Characterization of the mechanism of combined immunodeficiency due to ubiquitin modification abnormalities

2023 Fiscal Year Final Research Report

• Project/Area Number: 20K08158
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 52050:Embryonic medicine and pediatrics-related
• Research Institution: Hiroshima University
• Principal Investigator: Tsumura Miyuki 広島大学, 医系科学研究科(医), 研究員 (80646274)
• Co-Investigator(Kenkyū-buntansha): 岡田 賢 広島大学, 医系科学研究科(医), 教授 (80457241)
• Project Period (FY): 2020-04-01 – 2024-03-31
• Keywords: 複合免疫不全症 / ユビキチン修飾 / 原発性免疫不全症

Outline of Final Research Achievements

CYLD is a deubiquitinating enzyme that cleaves K63- and M1-linked polyubiquitin chains and is known as a tumor suppressor that inhibits inflammatory signaling. In humans, heterozygous mutations in CYLD cause familial cylindromatosis. We identified compound heterozygous mutations in CYLD in a patient with combined immunodeficiency. In addition to immunodeficiency, the patient exhibited syndromic features such as follicular epithelioma, osteoporosis, short stature, and mental retardation. These symptoms were similar to the phenotype observed in Cyld-deficient mice, suggesting that the patient represents the world's first case of autosomal recessive CYLD abnormality. In this study, we aimed to elucidate the pathogenesis of this disease through analysis of patient specimens and overexpression systems.

Free Research Field

原発性免疫不全症

Academic Significance and Societal Importance of the Research Achievements

NF-κBシグナル制御に関連する他のユビキチン制御分子群の異常による免疫不全症や自己炎症疾患が報告されており、修飾シグナル病という疾患概念も形成されている。一方、CYLDの複合へテロ変異による原発性免疫不全症は、論文や学会レベルで報告がない。本研究では、世界初となる常染色体潜性CYLD異常症を同定しその病態解析を行うことで、ヒトにおけるCYLDの機能と役割を理解し、ユビキチン修飾システム全体の理解にも寄与する成果を得た。新規疾患概念を提唱する発見であり、学術的意義は極めて高い。将来的には、未診断のCYLD異常症の診断やユビキチン創薬を含む治療法開発に繋がる可能性があり、広範な社会的意義を持つ。