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2007 Fiscal Year Final Research Report Summary

Investigation of the mechanism for clonal expansion of GPI negative cells in paroxysmal nocturnal hemoglobinuria

Research Project

Project/Area Number 18591060
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Hematology
Research InstitutionOsaka University

Principal Investigator

MURAKAMI Yoshiko  Osaka University, Research Institute for Microbial Diseases, Assistant Professor (00304048)

Co-Investigator(Kenkyū-buntansha) KINOSHITA Taroh  Osaka Univetsty, Research Institute for Microbial Diseases, Professor (10153165)
Project Period (FY) 2006 – 2007
Keywordsgenes / cells and tissues / signal transduction / carbohydrate / regulation of expression
Research Abstract

1. Investigation of the mechanism for clonal expansion of GPI negative cells (Taroh Kinoshita)
We reported 2 patients with PNH whose PIGA mutant cells had a concurrent, acquired rearrangement of chromosome 12. In both cases, der(12) had a break within the 3 untranslated region of HMGA2,the architectural transcription factor gene dereguated in many benign mesenchymal tumors, that caused ectopic expression of HMGA2 in the bone marrow. These observations suggest that aberrant HMGA2 expression,in concert with mutant PIGA, accounts for clonal hematopoiesis.To investigate whether ectopic expression of HMGA2 is also the case with other PNH patients without chromosomal abnormalities, we have established the method for stabilization and purification of mRNA from peripheral blood cells or bone marrow cells of patients and normal volunteers. We could detect mRNA in blood both from normal volunteers and the PNH patient who has ectopic expression of HMGA2 because of chromosomal abnormalities by Q-PCR, and its expression in the patient is significantly higher than in normal volunteers. We also analyzed the genomic sequences of 3'UTR of HMGA2 of granulocytes from four PNH patients who have no chromosomal abnormalities, and found no abnormalities in the genomic sequences.
2. Regulation of expression of GPI anchored proteins by the stimulations (Yoshiko Murakami)
We have identified a novel disease characterized by venous thrombosis and seizures in which deficiency of GPI is inherited in an autosomal recessive manner. In patients, a point mutation (c-g) at position -270 from the start codon of PIGM, a mannosyltransferase-encoding gene, disrupts binding of the transcription factor Sp1 to its cognate promoter motif and reduces transcription of PIGM, causing partial GPI deficiency. We have made the mouse model which has the same mutation as patients to investigate how the expression of Pigm is regulated during embryogenesis and how this down regulation causes the symptoms.

  • Research Products

    (20 results)

All 2008 2007 2006 Other

All Journal Article (7 results) (of which Peer Reviewed: 3 results) Presentation (7 results) Book (5 results) Remarks (1 results)

  • [Journal Article] Targeted Therapy for Inherited GPI Deficiency2007

    • Author(s)
      Almeida, A. M., *Y. Murakami*, A. Baker, Y. Maeda, I. A. G. Roberts, T. Kinoshita, D. M. Layton, and A. Karadimitris.(*equally contributed)
    • Journal Title

      N Engl J Med. 356・16

      Pages: 1641-1647

    • Description
      「研究成果報告書概要(和文)」より
    • Peer Reviewed
  • [Journal Article] (* equally contributed) Targeted therapy for inherited GPI deficiency2007

    • Author(s)
      Almeida, A M., Y., Murakami, A., Baker, Y., Maeda, I., A G., Roberts, T., Kinoshita, D M., Layton, A., Karadimitris
    • Journal Title

      N. Engl. J. Med 356

      Pages: 1641-1647

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Research in Japan has contributed to the understanding of GPI anchor deficiency2007

    • Author(s)
      Murakami, Y., T., Kinoshita
    • Journal Title

      In Glycoscience Lab Manual. Ed., Springer, Tokyo

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Hypomorphic promoter mutation in the mannosyltransfbrase-encoding PIG-M gene causes inherited glycosylphosphatidylinositol deficiency.2006

    • Author(s)
      Almeida, A., *Y. Murakami*, M. Layton, P. Hillmen, G. S. Sellick, Y. Maeda, S. Richards, S. Patterson, I. Kotsianidis, L. Mollica, D. Crawford, A. Baker, M. Ferguson, I. Roberts, R. Houlston, T. Kinoshita and A. Karadimitris.(*equally contributed)
    • Journal Title

      Nat. Med., 12

      Pages: 846-851

    • Description
      「研究成果報告書概要(和文)」より
    • Peer Reviewed
  • [Journal Article] Molecular basis of clonal expansion. of hematopoiesis in two patients with paroxysmal nocturnal hemoglobinuria(PNH).2006

    • Author(s)
      Inoue, N., T. Izui-Sarumaru, Y. Murakami, Y. Endo, J. Nishimura, K. Kurokawa, M. Kuwayama, H. Shime, T. Machii, Y. Kanakura, G. Meyers, C. Wittwer, Z. Chen, W. Babcock, D. Frei-Lahr, C. Parker and T. Kinoshita.
    • Journal Title

      Blood 108・13

      Pages: 4232-4236

    • Description
      「研究成果報告書概要(和文)」より
    • Peer Reviewed
  • [Journal Article] (*equally contributed) Hypomorphic promoter mutation in the mannosyltransferase-encoding PIG-Mgene causes inherited glycosylphosphatidylinositol deficiency2006

    • Author(s)
      Almeida, A., Y., Murakami, M., Layton, P., Hillmen, G S., Sellick, Y., Maeda, S., Richards, S., Patterson, I., Kotsianidis, L., Mollica, D., Crawford, A., Baker, M., Ferguson, I., Roberts, R., Houlston, T., Kinoshita, A., Karadimitris
    • Journal Title

