2007 Fiscal Year Final Research Report Summary
Investigation of the mechanism for clonal expansion of GPI negative cells in paroxysmal nocturnal hemoglobinuria
| Project/Area Number |
18591060
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Hematology
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| Research Institution | Osaka University |
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Principal Investigator |
MURAKAMI Yoshiko Osaka University, Research Institute for Microbial Diseases, Assistant Professor (00304048)
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| Co-Investigator(Kenkyū-buntansha) |
KINOSHITA Taroh Osaka Univetsty, Research Institute for Microbial Diseases, Professor (10153165)
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| Project Period (FY) |
2006 – 2007
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| Keywords | genes / cells and tissues / signal transduction / carbohydrate / regulation of expression |
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| 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.
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[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
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Journal Title
N. Engl. J. Med 356
Pages: 1641-1647
Description
「研究成果報告書概要(欧文)」より
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[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)
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Journal Title
Nat. Med., 12
Pages: 846-851
Description
「研究成果報告書概要(和文)」より
Peer Reviewed
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[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.
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Journal Title
Blood 108・13
Pages: 4232-4236
Description
「研究成果報告書概要(和文)」より
Peer Reviewed
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[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
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Journal Title
Nat. Med 12
Pages: 846-851
Description
「研究成果報告書概要(欧文)」より
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[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
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Journal Title
Blood 108
Pages: 4232-4236
Description
「研究成果報告書概要(欧文)」より
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[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
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[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
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