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

• 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
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2015: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2014: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2013: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
• Keywords: Aicardi-Goutieres症候群 / インターフェロン / IFIH1 / MDA5 / 寒冷刺激 / パターン認識受容体 / 炎症 / Aicardi-Goutieres 症候群 / CAPS / NLRP3

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.

Research Products

• [Journal Article] Aicardi-Goutières syndrome is caused by IFIH1 mutations. (2014)
  • Author(s): Oda, H., Nakagawa, K., Abe, J., Awaya, T., Funabiki, M., Hijikata, A., Nishikomori, R., Funatsuka, M., Ohshima, Y., Sugawara, Y., Yasumi, T., Kato, H., Shirai, T., Ohara, O., Fujita, T., Heike, T.
  • Journal Title: America Journal of Human Genetics Volume: 95 Issue: 1 Pages: 121-125
  • DOI: 10.1016/j.ajhg.2014.06.007
  • NAID: 120005460706
  • Peer Reviewed
• [Journal Article] Heterozygous TREX1 p.Asp18Asn mutation can cause variable neurological symptoms in a family with Aicardi-Goutieres syndrome/familial chilblain lupus. (2012)
  • Author(s): Abe J
  • Journal Title: Rheumatology Volume: 52 Issue: 2 Pages: 406-408
  • DOI: 10.1093/rheumatology/kes181
  • Peer Reviewed
• [Presentation] Aicardi-Goutières syndrome: Type I interferonopathy (2015)
  • Author(s): R. Nishikomori
  • Organizer: Pediatric Academic Societies Meeting
  • Place of Presentation: San Diego, USA
  • Year and Date: 2015-04-25
  • Int'l Joint Research
• [Presentation] 自己炎症性症候群アップデート. (2015)
  • Author(s): 西小森隆太
  • Organizer: 第59回日本リウマチ学会総会
  • Place of Presentation: 名古屋
  • Year and Date: 2015-04-23
  • Invited
• [Presentation] Aicardi-Goutieres syndrome is caused by IFIH1 mutations (2014)
  • Author(s): Oda, H. Nakagawa, K. Abe, J. Awaya, T. Funabiki, M. Hijikata, A. Nishikomori, R. Funatsuka, M. Ohshima, Y. Sugawara, Y. Yasumi, T. Kato, H. Shirai, T. Ohara, O. Fujita, T. Heike, T.
  • Organizer: Ameriacan Society of Human Genetics
  • Place of Presentation: San Diego, USA
  • Year and Date: 2014-10-19