title: A neutral variant involved in a complex CFTR allele contributes to a severe cystic fibrosis phenotype.
abstract: In order to further elucidate the contribution of complex alleles to the wide phenotypic variability of cystic fibrosis (CF), we investigated the structure-function relationships of a severe CF-associated complex allele [p.S912L;p.G1244V]. To evaluate the contribution of each mutation to the phenotype, cystic fibrosis transmembrane conductance regulator (CFTR) mutants were expressed in HeLa cells and analysed for protein processing and Cl- channel activity. Both p.G1244V and [p.S912L;p.G1244V] mutants had normal protein processing but markedly decreased Cl- channel activity compared with wild-type. Notably, the double mutant displayed a dramatic decrease in Cl- channel activity compared with p.G1244V (P<0.001). p.S912L had normal protein processing and no detectable impact on CFTR function. In other respects, the p.S912L variation was identified in compound heterozygosity with p.R709X in a healthy fertile man. Together, these data strongly support the view that p.S912L in isolation should be considered as a neutral variant but one that might significantly impair CFTR function when inherited in cis with another CFTR mutation. Our data also further document the contribution of complex alleles to the wide phenotypic variability of CF. The results of functional studies of such complex alleles in other genetic diseases are discussed.
authors.affiliation: Service de Biochimie et Génétique, Hôpital Henri Mondor, Institut National de la Santé et de la Recherche Médicale U.468, AP-HP, 94010, Créteil, France.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Clain
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Lehmann-Che
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Girodon
authors.forename: Joanna
authors.initials: J
authors.lastname: Lipecka
authors.forename: Aleksander
authors.initials: A
authors.lastname: Edelman
authors.forename: Michel
authors.initials: M
authors.lastname: Goossens
authors.forename: Pascale
authors.initials: P
authors.lastname: Fanen
mesh_terms: D000483:Alleles; D018118:Chloride Channels / Q000378:metabolism; D003550:Cystic Fibrosis / Q000235:genetics*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics*; D005808:Genes, Recessive; D014644:Genetic Variation; D006367:HeLa Cells; D006801:Humans; D009154:Mutation; D010641:Phenotype; D011110:Polymorphism, Genetic
chemical_list: C505032:CFTR protein, human; D018118:Chloride Channels; D019005:Cystic Fibrosis Transmembrane Conductance Regulator
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