Clarification of molecular pathophysiology and identification of therapeutic target in desmosome-related cardiomyopathy

2020 Fiscal Year Final Research Report

• Project/Area Number: 18K08069
• 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: Osaka University
• Principal Investigator: Hikoso Shungo 大阪大学, 医学系研究科, 准教授 (30423164)
• Co-Investigator(Kenkyū-buntansha): 肥後 修一朗 大阪大学, 医学系研究科, 特任准教授(常勤) (00604034)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: 拡張型心筋症 / デスモゾーム / iPS細胞 / 病態モデル

Outline of Final Research Achievements

We identified a homozygous stop-gain mutations in DSG2 (c.C355T, p.R119X) that led to complete desmoglein-2 deficiency in a patient with severe biventricular heart failure. Induced pluripotent stem cells were generated from the patient (R119X-iPSC), and the mutated DSG2 gene locus was heterozygously corrected to a normal allele via homology-directed repair (HDR-iPSC). We detected abnormal electrical excitation in R119X-iPSC-CMs but not HDR-iPSC-CMs.Three-dimensional self-organized tissue rings (SOTRs) revealed tissue fragility and a weak maximum force in SOTRs from R119X-iPSC-CMs. These phenotypes were significantly recovered in HDR-iPSC-CMs. Myocardial fiber structures in R119X-iPSC-CMs were severely aberrant, and desmosomes were disrupted in these cells. The absence of desmoglein-2 in R119X-iPSC-CMs led to decreased expression of desmocollin-2. Adeno-associated virus-mediated replacement of DSG2 significantly recovered the contraction force in SOTRs generated from R119X-iPSC-CMs.

Free Research Field

心不全

Academic Significance and Societal Importance of the Research Achievements

本研究により、デスモゾーム構成分子であるDSG2の欠損に伴う拡張型心筋症の患者由来iPS細胞由来心筋において、デスモゾーム構造の破壊やそれに伴う組織化の異常、異常電位の発生など、患者の病態を再現することができ、詳細な表現形や機序の検討に繋がる知見が得られた。また、他のデスモゾーム構成分子であるDSC2の発現低下を認めるなど、一つの構成分子の欠損によりデスモゾーム構造全体の異常につながることも見出した。これらの知見は、デスモゾーム関連分子異常による心筋症のメカニズム解明に有用であると考えられた。