ABCMdb

PMID: 23209179

Ferec C, Cutting GR
Assessing the Disease-Liability of Mutations in CFTR.
Cold Spring Harb Perspect Med. 2012 Dec 1;2(12):a009480. doi: 10.1101/cshperspect.a009480., [PubMed]

Sentences

No. Mutations Sentence Comment

35 ABCC7 p.Trp1282* However, mutations like the W1282X (p.Trp1282X) show a higher frequency than F508del in some populations such as Ashkenazi Jews (Abeliovich et al. 1992; Shoshani et al. 1992). Login to comment 37 ABCC7 p.Gly542* Worldwide, only a limited number of mutant alleles display a frequency higher than 1%, as for example the G542X (p.Gly542X), which is common in the Mediterranean area of Europe and Africa, which may be associated with the Phoenician migration around the Mediterranean Sea (Loirat et al. 1997). Login to comment 38 ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp ABCC7 p.Asn1303Lys ABCC7 p.Asn1303Lys The G551D (p.Gly551Asp) arose in the Celtic population more recently and is still prevalent in Ireland and Brittany (Scotet et al. 2003b), and the N1303K (p.Asn1303Lys) is also rather frequent in populations from the center of Europe (Osborne et al. 1992). Login to comment 39 ABCC7 p.Tyr122* Besides these rather common mutations, which are largely distributed in the Caucasian population, there are also some foundereffects of mutated allelesobserved C. Ferec and G.R. Cutting 2 Cite this article as Cold Spring Harb Perspect Med 2012;2:a009480 www.perspectivesinmedicine.org by Cold Spring Harbor Laboratory Press at SEMMELWEIS UNIV OF MEDICINE on December 5, as, for example, in the Reunion Island, where the Y122X (p.Tyr122X) mutation displays a frequency of 24% (Dugue &#b4;pe &#b4;roux et al. 2004), or the 394delTT (p.Leu88IlefsX22) referred to as aNordicmutationfoundincountriesbordering the Baltic sea (Schwartz et al. 1994). Login to comment 41 ABCC7 p.Gly551Asp ABCC7 p.Trp1282* ABCC7 p.Asn1303Lys ABCC7 p.Gly542* In North America, the distribution of CFTR mutations reflects European descent (the five more common mutations in the U.S. with afrequencyover 1% are F508del, G542X, G551D, W1282X, and N1303K) (Bobadilla et al. 2002). Login to comment 55 ABCC7 p.Trp1282* ABCC7 p.Arg553* ABCC7 p.Gly542* Mutations in CFTR including G542X, R553X (p.Arg553X), and W1282X have been shown to lead to NMRD in primary airway cells (Hamosh et al. 1991, 1992b; Will et al. 1995). Login to comment 57 ABCC7 p.Arg1162* A notable example is the R1162X (p.Arg1162X) mutation in which the transcript containing a PTC is stable (Rolfini and Cabrini 1993; Will et al. 1995). Login to comment 58 ABCC7 p.Arg1162* Patients homozygous for R1162X showed severe pancreatic exocrine deficiency and variable lung disease severity that overlapped with measures observed in F508del homozygotes (Gasparini et al. 1992). Login to comment 59 ABCC7 p.Arg1162* Measurements of CFTR function in vivo in two R1162X homozygotes were similar to those recorded in 74 F508del homozygotes (Stanke et al. 2008). Login to comment 72 ABCC7 p.Arg1070Gln ABCC7 p.Arg1070Gln ABCC7 p.Gly480Cys ABCC7 p.Gly480Cys Mutations elsewhere in the gene that caused loss of stability include missense mutations such as G480C (p.Gly480Cys) and others that affect domain-domain interactions in CFTR such as R1070Q (p.Arg1070Gln) (Smit et al. 1995; Serohijos et al. 2008). Login to comment 75 ABCC7 p.Gly551Asp Class III mutations affect the activation of the protein and a prime example is the G551D mutation that causes CFTR to be resistant to activation, even though normal levels of mutant protein are present at the cell surface (Drumm et al. 1991; Anderson and Welsh 1992; Schwiebert et al. 1995). Login to comment 89 ABCC7 p.Gly551Asp On the other hand, mutations such as G551D require compounds that can activate a mutant protein that is already at the cell surface in levels comparable to what is seen with a normal protein. Login to comment 93 ABCC7 p.Gly551Asp ABCC7 p.Gly542* On identification of the CFTR gene, it was shown that F508del and several other loss-of-function mutations including G551D and G542X are highly associated with pancreatic insufficiency. Login to comment 94 ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Arg347Pro ABCC7 p.Arg347Pro Other C. Ferec and G.R. Cutting 4 Cite this article as Cold Spring Harb Perspect Med 2012;2:a009480 www.perspectivesinmedicine.org by Cold Spring Harbor Laboratory Press at SEMMELWEIS UNIV OF MEDICINE on December , mutations that alter residual CFTR function such as R117H (p.Arg117His) and R347P (p.Arg347Pro) have been associated with the pancreatic sufficiency (Kristidis et al. 1992). Login to comment 101 ABCC7 p.Ala455Glu ABCC7 p.Ala455Glu However, when a sufficiently large number of patients with identical genotypes are found in a single geographic location such as Belgium and in French Canada, a correlation with decline in lung function becomes evident for the A455E (p.Ala455Glu) mutation (Gan et al. 1995; De Braekeleer et al. 1997). Login to comment 107 ABCC7 p.Arg117His As residual CFTR function is increased, such as in the case of the R117H mutation bearing the 7T variant, lung function is improved sufficiently such that a CF diagnosis may not be evident. Login to comment 108 ABCC7 p.Arg117His Males bearing the combination of F508del mutation panel with R117H-7T are generally discovered because of infertility caused by absence of the vas deferens (see below). Login to comment 114 ABCC7 p.Gly551Asp ABCC7 p.Gly542* PI-CF patients bearing nonsense mutation G542X have shown the highest rate of MI, whereasthosewith F508del have an intermediate rate, and patients with the G551D mutation have a relatively low rate of MI (Hamosh et al. 1992a; Kristidis et al. 1992; Feingold and Guilloud-Bataille 1999). Login to comment 128 ABCC7 p.Arg117His A role for CFTR in male infertility was extended by Anguiano et al. who provided evidence of compound heterozygosity for CFTR mutations (i.e., F508del and R117H) inCBA VDpatients(Anguianoetal.1992).Other groups confirmed the presence of two CFTR mutations in a subset of males with CBA VD (De Braekeleer and Ferec 1996; Wilschanski et al. 1996). Login to comment 132 ABCC7 p.Arg117His The second one is a complex haplotype with the R117H missense mutation in exon 7 associated in cis with the IVS8-7T (Kiesewetter et al. 1993; Mercier et al. 1995; Cuppens et al. 1998). Login to comment 144 ABCC7 p.Arg117His The two most common CFTR-RD alleles are the IVS8-5T, a poly T tract in intron 8 of the CFTR, and the R117H associatedwiththe 7Ttract (Chillo &#b4;net al.1995). Login to comment 148 ABCC7 p.Arg117His The IVS8 poly tract of T is also a genetic modifier of the R117H when associated in cis. Login to comment 149 ABCC7 p.Arg117His ABCC7 p.Arg117His The combination of R117H-7T is found in CBA VD, but R117H associated in cis with a 5T is a complex CFallele generally associated with a mild phenotype of CF (Kiesewetter et al. 1993). Login to comment