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CFTR mutation combinations producing frequent complex alleles with different clinical and functional outcomes
Author(s) -
ElSeedy Ayman,
Girodon Emmanuelle,
Norez Caroline,
Pajaud Julie,
Pasquet MarieClaude,
de Becdelièvre Alix,
Bienvenu Thierry,
des Georges Marie,
Cabet Faïza,
Lalau Guy,
Bieth Eric,
Blayau Martine,
Becq Frédéric,
Kitzis Alain,
Fanen Pascale,
Ladeveze Véronique
Publication year - 2012
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.22129
Subject(s) - biology , phenotype , allele , cystic fibrosis transmembrane conductance regulator , genotype , mutant , genetics , mutation , cystic fibrosis , gene , rna splicing , rna
Abstract Genotype–phenotype correlations in cystic fibrosis (CF) may be difficult to establish because of phenotype variability, which is associated with certain CF transmembrane conductance regulator ( CFTR ) gene mutations and the existence of complex alleles. To elucidate the clinical significance of complex alleles involving p.Gly149Arg, p.Asp443Tyr, p.Gly576Ala, and p.Arg668Cys, we performed a collaborative genotype–phenotype correlation study, collected epidemiological data, and investigated structure–function relationships for single and natural complex mutants, p.[Gly576Ala;Arg668Cys], p.[Gly149Arg;Gly576Ala;Arg668Cys], and p.[Asp443Tyr;Gly576Ala;Arg668Cys]. Among 153 patients carrying at least one of these mutations, only three had classical CF and all carried p.Gly149Arg in the triple mutant. Sixty‐four had isolated infertility and seven were healthy individuals with a severe mutation in trans, but none had p.Gly149Arg. Functional studies performed on all single and natural complex mutants showed that (1) p.Gly149Arg results in a severe misprocessing defect; (2) p.Asp443Tyr moderately alters CFTR maturation; and (3) p.Gly576Ala, a known splicing mutant, and p.Arg668Cys mildly alter CFTR chloride conductance. Overall, the results consistently show the contribution of p.Gly149Arg to the CF phenotype, and suggest that p.[Arg668Cys], p.[Gly576Ala;Arg668Cys], and p.[Asp443Tyr;Gly576Ala;Arg668Cys] are associated with CFTR‐related disorders. The present study emphasizes the importance of comprehensive genotype–phenotype and functional studies in elucidating the impact of mutations on clinical phenotype. Hum Mutat 33:1557–1565, 2012. © 2012 Wiley Periodicals, Inc.