Elucidation of pathomechanism common to inclusion body myopathies and search for therapeutic target molecules

• Project/Area Number: 17K16107
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Neurology
• Research Institution: Tohoku University
• Principal Investigator: Izumi Rumiko 東北大学, 大学病院, 医員 (60571453)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2017: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
• Keywords: ミオパチー / 筋炎 / 封入体 / 縁取り空胞 / 蛋白分解系 / 遺伝学 / 筋疾患

Outline of Final Research Achievements

We performed genetic analysis using a next-generation sequencer for a total of 25 cases of hereditary inclusion body myopathy (hIBM) and sporadic inclusion body myositis (sIBM) for the extraction of genomic variants related to the pathogenesis of inclusion body formation and skeletal muscle degeneration.In addition, whole-genome long-read sequencing was performed on 3 cases of hIBM to detect pathogenic repeat sequence structure. From these analyses, we identified 24 rare and 27 novel variants, besides known mutations in 3 hIBM cases. From transcriptome analysis of skeletal muscle tissue RNA, 39 genes that were significantly different in expression level were extracted in comparison between the hIBM group and the control group.

Academic Significance and Societal Importance of the Research Achievements

治療法は未確立であり進行性の筋萎縮・筋力低下のため著しい機能障害を起こす遺伝性封入体ミオパチー（hIBM）と孤発性封入体筋炎（sIBM）の遺伝子解析を行い、51の新規あるいはレアバリアントを検出した。今後のこれらのデータと新規症例のデータ照合、生検筋を用いた検討の継続により、封入体形成に関係する新規病因遺伝子を明らかとできる可能性がある。またトランスクリプトーム解析では39遺伝子にて発現有意差を認めており、この中に治療法開発の可能性標的分子が含まれている可能性がある。今後治療法確立へ向けて解析を継続する。

Research Products

• [Journal Article] AMPK Complex Activation Promotes Sarcolemmal Repair in Dysferlinopathy (2020)
  • Author(s): Ono Hiroya、Suzuki Naoki、Kanno Shin-ichiro、Kawahara Genri、Izumi Rumiko、Takahashi Toshiaki、Kitajima Yasuo、Osana Shion、Nakamura Naoko、Akiyama Tetsuya、Ikeda Kensuke、Shijo Tomomi、Mitsuzawa Shio、Nagatomi Ryoichi、Araki Nobukazu、Yasui Akira、Warita Hitoshi、Hayashi Yukiko K.、Miyake Katsuya、Aoki Masashi
  • Journal Title: Molecular Therapy Volume: 28 Issue: 4 Pages: 1133-1153
  • DOI: 10.1016/j.ymthe.2020.02.006
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Extranodal NK/T-cell Lymphoma Mimicking Granulomatous Myositis (2019)
  • Author(s): Kawaguchi Norihiko、Izumi Rumiko、Kobayashi Masahiro、Tateyama Maki、Suzuki Naoki、Fujishima Fumiyoshi、Fujimori Juichi、Aoki Masashi、Nakashima Ichiro
  • Journal Title: Internal Medicine Volume: 58 Issue: 2 Pages: 277-282
  • DOI: 10.2169/internalmedicine.0859-18
  • NAID: 130007579751
  • ISSN: 0918-2918, 1349-7235
  • Year and Date: 2019-01-15
• [Journal Article] Interstitial pneumonia and other adverse events in riluzole-administered amyotrophic lateral sclerosis patients: a retrospective observational study (2019)
  • Author(s): Inoue-Shibui Aya、Kato Masaaki、Suzuki Naoki、Kobayashi Junpei、Takai Yoshiki、Izumi Rumiko、Kawauchi Yuuko、Kuroda Hiroshi、Warita Hitoshi、Aoki Masashi
  • Journal Title: BMC Neurology Volume: 19 Issue: 1 Pages: 72-78
  • DOI: 10.1186/s12883-019-1299-1
  • Peer Reviewed / Open Access
• [Journal Article] The updated retrospective questionnaire study of sporadic inclusion body myositis in Japan (2019)
  • Author(s): Suzuki Naoki、Mori-Yoshimura Madoka、Yamashita Satoshi、…Nishino Ichizo、Aoki Masashi
  • Journal Title: Orphanet Journal of Rare Diseases Volume: 14 Issue: 1 Pages: 155-163
  • DOI: 10.1186/s13023-019-1122-5
  • NAID: 120006956841
  • Peer Reviewed / Open Access
• [Journal Article] Aberrant axon branching via Fos-B dysregulation in FUS-ALS motor neurons. (2019)
  • Author(s): Akiyama T, Suzuki N, Ishikawa M, Fujimori K, Sone T, Kawada J, Funayama R, Fujishima F, Mitsuzawa S, Ikeda K, Ono H, Shijo T, Osana S, Shirota M, Nakagawa T, et al.
  • Journal Title: EBioMedicine Volume: 45 Pages: 362-378
  • DOI: 10.1016/j.ebiom.2019.06.013
  • Peer Reviewed / Open Access
• [Journal Article] FDG-PET detects extensive calcinosis cutis in anti-NXP2 antibody-positive dermatomyositis (2019)
  • Author(s): Nakamura Naoko、Izumi Rumiko、Hoshi Yosuke、Takai Yoshiki、Ono Risako、Suzuki Naoki、Nagai Taichi、Ishii Yusho、Ishii Tomonori、Harigae Hideo、Okada Shuko、Aiba Setsuya、Okiyama Naoko、Fujimoto Manabu、Kuroda Hiroshi、Tateyama Maki、Aoki Masashi
  • Journal Title: Rheumatology Volume: kez083 Issue: 10 Pages: 1-1
  • DOI: 10.1093/rheumatology/kez083
  • Peer Reviewed
• [Journal Article] Five-year history of dysphagia as a sole initial symptom in inclusion body myositis (2017)
  • Author(s): Shibata Saori、Izumi Rumiko、Hara Tomonori、Ohshima Ryuji、Nakamura Naoko、Suzuki Naoki、Kato Kengo、Katori Yukio、Tateyama Maki、Kuroda Hiroshi、Aoki Masashi
  • Journal Title: J Neurol Sci. Volume: 381 Pages: 325-327
  • DOI: 10.1016/j.jns.2017.09.014
  • Peer Reviewed
• [Presentation] 次世代シークエンサーを用いた ジスフェルリン異常症の遺伝子解析 (2018)
  • Author(s): 井泉瑠美子, 他
  • Organizer: 日本筋学会第4回学術集会
• [Book] 神経内科 (2018)
  • Author(s): 井泉瑠美子, 鈴木直輝, 青木正志
  • Total Pages: 8
  • Publisher: 科学評論社
• [Book] 運動ニューロン疾患 (2017)
  • Author(s): 青木正志編, 井泉瑠美子, 他著
  • Total Pages: 352
  • Publisher: 中外医学社
  • ISBN: 9784498228887