CFTR haplotypic variability for normal and mutant genes in cystic fibrosis families from southern France |
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Authors: | M Claustres Marie Desgeorges Philippe Moine Núria Morral Xavier Estivill |
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Institution: | (1) Laboratoire de Biochimie Génétique, CNRS UPR-9008, CRBM U249 and GREPAM, Institut de Biologie, Bd Henri IV, Montpellier, France Tel.: +33-67-60-95-06; Fax: +33-67-60-11-81, FR;(2) Institut de Recerca Oncologica, Hospital Duran i Reynals, Autovia de Castelldefels km2.7, E-08907 Barcelona, Catalunya, Spain, ES |
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Abstract: | In order to contribute to a better understanding of the dispersion of cystic fibrosis (CF) mutations in the South of France,
seven diallelic and three multiallelic markers three upstream of the cystic fibrosis transmembrane conductance regulator
(CFTR) gene (XV-2c, KM.19 and J44) and seven intragenic polymorphisms (IVS6A, IVS8CA, M470V, T854T, IVS17BTA, IVS17BCA and TUB18)]
were analyzed for 143 ΔF508 chromosomes, 100 CF chromosomes carrying 85 non-ΔF508 and 15 unknown mutations, and 198 normal
CFTR alleles. The study provides haplotypic data for 39 different CF mutations, which should be useful in diagnosis by haplotypic
analysis and detection of the associated mutations. A major haplotype 2-1-2-7-16-2-1-(30/31)-13-1] was found in normal chromosomes,
which should be the most ancient in the Caucasoid population. The most frequent haplotypes in normal chromosomes were associated
with 16 different non-ΔF508 mutations, suggesting that there was no preferential haplotype on which these mutations arose.
Several mutations were each associated with more than one haplotype, as the result of slippage at one or two of the three
microsatellites (ΔF508, G542X, N1303K, G85E, E585X, K710X and 2184delA) or recombination (1717-1G→A, R334W, L206W, R1162X
and Y122X). Haplotypes for the most common CFTR mutations (ΔF508, G542X, N1303K) revealed that a large number of alleles were generated by slippage at the microsatellite
loci, suggesting that they are the most ancient CF mutations. Other mutations were associated with haplotypes that were different
either at several diallelic sites (R334W) or at both diallelic and microsatellite markers (R1162X and R1158X), which is more
suggestive of recurrence. Twenty recombinations were detected among the CF mutant alleles analyzed, 75% of them occurring
in the second half of the CFTR gene. The higher mutational heterogeneity and the haplotypic variability reported in this small population from the Mediterranean
area are consistent with an earlier appearance of CFTR mutations in southern Europe than in central and northern Europe, and an earlier origin and expansion of this population.
Received: 19 February 1996 / Revised: 10 April 1996 |
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