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Functional study of a KCNH2 mutant: Novel insights on the pathogenesis of the LQT2 syndrome.

ABSTRACT: The K⁺ voltage-gated channel subfamily H member 2 (KCNH2) transports the rapid component of the cardiac delayed rectifying K⁺ 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.

SUBMITTER: De Zio R

PROVIDER: S-EPMC6714209 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Functional study of a KCNH2 mutant: Novel insights on the pathogenesis of the LQT2 syndrome.

De Zio Roberta R Gerbino Andrea A Forleo Cinzia C Pepe Martino M Milano Serena S Favale Stefano S Procino Giuseppe G Svelto Maria M Carmosino Monica M

Journal of cellular and molecular medicine 20190730 9

The K<sup>+</sup> voltage-gated channel subfamily H member 2 (KCNH2) transports the rapid component of the cardiac delayed rectifying K<sup>+</sup> 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. Elect ...[more]

PMID: 31361068

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Functional study of a KCNH2 mutant: Novel insights on the pathogenesis of the LQT2 syndrome.

Publications

Functional study of a KCNH2 mutant: Novel insights on the pathogenesis of the LQT2 syndrome.

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