Elucidation of cold-induced gene induction mechanism by analyzing Mendelian-inherited diseases with cold-induced inflammation

2015 Fiscal Year Final Research Report

• Project/Area Number: 25670474
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Pediatrics
• Research Institution: Kyoto University
• Principal Investigator: NISHIKOMORI RYUTA 京都大学, 医学(系)研究科(研究院), 准教授 (70359800)
• Co-Investigator(Renkei-kenkyūsha): OHARA Osamu かずさDNA研究所, ヒトゲノム研究部, 副所長 (20370926)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Keywords: Aicardi-Goutieres症候群 / インターフェロン / IFIH1 / MDA5 / 寒冷刺激

Outline of Final Research Achievements

Aicardi-Goutieres syndrome (AGS) is an autoinflammatory disease with early-onset proggressive encephalopathy, caliciafication of basal ganglia, and cold-induced inflammation such as severe chilblain. The disease mechanism of AGS is overproduction of type I interferon caused by stimulation of intracellular nucleic acids sensors due to abnormalities of nucleic acids metabolism. In this study, we identified a new responsible gene, IFIH1 for AGS by performing whole exome sequencing on 3 patients and their families. The patients’ PBMCs showed type I interferon signature and in vitro overexpression study showed that the IFIH1 variants causing AGS (p.Ala452Thr, p.Leu372Phe, p.Arg779His) induce more type I inteferons, which suggested the IFIH1 variants are gain of function. On the other hand, we also found that the IFIH1 variants lacked ligand-specific responses, which is shared by the Ifih1 variant (p.Gly821Ser) identified in a mouse model of SLE.

Free Research Field

小児科学