Heart Rhythm 2007 Dec 01;412:1532-41. doi: 10.1016/j.hrthm.2007.07.022.

KCNQ1 mutation Q147R is associated with atrial fibrillation and prolonged QT interval.

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Atrial fibrillation (AF) and long QT syndrome (LQTS) are cardiac arrhythmia disorders that have been related to dysfunction of the voltage-gated potassium channel subunit Kv7.1 encoded by the KCNQ1 gene. The purpose of this study was functional assessment of a mutation in Kv7.1 identified in a proband with permanent AF and prolonged QT interval. We investigated whether this KCNQ1 missense mutation could form the genetic basis for AF and LQTS simultaneously in this patient. We investigated the functional consequences of the novel mutation KCNQ1 Q147R by heterologous expression of the channel and accessory subunits in Xenopus laevis oocytes and mammalian cells. The Q147R mutation does not affect the biophysical properties of Kv7.1 in the absence of accessory subunits. Upon coexpression with the beta-subunit KCNE1, the Q147R mutation induced a loss of function, observed as a decrease in current amplitude at depolarized potentials. Additionally, Q147R abolished the frequency dependence of charge carried by Kv7.1/KCNE1 channels. Coexpression with the beta-subunit KCNE2 revealed a gain of function for the mutant, seen as an increase in the current amplitude at depolarized potentials. The properties of channels formed by Kv7.1 and the subunits KCNE3 and KCNE4 were unaffected by the Q147R mutation. Our data indicate that the Q147R mutation can form the molecular substrate simultaneously for different arrhythmogenic conditions. The mechanism may be heterogeneous distribution of Kv7.1 accessory subunits in the heart leading to Kv7.1 gain of function in the atria (for AF) and Kv7.1 loss of function in the ventricles (for QT prolongation).

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Species referenced: Xenopus laevis
Genes referenced: kcne1 kcne2 kcne3 kcne4 kcnq1

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