Analysis of pathophysiological mechanisms of novel autism-related genes, COPS7A and PER3

2020 Fiscal Year Final Research Report

• Project/Area Number: 17K16315
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Embryonic/Neonatal medicine
• Research Institution: Institute for Developmental Research Aichi Developmental Disability Center
• Principal Investigator: Noda Mariko 愛知県医療療育総合センター発達障害研究所, 分子病態研究部門, 研究員 (50571311)
• Project Period (FY): 2017-04-01 – 2021-03-31
• Keywords: COPS7A / PER3 / ASD / 神経細胞移動 / 神経細胞成熟 / 大脳皮質形成 / 発達障害

Outline of Final Research Achievements

Autism Spectrum Disorder (ASD) is one of the most prevalent neurodevelopmental disorders, which is highly genetically heterogeneous and may be caused by both inheritable and de novo gene variations. Clinical and genetical investigations have revealed thousands of genes linked to ASD. However, the pathophysiological mechanisms of these gene mutation remain largely unclear, especially in developmental stage.
In this study, we analyzed pathophysiological mechanism of novel autism-related gene candidates, COPS7A (a nuclear protein complex, a signalosome constituent molecule) and PER3 (clock gene). As the result, Cops7a was revealed a crucial regulator in corticogenesis through the regulation of excitatory neuronal migration and maturation. Per3 was found to play a pivotal role in corticogenesis via regulation of excitatory neuron migration and synaptic network formation. Loss-of-function of Per3 was supposed to relate to ASD etiology and clinical features.

Free Research Field

解剖学、神経発生、神経免疫

Academic Significance and Societal Importance of the Research Achievements

遺伝学的解析技術の進歩により、疾患原因遺伝子（候補）の同定が進んでいる。一方、高効率の解析手法が無いこともあって、それらの遺伝子の生物学的な研究は大きく遅れている。本研究で解析したCOPS7Aは進化上高度に保存されていることから、その異常は重要な細胞機能に影響を与えると考えられる。一方、従来のASDの研究では、PER3などの時計遺伝子の異常によって引き起こされる概日リズムの異常とASD病態の関連性はほとんど明らかにされてこなかった。従って本研究でCops7aおよびPer3の機能を包括的に解析したことで、ASD病態研究に新たな視点を生み出す契機になる可能性がある。