Aims: 

Atrial fibrillation (AF) and long-QT syndrome (LQTS) are two cardiac arrhythmia diseases that have both been related to dysfunction of the voltage-gated potassium channel subunit Kv7.1 encoded by the KCNQ1 gene. The purpose of this study was the functional assessment of a mutation in Kv7.1 identified in a proband with permanent AF and prolonged QT-interval. We investigated if this KCNQ1 missense mutation can form the genetic basis for both conditions in the patient simultaneously.

Methods: 

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.

Results: 

The Q147R mutation does not affect the biophysical properties of Kv7.1 in the absence of accessory subunits. Upon co-expression with the b-subunit KCNE1 the Q147R mutation induced a loss-of-function observed as a decrease in the current amplitude at depolarized potentials. Additionally, Q147R abolished the frequency-dependence of charge carried by Kv7.1/KCNE1 channels. Co-expression with the b-subunit KCNE2 revealed a gain-of-function for the mutant evidenced 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.

Conclusion: 

Our data indicate that this particular mutation can form the molecular substrate for different arrhythmogenic conditions simultaneously. We suggest the mechanism to be due to heterogeneous distribution of Kv7.1 accessory subunits in the heart leading to Kv7.1 gain-of-function in the atria (AF) and Kv7.1 loss-of-function in the ventricles (QT-prolongation).