Elucidation of molecular mechanisms of NLRP3 mosaicism

• Project/Area Number: 24890096
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Single-year Grants
• Research Field: Pediatrics
• Research Institution: Kyoto University
• Principal Investigator: IZAWA Kazushi 京都大学, 医学(系)研究科(研究院), 医員 (90634931)
• Project Period (FY): 2012-08-31 – 2014-03-31
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥2,990,000 (Direct Cost: ¥2,300,000、Indirect Cost: ¥690,000); Fiscal Year 2013: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2012: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 自己炎症性疾患 / サイトカイン / 炎症

Research Abstract

CINCA syndrome is an autoinflammatory syndrome caused by gain-of-function NLRP3 mutations. The inheritance of CINCA syndrome is sporadic and autosomal dominant. It has been known that conventional genetic analyses fail to detect disease-causing mutations in approximately 50% of patients. We reported 70% of mutation negative patients have somatic mosaicism of NLRP3. However, the mechanism of inflammation by somatic mosaicism of NLRP3 is not elucidated.
To elucidate the mechanisms of NLPR3 mosaicism, we developed real-time single-cell imaging of IL-1 beta secretion. We found found that most of the IL-1 beta secreted cells lost their membrane integrity. Also, we found IL-1 beta secretion followed to the loss of cell membrane integrity with some lag time.

