A role of MYCN in neurodevelopment and in a novel syndrome
Project/Area Number |
18K19524
|
Research Category |
Grant-in-Aid for Challenging Research (Exploratory)
|
Allocation Type | Multi-year Fund |
Review Section |
Medium-sized Section 52:General internal medicine and related fields
|
Research Institution | Nagoya City University |
Principal Investigator |
Saitoh Shinji 名古屋市立大学, 医薬学総合研究院(医学), 教授 (00281824)
|
Co-Investigator(Kenkyū-buntansha) |
大石 久史 名古屋市立大学, 医薬学総合研究院(医学), 教授 (30375513)
永田 浩一 愛知県医療療育総合センター発達障害研究所, 分子病態研究部, 部長 (50252143)
|
Project Period (FY) |
2018-06-29 – 2020-03-31
|
Project Status |
Completed (Fiscal Year 2019)
|
Budget Amount *help |
¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000)
Fiscal Year 2019: ¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000)
Fiscal Year 2018: ¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000)
|
Keywords | 巨脳症 / 脳形成 / MYCN / 神経発生 |
Outline of Final Research Achievements |
We identified a novo c.173C>T mutation in MYCN which leads to stabilization and accumulation of the MYCN protein, leading to prolonged CCND1 and CCND2 expression. This may promote neurogenesis in the developing cerebral cortex, leading to megalencephaly. While loss-of-function mutations in MYCN are known to cause microcephaly, we for the first time uncovered that a germline gain-of-function mutation in MYCN causes a novel megalencephaly syndrome. Additionally, we successfully generated knock-in mice of the identified mutation in MYCN using the CRISPR/Cas9 technology. Our findings provide new insight into the critical role of MYCN in brain development, as well as the consequences of MYCN defects.
|
Academic Significance and Societal Importance of the Research Achievements |
MYCNはがん遺伝子、また、脳発生における役割について知られている。MYCN遺伝子の機能喪失型変異が小頭症を示すことも知られていた。しかし、MYCN遺伝子の機能亢進型変異についての知見はこれまで存在しなかった。私たちは世界に先駆けてMYCN遺伝子のミスセンス変異を巨脳症患者に同定した。この変異の機能解析を細胞レベル、神経幹細胞/前駆細胞レベル、発生期のマウス脳レベルで解析し、機能亢進型変異であることを証明した。更に、変異を導入したノックインマウスの作成に成功した。本研究はMYCN遺伝子の適切な発現調整が正常な脳形成に必須であることを証明し、脳の大きさ制御のメカニズム解明に資する意義がある。
|
Report
(3 results)
Research Products
(14 results)
-
-
-
-
-
-
-
-
[Presentation] Clinical, genetic, and biochemical analyses for PI3K-AKT-mTOR pathway-associated megalencephaly.2019
Author(s)
Hori I, Miya F, Nakamura Y, Ieda D, Negishi Y, Hattori A, Tsunoda T, Kanemura Y, Kosaki K, Saitoh S
Organizer
第61回日本小児神経学会学術集会
Related Report
-
-
-
[Presentation] Biallelic VPS35L pathogenic variants cause 3C/Ritscher-Schinzel-like syndrome through dysfunction of retriever complex.2019
Author(s)
Kato K, Oka Y, Muramatsu H, Vasilev F, Otomo T, Oishi H, Kawano Y, Nakazawa Y, Ogi T, Takahashi Y, Saitoh S
Organizer
Biallelic VPS35L pathogenic variants cause 3C/Ritscher-Schinzel-like syndrome through dysfunction of retriever complex.
Related Report
Int'l Joint Research
-
-
[Presentation] A de novo gain-of-function mutation in MYCN causes a novel megalencephaly syndrome2018
Author(s)
Kohji Kato1,2, Fuyuki Miya3,4, Nanako Hamada5, Yutaka Negishi1, Yoko Narumi-Kishimoto 6, Hiroshi Ozawa6, Hidenori Ito5, Ikumi Hori1, Ayako Hattori1, Nobuhiko Okamoto7, Mitsuhiro Kato8, Tatsuhiko Tsunoda3,4, Yonehiro Kanemura9,10, Kenjiro Kosaki11, Yoshiyuki Takahashi2, Koh-ichi Nagata5, Shinji Saitoh
Organizer
Annual Meeting of American Society of Human Genetics 2018
Related Report
Int'l Joint Research
-