Abstract 639: Destabilization Of The Open State Of IKs Potassium Channels By A KCNQ1 V205M Missense Mutation Causes An Inherited Form Of LQTS In A Canadian Aboriginal Community
Hereditary long QT syndrome (LQTS) is a genetic disease characterized by a prolonged QT interval in the electrocardiogram and an increased likelihood of serious ventricular arrhythmias. We have determined that LQTS is disproportionately prevalent in a Northern British Columbia aboriginal community. Genetic screening of affected individuals revealed a novel missense mutation (V205M) in the S3 transmembrane helix of KCNQ1, the pore forming domain of the IKs channel complex. Co-expression of V205M KCNQ1 in mammalian cells with the accessory subunit KCNE1 recapitulated IKs, with similar surface expression to wild type (Wt) channels, but with a 33.7 mV depolarizing shift in the V1/2 of activation. This was accompanied by a slowing of channel activation (294 ± 85 ms, n=5; and 878 ± 124 ms, n=4; for Wt and V205M channels, respectively, at +70 mV), and an acceleration of deactivation (53 ± 3.6 ms, n=5; and 14 ± 3.5, n=4; for Wt and V205M channels, at −100 mV), determined at 35°C. The heterozygous state of the channel complex was simulated by co-expressing Wt and V205M channel subunits, and this resulted in phenotypic IKs currents with properties intermediate between Wt and V205M homomultimeric channels. Using a ventricular action potential voltage clamp protocol applied at 3 Hz, Wt channels, but not V205M channels, accumulated in the open state, which resulted in large outward IKs currents only for Wt channels. The outward ionic charge through heteromultimeric channels during the action potential clamp was reduced by more than 75% compared to Wt channels, suggesting a functional dominant negative effect of the V205M mutation at high heart rates. The changes in IKs kinetics produced by the V205M mutation are expected to decrease current and reduce the repolarization reserve during the cardiac ventricular action potential, with a likely increased susceptibility to the initiation of arrhythmias, especially during periods of high sympathetic drive.