Elucidation of the pathology in ARVC caused by Japanese-specific DSG2 mutations using knock-in mice models: searching for the therapeutic targets

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K08119
• 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: National Cardiovascular Center Research Institute
• Principal Investigator: Zankov Dimitar P 国立研究開発法人国立循環器病研究センター, オープンイノベーションセンター, 室長 (20631295)
• Co-Investigator(Kenkyū-buntansha): 大野 聖子 国立研究開発法人国立循環器病研究センター, 研究所, 部長 (20610025)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: ARVC / dsg2 / knock-in mouse

Outline of Final Research Achievements

There are two DSG2 founder variants in Japanese ARVC, p.R292C and p.D494A. In human, most patients carry the variants in homozygous or compound heterozygous manner. We constructed knock-in (KI) mice model with these variants, dsg2 R297C and D499A. The survival of homozygous R297C mice was worse than others. In the echo cardiography and cardiac MRI, we could confirm the enlargement of both ventricles and decreased contraction function. Exercise stress training except for homozygous R297C exacerbated cardiac function and enlarged the cavities in mice models. In the histological analysis, we found severe fibrosis, especially in the right ventricular wall.

Free Research Field

Cardiovascular disease

Academic Significance and Societal Importance of the Research Achievements

Phenotype of ARVC caused by variants in DSG2 are different from those in PKP2. Our knock-in mice showed similar phenotype with human ARVC, therefore, we can use our mice to develop effective treatment for Japanese ARVC.