Investigation of lymphocyte differentiation defect caused by aberrant transcription programs in pathogenic IKZF variants.

2023 Fiscal Year Final Research Report

• Project/Area Number: 20K16884
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 52050:Embryonic medicine and pediatrics-related
• Research Institution: Institute of Physical and Chemical Research (2022-2023); Tokyo Medical and Dental University (2020-2021)
• Principal Investigator: Yamashita Motoi 国立研究開発法人理化学研究所, 生命医科学研究センター, 基礎科学特別研究員 (70869122)
• Project Period (FY): 2020-04-01 – 2024-03-31
• Keywords: 先天性免疫異常症 / AIOLOS / IKZF3 / IKZF

Outline of Final Research Achievements

In this study, we investigated two missense variants of AIOLOS (IKZF3), identified in the patients with inborn errors of immunity (IEI). We conducted in vitro functional assays, immunophenotyping and transcriptome analysis of knock-in mice harboring disease-causing variants, as well as lymphocyte subset analyses of the patient and transcriptome analyses of patient lymphocytes. Through these approaches, we elucidated the molecular pathogenesis by which these missense variants lead to lymphocyte differentiation defects observed in AIOLOS-associated IEI.

Free Research Field

先天性免疫異常症

Academic Significance and Societal Importance of the Research Achievements

本研究の学術的・社会的意義としては、AIOLOS異常症において機能喪失型のAIOLOSバリアントが、AIOLOS自身の機能障害だけでなく他のIKZF分子（IKAROS）の機能障害を引き起こし、分子病態の一端を担うことを証明しAIOLOS異常症の疾患概念の確立に寄与したことである。また、AIOLOS異常症以外の転写因子異常を原因とする先天性免疫異常症や単一遺伝子疾患においても同様の分子病態が存在しうる可能性を示唆した点も本研究の意義の一つと考えられる。