• Koshi Kinoshita, Hiroyuki Takahashi, Yukiko Hata, Kohki Nishide, Mario Kato, Hiroki Fujita, Sho Yoshida, Kazutaka Murai, Koichi Mizumaki, Kunihiro Nishida, Yoshiaki Yamaguchi, Masanobu Kano, Toshihide Tabata, and Naoki Nishida.
• Department of Legal Medicine, Graduate School of Medical and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama-shi, Toyama, Japan.
• Heart Rhythm. 2016 May 1; 13 (5): 1113-1120.

BackgroundBrugada syndrome (BrS) is an inherited lethal arrhythmic disorder characterized by syncope and sudden cardiac death from ventricular tachyarrhythmias. Here we identified a novel K817E mutation of SCN5A gene in a man with type 1 BrS electrocardiogram pattern using next-generation sequencing targeted for 73 cardiac disorder-related genes. SCN5A encodes the α-subunit of NaV1.5 voltage-gated Na(+) channel, and some of its mutations are linked to BrS. The proband had no mutation in any of the other arrhythmia-related genes sequenced.ObjectiveWe investigated whether the K817E mutation causes a functional change of NaV1.5 channel responsible for the BrS phenotype.MethodsWe compared the electrophysiological properties of the whole-cell currents mediated by wild-type and mutant channels heterologously expressed in human embryonic kidney 293 cells by using a voltage-clamp technique.ResultsThe K817E mutation reduced the Na(+) current density by 39.0%-91.4% at membrane potentials from -55 to -5 mV. This reduction resulted from a ~24-mV positive shift in the voltage dependence of activation. The mutation also decelerated recovery from both fast and intermediate inactivation, whereas it had little effect on the cell surface expression, single-channel conductance, voltage-dependence of fast inactivation, entry into intermediate inactivation, use-dependent loss of channel availability, or closed-state inactivation.ConclusionThe K817E mutation of SCN5A gene leads to loss of function of NaV1.5 channel and may underlie the BrS phenotype of the proband.Copyright © 2016 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.

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