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

Dagmar Keller 1, 2 Julie Grenier 3 Georges Christé 4 Frédérique Dubouloz 1 Stephan Osswald 2 Marijke Brink 1 Eckhard Ficker 5 Mohamed Chahine 3, *
* Auteur correspondant
1 Cardiobiology Research Laboratories
2 Cardiology Department
3 CRULRG - Centre de recherche Université Laval Robert Giffard
4 INSERM - Administration Déléguée Régionale Lyon
5 Case Western Reserve University [Cleveland]
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.
Keywords : Long QT Syndrome type 2 sudden cardiac death seizure KCNH2 potassium loss of IKr channel function
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Article dans une revue
Canadian Journal of Cardiology, Elsevier, 2009, 25 (8), pp.455-62
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Soumis le : mercredi 21 mai 2014 - 09:12:00
Dernière modification le : mercredi 10 janvier 2018 - 14:18:57
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Dagmar Keller, Julie Grenier, Georges Christé, Frédérique Dubouloz, Stephan Osswald, et al.. Characterization of novel KCNH2 mutations in type 2 long QT syndrome manifesting as seizures.: Characterizing novel KCNH2 mutations. Canadian Journal of Cardiology, Elsevier, 2009, 25 (8), pp.455-62. 〈inserm-00409709〉

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