Molecular mechanism in cardiomyopathy patients with DSC2 mutation

• Project/Area Number: 18K15890
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 53020:Cardiology-related
• Research Institution: Yamaguchi University
• Principal Investigator: FUKUDA Masakazu 山口大学, 医学部附属病院, 診療助教(4日/週) (30815668)
• Project Period (FY): 2018-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2019: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2018: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: デスモコリン / デスモゾーム / DSC2 / ARVC / デスモコリン２ / デスモコリン-2 / 遺伝性心筋症 / Ca2+ハンドリング

Outline of Final Research Achievements

We succeeded in creating, breeding and genotyping DSC2 (G790Δ) KI mice. DSC2 (G790Δ) KI mice were electrocardiogram and echocardiographically. In addition, VT induction test and exercise test were performed. However, no significant increase in arrhythmia was observed in DSC2 (G790Δ) KI mice. Fluorescent immunostaining showed no significant changes in the staining of various desmosome-related proteins including DSC2. Echocardiographic measurements revealed that DSC2 KI mice had mild dilation and reduced contractility, especially in homozygous mice.
In DSC2 (G790Δ) KI mice, a slight decrease in cell shortening was observed in homozygous mice.

Academic Significance and Societal Importance of the Research Achievements

DSC2 KIマウスを世界で初めて作成し、論文化できたことは学術的意義があったが、当初仮説を立てていたDSC2変異における催不整脈性や（可逆的な）細胞内Ca2+ハンドリング異常を誘導する可能性についてはnegativeなデータであった。

Research Products

• [Journal Article] G790del mutation in DSC2 alone is insufficient to develop the pathogenesis of ARVC in a mouse model (2020)
  • Author(s): Hamada Yoriomi、Yamamoto Takeshi、Nakamura Yoshihide、Sufu-Shimizu Yoko、Nanno Takuma、Fukuda Masakazu、Ono Makoto、Oda Tesuro、Okuda Shinichi、Ueyama Takeshi、Kobayashi Shigeki、Yano Masafumi
  • Journal Title: Biochemistry and Biophysics Reports Volume: 21 Pages: 100711-100711
  • DOI: 10.1016/j.bbrep.2019.100711
  • Peer Reviewed / Open Access
• [Journal Article] Correlation between asymptomatic gastroesophageal excessive transmural injury after pulmonary vein isolation and a bonus freeze protocol using the second-generation 28-mm cryoballoon for paroxysmal atrial fibrillation. (2019)
  • Author(s): Yoshiga Y, Okamoto T, Shimizu A, Ueyama T, Ono M, Mito T, Fukuda M, Ishiguchi H, Omuro T, Kobayashi S, Goto A, Nishikawa J, Sakaida I, Yano M.
  • Journal Title: J Cardiol Volume: 74 Issue: 6 Pages: 494-500
  • DOI: 10.1016/j.jjcc.2019.05.008
  • Peer Reviewed / Open Access
• [Journal Article] Addition of a β1-Blocker to Milrinone Treatment Improves Cardiac Function in Patients with Acute Heart Failure and Rapid Atrial Fibrillation (2019)
  • Author(s): Kobayashi Shigeki、Myoren Takeki、Kajii Toshiro、Kohno Michiaki、Nanno Takuma、Ishiguchi Hironori、Nishimura Shigehiko、Fukuda Masakazu、Hino Akihiro、Fujimura Tatsuhiro、Ono Makoto、Uchinoumi Hitoshi、Tateishi Hiroki、Mochizuki Mamoru、Oda Tetsuro、Okuda Shinichi、Yoshiga Yasuhiro、Kawano Reo、Yano Masafumi
  • Journal Title: Cardiology Volume: 142 Issue: 4 Pages: 195-202
  • DOI: 10.1159/000499400
  • Peer Reviewed / Open Access