doi: 10.1161/01.CIR.0000130409.72142.FE
(Circulation. 2004;109:2394-2397.)
© 2004 American Heart Association, Inc.
Review: Special Report |
Mutation in the KCNQ1 Gene Leading to the Short QT-Interval Syndrome
From the Laboratoire de Physiopathologie et de Pharmacologie Cellulaires et Moléculaires, INSERM U533, Hôtel-Dieu, Nantes, France (C.B., D.E., I.B.), and the Experimental and Molecular Cardiology Group (A.C.G.v.G., C.R.B., A.A.M.W.) and the Department of Clinical Genetics (C.R.B., M.A., M.M.A.M.M.), Academic Medical Center, Amsterdam, and the Interuniversity Cardiology Institute (A.A.M.W.), Utrecht, the Netherlands.
Correspondence to Dr A.A.M. Wilde, Department of Clinical and Experimental Cardiology, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands. E-mail a.a.wilde{at}amc.uva.nl
Received October 17, 2003; de novo received January 15, 2004; revision received March 10, 2004; accepted March 15, 2004.
Abstract
Background— The electrocardiographic short QT-interval syndrome forms a distinct clinical entity presenting with a high rate of sudden death and exceptionally short QT intervals. The disorder has recently been linked to gain-of-function mutation in KCNH2. The present study demonstrates that this disorder is genetically heterogeneous and can also be caused by mutation in the KCNQ1 gene.
Methods and Results— A 70-year man presented with idiopathic ventricular fibrillation. Both immediately after the episode and much later, his QT interval was abnormally short without any other physical or electrophysiological anomalies. Analysis of candidate genes identified a g919c substitution in KCNQ1 encoding the K+ channel KvLQT1. Functional studies of the KvLQT1 V307L mutant (alone or coexpressed with the wild-type channel, in the presence of IsK) revealed a pronounced shift of the half-activation potential and an acceleration of the activation kinetics leading to a gain of function in IKs. When introduced in a human action potential computer model, the modified biophysical parameters predicted repolarization shortening.
Conclusions— We present an alternative molecular mechanism for the short QT-interval syndrome. Functional and computational studies of the KCNQ1 V307L mutation identified in a patient with this disorder favor the association of short QT with mutation in KCNQ1.
Key Words: death, sudden • genetics • arrhythmia • ion channels • fibrillation, ventricular
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