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Molecular basis of Glanzmann's thromboasthenia

Research Project

Project/Area Number 04671517
Research Category

Grant-in-Aid for General Scientific Research (C)

Allocation TypeSingle-year Grants
Research Field Hematology
Research InstitutionTokyo Medical and Dental University

Principal Investigator

KOYAMA Takatoshi (1993)  Tokyo Medical & Dental Univ., The 1st Dept. of Medicine, M.D., 医学部, 助手 (20234916)

加藤 淳 (1992)  東京医科歯科大学, 医学部, 助手 (50183265)

Co-Investigator(Kenkyū-buntansha) KATO Atsushi  ditto, 医学部, 助手 (50183265)
小山 高敏  東京医科歯科大学, 医学部, 助手 (20234916)
Project Period (FY) 1992 – 1993
Project Status Completed (Fiscal Year 1993)
Budget Amount *help
¥2,100,000 (Direct Cost: ¥2,100,000)
Fiscal Year 1993: ¥900,000 (Direct Cost: ¥900,000)
Fiscal Year 1992: ¥1,200,000 (Direct Cost: ¥1,200,000)
KeywordsGlanzmann's thromboasthenia / glycoprotein (GP) IIb-IIIa / Classification of GT / 細胞内輸送 / GPIIb-IIIa(α_<IIb>β_3) / インテグリン / GPIIb‐IIIa(α_<2b>β_3)
Research Abstract

The genetic basis for Glanzmann's thromboasthinenia (GT) was elucidated on a compound heterozygote with glycoprotein (GP)IIb gene : an opal mutation at the end of exon 17(CGA->TGA) results in only a trace amount of GPIIb mRNA, and a splicing mutation at the acceptor site of exon 26 (CAG->GAG) causes an in-frame, exon skipping process from exon 25 to 27. This aberrant transcript encodes a single-chain polypeptide characterized by a 42-amino acid deletion, which includes the proteolytic cleavage site(s) and 3 unique, proline-rich region at the location corresponding to the carboxy-terminal of the normal GPIIb a-chain. These characteristics are shared by a previously reported defective GPIIb molecule, which is neither assembled with GPIIIa nor transported to the cellular surface. Despite its normal transcriptional level expression of the present defective GPIIb molecule was significantly decreased (-6% of the control level). Because the precursor GPIIb molecule is assembled with GPIIIa in … More the endoplasmic reticulum (ER) and its processing, as well as stability, is dependent on the GPIIIa subunit, the defective GPIIb molecule may be a rapidly degraded by the intrinsic quality control system of the ER due to its inability to form a stable heterodimer complex as a consequence of its misfolded structure. Although we did not confirm that the GPIIIa genes of this individual were normal, GPIIIa may be secondarily decreased(-11% of control), because a large part of it could not be complexed, making it vulnerable to proteolysis.
To elucidate the molecular basis for GT, we have proposed a classification of GT based on the biosynthetic pathway of the GPIIb-IIIa complex. The causative mutations of GT may be two categories in terms of the intracellular transport pathway of GP IIb-IIIa : preGolgi (preassembly) defects and postGolgi (postassembly) defects. If a mutation of the GPIIb or IIIa gene leads to the deficiency of mRNA (pretranslation defect) or misfolding of the subunit (posttranslation defect), formation of the stable complex in the ER or its transport to the Golgi complex may be impaired. Thus the Golgi defects result in the deficiency of GPIIb-IIIa on the platelet surface. In contrast, if a stable complex is formed and is transported to the Golgi, even the mutant heterodimer may be expressed comparably to the normal level (postGolgi defects). In the preGolgi-posttranslation defects, the mutant subunits may be rapidly degraded in the ER after binding to the molecular chaperones shch as Bip (binding protein). In the postGolgi defects, a part of the mutant complex may be sorted to the lysosomal degradation. In general, most cases of type I and type II GT may be caused primarily by the preGolgi defects and some cases of type II and variants by the post Golgi defects. Less

Report

(3 results)
  • 1993 Annual Research Report   Final Research Report Summary
  • 1992 Annual Research Report
  • Research Products

    (37 results)

All Other

All Publications (37 results)

