• Search Research Projects
  • Search Researchers
  • How to Use
  1. Back to previous page

Identification of TMEM168 protein mutation in familial Brugada syndrome

Research Project

Project/Area Number 18K08033
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 53020:Cardiology-related
Research InstitutionNational Cardiovascular Center Research Institute (2019-2020)
Shiga University of Medical Science (2018)

Principal Investigator

Zankov Dimitar Petrov  国立研究開発法人国立循環器病研究センター, 研究所, 室長 (20631295)

Co-Investigator(Kenkyū-buntansha) 扇田 久和  滋賀医科大学, 医学部, 教授 (50379236)
Project Period (FY) 2018-04-01 – 2021-03-31
Project Status Completed (Fiscal Year 2020)
Budget Amount *help
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
KeywordsInherited arrhythmia / Brugada syndrome / Sodium channel / Ubiquitination / Brugada Syndrome / TMEM168 gene / TMEM168 / 不整脈 / 遺伝子解析
Outline of Final Research Achievements

Brugada syndrome (BrS) is an inherited channelopathy identified as a cause of sudden cardiac death. Only 10-15% of Japanese BrS patients are diagnosed genetically. We used whole-exome sequencing to investigate candidate mutations in a BrS family. A heterozygous R539Q mutation was detected in TMEM168 gene of symptomatic individuals. Endogenous and transfected in HL-1 cells TMEM168 wild-type (WT) and mutant showed nuclear membrane localization. A significant decrease in Nav1.5 protein and Na+ current was observed in HL-1 cells expressing mutant TMEM168. Ventricular tachyarrhythmias and conduction disorders were pharmacologically induced in the heterozygous Tmem168 knock-in mice, but not in WT mice. Nav1.5 protein and Na+ current were reduced in ventricular myocytes in Tmem168 knock-in hearts. The impairment was dependent on increased Nedd4-2 binding to Nav1.5 and subsequent ubiquitination. Our results show a link between TMEM168 R539Q mutation and arrhythmogenesis in a family with BrS.

Academic Significance and Societal Importance of the Research Achievements

This study identified novel genetic variant associated with Brugada Syndrome. TMEM168 protein carrying the mutation is localized in the nuclear membrane and so far has unknown function. The mechanism of modulation of Na+ channel is unusual and will contribute to understanding of arrythmogenesis.

Report

(4 results)
  • 2020 Annual Research Report   Final Research Report ( PDF )
  • 2019 Research-status Report
  • 2018 Research-status Report
  • Research Products

    (4 results)

All 2021 2020 2019

All Journal Article (2 results) (of which Int'l Joint Research: 2 results,  Peer Reviewed: 2 results,  Open Access: 2 results) Presentation (2 results) (of which Int'l Joint Research: 1 results)

  • [Journal Article] Identification of transmembrane protein 168 mutation in familial Brugada syndrome.2020

    • Author(s)
      Shimizu A, Zankov DP, Sato A, Komeno M, Toyoda F, Yamazaki S, Makita T, Noda T, Ikawa M, Asano Y, Miyashita Y, Takashima S, Morita H, Ishikawa T, Makita N, Hitosugi M, Matsuura H, Ohno S, Horie M, Ogita H.
    • Journal Title

      FASEB Journal

      Volume: 34 Issue: 5 Pages: 6399-6417

    • DOI

      10.1096/fj.201902991r

    • Related Report
      2020 Annual Research Report 2019 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Mutant KCNJ3 and KCNJ5 potassium channels as novel molecular targets in bradyarrhythmias and atrial fibrillation.2019

    • Author(s)
      Yamada N, Asano Y, Fujita M, Yamazaki S, Inanobe A, Matsuura N, Kobayashi H, Ohno S, Ebana Y, Tsukamoto O, Ishino S, Takuwa A, Kioka H, Yamashita T, Hashimoto N, Zankov DP, Shimizu A, Asakura M, Asanuma H, Kato H, Nishida Y, Miyashita Y, Shinomiya H, Naiki N, Hayashi K, Makiyama T, Ogita H, et al.
    • Journal Title

      Circulation

      Volume: In press Issue: 18 Pages: 2157-2169

    • DOI

      10.1161/circulationaha.118.036761

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] Human-specific desmoglein 2 mutations in mice models of arrythmogenic right ventricular cardiomyopathy reproduce patients' phenotype2021

    • Author(s)
      D.P. Zankov & S. Ohno.
    • Organizer
      European heart rhythm association congress, April 23-25
    • Related Report
      2020 Annual Research Report
    • Int'l Joint Research
  • [Presentation] A Novel TMEM168 Gene Mutation in Familial Brugada Syndrome Attenuates Na+ channel Function by Modulating Nav1.5 Expression2019

    • Author(s)
      Dimitar Petrov Zankov
    • Organizer
      Japanese Circulation Society Meeting
    • Related Report
      2018 Research-status Report

URL: 

Published: 2018-04-23   Modified: 2022-01-27  

Information User Guide FAQ News Terms of Use Attribution of KAKENHI

Powered by NII kakenhi