Genetic analysis and pathological role in ventricular noncompaction associated with fatal arrhythmia

2017 Fiscal Year Final Research Report

• Project/Area Number: 15K09685
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pediatrics
• Research Institution: University of Toyama
• Principal Investigator: Ichida Fukiko 富山大学, 事務局, 学長補佐 (30223100)
• Co-Investigator(Kenkyū-buntansha): 西田 尚樹 富山大学, 大学院医学薬学研究部(医学), 教授 (10315088) ; 木下 耕史 富山大学, 大学院医学薬学研究部(医学), 助教 (10585920) ; 畑 由紀子 富山大学, 大学院医学薬学研究部(医学), 准教授 (30311674) ; 小澤 綾佳 富山大学, 附属病院, 診療助手 (40596540) ; 廣野 恵一 富山大学, 附属病院, 助教 (80456384)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Keywords: 心筋緻密化障害 / 遺伝子変異 / サルコメア遺伝子 / iPS細胞 / 次世代シーケンサー / 致死性不整脈 / 心筋細胞 / 突然死

Outline of Final Research Achievements

We targeted and sequenced 80 genes related to cardiomyopathy in 102 LVNC patients using NGS. We identified variants in a significant proportion of cases (30%), which were associated with poor prognosis, and independent risk factor for adverse events including heart transplantation and sudden death. To elucidate the pathological role, we developed and studied human induced pluripotent stem cells (hiPSCs) from a patient carrying a TPM1 p.Arg178His mutation, who underwent heart transplantation. These cells displayed pathological changes, with mislocalization of tropomyosin 1, causing disruption of the sarcomere structure in cardiomyocytes, and impaired calcium handling. Sarcomere genes are implicated as genetic triggers in the development of LVNC and fatal arrhythmia, regulating the expression of numerous genes involved in heart development, or modifying the severity of disease.

Free Research Field

小児循環器学