Analysis of the causative glycan for muscular dystrophy and exploration of the therapeutic possibility of its neuronal dysfunction

• Project/Area Number: 26670499
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Pediatrics
• Research Institution: Kobe University
• Principal Investigator: Kobayashi Kazuhiro 神戸大学, 医学(系)研究科(研究院), 准教授 (90324780)
• Project Period (FY): 2014-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000); Fiscal Year 2015: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2014: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
• Keywords: 糖鎖 / ジストログリカノパチー / 福山型筋ジストロフィー / 質量分析 / NMR構造解析 / 糖転移酵素 / a-dystroglycan / 神経機能障害 / α-dystroglycan

Outline of Final Research Achievements

In this study, we aimed to delineate the full O-Man glycan structure of a-dystroglycan (a-DG) whose abnormalities cause muscular dystrophy, to clarify the biosynthesis pathway of the glycan, to understand the pathology of neuronal dysfunction of the disease, and to explore its therapeutic possibility. We determined the unknown glycan structure in part by MS analysis of a large quantity of the purified a-DG recombinant protein. We also identified the functions of some genes that are responsible for muscular dystrophy, and determined the detailed structure of the glycan in part that was synthesized using the gene products by MS and NMR analyses. We could not find a novel protein modified with the O-Man glycan or a novel a-DG ligand. We could not see the phenotype of the model mice by behavioral analysis. We are trying the intracerebral administration of antisense oligonucleotides to the model mice. Further investigations are required.

Research Products

• [Int'l Joint Research] Peking University First Hospital(中国)
• [Journal Article] Identification of a post-translational modification with ribitol-phosphate and its defect in muscular dystrophy (2016)
  • Author(s): Kanagawa M, Kobayashi K, Tajiri M, Manya H, Kuga A, Yamaguchi Y, Akasaka-Manya K, Furukawa J, Mizuno M, Kawakami H, Shinohara Y, Wada Y, Endo T, Toda T.
  • Journal Title: Cell Reports Volume: 14 Issue: 9 Pages: 2209-2223
  • DOI: 10.1016/j.celrep.2016.02.017
  • NAID: 120005728438
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Fukutin is prerequisite to ameliorate muscular dystrophic phenotype by myofiber-selective LARGE expression. (2015)
  • Author(s): Ohtsuka Y, Kanagawa M, Yu CC, Ito C, Chiyo T, Kobayashi K, Okada T, Takeda S’I, Toda T.
  • Journal Title: Sci Rep Volume: 5 Issue: 1 Pages: 8316-8316
  • DOI: 10.1038/srep08316
  • NAID: 120005600773
  • Peer Reviewed / Open Access
• [Journal Article] Founder mutation causes classical Fukuyama congenital muscular dystrophy (FCMD) in Chinese patients (2015)
  • Author(s): Yang H, Kobayashi K, Wang S, Jiao H, Xiao J, Toda T, Wu X, Xiong H
  • Journal Title: Brain and Development Volume: 37 Issue: 9 Pages: 880-886
  • DOI: 10.1016/j.braindev.2015.02.010
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] A de novo mutation of the MYH7 gene in a large Chinese family with autosomal dominant myopathy (2015)
  • Author(s): Oda T, Xiong H, Kobayashi K, Wang S, Satake W, Jiao H, Yang Y, Cha PC, Hayashi Y, Nishino I, Suzuki Y, Sugano S, Wu X, Toda T.
  • Journal Title: Human Genome Variation Volume: 2 Issue: 1 Pages: 15022-15022
  • DOI: 10.1038/hgv.2015.22
  • Peer Reviewed / Open Access
• [Presentation] 糖転移酵素LARGE活性を応用したジストログリカノパチー治療の検討 (2015)
  • Author(s): 大塚 喜久、金川 基、千代 智子、小林 千浩、岡田 尚巳、武田 伸一、戸田 達史
  • Organizer: 第３４回日本糖質学会年会
  • Place of Presentation: 東京大学（東京都文京区）
  • Year and Date: 2015-07-31
• [Presentation] Fukutin is prerequisite to ameliorate muscular dystrophy by LARGE expression (2015)
  • Author(s): 大塚 喜久、金川 基、游 智傑、伊藤 千代美、千代 智子、小林 千浩、 岡田 尚巳、武田 伸一、戸田 達史
  • Organizer: 第５６回日本神経学会学術大会
  • Place of Presentation: 朱鷺メッセ（新潟県新潟市）
  • Year and Date: 2015-05-20
• [Remarks] 神戸大学大学院医学研究科分子脳科学分野ホームページ
  • URL: http://www.med.kobe-u.ac.jp/clgene/
• [Remarks] 神戸大学医学研究科分子脳科学ホームページ
  • URL: http://www.med.kobe-u.ac.jp/clgene/