title: SCN5A(K817E), a novel Brugada syndrome-associated mutation that alters the activation gating of NaV1.5 channel.
abstract: 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.
  
  
  
  We investigated whether the K817E mutation causes a functional change of NaV1.5 channel responsible for the BrS phenotype.
  
  
  
  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.
  
  
  
  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.
  
  
  
  The K817E mutation of SCN5A gene leads to loss of function of NaV1.5 channel and may underlie the BrS phenotype of the proband.
authors.affiliation: Department of Legal Medicine, Graduate School of Medical and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama-shi, Toyama, Japan.
authors.forename: Koshi
authors.initials: K
authors.lastname: Kinoshita
authors.affiliation: Laboratory for Neural Information Technology, Graduate School of Science and Engineering, University of Toyama, 3190 Gofuku, Toyama-shi, Toyama, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Takahashi
authors.affiliation: Department of Legal Medicine, Graduate School of Medical and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama-shi, Toyama, Japan.
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Hata
authors.affiliation: Laboratory for Neural Information Technology, Graduate School of Science and Engineering, University of Toyama, 3190 Gofuku, Toyama-shi, Toyama, Japan.
authors.forename: Kohki
authors.initials: K
authors.lastname: Nishide
authors.affiliation: Laboratory for Neural Information Technology, Graduate School of Science and Engineering, University of Toyama, 3190 Gofuku, Toyama-shi, Toyama, Japan.
authors.forename: Mario
authors.initials: M
authors.lastname: Kato
authors.affiliation: Laboratory for Neural Information Technology, Graduate School of Science and Engineering, University of Toyama, 3190 Gofuku, Toyama-shi, Toyama, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Fujita
authors.affiliation: Laboratory for Neural Information Technology, Graduate School of Science and Engineering, University of Toyama, 3190 Gofuku, Toyama-shi, Toyama, Japan.
authors.forename: Sho
authors.initials: S
authors.lastname: Yoshida
authors.affiliation: Laboratory for Neural Information Technology, Graduate School of Science and Engineering, University of Toyama, 3190 Gofuku, Toyama-shi, Toyama, Japan.
authors.forename: Kazutaka
authors.initials: K
authors.lastname: Murai
authors.affiliation: Clinical Research and Ethics Center, University of Toyama, 2630 Sugitani, Toyama-shi, Toyama, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Mizumaki
authors.affiliation: Second Department of Internal Medicine, Graduate School of Medical and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama-shi, Toyama, Japan.
authors.forename: Kunihiro
authors.initials: K
authors.lastname: Nishida
authors.affiliation: Second Department of Internal Medicine, Graduate School of Medical and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama-shi, Toyama, Japan.
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Yamaguchi
authors.affiliation: Department of Neurophysiology, Graduate School of Medicine, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo, Japan.
authors.forename: Masanobu
authors.initials: M
authors.lastname: Kano
authors.affiliation: Laboratory for Neural Information Technology, Graduate School of Science and Engineering, University of Toyama, 3190 Gofuku, Toyama-shi, Toyama, Japan.
authors.forename: Toshihide
authors.initials: T
authors.lastname: Tabata
authors.affiliation: Department of Legal Medicine, Graduate School of Medical and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama-shi, Toyama, Japan. Electronic address: nishida@med.u-toyama.ac.jp.
authors.forename: Naoki
authors.initials: N
authors.lastname: Nishida
mesh_terms: D000328:Adult; D058070:Asymptomatic Diseases; D053840:Brugada Syndrome / Q000175:diagnosis / Q000235:genetics / Q000503:physiopathology; D004562:Electrocardiography / Q000379:methods; D022062:Electrophysiologic Techniques, Cardiac; D006801:Humans; D008297:Male; D009154:Mutation; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000235:genetics*
chemical_list: D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human
keywords: Brugada syndrome; Genetics; Missense mutation; Sodium channel; Voltage sensor