Proteasome dysfunction and autoinflammatory diseases: A novel pathogenic mechanism caused by cell stress.

2014 Fiscal Year Final Research Report

• Project/Area Number: 24590403
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Human genetics
• Research Institution: Nagasaki University
• Principal Investigator: KINOSHITA Akira 長崎大学, 原爆後障害医療研究所, 講師 (60372778)
• Co-Investigator(Kenkyū-buntansha): KINOSHITA Naoe 長崎大学, 病院(医学系), 助教 (50380928)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Keywords: プロテアソーム / 自己炎症性疾患 / 中條-西村症候群 / PSMB8 / ジーンターゲッティング / 次世代型シーケンサー

Outline of Final Research Achievements

We have reported that G201V mutation in PSMB8 gene encoding immunoproteasome beta 5i subunit causes an autoinflammatory disease, Nakajo-Nishimura syndrome (NNS) in 2011. In this study, we established NNS model mice harboring G201V mutation by gene-targeting method and analyzed their phenotypes. Excess accumulation of ubiquitinated proteins and excess nuclear translocation of phosphorylated p38 were observed in mice as in NNS patients, but homozygous mutant mouse didn’t develop NNS-like phenotypes. However, female homozygous mutant mice developed severe inflammations of the endocervix and fingers after parturition, and died within a month. Additionally, mutational analyses were performed for four Japanese families with unidentified autoinflammatory diseases. A de novo mutation was identified in a patient with an autoinflammatory disease using Next Generation Sequencing systems.

Free Research Field

人類遺伝学