Molecular pathogenesis of beta1 tubulin disorders

• Project/Area Number: 26461413
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Hematology
• Research Institution: National Hospital Organization Nagoya Medical Center
• Principal Investigator: Kunishima Shinji 独立行政法人国立病院機構(名古屋医療センター臨床研究センター), その他部局等, 室長 (60373495)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2015: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2014: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 巨核球 / 血小板 / 微小管 / チューブリン / 先天性血小板減少症

Outline of Final Research Achievements

TUBB1/Tubb1 mutations identified in congenital macrothrombocytopenia of human, dog and big cats were functionally analyzed and classified in 1) abnormal oligomeric aggregation and the disruption of microtubule structure, 2) expression-level dependent abnormal microtubule structure and 3) normal microtubule structure (functional polymorphisms). The former type of mutation resulted in the decreased expression ofα tubulin and G1 arrest leading to the inhibition of cellular proliferation.

Research Products

• [Int'l Joint Research] CRBM-CNRS(フランス)
• [Int'l Joint Research] Auburn University(米国)
• [Journal Article] Rare variants in GP1BB are responsible for autosomal dominant macrothrombocytopenia (2017)
  • Author(s): Sivapalaratnam S, Westbury SK, Stephens JC, Greene D, Downes K, Kelly AM, Lentaigne CE, Astle W, Huizinga EG, Nurden P, Papadia S, Peerlinck K, Penkett CJ, Perry DJ, Rougley C, Simeoni I, Stirrups K, Hart DP, Tait RC, Mumford AD, NIHR BioResources, Laffan MA, Freson K, Ouwehand WH, Kunishima S, Turro E
  • Journal Title: Blood Volume: 129 Issue: 4 Pages: 520-4
  • DOI: 10.1182/blood-2016-08-732248
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Functional characterization of a novel GFI1B mutation causing congenital macrothrombocytopenia (2016)
  • Author(s): Kitamura K, Okuno Y, Yoshida K, Sanada M, Shiraishi Y, Muramatsu H, Kobayashi R, Furukawa K, Miyano S, Kojima S, Ogawa S, Kunishima S
  • Journal Title: J Thromb Haemost Volume: 14 Issue: 7 Pages: 1462-9
  • DOI: 10.1111/jth.13350
  • Peer Reviewed
• [Journal Article] ACTN1 rod domain mutation associated with congenital macrothrombocytopenia. (2016)
  • Author(s): Yasutomi M, Kunishima S, Okazaki S, Tanizawa A, Tsuchida S, Ohshima Y.
  • Journal Title: Ann Hematol Volume: 95 Issue: 1 Pages: 141-4
  • DOI: 10.1007/s00277-015-2517-6
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Diagnostic biomarker for ACTN1 macrothrombocytopenia. (2016)
  • Author(s): Kunishima S, Kitamura K, Yasutomi M, Kobayashi R.
  • Journal Title: Blood Volume: 126 Issue: 22 Pages: 2525-6
  • DOI: 10.1182/blood-2015-08-666180
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Linkage between the mechanisms of thrombocytopenia and thrombopoiesis. (2016)
  • Author(s): Eto K, Kunishima S.
  • Journal Title: Blood Volume: 127 Issue: 10 Pages: 1234-41
  • DOI: 10.1182/blood-2015-07-607903
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] IL-1 alpha induces rapid enhanced platelet biogenesis through rupture of Running title: Rupture thrombopoiesis regulated by IL-1alpha murine bone marrow megakaryocytes (2015)
