Role of the R1135H KCNH2 mutation in Brugada syndrome

Abstract

Recently, a novel mutation, R1135H, in KCNH2, the gene encoding the α-subunit of the rapid delayed rectifier K+ channel (IKr), has been identified in a patient with short QT interval as well as Brugada-type ECG. Voltage clamp experiments revealed larger tail currents and slowed deactivation of mutant IKr channels. We have carried out computer simulations to test the effects of the R1135H mutation on the action potential of human left and right ventricular myocytes. Our results demonstrate that this ‘gain-of-function’ mutation in KCNH2 shortens the action potential and enhances the susceptibility of right ventricular myocytes to all-or-none repolarization (epicardial loss of the action potential dome). Thus, the mutation induced changes in IKr cannot only explain the short QT interval but also the Brugada-type ECG of the patient.