Could a defective epithelial sodium channel lead to bronchiectasis |
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Authors: | Isabelle Fajac Marion Viel Sébastien Sublemontier Dominique Hubert Thierry Bienvenu |
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Affiliation: | 1.Service d''Explorations Fonctionnelles, AP-HP, Hôpital Cochin, Paris, France;2.Université Paris Descartes, UPRES EA 2511, Faculté de Médecine, Paris, France;3.Laboratoire de Biochimie et Génétique Moléculaires, AP-HP, Hôpital Cochin, Paris, France;4.Service de Pneumologie, AP-HP, Hôpital Cochin, Paris, France;5.Université Paris Descartes, Institut Cochin, CNRS (UMR 8104), Paris, France;6.Inserm U567, Paris, France |
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Abstract: | BackgroundBronchiectasis 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 ENaCβ 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.MethodsWe extensively analysed ENaCβ and γ 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.ResultsSequencing of the exons and flanking introns of the ENaCβ and γ gene identified five different amino-acid changes (p.Ser82Cys, p.Pro369Thr, p.Asn288Ser in ENaCβ ; and p.Gly183Ser, p.Glu197Lys in ENaCγ) 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.ConclusionOur results suggest that several variants in ENaCβ and γ genes might be deleterious for ENaC function and lead to bronchiectasis, especially in patients who are trans-heterozygotes for ENaCβ/CFTR mutations or variants. |
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