ABCMdb

PMID: 11504857

Chen JM, Cutler C, Jacques C, Boeuf G, Denamur E, Lecointre G, Mercier B, Cramb G, Ferec C
A combined analysis of the cystic fibrosis transmembrane conductance regulator: implications for structure and disease models.
Mol Biol Evol. 2001 Sep;18(9):1771-88., [PubMed]

Sentences

No. Mutations Sentence Comment

100 ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Ala455Glu ABCC7 p.Ala455Glu ABCC7 p.Arg334Trp ABCC7 p.Arg334Trp ABCC7 p.Arg347Pro ABCC7 p.Arg347Pro ABCC7 p.Asn1303Lys ABCC7 p.Asn1303Lys ABCC7 p.Gly85Glu ABCC7 p.Gly85Glu ABCC7 p.Ser549Asn ABCC7 p.Ser549Asn ABCC7 p.Arg560Thr ABCC7 p.Arg560Thr Moreover, all of the 11 most common missense mutations or single-amino-acid deletions (i.e., F508del, G551D, N1303K, R117H, R347P, I507del, G85E, R560T, A455E, R334W, and S549N) identified in classic and atypical CF patients worldwide (http://www.genet.sickkids.on.ca/cftr) occur in stringently conserved residues across the 15 CFTR sequences. Login to comment 542 ABCC7 p.Ser1455* ABCC7 p.Gln1476* Indeed, neither S1455X (Mickle et al. 1998) nor Q1476X (http:// www.genet.sickkids.on.ca/cftr) caused a severe CF phenotype. Login to comment 544 ABCC7 p.Arg1453Trp ABCC7 p.Asp993Tyr ABCC7 p.Arg1422Trp Consistent with this hypothesis, none of the three missense mutations identified in this region (fig. 2) can be confidently assigned as causal for CF disease; for example, R1422W was identified in a CF patient who also carried the mutations F508del and D993Y, and R1453W was identified in a patient with diffuse panbronchiolitis (http://www.genet.sickkids.on. ca/cftr). Login to comment 571 ABCC7 p.Arg1066Cys ABCC7 p.His1085Arg This stringent sequence conservation, coupled with a cluster of missense mutations identified in this subdomain (among which two homozygosities, H1085R [Yoshimura et al. 1999] and R1066C [Casals et al. 1997], cause a severe CF phenotype), undoubtedly underlies its functional significance within CFTR. Login to comment 590 ABCC7 p.Val754Met ABCC7 p.Phe693Leu ABCC7 p.Thr760Met Taking advantage of the previously redefined R domain, a systemic evaluation of the missense mutations occurring in this region was produced, and as a result, some of these mutations, such as F693L, V754M, and T760M, were identified as being likely to represent neutral polymorphisms (Chen, Scotet, and Ferec 2000). Login to comment 591 ABCC7 p.Gln890Arg ABCC7 p.Asn418Ser ABCC7 p.Lys1177Arg ABCC7 p.Gly424Ser Similarly, the missense mutations occurring in evolutionarily divergent regions, for example, N418S, G424S, Q890R, and K1177R, may also represent neutral polymorphisms. Login to comment 592 ABCC7 p.Phe508Cys ABCC7 p.Ile506Met At the other extreme, for example, the mutations I506M and F508C, which occur in stringently conserved residues in the functionally important NBD1, have also been confirmed to be nonfunctional variants (Kobayashi et al. 1990; Kalin, Dork, and Tummler 1992; Will et al. 1992). Login to comment 675 ABCC7 p.Arg1066Cys Missense mutation R1066C in the second transmembrane domain of CFTR causes a severe cystic fibrosis phenotype: study of 19 heterozygous and 2 homozygous patients. Login to comment 947 ABCC7 p.His1085Arg A Japanese patient homozygous for the H1085R mutation in the CFTR gene presents with a severe form of cystic fibrosis. Login to comment