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.

Torsades De Pointes Electrical Storm Induced by H1N1 in a Patient with KCNH2 Variant of Unknown Significance

“…Recognizing the genetic substrate underlying the inherited arrhythmia syndromes has remarkably improved the field of the molecular basis of cardiac electrophysiology, including arrhythmia mechanism and the role of the different ion channels [ 2 , 3 ]. Genotype-phenotype study relationships, performed mainly for the LQTS, have uncovered the importance of genetic aspects of disease and proved that the patient's management should consider the nature of the gene affected.…”

“…These genetic disorders include the LQTS, SQTS, catecholaminergic polymorphic ventricular tachycardia, idiopathic atrial fibrillation, and Brugada syndrome. One of these channels is the potassium channels that are the primary contributors to the repolarization process, which appeared to underlie LQTS in case of dysfunction especially when mutations in genes encoding for pore-forming α -subunits (KCNQ1, KCNH2) of these channels are detected [ 2 , 3 ]. KCNH2 (potassium voltage-gated channel subfamily H member 2), one of many genes, reported having a refractory fever-induced TdP and VF in two related LQT2 patients with the A558P mutation in KCNH2.…”

Role of Nuclear Lamin A/C in the Regulation of Nav1.5 Channel and Microtubules: Lesson From the Pathogenic Lamin A/C Variant Q517X

“…Nav1.5 GFP-tagged and β 1 subunit constructs were kindly provided by Paola Imbrici from Department of Pharmacy-Drug Sciences, University of Bari, Italy. GFP-tagged KCNH2 encoding plasmid was previously characterized by us ( De Zio et al, 2019 ).…”

“…Electrophysiology on KCNH2-expressing HEK293 cells was conducted as previously described ( De Zio et al, 2019 ).…”

KCNH2 Regulates the Growth and Metastasis of Pancreatic Cancer

“…KCNH2 is expressed in many tissues, including the heart and the brain. Previous evidence has demonstrated that KCNH2 plays an important role in the repolarization of the heart [9]. Recent ndings have also revealed that KCNH2 is also overexpressed in ductal, lobular, and invasive breast carcinomas [10].…”