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

Autor: De Zio R; Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, Bari, Italy., Gerbino A; Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, Bari, Italy., Forleo C; Cardiology Unit, Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy., Pepe M; Cardiology Unit, Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy., Milano S; Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, Bari, Italy., Favale S; Cardiology Unit, Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy., Procino G; Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, Bari, Italy., Svelto M; Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, Bari, Italy., Carmosino M; Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, Bari, Italy.; Department of Sciences, University of Basilicata, Potenza, Italy.
Jazyk: angličtina
Zdroj: Journal of cellular and molecular medicine [J Cell Mol Med] 2019 Sep; Vol. 23 (9), pp. 6331-6342. Date of Electronic Publication: 2019 Jul 30.
DOI: 10.1111/jcmm.14521
Abstrakt: 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.
(© 2019 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)
Databáze: MEDLINE
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