Elucidation of the pathogenic mechanism of epilepsy caused by somatic mutations of GATOR1 genes
| Project/Area Number |
18K14608
|
|---|
| Research Category |
Grant-in-Aid for Early-Career Scientists
|
| Allocation Type | Multi-year Fund |
|---|
| Review Section |
Basic Section 42040:Laboratory animal science-related
|
|---|
| Research Institution | The University of Tokyo (2020)
Tokyo Medical and Dental University (2018-2019) |
|---|
Principal Investigator |
Ishida Saeko 東京大学, 医科学研究所, 助教 (50777927)
|
|---|
| Project Period (FY) |
2018-04-01 – 2021-03-31
|
| Project Status |
Completed (Fiscal Year 2020)
|
| Budget Amount *help |
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2020: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
Fiscal Year 2019: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000)
Fiscal Year 2018: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000)
|
|---|
| Keywords | てんかん / 疾患モデル動物 / 遺伝子変異 / 体細胞変異 / 遺伝子 / 実験動物 |
|---|
| Outline of Final Research Achievements |
Autosomal dominant loss-of-function mutations in GATOR1 subunit genes cause various focal epilepsies. Since somatic loss-of-function mutations of GATOR1 subunit gene were identified in the patient's brain tissue, 2-hit -brain somatic and germline -mutational mechanism leading to loss of function in both alleles in the brain, was thought to be the pathogenesis.
In this study, we generated 2-hit model mice of GATOR1 subunit genes, but no epileptic seizure was observed. On the other hand, mice lacking GATOR1 subunit genes throughout the cerebral cortex reproduced the patient's phenotype. RNA-seq analysis in the cortex of these mice revealed changes in the expression of multiple genes, including epilepsy-related genes.
|
| Academic Significance and Societal Importance of the Research Achievements |
本研究では、GATOR1に変異を有する患者の表現型を再現するマウスモデルを用いたRNA-seq解析により、GATOR1変異によって引き起こされる複数の遺伝子の発現変動を明らかにした。それらの遺伝子にはてんかん関連遺伝子としてこれまでに報告がある遺伝子も含まれていたことから、本解析によって検出された遺伝子群の発現の変動はてんかん発作の発症に強く関連していると期待される。今後、これらの遺伝子がてんかんの治療標的として有効かどうか、またそれらの発現調整がてんかん抑制効果を示すかどうかを検証することにより、新たな治療法の開発につなげることができる。
|
Report
(4 results)
Research Products
(4 results)
-
[Journal Article] Depdc5 knockdown causes mTOR-dependent motor hyperactivity in zebrafish2018
Author(s)
de Calbiac H, Dabacan A, Marsan E, Tostivint H, Devienne G, Ishida S, Leguern E, Baulac S, Muresan RC, Kabashi E, Ciura S.
-
Journal Title
Annals of Clinical and Translational Neurology
Volume: -
Issue: 5
Pages: 510-523
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
-
-
-
