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THE ETIOLOGY OF SOMATIC MUTATIONS IN PAROXYSMAL NOCTURNAL HEMOGLOBINURIA (PNH)

Research Project

Project/Area Number 11671005
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Hematology
Research InstitutionKUMAMOTO UNIVERSITY

Principal Investigator

KAWAGUCHI Tatsuya  KUMAMOTO UNIVERSITY SCHOOL OF MEDICINE KOSHI (ASSISTANT PROFESSOR), 医学部・附属病院, 講師 (50244116)

Co-Investigator(Kenkyū-buntansha) HORIKAWA Kentaro  KUMAMOTO UNIVERSITY SCHOOL OF MEDICINE JYOSHU (SENIOR STUFF), 医学部, 助手 (40322309)
NAKAKUMA Hideki  KUMAMOTO UNIVERSITY SCHOOL OF MEDICINE JYOKYOJU (ASSOCIATE PROFESSOR), 医学部, 助教授 (90207746)
Project Period (FY) 1999 – 2000
Project Status Completed (Fiscal Year 2000)
Budget Amount *help
¥1,100,000 (Direct Cost: ¥1,100,000)
Fiscal Year 2000: ¥1,100,000 (Direct Cost: ¥1,100,000)
KeywordsParoxysmal nocturnal hemoglobinuria / Hemolytic anemia / Genetic instability / Monosomy 7 / HPRT gene / 造血幹細胞 / マイクロサテライト
Research Abstract

PNH is an acquired clonal stem cell disorder characterized by a somatic mutation in the PIG-A gene. Although the molecular mechanism of intravascular hemolysis is well understood, the etiology of PIG-A gene mutation and the mechanism of selective expansion of affected cells still remain unknown. Based on the presence of multiple PIG-A mutations, more than one PIG-A mutant clones in a single patient and a coexistence with MDS or leukemia clones in some patients, we hypothesize the genetic instability in the overeall genome in PNH.To test this, three distinct markers of genetic instability, microsatellite instability (MSI), chromosomal abnormality and mutation rate of the hypoxanthine-guanine phosphoribosyl-transferase (HPRT) gene were analyzed in PNH patients.
We first examined MSI in 20 patients and found rarity of MSI as reported (Eur J Haematol, 64 : 430-2, 2000).
To asses the chromosomal instability, aneuploidy for chromosome 7 and 8 was analyzed in 13 patients using G-banding and fluorescence in situ hybridization (FISH). Five (38%) had monosomy 7(-7) but none had trisomy 8, suggesting not only that chromosome 7 is genetically unstable in PNH but also that -7 is a useful marker for monitoring the disease progression to MDS or leukemia.
Using HPRT gene mutation assay combined with T cell colony formation, we examined the frequency of mutations in T cell colonies. Mutant colonies were found in 8 of 12 (67%) patients and 3 of 17 (l8%) age-matched health volunteers (p<0.02). The incidence of mutant colonies was extremely higher in the patients (mean 84, x10^<-6>) than in the healthy donors (mean 1.3, x10^<-6>). Thus, the HPRT gene mutate more frequently in patients with PNH than in healthy controls.
Taken together, we concluded that in PNH patients, conditions exist that favor the occurrence of diverse somatic mutations in blood cells.

Report

(3 results)
  • 2000 Annual Research Report   Final Research Report Summary
  • 1999 Annual Research Report
  • Research Products

    (18 results)

All Other

All Publications (18 results)

