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Characterization of novel KCNH2 mutations in type 2 long QT syndrome manifesting as seizures

Keller, Dagmar I. and Grenier, Julie and Christé, Georges and Dubouloz, Frédérique and Osswald, Stefan and Brink, Marijke and Ficker, Eckhard and Chahine, Mohamed. (2009) Characterization of novel KCNH2 mutations in type 2 long QT syndrome manifesting as seizures. The Canadian journal of cardiology = Journal canadien de cardiologie, Vol. 25. pp. 455-462.

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Official URL: http://edoc.unibas.ch/dok/A6004370

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Abstract

BACKGROUND: Long QT syndrome (LQTS) is characterized by corrected QT interval prolongation leading to torsades de pointes and sudden cardiac death. LQTS type 2 (LQTS2) is caused by mutations in the KCNH2 gene, leading to a reduction of the rapidly activating delayed rectifier K+ current and loss of human ether-à-go-go-related gene (hERG) channel function by different mechanisms. Triggers for life-threatening arrhythmias in LQTS2 are often auditory stimuli. OBJECTIVES: To screen KCNH2 for mutations in patients with LQTS2 on an electrocardiogram and auditory-induced syncope interpreted as seizures and sudden cardiac death, and to analyze their impact on the channel function in vitro. METHODS: The KCNH2 gene was screened for mutations in the index patients of three families. The novel mutations were reproduced in vitro using site-directed mutagenesis and characterized using the Xenopus oocyte expression system in voltage clamp mode. RESULTS: Novel KCNH2 mutations (Y493F, A429P and del234-241) were identified in the index patients with mostly typical LQTS2 features on their electrocardiograms. The biochemical data revealed a trafficking defect. The biophysical data revealed a loss of function when mutated hERG channels were coexpressed with the wild type. CONCLUSIONS: In all families, at least one patient carrying the mutation had a history of seizures after auditory stimuli, which is a major trigger for arrhythmic events in LQTS2. Seizures are likely due to cardiac syncope as a consequence of mutation-induced loss of function of the rapidly activating delayed rectifier K+ current.
Faculties and Departments:03 Faculty of Medicine > Bereich Medizinische Fächer (Klinik) > Kardiologie > Kardiologie Elektrophysiologie (Osswald)
03 Faculty of Medicine > Departement Klinische Forschung > Bereich Medizinische Fächer (Klinik) > Kardiologie > Kardiologie Elektrophysiologie (Osswald)
03 Faculty of Medicine > Departement Biomedizin > Division of Physiology > CardioBiology (Brink)
UniBasel Contributors:Osswald, Stefan and Brink, Marijke and Keller, Dagmar Iris
Item Type:Article, refereed
Article Subtype:Research Article
Bibsysno:Link to catalogue
Publisher:Pulsus
ISSN:0828-282X
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:24 May 2013 09:22
Deposited On:24 May 2013 09:02

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