| Project/Area Number |
18K19506
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| Research Category |
Grant-in-Aid for Challenging Research (Exploratory)
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| Allocation Type | Multi-year Fund |
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| Review Section |
Medium-sized Section 52:General internal medicine and related fields
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| Research Institution | The University of Tokyo |
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Principal Investigator |
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| Project Period (FY) |
2018-06-29 – 2020-03-31
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| Project Status |
Completed (Fiscal Year 2019)
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| Budget Amount *help |
¥6,370,000 (Direct Cost: ¥4,900,000、Indirect Cost: ¥1,470,000)
Fiscal Year 2019: ¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000)
Fiscal Year 2018: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000)
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| Keywords | リピート伸長変異 / リピート伸長病 / RNA分解 |
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| Outline of Final Research Achievements |
Benign adult familial myoclonic epilepsy type 1 (BAFME1) is an autosomal dominant disease which is characterized by infrequent seizures and myoclonic tremor. The cause of the disease have been identified as TTTTA and TTTCA repeat expansion mutation in intron 4 of SAMD12.
We focused on RNA-mediated pathomechanism in BAFME1 in this study. We identified RNA foci in autopsied brain in patients with BAFME1. RNA foci were not found in lymphoblastoid cell lines from patients with BAFME1. RNA-seq using autopsied brains revealed differentially expressed genes (40 downregulated and 44 upregulated). There seems no alternatively transcribed genes. In addition we found abortive transcription around the expanded repeats in SAMD12. We also cloned TTTTA, TTTCA, and TTTTA/TTTCA repeats in vectors and successfully expressed in HEK293 cells. Collectively, RNA-mediated toxicity is considered to play an important role in pathogenesis of BAFME and more investigation focusing on RNA metabolism should be paid.
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| Academic Significance and Societal Importance of the Research Achievements |
近年、イントロンなどタンパク質に翻訳されないと考えられている領域に存在するリピート伸長変異が様々な神経筋疾患を引き起こすことが明らかとなり注目されている。このような疾患では、RNAを介した病態機序の存在が考えられる。良性成人型家族性ミオクローヌスてんかんにおいても、これまでの検討からはRNAを介した機序が想定されている。今後研究の発展に伴い、さらに効果的な治療法の標的が同定されることが期待される。
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