Clarification for clinical significance of autophagy-related gene variants in dilated cardiomyopathy

2023 Fiscal Year Final Research Report

• Project/Area Number: 20K08460
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53020:Cardiology-related
• Research Institution: Nippon Medical School
• Principal Investigator: Saito Tsunenori 日本医科大学, 医学部, 助教 (00716631)
• Project Period (FY): 2020-04-01 – 2024-03-31
• Keywords: オートファジー / 拡張型心筋症 / 全エクソーム解析 / マイトファジー / 電子顕微鏡

Outline of Final Research Achievements

The purpose of this research project was to investigate whether autophagy-related gene mutations cause cardiomyocyte damage. Whole exome DNA analysis of 32 DCM patients focused on 116 genes related to cardiomyopathy and 44 genes related to autophagy, and mutations in ATG2B (c.1939C>T) and PSEN2 (c.1262C>T) were associated with DCM. It was shown that this may be the cause.
A functional analysis of PSEN2 revealed in May 2021 that PSEN2 is responsible for the intracellular transport of Parkin, a protein that controls mitophagy, from the cytoplasm to the mitochondria. We were able to prove that autophagy-related gene mutations can cause cardiomyocyte damage, achieving our research objective.

Free Research Field

循環器内科

Academic Significance and Societal Importance of the Research Achievements

拡張型心筋症（DCM）の心筋症関連遺伝子変異の電子顕微鏡所見との比較により、超微形態はそれぞれの遺伝子変異を示唆していた。本邦では初発心不全全例への遺伝子検査は保険診療上不可能である。電顕所見は遺伝子検査の要否を判断する一助となりうる。オートファジー関連遺伝子変異の網羅的探索ではPSEN2遺伝子がDCMの原因の一つとなることが示唆され、PSEN2遺伝子の機能解析では、同遺伝子変異がマイトファジー不全を惹起し、ミトコンドリアの恒常性を維持できなくなるため心筋細胞障害の原因となると結論付けられた。