SCN5A(K817E), a novel Brugada syndrome-associated mutation that alters the activation gating of Na_V1.5 channel

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• 作者：Koshi Kinoshita ; PhD^* ; Hiroyuki Takahashi ; BE^&dagger ; ; Yukiko Hata ; PhD^* ; Kohki Nishide ; ME^&dagger ; ; Mario Kato ; ME^&dagger ; ; Hiroki Fujita ; PhD^&dagger ; ; Sho Yoshida ; BE^&dagger ; ; Kazutaka Murai ; BE^&dagger ; ; Koichi Mizumaki ; MD ; PhD^&Dagger ; ; Kunihiro Nishida ; MD ; PhD ; FHRS^§ ; ; Yoshiaki Yamaguchi ; MD ; PhD^§ ; ; Masanobu Kano ; PhD^¶ ; ; Toshihide Tabata ; PhD^&dagger ; ; Naoki Nishida ; MD ; PhD^* ; ^{nishida@med.u-toyama.ac.jp" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Brugada syndrome ; Sodium channel ; Voltage sensor ; Missense mutation ; Genetics
• 刊名：Heart Rhythm
• 出版年：2016
• 出版时间：May 2016
• 年：2016
• 卷：13
• 期：5
• 页码：1113-1120
• 全文大小：725 K

文摘

Brugada 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 Na_V1.5 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.

Objective

We investigated whether the K817E mutation causes a functional change of Na_V1.5 channel responsible for the BrS phenotype.

Methods

We 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.

Results

The 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.

Conclusion

The K817E mutation of SCN5A gene leads to loss of function of Na_V1.5 channel and may underlie the BrS phenotype of the proband.