Exploration of the causative genes and elucidation of the pathophysiology on immune dysregulatory diseases with intractable inflammation

• Project/Area Number: 15H04876
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Pediatrics
• Research Institution: Kyoto University
• Principal Investigator: Ryuta Nishikomori 京都大学, 医学研究科, 准教授 (70359800)
• Co-Investigator(Kenkyū-buntansha): 八角 高裕 京都大学, 医学研究科, 講師 (00511891) ; 平家 俊男 京都大学, 医学研究科, 名誉教授 (90190173) ; 斎藤 潤 京都大学, iPS細胞研究所, 准教授 (90535486)
• Co-Investigator(Renkei-kenkyūsha): OHARA Osamu かずさDNA研究所, ヒトゲノム研究部, 部長 (20370926) ; TOGUCHIDA Junya 京都大学, iPS細胞研究所, 教授 (40273502) ; FUJITA Takashi 京都大学, ウイルス研究所, 教授 (10156870) ; KATO Hiroki 京都大学, ウイルス研究所, 准教授 (10597173)
• Research Collaborator: TANAKA Takayuki ; NAKAGAWA Kenji ; HONDA Yoshitaka ; SHIMODERA Saeko ; OHTO Taisuke ; ODA Hirotsugu
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥17,550,000 (Direct Cost: ¥13,500,000、Indirect Cost: ¥4,050,000); Fiscal Year 2017: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2016: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000); Fiscal Year 2015: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
• Keywords: NLRC4異常症 / FLNA異常症 / iPS細胞 / 全エクソーム解析 / メバロン酸キナーゼ欠損症 / Aicardi-Goutieres症候群 / 炎症性疾患 / 原発性免疫不全症 / 自己炎症性疾患 / 自然免疫 / PCYT1A / deep intron変異 / IFIH1 / 炎症 / 遺伝子探索 / CAPS / NLRC4 / 遺伝性炎症性疾患 / NLRP3 / 遺伝子異常 / 遺伝子改変マウス / MAFB

Outline of Final Research Achievements

To identify the responsible gene for the intractable inflammatory diseases, we performed genomic analysis including whole exome-sequencing. In addition, we utilized disease-specific iPS cells as well as gene-targeted mouse models to delineate the pathophysiology of the inflammatory diseases. First, we identified NLRC4 gene as a new responsible gene for the CINCA/NOMID. In particular, we demonstrated the identified NLRC4 variant was disease-causing by genetic modification of iPS cells by CRISPR/Cas9 system. We also diagnosed FLNA deficiency on the 2 brothers suffering from inflammatory bowel diseases, valvulopathy, malrotation of intestine, and chronic intestinal pseudo-obstruction. We created　and studied knock-in mice for mevalonate kinase deficiency and BAC transgenic mice for Aicardi-Goutieres syndrome.

