The G1006fs/49 KCNH2 mutation exerts a dominant-negative effect on wild-type KCNH2, altering activation and inactivation kinetics, which can be partially restored by a specific KCNH2 activator.
The G1006fs/49 KCNH2 mutation causes LQT2 via a dominant-negative effect that alters channel kinetics, which can be partially rescued by a KCNH2 activator, suggesting a potential pharmacological strategy.
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.
Zio et al. (Tue,) conducted a other in Long QT syndrome type II. G1006fs/49 KCNH2 mutation vs. Wild-type KCNH2 was evaluated on Biophysical properties of the G1006fs/49 channel. The G1006fs/49 KCNH2 mutation exerts a dominant-negative effect on wild-type KCNH2, altering activation and inactivation kinetics, which can be partially restored by a specific KCNH2 activator.
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: