Mutation in the KCNQ1 gene leading to the short QT-interval syndrome.

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 I(Ks). 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.

journal_name

Circulation

journal_title

Circulation

authors

Bellocq C,van Ginneken AC,Bezzina CR,Alders M,Escande D,Mannens MM,Baró I,Wilde AA

doi

10.1161/01.CIR.0000130409.72142.FE

subject

Has Abstract

pub_date

2004-05-25 00:00:00

pages

2394-7

issue

20

eissn

0009-7322

issn

1524-4539

pii

109/20/2394

journal_volume

109

pub_type

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