Functional Characterization of a Partial Loss-of-Function Mutation of the Epithelial Sodium Channel (ENaC) Associated with Atypical Cystic FibrosisHuber R.1 · Krueger B.1 · Diakov A.1 · Korbmacher J.1 · Haerteis S.1 · Einsiedel J.2 · Gmeiner P.2 · Azad A.K.3 · Cuppens H.3 · Cassiman J.-J.3 · Korbmacher C.1 · Rauh R.1
1Institut für Zelluläre und Molekulare Physiologie and2Department Chemie und Pharmazie, Emil Fischer Centrum, Universität Erlangen-Nürnberg,3Center of Human Genetics, KU Leuven
Prof. Dr. med. Christoph Korbmacher
Institut für Zelluläre und Molekulare Physiologie
Waldstr. 6, D-91054 Erlangen (Germany)
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Loss-of-function mutations of the epithelial sodium channel (ENaC) may contribute to pulmonary symptoms resembling those of patients with atypical cystic fibrosis (CF). Recently, we identified a loss-of-function mutation in the α-subunit of ENaC (αF61L) in an atypical CF patient without mutations in CFTR. To investigate the functional effect of this mutation, we expressed human wild-type αβγ-ENaC or mutant α F61Lβγ-ENaC in Xenopus laevis oocytes. The αF61L mutation reduced the ENaC mediated whole-cell currents by ñ90%. In contrast, the mutation decreased channel surface expression only by ñ40% and did not alter the single-channel conductance. These findings indicate that the major effect of the mutation is a reduction of the average channel open probability (Po). This was confirmed by experiments using the βS520C mutant ENaC which can be converted to a channel with a Po of nearly one, and by experiments using chymotrypsin to proteolytically activate the channel. These experiments revealed that the mutation reduced the average Po of ENaC by ñ75%. Na+ self inhibition of the mutant channel was significantly enhanced, but the observed effect was too small to account for the large reduction in average channel Po. The ENaC-activator S3969 partially rescued the loss-of-function phenotype of the αF61L mutation. We conclude that the αF61L mutation may contribute to respiratory symptoms in atypical CF patients.
© 2010 S. Karger AG, Basel
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