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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

Authors


  • This work was partly supported by a KAKENHI grant from MEXT, Japan, to Dr. Tabata (#23500384).

  • No disclosures.

Toshihide Tabata, M.S., Ph.D., Laboratory for Neural Information Technology, Graduate School of Sciences and Engineering, University of Toyama, 3190 Gofuku, Toyama, Toyama 930-8555, Japan. Fax: 81-76-445-6703; E-mail: ttabata@eng.u-toyama.ac.jp

Abstract

hERG(G487R) ChannelIntroduction: 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. (J Cardiovasc Electrophysiol, Vol. 23, pp. 1246–1253, November 2012)

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