Genome-wide analysis to discover the gene mutation that relates to ventricular fibrillation and its molecular mechanism

2017 Fiscal Year Final Research Report

• Project/Area Number: 15K09136
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Cardiovascular medicine
• Research Institution: Shiga University of Medical Science
• Principal Investigator: Zankov Dimitar P. 滋賀医科大学, 医学部, 特任助教 (20631295)
• Co-Investigator(Renkei-kenkyūsha): OGITA Hisakazu 滋賀医科大学, 医学部, 教授 (50379236)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Keywords: 不整脈 / ゲノム解析 / 遺伝子異常

Outline of Final Research Achievements

Ventricular fibrillations are critical arrhythmias that cause sudden cardiac death. Thus, it is essentially important to investigate the underlying mechanisms of the arrhythmias. In this project, we conducted exome sequencing analysis to identify novel culprit gene(s) in a family with inherited fatal ventricular arrhythmias, and found heterozygous variant (1616G>A; p. R539Q) in the TMEM168 gene. TMEM168 localized in the nuclear membrane. Variant TMEM168 ectopically expressed in HL-1 cardiomyocytes reduced Na+ current density in the patch-clamp recording, and attenuated the endogenous expression of Nav1.5, a Na+ channel subunit. We newly generated Tmem168 1616G>A knock-in mice. Pharmacological stimulations provoked ventricular tachycardias/fibrillations and conduction disorders in the knock-in mice. Analogous to HL-1 cells, Nav1.5 expression was reduced in the knock-in heart. Presented results associate the novel gene variant of TMEM168 with arrhythmogenicity.

Free Research Field

循環器学、生化学