Insertion of T at 3905 Exon 20 1 (0.1%) n.p. Liechti-Gallati et al. (1992) WI282X G---~Aat 3978 Exon 20 5 (0.7%) B3 Vidaud et al. (1990) Q1291R A--+G at 4004 Exon 20 1 (0.1%) B3 This study N1303K C---~Gat 4041 Exon 21 16 (2.3%) BI,A1 Osborne et al. (1991) 4114 ATA--~TT Deletion of A and A--~T at 41144116 Exon 22 1 (0.1%) B3 D6rk et al. (1993d) 4374+1 G-+T G--+T at 4374+1 Intron 23 1 (0.1%) D5 D6rk et al. (1993a) Total 668 (95.4%) ~'Mutations are designated according to the suggested nomenclature (Beaudet and Tsui 1993) b Numbers of nucleotides refer to the cDNA sequence (Riordan et al. 1989) c Exon and intron numbers are described (Zielenski et al. (1991a) a Frequency data are given as number (relative fraction) of alleles among 700 German CF chromosomes e Haplotypes of extragenic and intragenic dimorphic markers (Esti- viii et al. 1987; D0rk et al. 1992a) were classified as listed in the appendix (see below), n.p., noninformative phase. Login to comment 79 ABCC7 p.His199Tyr ABCC7 p.Leu558Ser ABCC7 p.Glu60* Minor haplotypes are indicated in italics f The following mutations (*) were reported to the Cystic Fibrosis Genetic Analysis Consortium as personal communications: E60X by G. Malone, M. Schwartz and M. Super; H199Y by T.DOrk and B.Tttmmler (in preparation); L558S by M. Maggio, M.Goossens and P. Fanen; 1811+1.6 kB A--+G by M.Chillon, T. D6rk, V. Nunes, T.Casals and X.Estivill; 1833delT by M.Schwartz, A.L. Palle and G. V. Christensen; 2789+5 G----~Aby W. E. Highsmith Jr., T.Strong, L. Burch, L.M.Silverman, F.S.Collins, R.C. Boucher and M.R. Knowles; 3849+10 kB C-+T by W.E. Highsmith Jr., L. Butch, T. Login to comment 82 ABCC7 p.Arg553* ABCC7 p.Leu1059* R. Knowles Table 1 Appendix marker haplotypes Dimorphic 537 Extragenic XV-2c KM.19 Intragenic (GATT)n M470V T854 TUB20 (TaqI) (PstI) A 1 1 B 1 2 C 2 1 D 2 2 1 6 1 1 2 2 7 2 1 2 3 7 1 2 1 4 6 1 2 2 5 7 1 1 2 6 7 1 2 2 7 6 1 1 1 This mutation was identified in a 20-year-old female patient who is compound heterozygous for the two nonsense mutations R553X (Cutting et al. 1990) and L1059X. Login to comment 86 ABCC7 p.Arg117Cys Whereas one heterozygote R117C/2184insA presents with borderline disease (see below), three compound heterozygotes AF508/2184insA are pancreatic insufficient with severe forms of CF. Login to comment 87 ABCC7 p.Arg117Cys We thus classify 2184insA as the "pancreas-insufficient" and R117C as the "pancreas-sufficient" allele. Login to comment 95 ABCC7 p.Arg117His ABCC7 p.Arg117Cys ABCC7 p.Arg117Cys ABCC7 p.Leu619Ser (1) In the first transmembrane domain, the mutation R117C was initially identified in a 12-year-old pancreatic sufficient German CF patient. This mutation occurs at the same CpG dinucleotide as the previously described and extensively characterized mutation Rll7H (Dean et al. 1990; Kiesewetter et al. 1993; Sheppard et al. 1993; The CF Genotype-Phenotype Consortium 1993) A G C T A G C T A G C T C G C T Control R 117 H R 117 C Fig. 5 Direct sequencing of the two mild missense mutations (arrows) R117H (middle) and R117C (right) in exon 4 in heterozygous patients A G C T A G C T G T T T_~- T Control L 619 S Fig.6 Direct sequencing of the missense substitution L619S (arrow, right) in exon 13 (Fig. 5). Login to comment 100 ABCC7 p.Leu619Ser (2) In a single pancreatic-insufficient patient, we identified the missense variant L619S within exon 13 (Fig.6). Login to comment 101 ABCC7 p.Ile1005Arg The predicted amino acid substitution occurs in a portion of the regulatory domain of CFTR; this region is conserved between A G C T A G C T G C G A T A T C G A / Control I 1005 R Fig.7 Direct sequencing of the missense mutation I1005R (arrow, right) within exon 17a human, mouse, bovine and Xenopus CFTR (Tucker et al. 1992). Login to comment 102 ABCC7 p.Leu619Ser As the L619S change was present in conjunction with the previously known rare sequence variant 1716 G--->A (Kerem et al. 1990) on the same allele, it was difficult to decide whether both sequence changes were required to cause the disease. Login to comment 103 ABCC7 p.Leu619Ser However, whereas the 1716 G---~A was also seen on a non-CF chromosome, the L619S substitution was only detected in this single family. Login to comment 105 ABCC7 p.Asn1303Lys ABCC7 p.Ile1005Arg Two patients were found to be heterozygous for AF508/I1005R; the third carried N1303K on the other allele. Login to comment 108 ABCC7 p.Gln1291Arg (4) The mutation Q1291R affects the last codon of exon 20, within the CFTR region coding for the second nucleotide-binding domain. Login to comment 110 ABCC7 p.Gln1291Arg The predicted amino acid substitution Q1291R might be located within the centre region of the conserved "ATP-binding cassette" (Riordan et al. 1989) and thus may impair the regulation of CFTR. Login to comment 111 ABCC7 p.Gln1291His Alternatively, it could affect the correct splicing of exon 20 in a similar way as described for the Q1291H mutation in the same codon (Jones et al. 1992). Login to comment 120 ABCC7 p.Gly551Asp ABCC7 p.Arg553* ABCC7 p.Arg347Pro ABCC7 p.Gly542* ABCC7 p.Ser1251Asn ABCC7 p.Arg553Gln ABCC7 p.Phe508Cys ABCC7 p.Arg668Cys ABCC7 p.Arg75* ABCC7 p.Leu619Ser There are, however, only six additional CFTR mutations with a frequency of approximately 1% or more of the CF chromosomes; two nonsense mutations, G542X and R553X, and the missense mutations G551D and NI303K were predominantly seen in severely affected patients, whereas the transmembrane missense mutation R347P and the splice mutation 3849 + 10 kB C---~T Table 2 Rare sequence variants in the CFTR promoter and coding region Sequence variant Nucleotide change Location Frequency Associated mutatiow' Reference 125 G--+C G--~C at 125 Promoter 1 (0.1%) R75X F508C T--~G at 1655 Exon 10 2 (0.3%) S1251N 1716 G---)A G---~Aat 1716 Exon 10 1 (0.1%) L619S R553Q G-~A at 1790 Exon I 1 I (0.1%) * R668C C--~T at 2134 Exon 13 1 (0.1%) 3849+10 kB C--eT 3030 G---~A G--+A at 3030 Exon 15 1 (0.1%) 405+1 G--~A I1027 T T--~C at 3212 Exon 17a 2 (0.3%) * 3417 A-+T A--->Tat 3417 Exon 17b 1 (0.1%) Unknown 4002 A--eG A--~G at 4002 Exon 20 2 (0.3%) Unknown Cutting et al. (1992) Kobayashi et al. (1990) Kerem et al. (1990) D6rk et al. ( 1991) Fanen et al. (1992) Chillon et al. (1992) Fanen et al. (1992) This study Ferec et al. (1992) ~'Marked (*) sequence variations were present on AF508 chromosomes were the most frequent in pancreas-sufficient patients. Login to comment 137 ABCC7 p.Arg553* Increased mutability of these particular sequences is demonstrated not only by the occurrence of different mutations at the same codon, but also by the presence of the mutations R553X and 2184insA in two incompatible dimorphic marker haplotypes; this suggests 539 recurrent mutational events. Login to comment