Analyses of pathogenic mechanism of mutation of mRNA untranslated region of the causative gene in autoinflammatory syndrome

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K08924
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 54020:Connective tissue disease and allergy-related
• Research Institution: Kurume University
• Principal Investigator: Yamasaki Satoshi 久留米大学, その他部局等, 准教授 (30367388)
• Co-Investigator(Kenkyū-buntansha): 井田 弘明 久留米大学, 医学部, 教授 (60363496)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: 自己炎症性疾患 / 転写後制御 / 3'非翻訳領域

Outline of Final Research Achievements

Autoinflammatory syndrome is caused by a genetic abnormality, but there are cases of gene mutations in which amino acid substitution does not occur. In this case, the pathogenic mechanism is unknown. In this study, we focused on mutations in the 3'un-translated region (3'UTR) of autoinflammatory diseases and examined their potential involvement in the pathology. Wild-type and mutant mRNA 3'UTR of 6 genes related to autoinflammatory disease were ligated to the reporter mRNA, and their expression in the cell line was confirmed. As a result, we succeeded in identifying tristetraprolin (TTP), which exerts an inhibitory effect on the expression of NLRP3, and RNA-binding protein "c", which has almost the same effect as TTP.

Free Research Field

リウマチ学

Academic Significance and Societal Importance of the Research Achievements

自己炎症生疾患に関連する6遺伝子、IL1RN(2), MEFV(6), MVK(3), NLRP3(2), NRLP7(6), NOD2(6) のmRNA 3’UTRにを介したこれらの遺伝子のmRNA制御メカニズムを検討した。その中で、クライオパイリン関連周期熱症候群の原因遺伝子NLRP3に関して、tristetraprolin (TTP)、さらにこれとほぼ同等の影響をもたらすRNA結合蛋白「c」の同定に成功した。今後の検討の足がかりとなる成果を得ることができた。自己炎症症候群の非コード領域の遺伝子変異と病態の関連に関して新たな解析の方向性を示す研究としての意義がある。