2023 Fiscal Year Final Research Report

An innovative diagnostic scheme for elucidating sudden death using genetically mutated model mice

Research Project

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Project/Area Number	20H03958
Research Category	Grant-in-Aid for Scientific Research (B)
Allocation Type	Single-year Grants
Section	一般
Review Section	Basic Section 58040:Forensics medicine-related
Research Institution	Hyogo Medical University
Principal Investigator	YAMAMOTO TAKUMA 兵庫医科大学, 医学部, 准教授 (50634458)
Co-Investigator(Kenkyū-buntansha)	大谷成人兵庫医科大学, 医学部, 講師 (10561772) 村瀬壮彦長崎大学, 医歯薬学総合研究科(医学系), 助教 (40823315) 今坂舞兵庫医科大学, 医学部, 助教 (50759553) 大村谷昌樹兵庫医科大学, 医学部, 教授 (60398229) 池松和哉長崎大学, 医歯薬学総合研究科(医学系), 教授 (80332857) 三浦綾兵庫医科大学, 医学部, 助教 (90814814)
Project Period (FY)	2020-04-01 – 2024-03-31
Keywords	突然死 / 死後遺伝子解析 / 遺伝子変異 / RBM20
Outline of Final Research Achievements	RBM20 is one of the genes predisposing to dilated cardiomyopathy (DCM). Variants in the RS domain have been reported in many DCM patients, but the pathogenicity of variants within the RNA-recognition motif remains unknown. A human patient with the I536T-RBM20 variant without an apparent DCM phenotype was identified in sudden death cohorts. An I538T knock-in mouse model was generated to determine the significance of this variant. In the mouse experiments, Rbm20 I538T mice showed different splicing patterns in Ttn, Ldb3, Camk2d, and Ryr2. The expressions of Casq1, Mybpc2, and Myot were upregulated in Rbm20 I538T mice, but Rbm20 I538T mice showed neither DCM nor cardiac dysfunction on histopathological examination and ultrasound echocardiography. The I536T-RBM20 (I538T-Rbm20) variant changes gene splicing and affects gene expression, but the splicing and expression changes in Ttn and Ca handling genes such as Casq1, Camk2d, and Ryr2 do not cause DCM morphology in the mouse model.
Free Research Field	法医学
Academic Significance and Societal Importance of the Research Achievements	実務上経験した突然死症例において検出された遺伝子変異に関して、モデル動物を用いた検討で病的意義を証明することができた。本研究はRbm20遺伝子変異の解析という点とともに、法医実務における課題をモデル動物を用いて解決したという点においても、法医学突然死研究の意義を示すことができたと考える。今後検出される遺伝子変異についても、変異動物モデルを用いた機能解析・病態再現を行うことで病的意義を持つpathogenic変異であるのかが判明し、家族への予防へと繋げることが期待される。