Research Products

• [Journal Article] Real-time single-cell imaging of protein secretion (2014)
  • Author(s): Shirasaki Y, Yamagishi M, Suzuki N, Izawa K, Nakahara A, Mizuno J, Shoji S, Heike T, Harada Y, Nishikomori R, Ohara O
  • Journal Title: scientific reports Volume: 4 Pages: 4736-4736
  • Peer Reviewed
• [Journal Article] Real-time single-cell imaging of protein secretion (2014)
  • Author(s): Yoshitaka Shirasaki, Mai Yamagishi, Nobutake Suzuki, Kazushi Izawa, Asahi Nakahara, Jun Mizuno, Shuichi Shoji, Toshio Heike, Yoshie Harada Ryuta Nishikomori, and Osamu Ohara
  • Journal Title: Scientific Reports Volume: 未定
  • Peer Reviewed
• [Journal Article] Autosomal dominant anhidrotic ectodermal dysplasia with immunodeficiency caused by a novel NFKBIA mutation, p.Ser36Tyr, presents with mild ectodermal dysplasia and non-infectious systemic inflammation (2013)
  • Author(s): Yoshioka T, Nishikomori R, Hara J, Okada K, Hashii Y, Okafuji I, Nodomi S, Kawai T, Izawa K, Ohnishi H, Yasumi T, Nakahata T, Heike T
  • Journal Title: J Clin Immunol. Volume: 33(7) Pages: 1165-74
  • Peer Reviewed
• [Journal Article] Heterozygous TREX1 p.Asp18Asn mutation can cause variable neurological symptoms in a family with Aicardi-Goutieres syndrome/familial chilblain lupus (2013)
  • Author(s): Abe J, Izawa K, Nishikomori R, Awaya T, Kawai T, Yasumi T, Hiragi N, Hiragi T, Ohshima Y, Heike T
  • Journal Title: Rheumatology (Oxford) Volume: 52(2) Pages: 406-408
  • Peer Reviewed
• [Journal Article] Somatic NLRP3 mosaicism in Muckle-Wells syndrome. A genetic mechanism shared by different phenotypes of cryopyrin-associated periodic syndromes. (2013)
  • Author(s): Nakagawa K, Gonzalez-Roca E, Souto A, Kawai T, Umebayashi H, Campistol JM, Canellas J, Takei S, Kobayashi N, Callejas-Rubio JL, Ortego-Centeno N, Ruiz-Ortiz E, Rius F, Anton J, Iglesias E, Jimenez-Trevino S, Vargas C, Fernandez-Martin J, Calvo I, Hernandez-Rodriguez J, Mendez M, Dordal MT et al.
  • Journal Title: Annals of the Rheumatic Diseases Volume: 未定
  • Peer Reviewed
• [Journal Article] A nationwide survey of Aicardi-Goutieres syndrome patients identifies a strong association between dominant TREX1 mutations and chilblain lesions : Japanese cohort study
  • Author(s): Abe J, Nakamura K, Nishikomori R, Kato M, Mitsuiki N, Izawa K, Awaya T, Kawai T, Yasumi T, Toyoshima I, Hasegawa K, Ohshima Y, Hiragi T, Sasahara Y, Suzuki Y, Kikuchi M, Osaka H, Ohya T, Ninomiya S, Fujikawa S, Akasaka M, Iwata N, Kawakita A, Funatsuka M, Shintaku H, Ohara O, Ichinose H, Heike T
  • Journal Title: Rheumatology Volume: (in press)
  • Peer Reviewed
• [Journal Article] Somatic NLRP3 mosaicism in Muckle-Wells syndrome. A genetic mechanism shared by different phenotypes of cryopyrin-associated periodic syndromes
  • Author(s): Nakagawa K, Gonzalez-Roca E, Souto A, Kawai T, Umebayashi H, Campistol JM, Cañellas J, Takei S, Kobayashi N, Callejas-Rubio JL, Ortego-Centeno N, Ruiz-Ortiz E, Rius F, Anton J, Iglesias E, Jimenez-Treviño S, Vargas C, Fernandez-Martin J, Calvo I, Hernández-Rodríguez J, Mendez M, Dordal MT, Basagaña M, Bujan S, Yashiro M, Kubota T, Koike R, Akuta N, Shimoyama K, Iwata N, Saito MK, Ohara O, Kambe N, Yasumi T, Izawa K, Kawai T, Heike T, Yagüe J, Nishikomori R, Aróstegui JI
  • Journal Title: Ann Rheum Dis. Volume: (in press)
  • Peer Reviewed
• [Presentation] gene expression and signaling in the immune system (2014)
  • Author(s): Yoshitaka Shirasaki, Mai Yamagishi, Kazushi Izawa Hirotsugu Oda, Toshio Heike, Ryuta Nishikomori, Osamu Ohara
  • Place of Presentation: New York
• [Presentation] Real-time single-cell imaging of IL-1β secretion by Inflammasomes (2014)
  • Author(s): Yoshitaka Shirasaki, Mai Yamagishi, Kazushi Izawa, Hirotsugu Oda, Toshio Heike, Ryuta Nishikomori, Osamu Ohara
  • Organizer: Gene Expression&Signaling in the Immune System meeting
  • Place of Presentation: New York
• [Presentation] Muckle-Wells症候群におけるNLRP3体細胞モザイク変異の検討 (2013)
  • Author(s): 中川権史, 西小森隆太, 井澤和司, 河合朋樹, 八角高裕, 河合利尚, 梅林宏明, 武井修治, 小林法元, 小原收, Eva Gonzalez-Roca, Juan I. Arostegui, 平家俊男
  • Organizer: 第41回日本臨床免疫学会
  • Place of Presentation: 下関
  • Year and Date: 2013-11-27
• [Presentation] Muckle-Wells症候群におけるNLRP3体細胞モザイク変異の検討 (2013)
  • Author(s): 中川権史, 西小森隆太, 井澤和司, 河合朋樹, 八角高裕, 河合利尚, 梅林宏明, 武井修治, 小林法元, 小原收, Eva Gonzalez-Roca, Juan I. Arostegui, 平家俊男
  • Organizer: 第23回日本小児リウマチ学会
  • Place of Presentation: 埼玉
  • Year and Date: 2013-10-12
• [Presentation] CAPSに対するアナキンラ治療の有効性及び安全性の後方視的検討 (2013)
  • Author(s): 中川権史, 井澤和司, 西小森隆太, 河合朋樹, 八角高裕, 津下充, 小林法元, 河島尚志, 谷口敦夫, 窪田哲朗, 松林正, 平家俊男
  • Organizer: 第57回日本リウマチ学会
  • Place of Presentation: 京都
  • Year and Date: 2013-04-18
• [Book] 自己炎症性疾患・自然免疫不全症とその近縁疾患（CAPSの項） (2012)
  • Author(s): 井澤和司
  • Total Pages: 280
  • Publisher: 診断と治療社