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


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.
Bellocq
Chloé
C
Laboratoire de Physiopathologie et de Pharmacologie Cellulaires et Moléculaires, INSERM U533, Hôtel-Dieu, Nantes, France.
van Ginneken
Antoni C G
AC
Bezzina
Connie R
CR
Alders
Mariel
M
Escande
Denis
D
Mannens
Marcel M A M
MM
Baró
Isabelle
I
Wilde
Arthur A M
AA
D000368:Aged; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D004553:Electric Conductivity; D004562:Electrocardiography; D006801:Humans; D051656:KCNQ Potassium Channels; D051657:KCNQ1 Potassium Channel; D008297:Male; D009154:Mutation; D015221:Potassium Channels / Q000235:genetics* / Q000378:metabolism; D024642:Potassium Channels, Voltage-Gated; D013577:Syndrome; D014693:Ventricular Fibrillation / Q000175:diagnosis / Q000235:genetics*
D051656:KCNQ Potassium Channels; D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated