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A novel missense mutation causing a G487R substitution in the S2-S3 loop of human ether-à-go-go-related gene channel.

Abstract：

INTRODUCTION:Mutations of human ether-à-go-go-related gene (hERG), which encodes a cardiac K(+) channel responsible for the acceleration of the repolarizing phase of an action potential and the prevention of premature action potential regeneration, often cause severe arrhythmic disorders. We found a novel missense mutation of hERG that results in a G487R substitution in the S2-S3 loop of the channel subunit [hERG(G487R)] from a family and determined whether this mutant gene could induce an abnormality in channel function. METHODS AND RESULTS:We made whole-cell voltage-clamp recordings from HEK-293T cells transfected with wild-type hERG [hERG(WT)], hERG(G487R), or both. We measured hERG channel-mediated current as the "tail" of a depolarization-elicited current. The current density of the tail current and its voltage- and time-dependences were not different among all the cell groups. The time-courses of deactivation, inactivation, and recovery from inactivation and their voltage-dependences were not different among all the cell groups. Furthermore, we performed immunocytochemical analysis using an anti-hERG subunit antibody. The ratio of the immunoreactivity of the plasma membrane to that of the cytoplasm was not different between cells transfected with hERG(WT), hERG(G487R), or both. CONCLUSION: hERG(G487R) can produce functional channels with normal gating kinetics and cell-surface expression efficiency with or without the aid of hERG(WT). Therefore, neither the heterozygous nor homozygous inheritance of hERG(G487R) is thought to cause severe cardiac disorders. hERG(G487R) would be a candidate for a rare variant or polymorphism of hERG with an amino acid substitution in the unusual region of the channel subunit.

journal_name

J Cardiovasc Electrophysiol

journal_title

Journal of cardiovascular electrophysiology

authors

Kinoshita K,Yamaguchi Y,Nishide K,Kimoto K,Nonobe Y,Fujita A,Asano K,Tabata T,Mori H,Inoue H,Hata Y,Fukurotani K,Nishida N

doi

10.1111/j.1540-8167.2012.02383.x

subject

Has Abstract

pub_date

2012-11-01 00:00:00

pages

1246-53

issue

eissn

1045-3873

issn

1540-8167

journal_volume

pub_type

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A novel missense mutation causing a G487R substitution in the S2-S3 loop of human ether-à-go-go-related gene channel.