2020 Fiscal Year Final Research Report
Identification of a novel gene for early-onset epilepsy and elucidation of its pathogenic mechanism
| Project/Area Number |
19K16921
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| Research Category |
Grant-in-Aid for Early-Career Scientists
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| Allocation Type | Multi-year Fund |
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| Review Section |
Basic Section 51030:Pathophysiologic neuroscience-related
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| Research Institution | Yokohama City University |
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Principal Investigator |
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| Project Period (FY) |
2019-04-01 – 2021-03-31
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| Keywords | 進行性ミオクローヌスてんかん / 全エクソームシーケンス / ゼブラフィッシュ |
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| Outline of Final Research Achievements |
In order to identify for novel candidate genes causing developmental and epileptic encephalopathies, we searched for genetic mutations using whole-exome sequencing data of 6,045 patients. As a result, we detected de novo mutations in SEMA6B, a novel gene, in five patients. These mutations resulted in a truncated protein and were all located in the last exon, which was prevented nonsense mediated mRNA decay. The effect of the mutations was verified by an in vivo model system using zebrafish, which mimicked neuronal abnormalities and myoclonus epilepsy-like behavior in humans. Thus, we hypothesized that the production of an abnormal truncated form of SEMA6B protein by the gene mutation is the cause of this disease.
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| Free Research Field |
分子遺伝学
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| Academic Significance and Societal Importance of the Research Achievements |
てんかんの発症はイオンチャネルに関わる遺伝子の異常が主な原因とされているが、本研究により新たに同定されたSEMA6B遺伝子は、神経軸索ガイダンスの伸長抑制作用を持つ。SEMA6B遺伝子を新規責任遺伝子として同定したことで、てんかんを引き起こす新たな発症経路が中枢神経系の発達と関連していることを明らかにした。本研究の成果は、早期発症型てんかんの分子診断や病態メカニズムの解明、治療薬の開発に寄与する。
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