Molecular cloning of the gene for cancer-prone syndrome characterized by abnormal mitotic spindle checkpoint.
| Project/Area Number |
14370776
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Human genetics
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| Research Institution | HIROSHIMA UNIVERSITY |
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Principal Investigator |
MATSUURA Shinya Hiroshima University, Research Institute for radiation Biology and Medicine, Professor, 原爆放射線医科学研究所, 教授 (90274133)
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| Co-Investigator(Kenkyū-buntansha) |
篠原 美紀 広島大学, 原爆放射線医科学研究所, 助手 (80335687)
小松 賢志 京都大学, 放射線生物研究センター, 教授 (80124577)
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| Project Period (FY) |
2002 – 2004
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| Project Status |
Completed (Fiscal Year 2004)
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| Budget Amount *help |
¥13,800,000 (Direct Cost: ¥13,800,000)
Fiscal Year 2004: ¥4,200,000 (Direct Cost: ¥4,200,000)
Fiscal Year 2003: ¥4,600,000 (Direct Cost: ¥4,600,000)
Fiscal Year 2002: ¥5,000,000 (Direct Cost: ¥5,000,000)
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| Keywords | Mosaic variegated aneuploidy / Mitotic checkpoint / PCS syndrome / p55cdc / BUB1B / BubR1 / Wilms tumor / chromosome instability / 紡錘体形成チェックポイント / キネトコア / 高発がん性遺伝病 / BubRl / 高発癌性遺伝病 / PCS / 細胞周期 / 分裂期 / チェックポイント / 遺伝病 / Dandy-Walker奇形 / MAD2 |
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| Research Abstract |
Cancer-prone syndrome of premature chromatid separation with mosaic variegated aneuploidy (PCS syndrome) is a rare autosomal recessive disorder characterised by growth retardation, microcephaly, childhood cancer, premature chromatid separation of all chromosomes and mosaicism for various trisomies and monosomies. Biallelic BUB1B mutations were recently reported in five of eight families with MVA syndrome (probably identical to the PCS syndrome). We here describe molecular analysis of BUB1B (encoding BubR1) in seven Japanese families with the PCS syndrome. Monoallelic BUB1B mutations were found in all seven families studied : a single base deletion (1833delT) in four families ; and a splice site mutation, a nonsense mutation, and a missense mutation in one family each. Transcripts derived from the patients with the 1833delT mutation and the splice site mutation were significantly reduced due to nonsense-mediated mRNA decay. No mutation was found in the second alleles in the seven families studied, but RT-PCR of BUB1B and Western blot and haplotype analysis of BubR1 indicated a modest decrease of their transcripts. BubR1 in the cells from two patients showed both reduced protein expression and diminished kinetochore localization. Their expression level of p55cdc, a specific activator of anaphase-promoting complex, was normal but its kinetochore association was abolished. Microcell-mediated transfer of chromosome 15 (containing BUB1B) into the cells restored normal BubR1 levels, kinetochore localization of p55cdc, and the normal responses to colcemid treatment. These findings indicate the involvement of BubR1 in p55cdc-mediated mitotic checkpoint signaling, and suggest that >50% decrease in expression (or activity) of BubR1 is involved in the PCS syndrome.
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Report
(4 results)
Research Products
(19 results)
