Molecular mechanisms of ACTN1-macrothrombocytopenia

• Project/Area Number: 18K07809
• 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: Gihu University of Medical Science
• Principal Investigator: Kunishima Shinji 岐阜医療科学大学, 保健科学部, 教授 (60373495)
• Project Period (FY): 2018-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 先天性血小板減少症 / 血小板 / 細胞骨格蛋白

Outline of Final Research Achievements

In vitro expression analysis of the novel seven ACTN1 variants identified in the genetic analysis of inherited macrothrombocytopenia was performed in CHO cells. Cells transfected with all of the ACTN1 variants showed abnormal formation of filopodia and lamellipodia and induced actin network disorganization and increased thickness of actin fibers. The rod domain variants may cause strong antiparallel dimerization of actinin-1 and result in the abnormal reorganization of platelet cytoskeleton.

Academic Significance and Societal Importance of the Research Achievements

先天性巨大血小板症の原因となるACTN1異常症の遺伝子異常の多くはアクチン結合部位およびカルモジュリン結合部位に同定されていたが、アクチニン二量体形成に関わるスペーサー領域異常はアクチニンの逆平行配位形成を強固にすることでFアクチンの異常構成に関連することが明らかとなった。

Research Products

• [Int'l Joint Research] Universidad de Murcia/Centro Regional de Hemodonacion/Hospital Universitario Morales Meseguer(スペイン)
• [Int'l Joint Research] Hospital Universitario Morales Meseguer/Centro Regional de Hemodonacion/Universidad de Murcia(スペイン)
• [Int'l Joint Research] Aix‐Marseille Univ(フランス)
• [Journal Article] Expanding the genetic spectrum of TUBB1- related thrombocytopenia (2021)
  • Author(s): Palma-Barqueros V, Bury L, Kunishima S, Lozano ML, Rodriguez Alen A, Revilla N, Bohdan N, Padilla J, Fernandez-Perez MP, de la Morena-Barrio ME, Marin-Quilez A, Benito R, Lopez-Fernandez MF, Marcellini-Antonio S, Zamora-Canovas A, Vicente V, Martinez C, Gresele P, Bastida JM, Rivera J
  • Journal Title: Blood Advances Volume: 5 Issue: 24 Pages: 5453-5467
  • DOI: 10.1182/bloodadvances.2020004057
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Novel ACTN1 variants in cases of thrombocytopenia (2019)
  • Author(s): Vincenot Anne、Saultier Paul、Kunishima Shinji、Poggi Marjorie、Hurtaud‐Roux Marie‐Fran?oise、Roussel Alain、ACTN1 study coinvestigators、Schlegel Nicole、Alessi Marie‐Christine
  • Journal Title: Human Mutation Volume: 40 Issue: 12 Pages: 2258-2269
  • DOI: 10.1002/humu.23840
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Microtubule polyglutamylation and acetylation drive microtubule dynamics critical for platelet formation (2018)
  • Author(s): 128.van Dijk J, Bompard G, Cau J, Kunishima S, Rabeharivelo G, Mateos-Langerak J, Cazevieille C, Cavelier P, Boizet-Bonhoure B, Delsert C, Morin N
  • Journal Title: BMC Biol Volume: 16 Issue: 1 Pages: 116-116
  • DOI: 10.1186/s12915-018-0584-6
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A novel CYCS mutation in the α‐helix of the CYCS C‐terminal domain causes non‐syndromic thrombocytopenia (2018)
  • Author(s): Uchiyama Yuri、Yanagisawa Kunio、Kunishima Shinji、Shiina Masaaki、Ogawa Yoshiyuki、Nakashima Mitsuko、Hirato Junko、Imagawa Eri、Fujita Atsushi、Hamanaka Kohei、Miyatake Satoko、Mitsuhashi Satomi、Takata Atsushi、Miyake Noriko、Ogata Kazuhiro、Handa Hiroshi、Matsumoto Naomichi、Mizuguchi Takeshi
  • Journal Title: Clinical Genetics Volume: 94 Issue: 6 Pages: 548-553
  • DOI: 10.1111/cge.13423
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Congenital thrombocytopenia (2018)
  • Author(s): 國島伸治
  • Journal Title: Rinsho Ketsueki Volume: 59 Issue: 6 Pages: 764-773
  • DOI: 10.11406/rinketsu.59.764
  • NAID: 130007393879
  • ISSN: 0485-1439, 1882-0824
  • Peer Reviewed
• [Presentation] 先天性血小板減少症・異常症の新しい診断体制とレジストリの確立 (2021)
  • Author(s): 石黒 精、内山 徹、要 匡、武部淳子、秦 健一郎、小原 收、 笹原洋二、國島伸治
  • Organizer: 第43回日本血栓止血学会学術集会
• [Presentation] Molecular genetic analysis of 10 families with chronic thrombocytopenia (2019)
  • Author(s): Yuri Uchiyama1,2, Yoshiyuki Ogawa3, Kunio Yanagisawa3, Shinji Kunishima4, Takeshi Mizuguchi1, Hideki Uchiumi3, Hiroshi Handa3 and Naomichi Matsumoto
  • Organizer: XXVII Congress of the International Society on Thrombosis and Haemostasis
  • Int'l Joint Research
• [Presentation] MYH9 Disorders in Thailand: Pediatric Case Series from Thai Macrothrombocytopenia Study Group (2019)
  • Author(s): Natesirinilkul R, Sosothikul D, Komiwilaisak P, Pongtanakul B, Mekjarusgul P, Kunishima S, Sirachainan N
  • Organizer: XXVII Congress of the International Society on Thrombosis and Haemostasis
  • Int'l Joint Research
• [Book] 臨床に直結する血栓止血学 (2018)
  • Author(s): 國島伸治
  • Total Pages: 687
  • Publisher: 中外医学社
  • ISBN: 9784498125797