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.