Construction of a mutation database for childhood-onset severe cardiomyopathy and elucidation of molecular mechanisms using animal models of the disease

2023 Fiscal Year Final Research Report

• Project/Area Number: 20K08177
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 52050:Embryonic medicine and pediatrics-related
• Research Institution: The University of Tokyo
• Principal Investigator: Inuzuka Ryo 東京大学, 医学部附属病院, 講師 (00597560)
• Co-Investigator(Kenkyū-buntansha): 松井 彦郎 東京大学, 医学部附属病院, 准教授 (40796819) ; 中釜 悠 大阪公立大学, 大学院医学研究科, 特任講師 (60846880)
• Project Period (FY): 2020-04-01 – 2024-03-31
• Keywords: 心筋症 / 網羅的遺伝子解析 / 疾患モデリング / iPS細胞

Outline of Final Research Achievements

(1) Establishment of a mutation database for childhood-onset cardiomyopathy: In a total of 22 cardiomyopathy cases (21 families, 9 DCM, 3 HCM, 5 RCM, 5 LVNC) under follow-up at our hospital, we performed whole exome sequencing and identified pathogenic mutations in 10 cases (45%), VUS in 5 cases (23%), and no mutations in 7 cases.
(2)Cardiomyopathy disease modeling: To analyze the molecular interaction of LZTR1, we performed a pull-down assay using a tagged LZTR1 overexpression system in cultured cells and attempted protein identification by mass spectrometry on spots detected by two-dimensional electrophoresis, but no proteins involved in functional expression of LZTR1 were identified.

Free Research Field

小児循環器

Academic Significance and Societal Importance of the Research Achievements

小児期発症心筋症症例における網羅的遺伝子解析を行う事で、成人期発症の心筋症の原因遺伝子との違いを明らかにすることが出来た。特に、小児期発症の重症拘束型心筋症例において、MYH7遺伝子の早期発症の機序に関わる可能性のある変異を認め、今後の変異と表現型の関連を調べる機能解析が有用である可能性が示唆された。
In vitroで行ったLZTR1の機能解析では、Noonan関連心筋症発症におけるLZTR1の役割を明らかにすることはできなかった。