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

• 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
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2013: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2012: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• 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 / 中條－西村症候群 / β5iサブユニット / ノックインマウス / 中条-西村症候群 / ユビキチン化タンパク質 / 細胞ストレス / IL-6 / 炎症 / ユビキチン化

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.

Research Products

• [Journal Article] Predominantly placenta-expressed mRNAs in maternal plasma as predictive markers for twin-twin transfusion syndrome (2014)
  • Author(s): Miura K, Higashijima A, Miura S, Mishima H, Yamasaki K, Abe S, Hasegawa Y, Kaneuchi M, Yoshida A, Kinoshita A, Yoshiura KI, Masuzaki H.
  • Journal Title: Prenatal Diagnosis Volume: 34 Issue: 4 Pages: 345-349
  • DOI: 10.1002/pd.4307
  • Peer Reviewed
• [Journal Article] Single human papillomavirus 16 or 52 infection and later cytological findings in Japanese women with NILM or ASC-US. (2014)
  • Author(s): Abe S, Miura K, Kinoshita A, Mishima H, Miura S, Yamasaki K, Hasegawa Y, Higashijima A, Jo O, Yoshida A, Kaneuchi M, Yoshiura K, Masuzaki H.
  • Journal Title: Journal of Human Genetics Volume: 59 (5) Issue: 5 Pages: 251-255
  • DOI: 10.1038/jhg.2014.9
  • Peer Reviewed
• [Journal Article] Genome-wide association study of HPV-associated cervical cancer in Japanese women. (2014)
  • Author(s): Miura K, Mishima H, Kinoshita A, Hayashida C, Abe S, Tokunaga K, Masuzaki H, Yoshiura KI.
  • Journal Title: Journal of Medical Virology Volume: 86 (7) Issue: 7 Pages: 1153-1158
  • DOI: 10.1002/jmv.23943
  • Peer Reviewed
• [Journal Article] Identification of endometrioid endometrial carcinoma-associated microRNAs in tissue and plasma. (2014)
  • Author(s): Tsukamoto O, Miura K, Mishima H, Abe S, Kaneuchi M, Higashijima A, Miura S, Kinoshita A, Yoshiura K, Masuzaki H.
  • Journal Title: Gynecologic Oncology Volume: 132 (3) Issue: 3 Pages: 715-721
  • DOI: 10.1016/j.ygyno.2014.01.029
  • Peer Reviewed
• [Journal Article] Initial viral load in cases of single human papillomavirus 16 or 52 persistent infection is associated with progression of later cytopathological findings in the uterine cervix (2013)
  • Author(s): Hamaguchi D, Miura K, Abe S, Kinoshita A, Miura S, Yamasaki K, Yoshiura K, Masuzaki H
  • Journal Title: Journal of Medical Virology Volume: 85 Issue: 12 Pages: 2093-2100
  • DOI: 10.1002/jmv.23709
  • Peer Reviewed
• [Journal Article] Copy number variation of the antimicrobial-gene, defensin beta 4, is associated with susceptibility to cervical cancer. (2013)
  • Author(s): Abe, S, Miura, K, Kinoshita, A, Mishima, H, Miura, S, Yamasaki, K, Hasegawa, Y, Higashijima, A, Jo, O, Sasaki, K, Yoshida, A, Yoshiura, KI, Masuzaki.
  • Journal Title: Journal of Human Genetics Volume: 58 Issue: 5 Pages: 250-253
  • DOI: 10.1038/jhg.2013.7
  • Peer Reviewed
• [Journal Article] Characterization of placenta-specific microRNAs in fetal growth restriction pregnancy (2013)
  • Author(s): Higashijima A
  • Journal Title: Prenat Diagn Volume: 33 Issue: 3 Pages: 214-222
  • DOI: 10.1002/pd.4045
  • Peer Reviewed
• [Journal Article] Mutations in UVSSA cause UV-sensitive syndrome and impair RNA polymerase IIo processing in transcription-coupled nucleotide-excision repair (2012)
  • Author(s): Nakazawa Y, Sasaki K, Mitsutake N, Yamashita S, Ogi T, et al
  • Journal Title: Nat Genet Volume: 44(5) Issue: 5 Pages: 586-92
  • DOI: 10.1038/ng.2229
  • NAID: 120006985586
  • Peer Reviewed
• [Journal Article] Mutations in PRRT2 responsible for paroxysmal kinesigenic dyskinesias also cause benign familialinfantile convulsions. (2012)
  • Author(s): Ono S, Yoshiura K , KinoshitaA, Kikuchi T, Nakane Y, Kato N,Sadamatsu M , Konishi T , Nagamitsu S , Matsuura M, Yasuda A, KomineM, Kanai K , Inoue T , Osamura T , Saito K , Hirose S, Koide H, Tomita H , Ozawa H , Niikawa N and Kurotaki N.
  • Journal Title: J Hum Genet Volume: 57 Issue: 5 Pages: 1-4
  • DOI: 10.1038/jhg.2012.23
  • Peer Reviewed
• [Journal Article] The role of Irf6 in tooth epithelial invagination. (2012)
  • Author(s): Blackburn J, Ohazama A, Kawasaki K, Otsuka-Tanaka Y, Liu B, Honda K, Rountree R, Hu Y, Kawasaki M, Birchmeier W, Schmidt-Ullrich R, Kinoshita A, Schutte B, Hammond N, Dixon M, Sharpe P.
  • Journal Title: Developmental Biology Volume: 365 Issue: 1 Pages: 61-70
  • DOI: 10.1016/j.ydbio.2012.02.009
  • Peer Reviewed
• [Journal Article] No evidence of association between 8q24 and susceptibility to nonsyndromic cleft lip with or without palate in Japanese population (2011)
  • Author(s): Hikida M, Tsuda M, Watanabe A
  • Journal Title: Cleft Palate Craniofac J Volume: (掲截確定) Issue: 6 Pages: 714-717
  • DOI: 10.1597/10-242
  • Peer Reviewed