ABCMdb

PMID: 7505767

Dork T, Fislage R, Neumann T, Wulf B, Tummler B
Exon 9 of the CFTR gene: splice site haplotypes and cystic fibrosis mutations.
Hum Genet. 1994 Jan;93(1):67-73., [PubMed]

Sentences

No. Mutations Sentence Comment

7 ABCC7 p.Gln414* ABCC7 p.Val456Phe We also identified a novel missense mutation (V456F) and a novel nonsense mutation (Q414X) within the coding region of exon 9. Login to comment 8 ABCC7 p.Val456Phe The missense mutation V456F adjacent to Walker motif A was present in a pancreas-sufficient CF patient. Login to comment 9 ABCC7 p.Gln414* In contrast, the pancreas-insufficient Q414X/AF508 compound heterozygote suffered from a severe form of the disease, indicating that alternative splicing of exon 9 does not overcome the deleterious effect of a stop codon within this exon. Login to comment 51 ABCC7 p.Gly551Asp ABCC7 p.Arg553* Family A: lanes 1, 4, father (G551D), sister (TG)IaT7/ (TG)10T7, respectively; lanes 2, 3, mother (R553X), CF (TG)lzTT/ (TG)10TT;respectively. Login to comment 52 ABCC7 p.Arg553* Family B: lanes 5, 6, CF, brother, (TG)lzT7/ (TG)IoT9, respectively; lane 7, mother (AF508) (TG)IoT7/(TG)IoT9; lane 8, father (R553X) (TG)IzTv/(TG)12T7 by using SSCP analysis of RsaI digested PCR products spanning the exon 9 coding region and adjacent intron sequences (Zielenski et al. 1991). Login to comment 61 ABCC7 p.Gly551Asp ABCC7 p.Arg117His ABCC7 p.Ala455Glu ABCC7 p.Arg553* ABCC7 p.Arg553* ABCC7 p.Arg334Trp ABCC7 p.Arg347Pro ABCC7 p.Gly542* ABCC7 p.Arg1162* ABCC7 p.Ser1251Asn ABCC7 p.Arg1066Cys ABCC7 p.Tyr1092* ABCC7 p.Ile1005Arg ABCC7 p.Ile1005Arg ABCC7 p.Gln39* ABCC7 p.Arg117Cys ABCC7 p.Arg117Cys ABCC7 p.Leu1077Pro ABCC7 p.Glu60* ABCC7 p.Glu92* ABCC7 p.Glu92* ABCC7 p.Gln414* ABCC7 p.Gln414* ABCC7 p.Val456Phe ABCC7 p.Val456Phe ABCC7 p.Leu1059* ABCC7 p.Leu1059* Association of (TG),Tm alleles with CFTR mutations (TG),Tm CFTR mutationsa (TG)llT7 E60X, E92X, R117C, 1078delT, R347P, R553X, 2184delA, 2184insA, I1005R, 3272-26A--~G, L1059X, Y1092X, R1162X, 3659delC, 3850-3T-oG, S1251N Q39X, R117H, Q414X, V456F, AI507, 1717-1G--~A, G551D, 2043delG, 2183AA---~G, 2184insA, 2789 + 5 G---~A,3272-26A---~G, R1066C, L1077P, 3849 + l0 kB C---~T,4374 + 1 G---~T 621 + 1 G---~T,R334W, A455E, AF508, G542X, 2143delT, 3849 + 10 kB C---~T,NI303K 405 + 1 G----~A,1342-2 A---~C,R553X (TG)IoT7 (TG)10T9 (TG)12T7 a References are compiled in Tsui (1992), except for 2143delT (Dtrk et al. 1992b), 3850-3 T---~G,4374 + 1 G---~T,1342-2 A---~C (Dtrk et al. 1993a, b), Q414X, V456F (this work), 405 + 1 G---~A, E92X, R117C, 2184delA, 2184insA, I1005R, L1059X (T. Login to comment 65 ABCC7 p.Arg553* A few CFTR mutations with two different splice site haplotypes may be explained by a recurrent mutational event (e.g. R553X) or intragenic recombination (Table 3 ). Login to comment 71 ABCC7 p.Val456Phe ABCC7 p.Val456Phe Direct sequencing of the V456F mutation. Left, Control; right, patient heterozygous for V456F above. Login to comment 75 ABCC7 p.Ala455Glu ABCC7 p.Val456Phe The missense mutations A455E and V456F are both located in front of the conserved Walker motif A (Riordan et al. 1989; Walker et al. 1982). Login to comment 76 ABCC7 p.Ala455Glu A455E has previously been described (Kerem et al. 1990) and is reported to be frequent in French-Canadians (Rozen et al. 1992). Login to comment 77 ABCC7 p.Ala455Glu We confirmed A455E in a single German CF female with AF508 on her other chromosome. Login to comment 78 ABCC7 p.Val456Phe The other missense mutation, V456F, represents a novel G--~T transversion at nucleotide position 1498, changing the valine codon 456 to a phenylalanine codon (Fig. 4). Login to comment 81 ABCC7 p.Ala455Glu ABCC7 p.Val456Phe The mutations A455E and V456F both destroy the same recognition site for the restriction enzyme AciI. Login to comment 83 ABCC7 p.Gln414* The novel nonsense mutation Q414X was detected in another German CF family by direct sequencing of a PCR product whose SSCP pattern did not match the pattern that we expected from the repeat genotype. Login to comment 86 ABCC7 p.Gln414* His notable clinical symptoms, including pancreatic insufficiency, bronchiectasis and airway colonisation with Pseudomonas aeruginosa, indicate that Q414X Fig. 5. Login to comment 87 ABCC7 p.Gln414* ABCC7 p.Gln414* Direct sequencing of the Q414X mutation. Left, Control; right, patient heterozygous