Functional characterization of a partial loss-of-function mutation of the epithelial sodium channel (ENaC) associated with atypical cystic fibrosis

Huber R, Krüger B, Diakov A, Korbmacher J, Härteis S, Einsiedel J, Gmeiner P, Azad AK, Cuppens H, Cassiman JJ, Korbmacher C, Rauh R (2010)

Publication Type: Journal article, Original article

Publication year: 2010

Journal

Original Authors: Huber R., Krueger B., Diakov A., Korbmacher J., Haerteis S., Einsiedel J., Gmeiner P., Azad A., Cuppens H., Cassiman J.-J., Korbmacher C., Rauh R.

Publisher: Karger

Book Volume: 25

Pages Range: 145-158

Journal Issue: 1

DOI: 10.1159/000272059

Abstract

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 βγ-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 (P ). This was confirmed by experiments using the βS520C mutant ENaC which can be converted to a channel with a P of nearly one, and by experiments using chymotrypsin to proteolytically activate the channel. These experiments revealed that the mutation reduced the average P 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 P . 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. Copyright © 2010 S. Karger AG, Basel.

Authors with CRIS profile

Involved external institutions

Katholieke Universiteit Leuven (KUL) / Catholic University of Leuven Belgium (BE)

How to cite

APA:

Huber, R., Krüger, B., Diakov, A., Korbmacher, J., Härteis, S., Einsiedel, J.,... Rauh, R. (2010). Functional characterization of a partial loss-of-function mutation of the epithelial sodium channel (ENaC) associated with atypical cystic fibrosis. Cellular Physiology and Biochemistry, 25(1), 145-158. https://doi.org/10.1159/000272059

MLA:

Huber, Regina, et al. "Functional characterization of a partial loss-of-function mutation of the epithelial sodium channel (ENaC) associated with atypical cystic fibrosis." Cellular Physiology and Biochemistry 25.1 (2010): 145-158.

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