| Project/Area Number |
21390319
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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 |
Pediatrics
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| Research Institution | Institute for Developmental Research, Aichi Human Service Center |
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Principal Investigator |
WAKAMATSU Nobuaki 愛知県心身障害者コロニー発達障害研究所, 遺伝学部, 部長 (60274198)
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| Co-Investigator(Kenkyū-buntansha) |
YAMADA Yasukazu 愛知県心身障害者コロニー発達障害研究所, 遺伝子学部, 室長 (70191343)
YAMADA Kenichiro 愛知県心身障害者コロニー発達障害研究所, 遺伝学部, 主任研究員 (30291173)
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| Co-Investigator(Renkei-kenkyūsha) |
MIZUNO Seiji 愛知県心身障害者コロニー発達障害研究所, 遺伝学部, 研究員 (20393150)
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| Project Period (FY) |
2009 – 2012
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| Project Status |
Completed (Fiscal Year 2012)
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| Budget Amount *help |
¥17,550,000 (Direct Cost: ¥13,500,000、Indirect Cost: ¥4,050,000)
Fiscal Year 2011: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000)
Fiscal Year 2010: ¥5,720,000 (Direct Cost: ¥4,400,000、Indirect Cost: ¥1,320,000)
Fiscal Year 2009: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
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| Keywords | 小児神経学 / 重度知的障害 / 病因遺伝子 / PLEKHA5 / SLC19A3 / 疾患モデルマウス / 重度精神遅滞 / 遺伝子改変マウス / 精神遅滞 / ノックインマウス / Sandhoff病 |
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| Research Abstract |
We identified mutations in candidate genes associated with 2 different diseases characterized by severe intellectual disability. Patient 1 had a balanced translocation t(6;12)(ql6;pl2). We analyzed the brains of homozygous Plekha5 knockout mice produced using exon trap method at the Kumamoto University. The mice survived more than 1 year, and typical pathological findings were not noted by hematoxylin-eosin staining. The results suggested that haploinsufficiency of PLEKHA5 and a fusion protein (c-terminal PLEKHA5 expression driven by SFRS18 promoter) caused by the translocation were involved in the pathogenesis of the disease in patient 1. Analysis of Plekha5 knockout mice produced by conventional or Cre/loxP system is necessary to confirm the phenotype of Plekha5 deficient mouse. Patient 2 had severe intellectual disability and specific magnetic resonance imaging findings, including abnormal density of basal ganglions and severe brain atrophy. We identified a missense mutation (E320Q) in SLC19A3 encoding thiamine (vitamin B1) transporter in the patient and generated a knock-in (NI) mouse that had the equivalent mutation as in the patient. The NI mice survived more than 1 year when fed standard mouse chow, CE-2 (Clea Japan Inc., Tokyo, Japan). However, when the homozygous NI mice were provided special feed CE-2 containing 35% vitamin B1, they died after 24 days; however, the feed did not affect the survival of wild-type and heterozygous NI mice. Theses results suggest that the patients harboring E320Q mutation in SLC19A3 have specific sensitivity for vitamin B1, and intake of high dose vitamin B1 is the possible treatment for the patients.
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