Research Products

• [Journal Article] Autoinflammatory phenotypes in Aicardi-Goutieres syndrome with interferon upregulation and serological autoimmune features. (2018)
  • Author(s): Sugawara, Y., Imai, K., Kashimada, A., Moriyama, K., Baba, S., Nishikomori, R., Motegi, M., Takeuchi, Y. & Morio, T.
  • Journal Title: J Allergy Clin Immunol Volume: 141 Issue: 3 Pages: 1135-1138
  • DOI: 10.1016/j.jaci.2017.10.019
  • Peer Reviewed
• [Journal Article] Fever of unknown origin with rashes in early infancy is indicative of adenosine deaminase type 2 deficiency (2017)
  • Author(s): Nihira H、Nakagawa K、Izawa K、Kawai T、Yasumi T、Nishikomori R、Nambu M、Miyagawa-Hayashino A、Nomura T、Kabashima K、Ito M、Iwaki-Egawa S、Sasahara Y、Nakayama M、Heike T
  • Journal Title: Scandinavian Journal of Rheumatology Volume: 47 Issue: 2 Pages: 170-172
  • DOI: 10.1080/03009742.2017.1324912
  • Peer Reviewed
• [Journal Article] A CD57+ CTL degranulation assay effectively identifies familial hemophagocytic lymphohistiocytosis type 3 patients (2017)
  • Author(s): Masayuki Hori, Takahiro Yasumi, Saeko Shimodera, Hirofumi Shibata, Eitaro Hiejima, Hirotsugu Oda, Kazushi Izawa, Tomoki Kawai, Masataka Ishimura, Naoko Nakano, Ryutaro Shirakawa, Ryuta Nishikomori, Hidetoshi Takada, Satoshi Morita, Hisanori Horiuchi, Osamu Ohara, Eiichi Ishii, and Toshio Heike
  • Journal Title: Journal of Clinical Immunology Volume: 37 Issue: 1 Pages: 92-99
  • DOI: 10.1007/s10875-016-0357-3
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Accurate clinical genetic testing for autoinflammatory diseases using the next-generation sequencing platform MiSeq (2017)
  • Author(s): Nakayama Manabu、Oda Hirotsugu、Nakagawa Kenji、Yasumi Takahiro、Kawai Tomoki、Izawa Kazushi、Nishikomori Ryuta、Heike Toshio、Ohara Osamu
  • Journal Title: Biochemistry and Biophysics Reports Volume: 9 Pages: 146-152
  • DOI: 10.1016/j.bbrep.2016.12.002
  • NAID: 120006355733
  • Peer Reviewed
• [Journal Article] Cryopyrin-associated Periodic Syndromes in Italian Patients: Evaluation of the Rate of Somatic NLRP3 Mosaicism and Phenotypic Characterization. (2017)
  • Author(s): Lasiglie, D., Mensa-Vilaro, A., Nakagawa, K., Nishikomori, R., Gattorno, M., Arostegui, J.I. & Borghini, S.
  • Journal Title: The Journal of rheumatology Volume: 44 Issue: 11 Pages: 1667-1673
  • DOI: 10.3899/jrheum.170041
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] High level of serum human interleukin-18 in a patient with pyogenic arthritis, pyoderma gangrenosum and acne syndrome (2017)
  • Author(s): Kanameishi, S. Nakamizo, S. Endo, Y. Fujisawa, A. Dainichi, T. Tanaka, T. Izawa, K. Nishikomori, R. Kabashima, K.
  • Journal Title: J Eur Acad Dermatol Venereol Volume: 31 Issue: 2
  • DOI: 10.1111/jdv.13856
  • Peer Reviewed
• [Journal Article] Hematopoietic stem cell transplantation in 29 patients hemizygous for hypomorphicIKBKG/NEMO mutations (2017)
  • Author(s): Miot C, Imai K, Imai C, Mancini AJ, Kucuk XY, Kawai T, Nishikomori R, Ito E, Pellier I, Girod SD, Rosain J, Sasaki S, Casanova JL, Orange JS, and Picard C et al.
  • Journal Title: Blood. Volume: 130 Issue: 12 Pages: 1456-1467
  • DOI: 10.1182/blood-2017-03-771600
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Live-attenuated vaccines in a cryopyrin-associated periodic syndrome patient receiving canakinumab treatment during infancy (2017)
  • Author(s): Watanabe, M. Nishikomori, R. Fujimaki, Y. Heike, T. Ohara, A. Saji, T.
  • Journal Title: Clin Case Rep Volume: 11 Issue: 11 Pages: 1750-1755
  • DOI: 10.1002/ccr3.1149
  • NAID: 120006533285
  • Peer Reviewed
• [Journal Article] Identification of a High-Frequency Somatic NLRC4 Mutation as a Cause of Autoinflammation by Pluripotent Cell-Based Phenotype Dissection. (2017)
  • Author(s): Kawasaki Y, Oda H, Ito J, Niwa A, Tanaka T, Hijikata A, Seki R, Nagahashi A, Osawa M, Asaka I, Watanabe A, Nishimata S, Shirai T, Kawashima H, Ohara O, Nakahata T, Nishikomori R, Heike T, Saito MK.
  • Journal Title: Arthritis Rheumatol. Volume: 69 Issue: 2 Pages: 447-459
  • DOI: 10.1002/art.39960
