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Title: A single hERG mutation underlying a spectrum of acquired and congenital long QT syndrome phenotypes
Authors: Saenen, J. B ×
Paulussen, A. D. C
Jongbloed, R. J
Marcelis, C. L
Gilissen, R. A. H. J
Aerssens, J
Snyders, D. J
Raes, Adam #
Issue Date: Jul-2007
Publisher: Academic press ltd elsevier science ltd
Series Title: Journal of Molecular and Cellular Cardiology vol:43 issue:1 pages:63-72
Abstract: The long QT syndrome (LQTS) is a multi-factorial disorder that predisposes to life-threatening arrhythmias. Both hereditary and acquired subforms have been identified. Here, we present clinical and biophysical evidence that the hERG mutation c. 1039 C>T (p.Pro347Ser or P347S) is responsible for both the acquired and the congenital phenotype. In one case the genotype remained silent for years until the administration of several QT-prolonging drugs resulted into a full-blown phenotype, that was reversible upon cessation of these compounds. On the other hand the mutation was responsible for a symptomatic congenital LQTS in a Dutch family, displaying a substantial heterogeneity of the clinical symptoms. Biophysical characterization of the p.Pro347Ser potassium channels using whole-cell patch clamp experiments revealed a novel pathogenic mechanism of reciprocal changes in the inactivation kinetics combined with a dominant-negative reduction of the functional expression in the heterozygous situation, yielding a modest genetic predisposition for LQTS. Our data show that in the context of the multi-factorial aetiology underlying LQTS a modest reduction of the repolarizing power can give rise to a spectrum of phenotypes originating from one mutation. This observation increases the complexity of genotype-phenotype correlations in more lenient manifestations of the disease and underscores the difficulty of predicting the expressivity of the LQTS especially for mutations with a more subtle impact such as p.Pro347Ser. (C) 2007 Elsevier Inc. All rights reserved.
URI: 
ISSN: 0022-2828
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Laboratory for Biological Psychology
× corresponding author
# (joint) last author

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