Molecular pathological analysis of autism spectrum disorder caused by haploinsufficiency of a gene encoding histone methyltransferase

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K15752
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 52030:Psychiatry-related
• Research Institution: Institute of Physical and Chemical Research
• Principal Investigator: Nakamura Takumi 国立研究開発法人理化学研究所, 脳神経科学研究センター, 研究員 (40881123)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: 自閉スペクトラム症 / KMT2C / トランスクリプトーム解析 / LSD1阻害剤

Outline of Final Research Achievements

In this study, we analyzed the molecular pathology of autism spectrum disorder (ASD) caused by haploinsufficiency of the KMT2C gene. We performed transcriptomic analyses using mouse brains derived from Kmt2c heterozygous mutant mice. Our results demonstrated that known ASD genetic risks were enriched among differentially associated genes (DEGs) in the Kmt2c mutant mice. Additionally, we found that the number of DEGs and the enrichment of ASD genetic risks were significantly higher in cells at early stages of neural differentiation. Furthermore, we showed that treatment with an LSD1 inhibitor rescued social deficits and transcriptomic dysregulation in the Kmt2c mutant mice.

Free Research Field

精神神経科学

Academic Significance and Societal Importance of the Research Achievements

本研究は、ASDおよびヒストンメチル化パスウェイの研究に寄与する新たなモデルマウスを提供するとともに、ヒストン修飾や転写異常が原因の精神神経疾患の大人の患者に対しての治療介入の可能性を示すものである。ASDは、近年のアメリカでの疫学調査によると8歳の子どもの2.8％程度がASDと診断されると報告されているなど、有病率の高い疾患であるため、その治療方法の発展は社会的な意義が大きいと考えられる。