2017 Fiscal Year Final Research Report
The screening of somatic mutations using whole exome sequencing in brain malformations
| Project/Area Number |
15K10367
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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 |
Neurosurgery
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| Research Institution | Hamamatsu University School of Medicine (2017)
Yokohama City University (2015-2016) |
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Principal Investigator |
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| Project Period (FY) |
2015-04-01 – 2018-03-31
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| Keywords | 体細胞変異 / 全エクソーム解析 / TAS変異 / droplet digital PCR / GNAQ / MTOR / ラパマイシン |
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| Outline of Final Research Achievements |
We performed whole exome sequencing using paired samples from Sturge Weber syndrome and FCD Type IIb subjects and further investigated using deep sequencing. We identified lesion-specific somatic GNAQ mutation in individuals with Sturge Weber syndrome and MTOR mutations in individuals with FCD Type IIb. Functional analyses showed that phosphorylation of ribosomal protein S6 in FCD Type IIb brain tissues with MTOR mutations was clearly elevated compared with control samples. Transfection of any of the four MTOR mutants into HEK293T cells led to elevated phosphorylation of 4EBP, the direct target of mTOR kinase. These findings suggest that mutations in MTOR are likely to cause hyperactivation of the mTOR signaling pathway and induce dysregulation of growth of neurons and glia, or presumably of their progenitors during brain development. MTOR mutations are sensitive to rapamycin, therefore, mTOR inhibitors would be able to alleviate intractable epilepsy caused by MTOR mutations.
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| Free Research Field |
分子遺伝学
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