  • [Publications] Kawaguchi T, et al.: "A novel type of factor XI deficiency showing compound genetic abnormalities : a nonsense mutation and an impaired transcription."Internal Journal of Hamatology. 71. 84-89 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Li K,Kawaguchi T, et al.: "Rarity of microsatellite alterations in patients with paroxysmal nocturnal haemoglobinuria."European Journal of Haematology. 64. 430-432 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Ishihara S,Horikawa K,Kawaguchi T, et al.: "3H9,a monoclonal antibody capable of discriminating neutrophilic from basophilic and eosinophilic granulocytes."European Journal of Haematology. 64. 275-276 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Ishihara S,Nakakuma H,Kawaguchi T, et al.: "Two cases showing clonal progression with full evolution from aplastic anemia-paroxysmal nocturnal hemoglobinuria syndrome to myelodysplastic syndromes and leukemia."Internal Journal of Hamatology. 72. 206-209 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] 川口辰哉,中熊秀喜: "幹細胞異常による貧血「発作性夜間ヘモグロビン尿症」"カレントテラピー. 18. 101-105 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Kawaguchi T., Koga S., Hongo H., Komiyama Y., Li K., Ishihara S., Horikawa K., Hidaka M., Mitsuya H., Nakakuma H.: "A novel type of factor XI deficiency showing compound genetic abnormalities : a nonsense mutation and an impaired transcription."International Journal of Hematology. 71. 84-89 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Li K., Kawaguchi T., Ishihara S., Horikawa K., Hidaka M., Sakaguchi M., Tsuruzaki R., Kawakita M., Kagimoto T., Mitsuya H., Nakakuma H.: "Rarity of microsatellite alterations in patients with paroxysmal nocturnal haemoglobinuria."Europian Journal of Haematology. 64. 430-432 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Ishihara S., Horikawa K., Kawaguchi T., Li K., Hidaka M., Nagakura S., Mitsuya H., Sendo F., Nakakuma H.: "3H9, a monoclonal antibody capable of discriminating neutrophilic from basophilic and eosinophilic granulocytes."Europian Journal of Haematology. 64. 275-276 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Ishihara S., Nakakuma H., Kawaguchi T., Nagakura S., Horikawa K., Hidaka M., Asou N., Mitsuya H.: "Two cases showing clonal progression with full evolution from aplastic anemia-paroxysmal nocturnal hemoglobinuria syndrome to myelodysplastic syndromes and leukemia."International Journal of Hematology. 72. 206-209 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Kawaguchi T., Nakakuma H.: "Anemia caused by stem cell disorders : Paroxysmal nocturnal hemoglobinuria."Current Therapy. 18. 865-869 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Kawaguchi T, et al.: "A novel type of factor XI deficiency showing compound genetic abnormalities : a nonsense mutation and an impaired transcription."Internal Journal of Hamatology. 71. 84-89 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Li K,Kawaguchi T, et al.: "Rarity of microsatellite alterations in patients with paroxysmal nocturnal haemoglobinuria."European Journal of Haematology. 64. 430-432 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Ishihara S,Horikawa K,Kawaguchi T et al.: "3H9, a monoclonal antibody capable of discriminating neutrophilic from basophilic and eosinophilic granulocytes."European Journal of Haematology. 64. 275-276 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Ishihara S,Nakakuma H,Kawaguchi T, et al.: "Two cases showing clonal progression with full evolution from aplastic anemia-paroxysmal nocturnal hemoglobinuria syndrome to myelodysplastic syndromes and leukemia."Internal Journal of Hamatology. 72. 206-209 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] 川口辰哉,中熊秀喜: "幹細胞異常による貧血「発作性夜間へモグロビン尿症」"カレントテラピー. 18. 101-105 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] T.Kawaguchi,他9名: "A novel type of factor XI deficiency showing compound genetic abnormalities:a nonsense mutation and an impaired transcription."International Journal of Hematology. 71. 84-89 (2000)

    • Related Report
      1999 Annual Research Report
  • [Publications] S.Ishihara,他8名: "3H9,a monoclonal antibody capable of discriminating neutrophilic from basophilic and eosinophilic granulocytes."Eur.J.Haematol.. (in press).

    • Related Report
      1999 Annual Research Report
  • [Publications] K.LI,他10名: "Rarity of microsatellite alterations in patients with paroxysmal nocturnal haemoglobinuria."Eur.J.Haematol.. (in press).

    • Related Report
      1999 Annual Research Report

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Published: 2000-04-01   Modified: 2016-04-21  

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