2013 Fiscal Year Final Research Report
Clarification of the molecular pathogenesis of familial moyamoya disease and the establishment of preventive medicine for cerebrovascular disease
| Project/Area Number |
23590741
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Research Field |
Hygiene
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| Research Institution | Kyoto University |
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Principal Investigator |
HITOMI Toshiaki 京都大学, 医学(系)研究科(研究院), 講師 (90405275)
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| Co-Investigator(Renkei-kenkyūsha) |
KOIZUMI Akio 京都大学, 大学院医学研究科, 教授 (50124574)
KOBAYASHI Hatasu 京都大学, 大学院医学研究科, 助教 (70542091)
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| Project Period (FY) |
2011 – 2013
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| Keywords | 予防医学 / Moyamoya病 / 脳血管疾患 / iPS細胞 / Mysterin (RNF213) / Securin / MAD2 / M期関連遺伝子 |
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| Research Abstract |
Mysterin was recently identified as the susceptibility gene for moyamoya disease and its coding variant, p.R4810K, was identified as a common founder variant in East Asian countries. Induced pluripotent stem cells (iPSCs) were established from unaffected fibroblast donors with wild-type mysterin alleles and carriers/patients with one or two mysterin p.R4810K alleles. Angiogenic activities of iPSC-derived vascular endothelial cells (iPSECs) from patients and carriers were lower than those from wild-type subjects. Furthermore, their gene expression profiles revealed that mitotic phase-associated genes, including Securin, were down-regulated in carriers and patients. Overexpression of mysterin p.R4810K induced MAD2 functional inhibition, delay of mitotic progression, mitotic abnormalities, and an increased risk of genomic instability. Thus, mysterin p.R4810K causes endothelial cell dysfunction and is considered to lead to stenosis of cerebral blood vessels.
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