for Q414X represents a severe allele. Login to comment 89 ABCC7 p.Gln414* These results strongly suggest that Q414X is disease-causing by itself and produces a severe phenotype despite alternative splicing. Login to comment 95 ABCC7 p.Arg553* A few mutations have been found on two different repeat alleles linked to different intragenic dimorphic marker haplotypes; this favours the hypothesis of recurrent mutational events (e.g. R553X, 2184insA, 3272-26 A---~G, 3849 + 10 kB C--~T). Login to comment 108 ABCC7 p.Gly551Asp Mutations associated with a clinical course similar to AF508 (e.g. G551D; Hamosh et al. 1992) can be linked to a different haplotype, whereas "mild" mutations retaining pancreatic sufficiency (e.g. 3849 + 10 kB C---~T; W.E. Highsmith et al., personal communication; Augarten et al. 1993) can be found on the "AF508 haplotype" (Table 3). Login to comment 111 ABCC7 p.Gln414* ABCC7 p.Val456Phe The apparent abundance of exon 9 skipping in healthy individuals needs to be taken into consideration when a disease-causing role is attributed to mutations within the coding region of exon 9, such as the Q414X and V456F mutations identified in this study. Login to comment 115 ABCC7 p.Ala455Glu ABCC7 p.Lys464Ala ABCC7 p.Gly458Val Early evidence for a crucial role of exon 9 sequences came from the findings that mutations 71 within or adjacent to the Walker motif A produce a CF phenotype in vivo (A455E, G458V; Kerem et al. 1990; Cuppens et al. 1990) and in vitro (K464A; Anderson and Welsh 1992). Login to comment 116 ABCC7 p.Val456Phe The novel mutation V456F adds to these mutations that may affect nucleotide binding. Login to comment 119 ABCC7 p.Val520Phe Phenylalanine residues within the amino-terminal nucleotide-binding domain may be critical for the structure and function of CFTR, as exemplified by the mutations V520F and AF508 in exon 10 (Tsui 1992). Login to comment 120 ABCC7 p.Arg1162* ABCC7 p.Val456Phe Thus, the nature and location of the V456F substitution seem to be in agreement with the mild disease observed in our index patient who is compound heterozygous for the pancreas-insufficient R1162X mutation (Gasparini et al. 1991). Login to comment 121 ABCC7 p.Val456Phe In principle, the V456F change and the other identified missense mutations in exon 9 can be by-passed through alternative splicing. Login to comment 124 ABCC7 p.Gln414* Here, we have described the first case of a nonsense mutation Q414X within this alternatively spliced exon in a patient with prominent pulmonary and gastrointestinal CF symptoms. Login to comment 126 ABCC7 p.Gln414* Any CFTR gene product produced by the Q414X allele would be truncated or lacking exon 9. Login to comment 127 ABCC7 p.Gln414* ABCC7 p.Gln414* The most simple conclusion drawn from the severe clinical course of the compound heterozygote Q414X/AF508 is that the deleterious effects of the Q414X mutation cannot be overcome by exon skipping because exon 9- CFTR cannot compensate for full-length CFTR. Login to comment 128 ABCC7 p.Glu585* Interestingly, a similar situation has been found in patients carrying a nonsense mutation (E585X) within the alternatively spliced exon 12 that codes for the last part of the amino-terminal nucleotide-binding domain in CFTR (Cremonesi et al. 1992). Login to comment 135 ABCC7 p.Val456Phe Michael J. Lentze for providing the DNA sample of the V456F heterozygote. Login to comment 146 ABCC7 p.Arg347His ABCC7 p.Arg352Gln ABCC7 p.Glu585* Nature Genet 3:151-156 Cremonesi L, Ferrari M, Belloni E, Magnani C, Seia M, Ronchetto P, Rady M, Russo MP, Romeo G, Devoto M (1992) Four new mutations of the CFTR gene (541delC, R347H, R352Q, E585X) detected by DGGE analysis in Italian patients, associated with different clinical phenotypes. Login to comment 157 ABCC7 p.Arg553* Proc Natl Acad Sci USA 85 :7652-7656 Hamosh A, Trapnell BC, Zeitlin PL, Montrose-Rafizadeh C, Rosenstein BJ, Crystal RG, Cutting GR (1991) Severe deficiency of cystic fibrosis transmembrane conductance regulator messenger RNA carrying nonsense mutations R553X and WI316X in respiratory cells of patients with cystic fibrosis. Login to comment 158 ABCC7 p.Trp1282* ABCC7 p.Gly542* J Clin Invest 88:1880-1885 Hamosh A, Rosenstein BJ, Cutting GR (1992) CFTR nonsense mutations G542X and W1282X associated with severe reduction of CFTR mRNA in nasal epithelial cells. Login to comment