| Functional characterization of a partial loss-of-function mutation of the epithelial sodium channel (ENaC) associated with atypical cystic fibrosis. | |
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MedLine Citation:
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PMID: 20054153 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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 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. |
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Authors:
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Regina Huber; Bettina Krueger; Alexei Diakov; Judit Korbmacher; Silke Haerteis; J?rgen Einsiedel; Peter Gmeiner; Abul Kalam Azad; Harry Cuppens; Jean-Jaques Cassiman; Christoph Korbmacher; Robert Rauh |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2009-12-22 |
Journal Detail:
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Title: Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology Volume: 25 ISSN: 1421-9778 ISO Abbreviation: Cell. Physiol. Biochem. Publication Date: 2010 |
Date Detail:
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Created Date: 2010-01-07 Completed Date: 2010-02-25 Revised Date: 2010-04-15 |
Medline Journal Info:
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Nlm Unique ID: 9113221 Medline TA: Cell Physiol Biochem Country: Switzerland |
Other Details:
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Languages: eng Pagination: 145-58 Citation Subset: IM |
Copyright Information:
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2010 S. Karger AG, Basel |
Affiliation:
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Institut f?r Zellul?re und Molekulare Physiologie, Erlangen, Germany. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Chymotrypsin / metabolism Cystic Fibrosis / genetics*, metabolism Epithelial Sodium Channel / analysis, genetics*, metabolism* Female Gene Expression Humans Mutation* Oocytes / metabolism Sodium / metabolism Xenopus laevis |
| Chemical | |
Reg. No./Substance:
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0/Epithelial Sodium Channel; 7440-23-5/Sodium; EC 3.4.21.1/Chymotrypsin |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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