1997 Fiscal Year Final Research Report Summary
Molecular study on Nijmegen breakage sybdrome
| Project/Area Number |
08044294
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| Research Category |
Grant-in-Aid for international Scientific Research
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| Allocation Type | Single-year Grants |
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| Section | Joint Research |
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| Research Field |
環境影響評価(含放射線生物学)
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| Research Institution | HIROSHIMA UNIVERSITY |
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Principal Investigator |
KOMATSU Kenshi Research Institute for Radiation Biology and Medicine, Professor, 原爆放射能医学研究所, 教授 (80124577)
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| Co-Investigator(Kenkyū-buntansha) |
DOMINIQUE Sm University Hospital Nijmegen, Human Genet, Associate
CORRY Weemae University Hospital Nijmegen, Pediatrc Im, Associate
TAUCHI Hiroshi Research Institute for Radiation Biology and Medicine, Hiroshima University. Res, 原爆放射能医学研究所, 助手 (70216597)
MATSUURA Shinya Research Institute for Radiation Biology and Medicine, Hiroshima University. Res, 原爆放射能医学研究所, 助手 (90274133)
WEEMAES Corry University Hospital Nijmegen Pediatrc Immunology Associate Professor
SMEETS Dominique University Hospital Nijmegen Human Genetics, Associate Professor
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| Project Period (FY) |
1996 – 1997
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| Keywords | Nijmegen breakage syndrome / Radiation sensitivity / Positional cloning / p53 tumor suppressor protein / Chromosome transfer uia microcell / Founder effect / Homozygosity mapping / YAC contig |
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| Research Abstract |
ATM underlying gene for Ataxia Telangiectasia, is still mysterious for the phenotypic expression of AT and AT Iike gene could be helpful to understand this mechanism. Nijmegen Breakage Syndrome (NBS) has quite different clinical features from AT,since patients with NBS do not show elevation of alpha-fetoprotein, cerebellar ataxia, or telangiectasia but do have microcephaly and growth retardation. However, the cell-biological findings, such as chromosome instability, increased radiation sensitivity and abnormal cell cycle check point, resemble those in AT,suggesting that the same pathway is impaired in both syndromes.
Similarity between NBS and AT was observed in p53 induction after irradiation. Although the induction of p53 was dose-dependent, the onset of induction was delayd and the maximum p53 at several hrs after irradiation was lower than that of normal cells. Consequently, p53 induction in NBS Iymphoblasts was intermediate between normal cells and AT cells, and this corresponds to a mild radiation sensitivity of NBS to cell killing in comparison with AT cells. However, different underlying genes for NBS and AT were confirmed by complementation assay using fused cells with NBS cells and AT cells. To identify the chromosome carrying NBS gene, we introduced a single human chromosome or their fragments into NBS established cells through microcell and assayd the complementation based on radiation sensitivity. Only hybrid cells containing a human chromosome region 8q21-23 was restored the radiation resistance. Furtermore, the haploid DNA analysis of a patient family with consanguinity strongly suggests the 1-2 cM DNA region around D8S1811 as the candidate locus.
These results are useful information for the next step of gene cloning and understanding of AT-Iike gene function.
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[Publications] Komatsu, K., Matsuura, S., Tauchi, H., Endo, S., Kodama, S., Smeets, D., Weemaes, C., Oshimura, M.: "The Gene for Nijmegen Beakage Syndrome (V2) is not located on chromosome II." Am.J.Hum.Genet.58. 885-888 (1996)
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「研究成果報告書概要(欧文)」より
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[Publications] Matsuura, K., Balmukhanov, T., Tauchi, H., Weemaes, C., Smeets, D., Chrzanowska, K., Endo, S., Matsuura, S., Komatsu, K.: "Radiation induction of p53 in cells from Nijmegen breakage syndrome is defective but not similar to ataxia-telangiectasia." Biochem.Biophys.Res.Commun. (in press).
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[Publications] Imai, H., Nakagawa, H., Komatsu, K., Shiraishi, T., FukudaH., Sugimura, T., Nagao, M.: "Minisatellite instability in severe combined immunodeficiency mouse cells." Proc.Natl.Acad.Sci.USA.94. 10817-10820 (1997)
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「研究成果報告書概要(欧文)」より
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[Publications] Komatsu, K., Matsuura, K., Matsuura, S., Kondo, N., Tauchi, H., Oshimura.M,, Smeets, D., Weemaes, C.: "Radiation induction of p53 in cells from Nijmegen Breakage Syndrome and functional mapping of the underlying gene at 8q21." Disease Markers.(in press).
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「研究成果報告書概要(欧文)」より
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[Publications] Shoji, S., Watanabe, H,, Katoh, O., Masaoka, Y., Matsuura, S., Tauchi, H., Endo, S., Komatsu, K.: "Developmental malformations and intrauterin death in gamma-ray-irradiated scid mice embryos." Int.J.Rad.Biol.(in press).
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[Publications] Matsuura, S., Weemaes, C., Smeets, D., Takami, H., Kondo, N., Sakamoto, S., Yano, N., Nakamura, A., Tauchi, H., Endo, S., Oshimura, M., Komatsu, K.: "Genetic mapping using microcell-mediated chromosome transfer suggests a locus for Nijmegen Breakage Syndrome at chromosome 8q21-24." Am.J.Hum.Genet.60. 1487-1494 (1997)
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