      Nat. Med 12

      Pages: 846-851

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Molecular basis of clonal expansion of hematopoiesis in two patients with paroxysmal nocturnal hemoglobinuria (PNH)2006

    • Author(s)
      Inoue, N., T., Izui-Sarumaru, Y., Murakami, Y., Endo, J., Nishimura, K., Kurokawa, M., Kuwayama, H., Shime, T., Machii, Y., Kanakura, G., Meyers, C., Wittwer, Z., Chen, W., Babcock, D., Frei-Lahr, C., Parker, T., Kinoshita
    • Journal Title

      Blood 108

      Pages: 4232-4236

    • Description
      「研究成果報告書概要(欧文)」より
  • [Presentation] 遺伝性GPIアンカー欠損症と治療について2007

    • Author(s)
      村上良子、前田裕輔、Antonio Almeida、Anastasios Karadimitris、木下タロウ
    • Organizer
      第44回補体シンポジウム
    • Place of Presentation
      平塚市
    • Year and Date
      20070824-25
    • Description
      「研究成果報告書概要(和文)」より
  • [Presentation] A point mutation in an Sp1 binding motif in the promoter of the mannosyltransferase-encoding PIG-M gene causes inherited glycosylphosphatidylinositol deficiency.2006

    • Author(s)
      Yoshiko Murakami, Antonio Almeida, Mark Layton, Peter Hillmen, Yusuke Maeda, Anastasios Karadimitris and Taroh Kinoshita
    • Organizer
      XXIth International Complement Workshop
    • Place of Presentation
      Beijing China
    • Year and Date
      20061022-27
    • Description
      「研究成果報告書概要(和文)」より
  • [Presentation] A point mutation in an Spl binding motif in the promoter of the mannosyltransferase-encoding PIG-Mgene causes inherited glycosylphosphatidylinositol deficiency2006

    • Author(s)
      Yoshiko, Murakami, Antonio, Almeida, Mark, Layton, Peter, Hillmen, Yusuke, Maeda, Anastasios, Karadimitris, Taroh, Kinoshita
    • Organizer
      XXIth International Complement Workshop
    • Place of Presentation
      Beijing China
    • Year and Date
      20061022-27
    • Description
      「研究成果報告書概要(欧文)」より
  • [Presentation] 遺伝性GPIアンカー欠損症の2家系2006

    • Author(s)
      村上良子、前田裕輔、木下タロウ
    • Organizer
      第68回日本血液学会総会 第48回日本臨床血液学会合同総会
    • Place of Presentation
      福岡
    • Year and Date
      20061006-08
    • Description
      「研究成果報告書概要(和文)」より
  • [Presentation] 遺伝性GPIアンカー欠損症2006

    • Author(s)
      木下タロウ、村上良子、前田裕輔、Antonio Almeida、 Anastasios Karadimitris
    • Organizer
      第43回補体シンポジウム
    • Place of Presentation
      福岡
    • Year and Date
      20060818-19
    • Description
      「研究成果報告書概要(和文)」より
  • [Presentation] A point mutation in an Sp1 binding motif in the promoter of the mannosyltransferase-encoding PIG-M gene causes inherited glycosylphosphatid ylinositol deficiency.2006

    • Author(s)
      Yoshiko Murakami, Antonio Almeida, Mark Layton, Peter Hillmen, Yusuke Maeda, Anastasios Karadimitris and Taroh Kinoshita
    • Organizer
      20th IUBMB International Congress
    • Place of Presentation
      Kyoto
    • Year and Date
      20060618-23
    • Description
      「研究成果報告書概要(和文)」より
  • [Presentation] A point mutation in an Spl binding motif in the promoter of the mannosyltransferase-encoding PIG-M gene causes inherited glycosylphosphatidylinositol deficiency2006

    • Author(s)
      Yoshiko, Murakami, Antonio, Almeida, Mark, Layton, Peter, Hillmen, Yusuke, Maeda, Anastasios, Karadimitris, Taroh Kinoshita
    • Organizer
      20th IUBMB International Congress
    • Place of Presentation
      Kyoto
    • Year and Date
      20060600
    • Description
      「研究成果報告書概要(欧文)」より
  • [Book] 先天性GPI欠損症 分子細胞治療 vol.7 no.12008

    • Author(s)
      村上良子、木下タロウ
    • Total Pages
      74-75
    • Publisher
      先端医学社
    • Description
      「研究成果報告書概要(和文)」より
  • [Book] 先天性と後天性GPI欠損症 Annual Review 血液2008

    • Author(s)
      村上良子、木下タロウ
    • Total Pages
      50-58
    • Publisher
      中外医学社
    • Description
      「研究成果報告書概要(和文)」より
  • [Book] Diseases associated with GPI anchors. In Comprehensive Glycoscience.2007

    • Author(s)
      Kinoshita, T., Y. Murakami and Y. S. Morita.
    • Total Pages
      393-419
    • Publisher
      Elsevier Ltd. , Amsterdam.
    • Description
      「研究成果報告書概要(和文)」より
  • [Book] PNHクローン拡大の自己免疫反応による選択、最新・内科シリーズ Vision, 212007

    • Author(s)
      村上良子
    • Total Pages
      10-13
    • Publisher
      株式会社 インターメディカ
    • Description
      「研究成果報告書概要(和文)」より
  • [Book] 発作性夜間血色素尿症を代表とするGPI病、実験医学増刊 糖鎖研究 vol.25 No.72007

    • Author(s)
      村上良子、木下タロウ
    • Total Pages
      1072-1078
    • Publisher
      羊土社
    • Description
      「研究成果報告書概要(和文)」より
  • [Remarks] 「研究成果報告書概要(和文)」より

    • URL

      http://www.biken.osaka-u.ac.jp/act/act_kinoshita.php

URL: 

Published: 2010-02-04  

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