© 2001 by European Society of Cardiology
Copyright © 2001, European Society of Cardiology
Transgenic mice overexpressing human KvLQT1 dominant-negative isoform Part I: Phenotypic characterisation
aINSERM U533, Laboratoire de Physiopathologie et de Pharmacologie Cellulaires et Moléculaires G & R Laennec, Faculté de Médecine, 1 rue Gaston Veil, 44035 Nantes cedex 01, France
bExperimental and Molecular Cardiology Group, and Facility for Genetically Modified Mice, Academic Medical Center, Amsterdam, The Netherlands
cHMR, Romainville, France
* Corresponding author. Tel.: +33-2-4041-2949; fax: +33-2-4041-2950 denis.escande{at}nantes.inserm.fr
Objectives: The KCNQ1 gene encodes the KvLQT1 potassium channel, which generates in the human heart the slow component of the cardiac delayed rectifier current, IKs. Mutations in KCNQ1 are the most frequent cause of the congenital long QT syndrome. We have previously cloned a cardiac KCNQ1 human isoform, which exerts a strong dominant-negative effect on KvLQT1 channels. We took advantage of this dominant-negative isoform to engineer an in vivo model of KvLQT1 disruption, obtained by overexpressing the dominant-negative subunit under the control of the 
-myosin heavy chain promoter. Results: Three different transgenic lines demonstrated a phenotype with increasing severity. Functional suppression of KvLQT1 in transgenic mice led to a markedly prolonged QT interval associated with sinus node dysfunction. Transgenic mice also demonstrated atrio-ventricular block leading to occasional Wenckebach phenomenon. The atrio-ventricular block was associated with prolonged AH but normal HV interval in His recordings. Prolonged QT interval correlated with prolonged action potential duration and with reduced K+ current density in patch-clamp experiments. RNase protection assay revealed remodeling of K+ channel expression in transgenic mice. Conclusions: Our transgenic mouse model suggests a role for KvLQT1 channels not only in the mouse cardiac repolarisation but also in the sinus node automaticity and in the propagation of the impulse through the AV node.
KEYWORDS Antiarrhythmic agents; Congenital defects; ECG; K-channel; Long QT syndrome; Repolarisation
1 S. Demolombe held a post-doctoral position at the Academic Medical Center.
2 Present address: Department of Medical Physiology and Sports Medicine, University of Utrecht, The Netherlands.
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