Pathophysiological mechanisms of neurodevelopmental disorders caused by abnormalities of cell cycle-regulatory genes

2022 Fiscal Year Final Research Report

• Project/Area Number: 19H03629
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 52050:Embryonic medicine and pediatrics-related
• Research Institution: Institute for Developmental Research Aichi Developmental Disability Center
• Principal Investigator: Nagata Koh-ichi 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): 2019-04-01 – 2022-03-31
• Keywords: CEP152 / 遺伝性小頭症 / モデルマウス

Outline of Final Research Achievements

Centrosomal protein 152 (CEP152) regulates the centriole duplication/shape and cell polarity during the cell cycle. CEP152 gene abnormalities are responsible for autosomal recessive primary microcephaly 9 (MCPH9). We here identified two novel de novo compound heterozygous CEP152 variants, c.314G>A/p.(Trp105*) and c.2689A>T/p.(Lys897*), in a patient. While the p.Trp105* variant underwent protein degradation, the p.Lys897* variant was abnormally distributed in cytoplasm of neuronal cells. We then developed a mouse model harboring the variants equivalent to the human condition. The mice displayed abnormal centrosome maturation and increased apoptosis in cortical neurons. Electrophysiological analyses revealed abnormal synaptic properties in cortical neurons in the mice. The CEP152 variants may be associated not only with defects in neural proliferation, but also with impaired synaptic function. This study should highlight a connection between centrosomal biology and synaptic network.

Free Research Field

小児発達障害

Academic Significance and Societal Importance of the Research Achievements

本研究では、これまでに神経細胞増殖障害によって発症するとされてきた遺伝性小頭症の病態形成メカニズムに新たな視点を見出した点に学術的意義がある。すなわち、中心体蛋白質CEP152の遺伝子異常が、神経細胞の増殖障害（中心体固有の機能障害）のみでなく、分化後の神経細胞のシナプス機能にも障害を引き起こすことを見出した。この成果は、CEP152に従来想定されていなかった新規機能があることを示している。中心体生物学とシナプスネットワーク形成の相互連間を明らかにして点でも本研究の意義は大きいと考えている。