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.
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Acknowledgements
This work was supported by grants from the Institut National de la Santé et de la Recherche Médicale (INSERM), the Centre National de la Recherche Scientifique (CNRS) and the French association, Vaincre la Mucoviscidose. The authors are grateful to Régis Labarthe.
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Clain, J., Lehmann-Che, J., Girodon, E. et al. A neutral variant involved in a complex CFTR allele contributes to a severe cystic fibrosis phenotype. Hum Genet 116, 454–460 (2005). https://doi.org/10.1007/s00439-004-1246-z
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DOI: https://doi.org/10.1007/s00439-004-1246-z