ENaCβ and γ genes as modifier genes in cystic fibrosis

Background: Clinical phenotype varies among cystic fibrosis (CF) patients with identical CF transmembrane conductance regulator (CFTR) genotype, suggesting that genetic modifiers exist. Transgenic mice that overexpress SCNN1 beta present CF-like lung disease symptoms. Mutations or variants in SCNN1 beta may therefore potentially modulate the clinical phenotype in CF patients. Methods: We analysed by DHPLC SCNN1 beta and SCNN1 gamma genes in 56 patients with classical CF. Patients were classified into two groups according to their CFTR genotype and their severity: 38 patients with severe genotype and an unexpectedly mild lung phenotype, and 18 patients with mild genotype and a severe lung phenotype. Results: We found 3 patients out of 56 carrying at least one missense mutation. Two were novel (p.Thr313Met in SCNN1 beta, p.Leu481Gln in SCNN1 gamma) and two were previously described (p.Gly589Ser in SCNN1 beta and p.Val546Ileu in SCNN gamma). p.Thr313Met has been identified in a CF patient with mild genotype and severe lung phenotype suggesting that it could act in increasing ENaC activity. The three other variants have been identified in CF patients with severe genotype and mild lung phenotype suggesting that they might decrease ENaC activity. However, the function of ENaC in the nasal epithelia of these patients, evaluated by nasal potential difference measurements, did not support the fact that these variants were functional, at least in nasal epithelium. Conclusion: Our results suggest that genetic variants in ENaC beta and gamma genes do not modulate disease severity in the majority of CF patients. (C) 2007 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.