2020 Fiscal Year Annual Research Report
Identification of TMEM168 protein mutation in familial Brugada syndrome
| Project/Area Number |
18K08033
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| Research Institution | National Cardiovascular Center Research Institute |
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Principal Investigator |
ZANKOV DimitarP 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)
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| Co-Investigator(Kenkyū-buntansha) |
扇田 久和 滋賀医科大学, 医学部, 教授 (50379236)
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| Project Period (FY) |
2018-04-01 – 2021-03-31
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| Keywords | Brugada Syndrome / Sodium channel / TMEM168 gene |
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| Outline of Annual Research Achievements |
Brugada syndrome (BrS) is an inherited channelopathy responsible for almost 20% of sudden cardiac deaths in patients with nonstructural cardiac diseases. Approximately 70% of BrS patients, the causative gene mutation(s) remains unknown. In this study, we used whole exome sequencing to investigate candidate mutations in a family clinically diagnosed with BrS. A heterozygous 1616G>A substitution (R539Q muta- tion) was identified in the transmembrane protein 168 (TMEM168) gene of symp- tomatic individuals. Similar to endogenous TMEM168, both TMEM168 wild-type (WT) and mutant proteins that were ectopically induced in HL-1 cells showed nuclear membrane localization. A significant decrease in Na+ current and Nav1.5 proteinexpression was observed in HL-1 cardiomyocytes expressing mutant TMEM168. Ventricular tachyarrhythmias and conduction disorders were induced in the heterozy- gous Tmem168 1616G>A knock-in mice by pharmacological stimulation, but not in WT mice. Na+ current was reduced in ventricular cardiomyocytes isolated from the Tmem168 knock-in heart, and Nav1.5 expression was also impaired. This impairment was dependent on increased Nedd4-2 binding to Nav1.5 and subsequent ubiquitina- tion. Collectively, our results show an association between the TMEM168 1616G>A mutation and arrhythmogenesis in a family with BrS.
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