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Brief Report: Late-Onset Cryopyrin-Associated Periodic Syndrome Due to Myeloid-Restricted Somatic NLRP3 Mosaicism (2016)
  • Author(s): Mensa-Vilaro, A. Teresa Bosque, M. Magri, G. Honda, Y. Martinez-Banaclocha, H. Casorran-Berges, M. Sintes, J. Gonzalez-Roca, E. Ruiz-Ortiz, E. Heike, T. Martinez-Garcia, J. J. Baroja-Mazo, A. Cerutti, A. Nishikomori, R. Yague, J. Pelegrin, P. Delgado-Beltran, C. Arostegui, J. I.
  • Journal Title: Arthritis Rheumatol Volume: 68 Issue: 12 Pages: 3035-3041
  • DOI: 10.1002/art.39770
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Genetic and clinical features of cryopyrin-associated periodic syndromes in Turkish children (2016)
  • Author(s): Eroglu, F. K. Kasapcopur, O. Besbas, N. Ozaltin, F. Bilginer, Y. Barut, K. Mensa-Vilaro, A. Nakagawa, K. Heike, T. Nishikomori, R. Arostegui, J. Ozen, S.
  • Journal Title: Clin Exp Rheumatol Volume: 34
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Febrile attacks triggered by milk allergy in an infant with mevalonate kinase deficiency (2016)
  • Author(s): Nakashimai, H. Miyake, F. Ohki, S. Hattori, S. Matsubayashi, T. Izawa, K. Nishikomori, R. Heike, T. Honda, Y. Shigematsu, Y.
  • Journal Title: Rheumatol Int Volume: 36 Issue: 10 Pages: 1477-1478
  • DOI: 10.1007/s00296-016-3522-3
  • Peer Reviewed
• [Journal Article] Clinical and Genetic Features of Patients With TNFRSF1A Variants in Japan: Findings of a Nationwide Survey (2016)
  • Author(s): Ueda, N. Ida, H. Washio, M. Miyahara, H. Tokunaga, S. Tanaka, F. Takahashi, H. Kusuhara, K. Ohmura, K. Nakayama, M. Ohara, O. Nishikomori, R. Minota, S. Takei, S. Fujii, T. Ishigatsubo, Y. Tsukamoto, H. Tahira, T. Horiuchi, T.
  • Journal Title: Arthritis Rheumatol Volume: 68 Issue: 11 Pages: 2760-2771
  • DOI: 10.1002/art.39793
  • Peer Reviewed / Open Access
• [Journal Article] Exon skipping causes atypical phenotypes associated with a loss-of-function mutation in FLNA by restoring its protein function (2016)
  • Author(s): Oda H., Sato T., Kunishima S., Nakagawa K., Izawa K., Hiejima E., Kawai T., Yasui T., Doi H., Katamura K., Numabe H., Okamoto S., Nakase H., Hijikata A., Ohara O., Suzuki H., Morisaki H., Morisaki T., Nunoi H., Hattori S., Nishikomori R., Heike T.
  • Journal Title: Eur J Hum Genet Volume: 24 Issue: 3 Pages: 408-414
  • DOI: 10.1038/ejhg.2015.119
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Presentation] 自己炎症性疾患 病態と治療 PFSを中心に (2017)
  • Author(s): 西小森隆太
  • Organizer: 第60回 日本リウマチ学会総会
• [Presentation] 大学院を、小児科医キャリア形成の中で、どう位置づけ、どう活用するか フロントランナーからのメッセージ ケーススタディ 大学院教育の小児科医師におけるインパクト (2017)
  • Author(s): 西小森隆太
  • Organizer: 第120回 日本小児科学会総会
• [Presentation] 知っておきたい稀少疾患 自己炎症性疾患 特に蕁麻疹様発疹をきたす疾患 (2017)
  • Author(s): 西小森隆太
  • Organizer: 第34回 日本小児難治喘息・アレルギー疾患学会総会
  • Invited
• [Presentation] PFAPAの臨床像で発症し、長期経過後に腸管炎症、陰部潰瘍を合併したため診断に至った孤発性のTNFA1P3異常症の1例 (2016)
  • Author(s): 本田吉孝, 河合朋樹, 西小森隆太, 八角高裕, 井澤和司, 日衛嶋栄太郎, 中川権史, 柴田洋史, 下寺佐栄子, 大音泰介, 芝剛, 仁平寛士, 小田紘嗣, 小原收, 平家俊男
  • Organizer: 小児リウマチ学会
  • Place of Presentation: 千葉
  • Year and Date: 2016-10-21
• [Presentation] 小児免疫疾患における分子標的薬 (2016)
  • Author(s): 西小森隆太
  • Organizer: 日本臨床免疫学会
  • Place of Presentation: 東京
  • Year and Date: 2016-09-08
• [Presentation] 本邦でのメバロン酸キナーゼ欠損症のまとめ (2016)
  • Author(s): 田中孝之, 西小森隆太, 中川権史, 井澤和司, 河合朋樹, 八角高裕, 平家俊男
  • Organizer: 日本リウマチ学会
  • Place of Presentation: 横浜
  • Year and Date: 2016-04-21
• [Presentation] 本邦でのメバロン酸キナーゼ欠損症のまとめ (2015)
  • Author(s): 田中孝之, 吉岡耕平, 酒井秀政, 西小森隆太, 阿部純也, 日衛嶋栄太郎, 小原收, 河合朋樹, 八角高裕, 平家俊男
  • Organizer: 日本小児リウマチ学会総会
  • Place of Presentation: 金沢
  • Year and Date: 2015-10-09
• [Presentation] Understanding the pathophysiology of NOMID arthropathy for drug discovery by iPSCs technology. (2015)
  • Author(s): Nakagawa K., Okuno Y., Nishikomori R., Yokoyama K., Tanaka T., Kawai T., Yasumi T., Umeda K., Nakayama N., Toguchida J., Hagiwara M., Heike T.
  • Organizer: 8th International Society of Systemic Autoinflammatory Diseases Meeting 2015 (2015)
  • Place of Presentation: Dresden, Germany
  • Year and Date: 2015-09-29
  • Int'l Joint Research