Study of molecular pathology in which STAT1 gain-of-function mutations cause autoimmune endocrine disorders

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K17301
• 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: Hiroshima University
• Principal Investigator: Kagawa Reiko 広島大学, 病院(医), 助教 (40806634)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: STAT1-GOF / CMCD / 複合型免疫不全症 / 脱リン酸化酵素 / ISG

Outline of Final Research Achievements

The gain-of-function research mutation of STAT1 has chronic mucocutaneous Candida infection as the main symptom. But some of the cases are detected such as complicated with combined immunodeficiency disease and autoimmune polyglandular syndrome. In this study, I identified a novel case of the severe T385M mutation. The two cases of this T385M mutation were clinically different in severity.
In order to evaluate the factors that cause the severe symptones, we analyzed the specific gene expression by IFN-γ stimulation. I analysed comprehensive gene expression profile by the T cells isolated from the patient's peripheral blood with stimulated by IFN-γ. It was showed the overexpression of ISG (Interferon-stimulated genes). For the next study, It was also shown that the STAT1-GOF mutation is resistant to specific dephosphorylating enzymes. Both of the finding were some of the factors that induced the sevirty symptones of T385M mutation.

Free Research Field

小児内分泌・先天代謝異常

Academic Significance and Societal Importance of the Research Achievements

STAT1-GOF変異を有する患者で認める遺伝子型と表現系相関の背景に存在する分子メカニズムの一部の解明が可能であった。これまで、同変異における標的分子の転写因子の減増により臨床的な重症度が相関することが多くの仮説とされており、網羅的な変異体における機能評価がなされてきた背景がある。標的分子の量的変化に着目されることが多いが、この度は標的分子の質的な変化により、臨床的な重症度が変化することが示された。