Analysis of the 27 exons and flanking regions of the cystic fibrosis gene: 40 different mutations account for 91.2% of the mutant alleles in Southern France

Abstract

In order to characterize the non-delta F508 mutations that account for 36% of cystic fibrosis (CF) chromosomes in Southern France in a sample of 137 patients, we have systematically screened the entire coding region and adjacent sequences of the cystic fibrosis transmembrane conductance regulator (CFTR) gene by the single strand conformation polymorphism (SSCP) technique followed by direct sequencing of the mutant DNAs. We identified 13 novel mutations (9 reported in this paper) and 4 novel rare nucleotide sequence variations. Forty different mutations including delta F508, located in 15 exons, account for only 91.2% of mutants in a population originating from Southern France, in contrast with a recent report on the Celtic population of Brittany demonstrating that 90% of mutations can be detected with only three mutations. We present a very large spectrum of different CF mutations identified in a small geographical area.

A new approach for identifying non-pathogenic mutations. An analysis of the cystic fibrosis transmembrane regulator gene in normal individuals

“…This condition is fulfilled if f obs -2.5SE is greater than the threshold. In the case of CF in southern Europe, the threshold is 0.004, since the global frequency of CF mutations in Europe is about 0.02, that of ∆F508 is about 0.01 in Italy (Bonizzato et al 1994;Rendine et al 1997), in Southern France (Claustres et al 1993), and in Spain (Estivill et al 1997), and the combined frequency of the other most common CF mutations is about 0.006. Therefore the probability that a C mutation is classified as being common (hence non-CF-causing) was calculated as follows: f obs must be at least equal to 0.004+2.5SE; this value f minimal is 0.025, 0.015, 0.012, and 0.009 when N is 380, 1000, 1500, and 3000, respectively.…”

Cytoplasmic Loop Three of Cystic Fibrosis Transmembrane Conductance Regulator Contributes to Regulation of Chloride Channel Activity

“…The aim of the present study was to examine the functional significance of a previously uninvestigated domain, CL3 (predicted residues: 933-990, connecting TMs 8 and 9 of CFTR; Fig. 1), by characterizing the three different point-mutations that have been identified in CL3 from patients with CF (S945L (Claustres et al, 1993), H949Y (Ghanem et al, 1994), and G970R (Cuppens et al, 1993)). …”

Cystic Fibrosis Diagnosed in an Elderly Man

“…The 394delTT frameshift mutation in exon 3 was first described in a French patient [6]and is, after ΔF508, the second most common mutation in the Nordic countries. P99L is a missense mutation in exon 4 that was originally described in a patient with the ΔF508 mutation on the other allele and presenting with very mild CF [7].…”