ABCMdb

PMID: 24631642

Fanen P, Wohlhuter-Haddad A, Hinzpeter A
Genetics of cystic fibrosis: CFTR mutation classifications toward genotype-based CF therapies.
Int J Biochem Cell Biol. 2014 Jul;52:94-102. doi: 10.1016/j.biocel.2014.02.023. Epub 2014 Mar 12., [PubMed]

Sentences

No. Mutations Sentence Comment

70 ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Asp1270Asn ABCC7 p.Arg74Trp ABCC7 p.Arg74Trp ABCC7 p.Ile148Thr ABCC7 p.Met952Ile ABCC7 p.Phe508Cys ABCC7 p.Arg668Cys ABCC7 p.Gly576Ala ABCC7 p.Asp443Tyr ABCC7 p.Ile506Val ABCC7 p.Leu997Phe ABCC7 p.Ile807Met ABCC7 p.Ile521Phe Group A Group B Group C Group D Classic-CF CF-causing mutations Non-classic CF CFTR-related disorder associated mutations No clinical consequence Unknown clinical relevance All mutations in Table 2 and 711 + 3A > G*, R117H-T5*, D1152H*, L206W*, TG13-T5* TG13-T5a , R117H-T5a , D1152Ha , L206Wa , L997F, M952I, D565Ga , TG11-T5b , R117H-T7b , D443Y-G576A-R668C, R74W-D1270N, R75Qb TG11-T5b , R117H-T7b , R75Qb , 875 + 40A/G, M470V, T854T, P1290P, I807M, I521F, R74W, F508C, I506V, I148T All mutations (mostly missense) not yet analyzed or undergoing functional analysis a Mutations that may belong either to Group A or to Group B. b Mutations that may belong either to Group B or to Group C. Login to comment 74 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.Arg1162* ABCC7 p.Gly85Glu ABCC7 p.Arg560Thr 23 ACMG recommended panel of classic CF-causing mutations G85E R117H R334W R347P A455E I507del F508del G542X G551D R553X R560T R1162X W1282X N1303K 621 + 1G > T 711 + 1G > T 1717 - 1G > A 1898 + 1G > A 2184delA 2789 + 5G > A 3120 + 1G > A 3659delC 3849 + 10kbC > T Additional or alternative mutations present at significant frequencies in an ethnic population served by a newborn screening program may be assessed. Login to comment 81 ABCC7 p.Arg117His These 23 mutations fall into Group A, as classic CF-causing mutations, with the exception of p.Arg117His, which is discussed later in a paragraph dedicated to complex alleles. Login to comment 85 ABCC7 p.Asp1152His For example, the p.Asp1152His mutation may result in isolated congenital bilateral absence of the vas deferens (CBAVD), or in a fully expressed CF lung disease with pancreatic sufficiency. Login to comment 106 ABCC7 p.Leu206Trp ABCC7 p.Arg1066Cys Depending on the mutation, one may observe either a partial reduction (p.Leu206Trp, third transmembrane segment) or a complete absence (p.Arg1066Cys, fourth intracellular loop or p.Phe508del, NBD1) of mature CFTR. Login to comment 111 ABCC7 p.Leu206Trp ABCC7 p.Arg1066Cys Initially, mutations belonging to this class were thought to cause severe CF similarly to p.Phe508del or p.Arg1066Cys, but p.Leu206Trp was shown to be associated with variable phenotype (Clain et al., 2005a). Login to comment 115 ABCC7 p.Gly551Asp The main example is p.Gly551Asp, which abolishes ATP-dependent gating, resulting in an open probability that is ~100-fold lower than that of the wild type channel (Anderson and Welsh, 1992). Login to comment 116 ABCC7 p.Arg560Thr ABCC7 p.Gly970Arg Other class III mutations such as the frequent mutations p.Arg560Thr or p.Gly970Arg are listed in Fig. 3 (Seibert et al., 1996). Login to comment 122 ABCC7 p.Arg117His The p.Arg117His mutation is the best-characterized class IV mutation. Login to comment 125 ABCC7 p.Ile148Thr ABCC7 p.Arg75Gln As of today, only a few of such mutants have been identified, namely p.Arg75Gln and p.Ile148Thr (Choi et al., 2001; Schneider et al., 2011). Login to comment 126 ABCC7 p.Ile148Thr ABCC7 p.Arg75Gln While p.Ile148Thr appears not to be deleterious (Claustres et al., 2004), p.Arg75Gln was found in some studies Fig. 3. Classification of CF mutations according to CFTR structure and function assessment. Login to comment 149 ABCC7 p.Arg117His ABCC7 p.Arg117His This can be illustrated by the class IV R117H mutation (c.350G > A, p.Arg117His) whose severity is modulated in cis by the 5/7/9T polypyrimidine tract (c.1210-12T(5 9)) in intron 9. Login to comment 150 ABCC7 p.Arg117His ABCC7 p.Arg117His While the R117H-T7 genotype is associated with milder forms of CF such as CBAVD, and most of the time even absence of symptoms, the R117H-T5 can be identified in patients having elevated sweat chloride and clinical cystic fibrosis, which in some cases is severe (Thauvin-Robinet et al., 2009). Login to comment 226 ABCC7 p.Gly551Asp This molecule specifically targets the p.Gly551Asp gating mutation by increasing the channel open probability and consequently the flow of ions transported through the channel (Ramsey et al., 2011; Eckford et al., 2012). Login to comment 227 ABCC7 p.Arg117His It also has the ability to increase the open probability of the wild-type channel and other mutants, namely p.Phe508del (Van Goor et al., 2009) and p.Arg117His (Van Goor et al., 2012). Login to comment