Identification of a driver gene for 15q11-q13 duplication syndrome and elucidation of the molecular mechanism

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K07348
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 49010:Pathological biochemistry-related
• Research Institution: Kobe University
• Principal Investigator: Tamada Kota 神戸大学, 医学研究科, 助教 (10550957)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: 自閉症 / Necdin / 樹状突起スパイン / 15q11-q13 / マウスモデル

Outline of Final Research Achievements

Duplication of chromosome 15q11-q13(Dup15q) is known as a pathogenic copy number variation(CNV) associated with autism spectrum disorder(ASD). However, we still don't know a key gene for the pathogenesis for ASD in Dup15q. In this study, we conducted genetic and overexpression screening, and identified Necdin(Ndn) as a driver gene for paternal Dup15q syndrome, resulting in the development of ASD-like behavioral phenotypes and dendritic spine abnormalities in mice. We then tried to evaluate whether nuclear or cytoplasmic Ndn is important for abnormal spine development. We found NLS(Nuclear localization signal) tagged Ndn affected dendritic spine density and maturity as similar to WT-NDN. We next establish in utero electroporation based target nuclei RNA seq to identify the downstream genes of Ndn in cortical neurons. We successfully extract high purity neuronal nuclei from adult cerebral cortex in mice. Our study provides a new insight into the role of Ndn in paternal 15q duplication.

Free Research Field

神経科学

Academic Significance and Societal Importance of the Research Achievements

15q11-q13領域のように、大きな単位で染色体が欠失/重複/転座などの異常が生じる場合が、自閉症だけでなく、統合失調症などでもよく見受けられる。しかし、それぞれの染色体領域は往々にして大きなサイズであり、含まれている遺伝子も10個を超えることが多い。そのため、どの遺伝子が鍵となっているかを同定することは困難を極める。このため本研究で行ったような、生物学的根拠をもって１つの遺伝子に絞り込む研究の例は非常に少ない。