  • Author(s): Satoshi Nishimura, Mika Nagasaki, Shinji Kunishima, Asuka Sakata, Hiroyasu Sakaguchi, Naoya Takayama, Issei Komuro, Joe Italiano Jr., Tomiko Ryu, Tsukasa Ohmori, Takashi Kadowaki, Koji Eto, Ryozo Nagai
  • Journal Title: Journal of cell biology Volume: 未 Issue: 3 Pages: 453-66
  • DOI: 10.1083/jcb.201410052
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Genotype-phenotype Correlation of the p.R1165C Mutation in the MYH9 Disorder: Report of a Japanese Pedigree. (2015)
  • Author(s): Okano S, Takase M, Iseki K, Toriumi N, Kaneda M, Kunishima S.
  • Journal Title: J Pediatr Hematol Oncol Volume: 37 Issue: 6 Pages: e352-e355
  • DOI: 10.1097/mph.0000000000000379
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] ACTN1-related thrombocytopenia: identification of novel families for phenotypic characterization (2015)
  • Author(s): Bottega R, Marconi C, Faleschini M, Baj G, Cagioni C, Pecci A, Pippucci T, Ramenghi, U, Pardini S, Ngu L, Baronci C, Kunishima S, Balduini CL, Seri M, Savoia A, Noris P
  • Journal Title: Blood Volume: 125 Issue: 5 Pages: 869-872
  • DOI: 10.1182/blood-2014-08-594531
  • Peer Reviewed
• [Journal Article] The first two cases of MYH9 disorders in Thailand: an international collaborative study (2015)
  • Author(s): Sirachainan N, Komwilaisak P, Kitamura K, Hongeng S, Sekine T, Kunishima S
  • Journal Title: Ann Hematol Volume: 94 Issue: 4 Pages: 707-709
  • DOI: 10.1007/s00277-014-2234-6
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Somatic mosaicism in MYH9 disorders : the need to carefully evaluate apparently healthy parents (2014)
  • Author(s): Kunishima S, Kitamura K, Matsumo T, Sekine T, Saito H
  • Journal Title: British Journal of Haematology Volume: 165 Issue: 6 Pages: 885-887
  • DOI: 10.1111/bjh.12797
  • Peer Reviewed
• [Journal Article] Platelet diameters in inherited thrombocytopenias: Analysis of 376 patients with all known disorders (2014)
  • Author(s): Noris P, Biino G, Pecci A, Civaschi E, Savoia A, Seri M, Melazzini F, Loffredo G, Russo G, Bozzi V, Notarangelo LD, Gresele P, Heller P, Pujol-Moix N, Kunishima S, Cattaneo M, Bussel J, De Candia E, Cagioni C, Ramenghi U, Cagioni C, Fabris F, Balduini CL
  • Journal Title: Blood Volume: 124 Issue: 6 Pages: e4-e10
  • DOI: 10.1182/blood-2014-03-564328
  • Peer Reviewed
• [Journal Article] Spectrum of the mutations in Bernard-Soulier syndrome (2014)
  • Author(s): Savoia A, Kunishima S, et al
  • Journal Title: Hum Mut Volume: 35 Issue: 9 Pages: 1033-1045
  • DOI: 10.1002/humu.22607
  • Peer Reviewed
• [Presentation] 新規検査法により診断された先天性巨大血小板症 (2016)
  • Author(s): 國島伸治 北村勝誠 山村喜美
  • Organizer: 第70回国立病院総合医学会
  • Place of Presentation: 那覇
  • Year and Date: 2016-11-11
• [Presentation] Differential diagnosis of congenital macrothrombocytopenia -12-year experience in Nagoya- (2016)
  • Author(s): Kunishima S, Saito H
  • Organizer: Platelets2016: 9th International Symposium
  • Place of Presentation: Wellesley, Massachusette, USA
  • Year and Date: 2016-09-16
• [Presentation] MYH9異常症遺伝子診断のための好中球ミオシン局在解析の細分類 (2016)
  • Author(s): 國島伸治 嘉田晃子 Hao Jihong 北村勝誠
  • Organizer: 第38回日本血栓止血学会学術集会
  • Place of Presentation: 奈良
  • Year and Date: 2016-06-16
• [Presentation] Further classification of neutrophil non-muscle myosin heavy chain IIA localization for efficient genetic diagnosis of MYH9 disorders (2016)
