ABCMdb

PMID: 1371263

Dork T, Neumann T, Wulbrand U, Wulf B, Kalin N, Maass G, Krawczak M, Guillermit H, Ferec C, Horn G, et al.
Intra- and extragenic marker haplotypes of CFTR mutations in cystic fibrosis families.
Hum Genet. 1992 Feb;88(4):417-25., [PubMed]

Sentences

No. Mutations Sentence Comment

6 ABCC7 p.Arg553* Whereas all analysed AF508 chromosomes carried the same KM. 19-D9-J44-GATT-TUB9- M470V-T854T haplotype, another frequent mutation in Germany, R553X, was identified on two different major haplotypes. Hence, a priori haplotyping cannot exclude a particular CF mutation, but in combination with population genetic data, enables mutations to be ranked by decreasing probability. Login to comment 25 ABCC7 p.Gly551Asp ABCC7 p.Ala455Glu ABCC7 p.Trp1282* ABCC7 p.Arg553* ABCC7 p.Arg334Trp ABCC7 p.Arg347Pro Most CFTR mutations were investigated by restriction analysis of PCR products (R334W, R347P, A455E, G551D, R553X, 2789+5 G---~A,Rl162X, W1282X) (Cutting et al. 1990; Dean et al. 1990b; Gasparini et al. 1991b; Highsmith et al. 1990; Kerem et al. 1990;Vidaud et al. 1990) (see Table 4). Login to comment 26 ABCC7 p.Arg347Pro ABCC7 p.Gly542* ABCC7 p.Gly542* A few other mutations were analysed either by allele-specific oligonucleotide hybridization (Rl17H, G542X, 1717-1 G---~A) (Dean et al. 1990b; Guillermit et al. 1990; Kerem et al. 1990), single strand conformation polymorphism (Orita et al. 1989) (R347P, 3659delC) (Dean et al. 1990b; Kerem et al. 1990), temperature gradient gel electrophoresis (Rosenbaum and Riesner 1987) (1717-1 G--~A) (Guillermitet al. 1990; Kerem et al. 1990) or by allele-specific PCR (G542X, NI303K) (Kerem et al. 1990; Osborne et al. 1991). Login to comment 27 ABCC7 p.Asn1303Lys In the case of N1303K, a mismatch primer was synthesized that artificially created a DdeI site on the normal N1303 allele; the site was lost on the mutated allele, All non-AF508mutations detected by PCR screeningwere confirmed by direct genomic sequencing(Gyllensteinand Erlich 1988) of the respective exon. Login to comment 57 ABCC7 p.Asn1303Lys The same PCR product could be analysed for the N1303K mutation because of the artificial DdeI RFLP introduced by the mismatch upstream primer (Table 1). Login to comment 92 ABCC7 p.Gly551Asp ABCC7 p.Arg553* ABCC7 p.Gly542* The more frequent mutations G542X, G551D, R553X are located in sequence motifs that are evolutionarily conserved amongst the members of ABC transport proteins (Riordan et al. 1989; Hyde et al. 1990). Login to comment 93 ABCC7 p.Arg117His ABCC7 p.Arg334Trp ABCC7 p.Arg347Pro The other identified CFTR mutations either perturb acceptor (1717-1 G---~A) (Guillermit et al. 1990; Kerem et al. 1990) or donor splice sites (2789 + 5 G---~A) (Highsmith et al. 1990), or abolish positive charges in the transmembrane domains of CFTR (R117H, R334W, R347P) (Dean et al. 1990b; Gasparini et al. 1991b). Login to comment 98 ABCC7 p.Gly551Asp ABCC7 p.Arg117His ABCC7 p.Ala455Glu ABCC7 p.Trp1282* ABCC7 p.Arg553* ABCC7 p.Arg334Trp ABCC7 p.Arg347Pro ABCC7 p.Asn1303Lys ABCC7 p.Gly542* ABCC7 p.Phe508Cys ASO, Allele-specificoligonucleotide hybridization; TGGE, temperature gradient gel electrophoresis; SSCP, single strand conformation polymorphism Mutation Localization No. % Method of detectiona Reference R117H Exon 4 2 0.4 ASO Dean et al. (1990b) R334W Exon 7 2 0.4 RFLP MspI Gasparini et al. (1991b) R347P Exon 7 5 1.0 RFLP NcoI Dean et al. (1990b) A455E Exon 9 1 0.2 RFLP AciI Kerem et al. (1990) F508C2 Exon 10 1 0.2 Nondenaturing PAGE Kobayashi et al. (1990) AF508 Exon 10 370 74.0 Nondenaturing PAGE Kerem et al. (1989) 1717-1 G---~A Intron 10 2 0.4 TGGE Kerem et al. (1990) G542X Exon 11 5 1.0 Allele-specificPCR Kerem et al. (1990) G551D Exon 11 5 1.0 RFLP DpnII Cutting et al. (1990) R553X Exon 11 12 2.4 RFLP HincII Cutting et al. (1990) 2789 + 5 G---~A Intron 14B 3 0.6 RFLP SspI Highsmith et al. (1990) Rl162X Exon 19 1 0.2 RFLP DdeI Gasparini et al. (1991b) 3659delC Exon 19 3 0.6 SSCP Kerem et al. (1990) W1282X Exon 20 2 0.4 RFLP MnlI Vidaud et al. (1990) N1303K Exon 21 7 1.4 Allele-specificPCR Osborne et al. (1991) Unpublished 