Title: Functional characterization of a partial loss-of-function mutation of the epithelial sodium channel (ENaC) associated with atypical cystic fibrosis
Authors: Huber, Regina ×
Krueger, Bettina
Diakov, Alexei
Korbmacher, Judit
Haerteis, Silke
Einsiedel, Jürgen
Gmeiner, Peter
Azad, Abul Kalam
Cuppens, Harry
Cassiman, Jean-Jacques
Korbmacher, Christoph
Rauh, Robert #
Issue Date: 2010
Publisher: S. Karger
Series Title: Cellular Physiology and Biochemistry vol:25 issue:1 pages:145-58
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 alpha-subunit of ENaC (alphaF61L) in an atypical CF patient without mutations in CFTR. To investigate the functional effect of this mutation, we expressed human wild-type alpha beta gamma-ENaC or mutant alpha(F61L) beta gamma-ENaC in Xenopus laevis oocytes. The alphaF61L mutation reduced the ENaC mediated whole-cell currents by approximately 90%. In contrast, the mutation decreased channel surface expression only by approximately 40% 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(o)). This was confirmed by experiments using the betaS520C mutant ENaC which can be converted to a channel with a P(o) of nearly one, and by experiments using chymotrypsin to proteolytically activate the channel. These experiments revealed that the mutation reduced the average P(o) of ENaC by approximately 75%. 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(o). The ENaC-activator S3969 partially rescued the loss-of-function phenotype of the alphaF61L mutation. We conclude that the alphaF61L mutation may contribute to respiratory symptoms in atypical CF patients.
ISSN: 1015-8987
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Clinical Genetics
Department of Human Genetics - miscellaneous
Forensic Biomedical Sciences
× corresponding author
# (joint) last author

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