Key result
KCNH2 activator NS1643 partially restores delayed activation caused by dominant-negative G1006fs/49 mutation.
Why the study?
The study aimed to characterize the biophysical properties of G1006fs/49, a C-terminus-truncated KCNH2 channel causing long QT syndrome type II in heterozygous members of an Italian family.
The G1006fs/49 mutation causes LQT2 via a dominant-negative electrophysiological effect that can be partially rescued in vitro by the KCNH2 activator NS1643, suggesting a potential mutation-specific pharmacological strategy.
Partial NS1643 rescue of dominant-negative KCNH2 effects in vitro; hypothesis-generating for mutation-specific LQT2 therapies.
current. The aim of this study was to characterize the biophysical properties of a C-terminus-truncated KCNH2 channel, G1006fs/49 causing long QT syndrome type II in heterozygous members of an Italian family. Mutant carriers underwent clinical workup, including 12-lead electrocardiogram, transthoracic echocardiography and 24-hour ECG recording. Electrophysiological experiments compared the biophysical properties of G1006fs/49 with those of KCNH2 both expressed either as homotetramers or as heterotetramers in HEK293 cells. Major findings of this work are as follows: (a) G1006fs/49 is functional at the plasma membrane even when co-expressed with KCNH2, (b) G1006fs/49 exerts a dominant-negative effect on KCNH2 conferring specific biophysical properties to the heterotetrameric channel such as a significant delay in the voltage-sensitive transition to the open state, faster kinetics of both inactivation and recovery from the inactivation and (c) the activation kinetics of the G1006fs/49 heterotetrameric channels is partially restored by a specific KCNH2 activator. The functional characterization of G1006fs/49 homo/heterotetramers provided crucial findings about the pathogenesis of LQTS type II in the mutant carriers, thus providing a new and potential pharmacological strategy.
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Zio et al. (2019) studied Long QT syndrome type II (n=5). G1006fs/49 mutation vs. Wild-type KCNH2 was evaluated on Electrophysiological properties of the channel. The G1006fs/49 mutant channel exerted a dominant-negative effect on wild-type KCNH2, causing delayed activation that was partially restored by the activator NS1643.
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