  • [Publications] Atsushi Kato et al.: "Molecular basis for Glanzmann's thromboasthenia(GT) in a compound heterozygote with glycoprotein IIb gene:A proposal for the classification of GT based on the biosynthetic pathway of glycoprotein IIb-IIIa complex." Blood. 79. 3212-3218 (1992)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Atsushi Kato et al.: "Classification of Glanzmann's thromboasthenia based on the intracellular transport pathway of GPIIb-IIIa." Thromb Hemost. 68. 615-616 (1992)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] 加藤 淳: "血小板無力症の成因の分子機構" 医学のあゆみ. 160. 685-689 (1992)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] 加藤 淳: "血小板無力症の分子機構と病因分類" 医学のあゆみ. 164. 811 (1993)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] 加藤 淳: "血小板無力症-遺伝子解析による成因分析" 血液・腫瘍科. 26. (1993)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] 加藤 淳: "血小板無力症の分子機構" 医学のあゆみ. 167. 225 (1993)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] 加藤 淳: "GPIIb-IIIaを介する2方向のシグナル伝達機構" 医学のあゆみ. 168(印刷中). (1994)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] 加藤 淳: "血小板無力症" 小児科. (印刷中). (1994)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] 加藤 淳(他共著): "血小板受容体" 大熊稔,日高弘義,青木延雄,山崎博男,蔵本淳 編 金芳堂, 230 (1992)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] 加藤 淳(他共著): "遺伝子診断実践ガイド" 中井利昭編 中外医学社 (印刷中), (1994)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] 加藤 淳(他共著): "遺伝子診断と遺伝子治療" 村松正実,平井久丸編 現代化学 (印刷中), (1994)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Kato A et al.: "Classification of Glanzmann's thrombasthenia based on the intracellular transport pathway of GP IIb-IIIa" Thromb Haemost. 68. 615-616 (1992)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Kato A: "Molecular pathology of Glanzmann's thrombasthenia." Journal of Clinical and Experimental Medicine (IGAKU NO AYUMI). 160. 685-689 (1992)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Kato A: "Molecular pathology and classification of Glanzmann's thrombasthenia." Journal of Clinical and Experimental Medicine (IGAKU NO AYUMI). 164 : 811. (1993)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Kato A: "Classification of Glanzmann's thrombasthenia based on the molecular pathology." Hematology & Oncology. 26 : 303. (1993)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Kato A: "Molecular pathology of Glanzmann's thrombasthenia." Journal of Clinical and Experimental Medicine (IGAKU NO AYUMI). 167 : 225. (1993)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Kato A: "Mechanism of two way signal transduction by GPIIb-IIIa" Journal of Clinical and Experimental Medicine (IGAKU NO AYUMI). in press. (1994)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Kato A et al.: "Molecular basis for Glanzmann's thrombasthenia (GT) in a compound heterozygote with glycoprotein IIb gene : A proposal for the classification of GT based on the biosynthetic pathway of glycoprotein IIb-IIIa complex" Blood. 79. 3212-3218 (1992)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] 加藤淳: "血小板無力症の分子機構と病因分類" 医学のあゆみ. 164. 811 (1993)

    • Related Report
      1993 Annual Research Report
  • [Publications] 加藤淳: "血小板無力症-遺伝子解析による成因分析" 血液・腫瘍科. 26. 303-312 (1993)

    • Related Report
      1993 Annual Research Report
  • [Publications] 小山高敏: "生理的止血・病的血栓形成の機序" Medical Practice. 11. 6-14 (1994)

    • Related Report
      1993 Annual Research Report
  • [Publications] 小山高敏: "凝固系の働き" medicina. 30. 6-9 (1993)

    • Related Report
      1993 Annual Research Report
  • [Publications] 小山高敏: "TTPとトロンボモジュリン" 血液・腫瘍科. 27. 109-116 (1993)

    • Related Report
      1993 Annual Research Report
  • [Publications] 小山高敏: "組織因子(TF)/TFPI" 臨床検査. 37. 1227-1232 (1993)

    • Related Report
      1993 Annual Research Report
  • [Publications] 加藤淳: "血小板無力症の分子機構" 医学のあゆみ. 167. 225 (1993)

    • Related Report
      1993 Annual Research Report
  • [Publications] 加藤淳: "GPIIb-IIIaを介する2方向のシグナル伝達機構" 医学のあゆみ. 168 (印刷中). (1994)

    • Related Report
      1993 Annual Research Report
  • [Publications] 加藤淳: "血小板無力症" 小児科. (印刷中). (1994)

    • Related Report
      1993 Annual Research Report
  • [Publications] 小山高敏(他共著) 溝口秀昭.平井久丸.坂田洋一 編: "別冊・医学のあゆみ 血液疾患" 医歯薬出版, 462 (1993)

    • Related Report
      1993 Annual Research Report
  • [Publications] 小山高敏(他共著) 藤巻道男,巽典之,渡辺清明 編: "臨床病理臨時増刊特集第97号 検査血液学 血液凝固異常の検査診断" 臨床病理刊行会 宇宙堂八木書店, (1994)

    • Related Report
      1993 Annual Research Report
  • [Publications] 加藤淳(他共著) 中井利昭編: "遺伝子診断実践ガイド" 中外医学社 (印刷中), (1994)

    • Related Report
      1993 Annual Research Report
  • [Publications] 加藤淳(他共著) 村松正実,平井久丸 編: "遺伝子診断と遺伝子治療" 現代化学 (印刷中), (1994)

    • Related Report
      1993 Annual Research Report
  • [Publications] Atsushi Kato: "Molecular basis for Glangmann's thrombathenia(GT)in a compound heterozygote with glycoprotein 2b gene: A proposal for classification of GT based on the biosynthetic pathway of glycoprotein IIb‐IIIa complex." Blood. 79. 3212-3218 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] Atsushi Kato: "Classification of Glanzmann's thrombasthenia based on the intracellalar transport pathway of GPIIb‐IIIa." Thromb Haevest. 68. 615-616 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] 加藤 淳: "血小板無力症の成因の分子機構" 医学のあゆみ. 160. 685-689 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] 加藤 淳: "血小板無力症の分子機構と病因分類" 医学のあゆみ. 164. (1993)

    • Related Report
      1992 Annual Research Report
  • [Publications] 加藤 淳: "血小板無力症ー遺伝子解析による成因分析" 血液・腫瘍科. 26. (1993)

    • Related Report
      1992 Annual Research Report
  • [Publications] 加藤 淳(他、共著): "血小板受容体" 大熊 稔、日高 弘義、青木 延雄、山崎 博男、蔵本 淳 編.金芳堂, 230 (1992)

    • Related Report
      1992 Annual Research Report

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Published: 1992-04-01   Modified: 2016-04-21  

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