13 2.6 Unknown 66 13.2 Total 500 a All non-AF508 mutations were subsequently verified by direct genomic sequencing of the respective PCR product b F508C was first detected on an N chromosome (Kobayashi et al. 1990) and hence is suspected to represent a benign missense mutation Table 5. Login to comment 100 ABCC7 p.Gly551Asp ABCC7 p.Arg117His ABCC7 p.Ala455Glu ABCC7 p.Trp1282* ABCC7 p.Arg553* ABCC7 p.Arg553* ABCC7 p.Arg334Trp ABCC7 p.Arg347Pro ABCC7 p.Asn1303Lys ABCC7 p.Gly542* ABCC7 p.Arg1162* ABCC7 p.Phe508Cys The four major haplotypes are indicated in bold type KM.19 D9 J44 GATT TUB9 M470V T854T TUB18 TUB20 Mutation 1 l 2 1 2 2 1 1 2 2 2 1 1 2 1 2 2 1 2 2 1 1 2 1 2 1 2 2 2 1 2 1 1 1 1 2 2 2 1 2 1 1 1 2 i 1 2 1 2 1 1 2 1 2 R347P, F508C, R1162X, 3659delC 1717-1 G--~A, G551D, R553X (n = 2), 2789 + 5 G---~A,W1282X R117H R334W, A455E, G542X, N1303K, AF508 (96%) ~F508 (4%) R553X (n = 10) a Haplotypes were assigned from the individual pedigrees mutation was located on a single KM. 19-D9-J44-GATT-TUB9-M470V-T854T haplotype. Login to comment 101 ABCC7 p.Arg553* A notable exception turned out to be the second most frequent mutation in the German CF population, R553X. Login to comment 102 ABCC7 p.Arg553* Major and minor haplotypes differ by six out of the ten alleles; this may be explained by two separate origins of the R553X nonsense mutation in mid-European Caucasians. Login to comment 104 ABCC7 p.Arg347Pro ABCC7 p.Phe508Cys Four mutations, R347P, F508C, Rl162X, and 3659delC were found to be linked with the most common haplotype, whereas five mutations were identified on the second most frequent haplotype. Login to comment 105 ABCC7 p.Arg553* In our panel, all CF chromosomes that carried the fourth frequent CF haplotype harboured the R553X stop mutation. Login to comment 106 ABCC7 p.Ala455Glu ABCC7 p.Arg334Trp ABCC7 p.Asn1303Lys ABCC7 p.Gly542* Several more frequent disease-causing sequence variations, such as R334W, A455E, G542X, and N1303K, reside on the typical AF508 haplotype. Login to comment 122 ABCC7 p.Gly551Asp ABCC7 p.Asn1303Lys In general, the more frequent CFTR mutations, such as AF508, G551D, and N1303K, are linked to only one of the four common haplotypes. Login to comment 134 ABCC7 p.Gly551Asp ABCC7 p.Ala455Glu ABCC7 p.Trp1282* ABCC7 p.Asn1303Lys 1) A455E, G551D, 3659delC, W1282X, and N1303K were first detected on chromosomes of Anglo-Saxon or French origin (Cutting et al. 1990; Kerem et al. 1990; Vidaud et al. 1990; Osborne et al. 1991). Login to comment 136 ABCC7 p.Arg1162* 2) Two XV-2c-KM.19-D9 haplotypes were reported for the R1162X mutation in Italy (Gasparini et al. 1991b). Login to comment 137 ABCC7 p.Arg334Trp The patient from Hanover carries one of these haplotypes: 2-1-1.3) R334W was first detected in a Spanish patient with the XV-2c-KM. 19-D9 haplotype 1-1-1 (Gasparini et al. 1991b). Login to comment 140 ABCC7 p.Arg117His 4) In addition, the two cases R117H in our pool may also represent an independent mutational event. Login to comment 142 ABCC7 p.Arg334Trp The Rll7H and R334W mutations each affect a CG-dinucleotide that is known to be a 'hotspot of mutation' (Cooper and Krawczak 1990). Login to comment 144 ABCC7 p.Arg553* The most intriguing example in this respect is the R553X mutation. Login to comment 146 ABCC7 p.Arg553* The nucleotide substitution, which follows the CG-TG rule (Cooper and Krawczak 1990), was first described in two American Blacks (Cutting et al. 1990) who carry the same XV-2c-KM. 19-D9 haplotype as two German R553X compound heterozygotes. Login to comment 147 ABCC7 p.Arg553* Another ten German R553X chromosomes harbour a different, yet common, 10-marker haplotype (Table 5). Login to comment 148 ABCC7 p.Arg553* The occurrence of R553X in separate ethnic populations and on different haplotypes strongly suggests the existence of at least two (probably even more) founders of this stop mutation. Login to comment 156 ABCC7 p.Asn1303Lys The generous supply of oligodeoxy-nucleotides by Michael Dean and Lucy Osborne for the detection of the Rl17H and N1303K mutations is gratefully acknowledged. Login to comment