pathological mechanism of Takenouchi-Kosaki syndrome

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K08314
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 52050:Embryonic medicine and pediatrics-related
• Research Institution: Osama Woman's and Children's Hospital
• Principal Investigator: Shibukawa Yukinao 地方独立行政法人大阪府立病院機構大阪母子医療センター(研究所), 分子遺伝病研究部門, 主任研究員 (90393264)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: CDC42 / CDC42異常症 / 武内・小崎症候群 / 巨大血小板性血小板減少症

Outline of Final Research Achievements

Takenouchi-Kosaki syndrome (TKS) exhibits a variety of clinical manifestations, including immunological and hematological anomalies. In the present study, we investigated the functional abnormalities of the TKS mutant in HEK293 cells and elucidated the mechanism of macrothrombocytopenia, one of the symptoms of TKS patients, by monitoring the production of platelet-like particles (PLP) using MEG-01 cells. We found that the TKS mutant was concentrated at the membrane compartment due to impaired binding to Rho-GDI and more active than the wild-type. Y64C mutant-expressing MEG-01 cells demonstrated short cytoplasmic protrusions with aberrant F-actin and microtubules, and reduced PLP production. Furthermore, such dysfunction was ameliorated by either suppression of Cdc42 activity or prenylation using chemical inhibitors. Our study may lead to pharmacological treatments for TKS patients.

Free Research Field

細胞生物学

Academic Significance and Societal Importance of the Research Achievements

希少疾患であるTKSの原因となるCDC42の異常な活性化メカニズムを明らかにしたことはCDC42の活性化を制御する研究において学術的意義が高いと考えられる。また巨大血小板性血小板減少症に着目した解析ではMEG01細胞を用いて臨床症状を細胞レベルで再現し薬剤のスクリーニング系を確立したこと、さらに低下した血小板産生能を回復させる効果的な薬剤を複数提示したことは将来的な治療や症状の緩和法に繋がると考えられ社会的意義は非常に高いと考えられる。