Mutations in the amiloride-sensitive epithelial sodium channel in patients with cystic fibrosis-like disease

Abul Kalam Azad, Robert Rauh, François Vermeulen, Martine Jaspers, Judit Korbmacher, Brigitte Boissier, Laurence Bassinet, Yann Fichou, Marie Des Georges, Frauke Stanke, Kris De Boeck, Lieven Dupont, Miroslava Balaščáková, Lena Hjelte, Patrick Lebecque, Dragica Radojkovic, Carlo Castellani, Marianne Schwartz, Manfred Stuhrmann, Martin SchwarzVeronika Skalicka, Isabelle De Monestrol, Emmanuelle Girodon, Claude Férec, Mireille Claustres, Burkhard Tümmler, Jean Jacques Cassiman, Christoph Korbmacher, Harry Cuppens

Research output: Contribution to journalArticlepeer-review

74 Scopus citations


We investigated whether mutations in the genes that code for the different subunits of the amiloride-sensitive epithelial sodium channel (ENaC) might result in cystic fibrosis (CF)-like disease. In a small fraction of the patients, the disease could be potentially explained by an ENaC mutation by a Mendelian mechanism, such as p.V114I and p.F61L in SCNN1A. More importantly, a more than three-fold significant increase in incidence of several rare ENaC polymorphisms was found in the patient group (30% vs. 9% in controls), indicating an involvement of ENaC in some patients by a polygenetic mechanism. Specifically, a significantly higher number of patients carried c.-5515G > C or p.W493R in SCNN1A in the heterozygous state, with odds ratios (ORs) of 13.5 and 2.7, respectively. The p.W493R-SCNN1A polymorphism was even found to result in a four-fold more active ENaC channel when heterologously expressed in Xenopus laevis oocytes. About 1 in 975 individuals in the general population will be heterozygous for the hyperactive p.W493R-SCNN1A mutation and a cystic fibrosis transmembrane conductance regulator (CFTR) gene that results in very low amounts (0-10%) functional CFTR. These ENaC/CFTR genotypes may play a hitherto unrecognized role in lung diseases.

Original languageEnglish (US)
Pages (from-to)1093-1103
Number of pages11
JournalHuman Mutation
Issue number7
StatePublished - Jul 2009
Externally publishedYes


  • CF
  • CFTR
  • ENaC
  • SCNN1A

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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