Could a defective epithelial sodium channel lead to bronchiectasis.
BACKGROUND
Bronchiectasis is defined as a permanent dilation of the airways arising from chronic bronchial inflammation/infection. In 50% of cases, no etiology can be identified. Recently, the role of the epithelial sodium channel ENaC has been pointed out in the pathophysiology of cystic fibrosis, a disease due to mutations in the CFTR gene and causing bronchiectasis in the airways. Moreover, it was found that transgenic mice overexpressing ENaCbeta present cystic fibrosis-like lung disease symptoms. Our aim was to evaluate if a defective ENaC protein could be involved in the development of bronchiectasis.


METHODS
We extensively analysed ENaCbeta and gamma genes in 55 patients with idiopathic bronchiectasis and without two mutations in the coding regions of CFTR. Thirty-eight patients presented functional abnormalities suggesting impaired sodium transport (abnormal sweat chloride concentration or nasal potential difference measurement), and 17 had no such evidence.


RESULTS
Sequencing of the exons and flanking introns of the ENaCbeta and gamma gene identified five different amino-acid changes (p.Ser82Cys, p.Pro369Thr, p.Asn288Ser in ENaCbeta ; and p.Gly183Ser, p.Glu197Lys in ENaCgamma) in heterozygous state in 8 patients. The p.Ser82Cys amino-acid change was found in 3 unrelated patients who were also heterozygous for a CFTR mutation or variant (1 p.F508del, 1 IVS8-5T, and 1 IVS8-5T:1716G>A (p.E528E)). The other mutations were found in patients without CFTR mutation, the p.Glu197Lys mutation in 2 patients and the other variants in single patients. Among the 8 patients bearing an ENaC mutation, 5 had functional abnormalities suggesting impaired sodium transport.


CONCLUSIONS
Our results suggest that several variants in ENaCbeta and gamma genes might be deleterious for ENaC function and lead to bronchiectasis, especially in patients who are trans-heterozygotes for ENaCbeta/CFTR mutations or variants.
Fajac
Isabelle
I
Service d'Explorations Fonctionnelles, AP-HP, Hôpital Cochin, Paris, France. ifajac@cochin.univ-paris5.fr
Viel
Marion
M
Sublemontier
Sébastien
S
Hubert
Dominique
D
Bienvenu
Thierry
T
D000328:Adult; D000368:Aged; D001987:Bronchiectasis / Q000235:genetics*; D016022:Case-Control Studies; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics; D053503:Epithelial Sodium Channels / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D017136:Ion Transport / Q000235:genetics; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense / Q000235:genetics*; D011110:Polymorphism, Genetic / Q000235:genetics; D021122:Protein Subunits / Q000235:genetics; D012964:Sodium / Q000378:metabolism
D053503:Epithelial Sodium Channels; D021122:Protein Subunits; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D012964:Sodium