  • Author(s): Kunishima S, Kada A, Hao J
  • Organizer: XXIX International Symposium on Technical Innovations in Laboratory Hematology
  • Place of Presentation: Milano, Italy
  • Year and Date: 2016-05-12
  • Int'l Joint Research
• [Presentation] Functional Characterization of a Novel GFI1B Mutation Causing Congenital Macrothrombocytopenia (2015)
  • Author(s): Katsumasa Kitamura, Yusuke Okuno, Kenichi Yoshida, Masashi Sanada, Yuichi Shiraishi, Hideki Muramatsu, Ryoji Kobayashi, Satoru Miyano, Seiji Kojima, Seishi Ogawa, Shinji Kunishima
  • Organizer: 57th American Society for Hematology Annual Meeting and Exposition, 5-8 December 2015, Orlando, FL, USA.
  • Place of Presentation: 米国、オーランド
  • Year and Date: 2015-12-05
  • Int'l Joint Research
• [Presentation] 原因不明の血小板減少症と診断されていた2B型von Willebrand病の親子例 (2015)
  • Author(s): 國島伸治 北村勝誠 八田京子
  • Organizer: 第16回日本検査血液学会学術集会
  • Place of Presentation: 名古屋
  • Year and Date: 2015-07-11
• [Presentation] 診断の迷宮-判断に迷う疾患へのアプローチ- (2015)
  • Author(s): 國島伸治
  • Organizer: 第16回日本検査血液学会学術集会
  • Place of Presentation: 名古屋
  • Year and Date: 2015-07-11
  • Invited
• [Presentation] Genetic basis of congenital macrothrombocytopenia (2015)
  • Author(s): Shinji Kunishima
  • Organizer: International Society on Thrombosis and Haemostasis Academy
  • Place of Presentation: Webinar
  • Year and Date: 2015-03-25
  • Invited
• [Presentation] Differential diagnosis of congenital macrothrombocytopenia (2014)
  • Author(s): Shinji Kunishima
  • Organizer: 8th Congress of the Asian-Pacific Society of Thrombosis and Hemostasis
  • Place of Presentation: Hanoi
  • Year and Date: 2014-10-09 – 2014-10-11
  • Invited
• [Presentation] 幹細胞技術の検査医学研究への応用 (2014)
  • Author(s): 國島伸治
  • Organizer: 第33回日本臨床検査医学会東海北陸支部例会
  • Place of Presentation: 名古屋
  • Year and Date: 2014-08-02
  • Invited
• [Presentation] MYH9異常症の体細胞モザイク (2014)
  • Author(s): 國島伸治 北村勝誠 松本多絵 関根孝司
  • Organizer: 第15回日本検査血液学会学術集会
  • Place of Presentation: 仙台
  • Year and Date: 2014-07-20 – 2014-07-21
• [Presentation] Molecular mechanisms for congenital macrothrombocytopenia (2014)
  • Author(s): 國島伸治
  • Organizer: 第36回日本血栓止血学会学術集会
  • Place of Presentation: 大阪
  • Year and Date: 2014-05-29 – 2014-05-31
  • Invited
• [Presentation] 巨核球特異的β1-tubulin異常は微小管構成阻害により胞体突起形成不全を来す (2014)
  • Author(s): 國島伸治 北村勝誠 西村智 鈴木英紀 今泉益栄 齋藤英彦
  • Organizer: 第36回日本血栓止血学会学術集会
  • Place of Presentation: 大阪
  • Year and Date: 2014-05-29 – 2014-05-31
• [Book] 小児の症候群 (2016)
  • Author(s): 國島伸治
  • Total Pages: 511
  • Publisher: 診断と治療社
• [Book] 血液科研修ノート (2016)
  • Author(s): 國島伸治
  • Total Pages: 533
  • Publisher: 診断と治療社
• [Book] 小児血液・腫瘍学 (2015)
  • Author(s): 國島伸治
  • Total Pages: 8
  • Publisher: 診断と治療社
• [Book] 小児慢性特定疾病―診断の手引き̶ (2015)
  • Author(s): 國島伸治
  • Total Pages: 7
  • Publisher: 診断と治療社
• [Book] Annual Review 2015 血液 (2015)
  • Author(s): 兼松 毅 國島伸治
  • Total Pages: 240
  • Publisher: 中外医学社
• [Book] 血栓・止血異常の診療 (2014)
  • Author(s): 國島伸治
  • Total Pages: 297
  • Publisher: 中山書店
• [Remarks] 名古屋医療センター
  • URL: http://www.nnh.go.jp
• [Remarks] 名古屋医療センター
  • URL: http://www.nnh.go.jp/crc/
• [Remarks] 名古屋医療センター臨床研究センター
  • URL: http://www.nnh.go.jp/crc/