A frame-shift mutation in the cystic fibrosis gene

Abstract

Cystic fibrosis (CF) is a common recessive lethal genetic disorder, affecting 1 in 1,600 Caucasians. The disease causes defective regulation of chloride-ion transport in exocrine cells. Although in all CF families the disease is linked to a locus on chromosome 7q31, there is clinical heterogeneity in the severity of the disease and the age at which it is diagnosed. CF is caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. A three-nucleotide deletion (delta F508) causing the loss of a phenylalanine residue in the tenth exon of the CFTR gene has been found on 70% of CF chromosomes. We have now characterized a CF family in which neither parent of the affected individual carries the common mutation, and identified a two-nucleotide insertion in the CF allele of the mother. The mutation introduces a termination codon in exon 13 of the CFTR gene at residue 821, and is predicted to result in the production of a severely truncated nonfunctional protein.

Evolutionary Analyses of ABC Transporters of Dictyostelium discoideum

“…ABCC.8 is also the closest Dictyostelium homolog to the human protein CFTR. This protein has been extensively studied, since mutations in CFTR result in cystic fibrosis, one of the most common genetic diseases (10,12,40). CFTR acts not only as a transporter but also as a chloride channel (1).…”

Identification of mutations in regions corresponding to the two putative nucleotide (ATP)-binding folds of the cystic fibrosis gene.

“…It is also somewhat surprising that no mutation was found in the R-domain, a region that was thought to have a regulatory function (2). The only mutation reported for the region so far was a 2-bp insertion toward the end of this domain (19). The paucity of mutations in this region suggests that either the R-domain is not critical for function or mutations in this part of the protein cannot be tolerated.…”

“…There appeared to be a difference in distribution of mutations between the two NBFs-the number of mutations detected in the first NBF (exons 9-12) and 6 times that in the second NBF (exons [19][20][21][22][23]. In addition, although the sample size is small, exon 11 seems to contain the most mutations (this study; ref.…”

cAMP-inducible chloride conductance in mouse fibroblast lines stably expressing the human cystic fibrosis transmembrane conductance regulator.

“…The recent identification of the gene (2)(3)(4) and mutations (4)(5)(6)(7)(8)(9) responsible for CF has provided insight into the basic defect in this disease. The protein product of this gene has an estimated molecular mass of 170 kDa with transmembrane and nucleotidebinding-fold domains.…”