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Study on Outsode-in Signal Transduction via Platelet Membrane Glycoprotein lb

Research Project

Project/Area Number 09671143
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Hematology
Research InstitutionTHE TOKYO METROPOLITAN INSTITUT OF MEDICAL SCIENCE

Principal Investigator

YAMAMOTO Naomasa  Tokyo Metro.Institute of Med.Science, Researcher, 循環器病, 研究員 (50150884)

Co-Investigator(Kenkyū-buntansha) TANOUE Kenjiro  Tokyo Metro.Institute of Med.Science, Researcher, 循環器病, 研究員 (30014137)
MATSUNO Kazuhiko  Hokkaido University, Professor, 医療技術短期大学部, 教授 (70102332)
KASE Ryoichi  Tokyo Metro.Institute of Med.Science, Researcher, 臨床遺伝, 研究員 (20150203)
Project Period (FY) 1997 – 1998
Project Status Completed (Fiscal Year 1998)
Budget Amount *help
¥3,000,000 (Direct Cost: ¥3,000,000)
Fiscal Year 1998: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 1997: ¥2,000,000 (Direct Cost: ¥2,000,000)
KeywordsGPlbalpha / 14-3-3 / ATP-release / ristocetin-induced agglutination / GPlb / IX / V complex / BSS Tokyo / Signal trunsduction / Bernard-Soulier syndrome / リストセチ凝集 / BSS Tokyo II.
Research Abstract

GPIb/IX/V complex is a receptor for von Willebrand factor and thrombin and plays important roles in platelet adhesion and aggregation. Congenital abnormalities in the complex result in BSS with giant platelets, thrombocytopenia and sever bleeding disorder. We have found a mutation Q545 (CAA)-to-Stop (TAA) in the gene coding GPlbalpha of a patient with BSS.The patient is 23 years old female with diagnosis of BSS at the age of two because of absence of ristocetin-induced agglutination (Matsuno et al, 1976). In this study, flow cytometric analysis revealed the expression of GPlbalpha, GPIX and GPV.The patient's platelets showed 30% of normal agglutination at 2 min after addition of 1.2 mg/ml ristocetin which was completely dissociated at 10 min. Agglutination in response to 1.5 mg/ml ristocetin was 50% of normal agglutination that was partially dissociated. ATP-release was markedly impaired. A homozygous mutation Q545 (CAA)-to-Stop (TAA) in the cytoplasmic domain of GPlbalpha was identified by sequencing the PCR-amplified genomic DNA fragments covering full coding region of GPlbalpha. Truncated GPlbalpha was expressed on the surface and was formed a disulfide-bond with GPlbbeta while the truncated GPlbalpha in the cytosol did not form. Variable number of tandem repeats of the patient was C/C type. These results suggest that the nonsense mutation at Q545 in the cytoplasmic domain of GPlbalpha is responsible for BSS Tokyo II.The reversible ristocetin-induced agglutination of the platelets is possibly due to incomplete association of the truncated GPlbalpha with actin-binding protein which may disrupt reorganization of cytoskeletal proteins. In conclusion, C-terminal region of GPlbalpha starting from Q545 absent in BSS Tokyo II plays an important role in transducing GPlb-dependentoutside-in signal via reorganization of cytoskeletal proteins such as 14-3-3 and actin-binding protein.

Report

(3 results)
  • 1998 Annual Research Report   Final Research Report Summary
  • 1997 Annual Research Report
  • Research Products

    (15 results)

All Other

All Publications (15 results)

  • [Publications] 山本正雅: "血小板膜受容体研究の進歩" MEDICO. 29. 4-7 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] 山本正雅: "Montreal platelet syndrome (モントリオール血小板症候群)" 症候群辞典 診断と治療. 86 Suppl.267 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] 山本正雅,山崎博男: "血小板の分子生物学" 分子アレルギー学. 217 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Tadokoro S et al: "A Gln →Pro susbstitution in the、α llb subunit is a responsible for a moderate α llbβ3 deficiency in Glanzmman Thrombasthenia." Blood. 92. 2750-2758 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Ichinohe T et al.: "Collagen-stimulated activation of Syk but not c-Src is severely,compromised in human platelets lacking membrane glycoprotein Vl." J Biol.Chem. 272. 63-69 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Naomasa Yamamoto: "New aspect of platelet membrane glycoproteins" MEDICO. 29. 4-7 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Tadokoro S, Tomiyama Y, Honda S, Arai M, Yamamoto N, Shiraga M, Kusugi S, Kanakura Y, Kurata Y, Matsuzawa Y.: "A Gln*Pro susbstitution in teh alpha llb subunit is a responsible for a moderate alpha llb beta3 deficiency in Glanzmman Thrombasthenia" Blood. 92. 2750-2758 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Ichinohe T, Takayama H, Ezumi Y,Arai M, Yamamoto N, Takahashi H, Okuma M.: "Collagen-stimulated activation of Syk but not c-Src is severely compromised in human platelets lacking membrane glycoprotein VI." J Biol Chem. 272. 63-69 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] 山本正雅: "血小板膜受容体研究の進歩" MEDICO. 29. 4-7 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] 山本正雅: "Montreal platelet syndrome(モントリオール血小板症候群)" 症候群辞典 診断と治療. 86 Suppl.267 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] 山本正雅, 山崎博男: "血小板の分子生物学" 分子アレルギー学. 217-224 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Tadokoro S et al: "A Gin →Pro susbstitution in the αIIb.subunit is a responsible for a moderate αIIbβ3 deficiency in Glanzmman Thrombasthenia." Blood. 92. 2750-2758 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Ichinohe T et al.: "Collagen-stimulated activation of Syk but not c-Src is severely compromised in human platelets lacing membrane glycoprotein VI." J Biol Chem. 272. 63-69 (1997)

    • Related Report
      1998 Annual Research Report
  • [Publications] 山本正雅: "血小板膜受容体研究の進歩" MEDICO. (印刷中). (1998)

    • Related Report
      1997 Annual Research Report
  • [Publications] 山本正雅: "Montreal platelet syndrome(モントリオール血小板症候群)" 診断と治療 症候群辞典. 86(印刷中). (1998)

    • Related Report
      1997 Annual Research Report

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Published: 1997-04-01   Modified: 2016-04-21  

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