Genetic analysis for autism spectrum disorder and intellectual disability focusing on synaptic network abnormality

2018 Fiscal Year Final Research Report

• Project/Area Number: 16K09995
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pediatrics
• Research Institution: Jichi Medical University
• Principal Investigator: Yamagata Takanori 自治医科大学, 医学部, 教授 (00239857)
• Research Collaborator: Matsumoto Ayumi ; Goto Masahide ; Kojima Karin ; Jimbo Eriko ; Nagata Ko-ichi
• Project Period (FY): 2016-04-01 – 2019-03-31
• Keywords: 自閉スペクトラム症 / シナプス / 概日リズム関連遺伝子 / マイクロRNA

Outline of Final Research Achievements

To detect the pathogenic gene mutations for autism spectrum disorder (ASD) and their function, we analyzed patients samples by aCGH, candidate gene sequence and exome sequence. Several copy number variations (CNVs) were detected and candidate genes were selected. Among them, several genes such as GAS2, and also, microRNAs such as Mir935 were considered to relate with ASD. Addition to that, we detected several mutations on circadian relevant genes. Among them, Nr1d1 and Per3 were analyzed firstly. By intra-utero gene knock down of each gene by RNAi electropolation, neuronal migration and neurite elongation were disturbed. Addition to the mutations in ASD patients, these genes were considered to relate with ASD through the function on synaptic and neural network formation.
And we started the clinical study of a drug that relate the oxytocin function for ASD patients.

Free Research Field

小児科学、小児神経学、分子遺伝学、遺伝子治療

Academic Significance and Societal Importance of the Research Achievements

学術的意義として、ASDの病因となるコピー数多型、遺伝子変異、マイクロRNAなどを同定したことが挙げられる。特に、概日リズム関連遺伝子がASD患者で変異の頻度が高いことを示したことは意義が大きい。その中で、NR1D1とPER3が、概日リズム形成以外に神経形成にも重要な機能を有していることは知られていなかったことであり、概日リズム形成の解明研究に対しても重要な結果である。ASDの病因、病態が明らかになることは、患者の診断、予後判定、さらに治療法開発に重要である。現在、治療候補薬の臨床研究に着手しており、治療効果が示されれば、社会的意義も大きい。