2. Academic Validation
  3. SCN5A(K817E), a novel Brugada syndrome-associated mutation that alters the activation gating of NaV1.5 channel

SCN5A(K817E), a novel Brugada syndrome-associated mutation that alters the activation gating of NaV1.5 channel

  • Heart Rhythm. 2016 May;13(5):1113-1120. doi: 10.1016/j.hrthm.2016.01.008.
Koshi Kinoshita 1,  Hiroyuki Takahashi 2,  Yukiko Hata 1,  Kohki Nishide 2,  Mario Kato 2,  Hiroki Fujita 2,  Sho Yoshida 2,  Kazutaka Murai 2,  Koichi Mizumaki 3,  Kunihiro Nishida 4,  Yoshiaki Yamaguchi 4,  Masanobu Kano 5,  Toshihide Tabata 2,  Naoki Nishida 6
Affiliations

Affiliations

  • 1 Department of Legal Medicine, Graduate School of Medical and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama-shi, Toyama, Japan.
  • 2 Laboratory for Neural Information Technology, Graduate School of Science and Engineering, University of Toyama, 3190 Gofuku, Toyama-shi, Toyama, Japan.
  • 3 Clinical Research and Ethics Center, University of Toyama, 2630 Sugitani, Toyama-shi, Toyama, Japan.
  • 4 Second Department of Internal Medicine, Graduate School of Medical and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama-shi, Toyama, Japan.
  • 5 Department of Neurophysiology, Graduate School of Medicine, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo, Japan.
  • 6 Department of Legal Medicine, Graduate School of Medical and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama-shi, Toyama, Japan. Electronic address: [email protected].
PMID: 26776555 DOI: 10.1016/j.hrthm.2016.01.008
Abstract

Background: 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 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.

Objective: We investigated whether the K817E mutation causes a functional change of NaV1.5 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 NaV1.5 channel and may underlie the BrS phenotype of the proband.

Keywords

Brugada syndrome; Genetics; Missense mutation; Sodium channel; Voltage sensor.

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