Elucidation of molecular pathogenesis and development of treatment for muscular dystrophy and neurodevelopmental disorder caused by abnormal glycosylation

• Project/Area Number: 21689030
• Research Category: Grant-in-Aid for Young Scientists (A)
• Allocation Type: Single-year Grants
• Research Field: Pediatrics
• Research Institution: Kobe University
• Principal Investigator: KOBAYASHI Kazuhiro 神戸大学, 医学研究科, 准教授 (90324780)
• Project Period (FY): 2009 – 2011
• Project Status: Completed (Fiscal Year 2011)
• Budget Amount: ¥27,300,000 (Direct Cost: ¥21,000,000、Indirect Cost: ¥6,300,000); Fiscal Year 2011: ¥7,020,000 (Direct Cost: ¥5,400,000、Indirect Cost: ¥1,620,000); Fiscal Year 2010: ¥9,620,000 (Direct Cost: ¥7,400,000、Indirect Cost: ¥2,220,000); Fiscal Year 2009: ¥10,660,000 (Direct Cost: ¥8,200,000、Indirect Cost: ¥2,460,000)
• Keywords: 小児神経学 / 福山型筋ジス / 筋眼脳病 / 糖鎖 / 高次脳機能 / ゲノム / 遺伝子治療

Research Abstract

The structure of the O-Man type glycan ofα-dystroglycan is still unknown in spite of our many efforts for mass spectrometry. We found that some known proteins involved in the O-Man type glycan synthesis are bound to one another and we are searching for other unknown binding molecules. We showed potential in vivo of the gene therapy by adeno-associaterd viral vector and the antisense therapy for the SVA insertion mutation as treatments ofα-DGpathy. We successfully made central nervous system-specific fukutin-deficient mice, and observed abnormality of the brain.

Research Products

• [Journal Article] Mislocalization of fukutin protein by disease-causing missense mutations can be rescued with treatments directed at folding amelioration (2012)
  • Author(s): Tachikawa M, Kanagawa M, Yu CC, Kobayashi K, Toda T
  • Journal Title: J Biol Chem Volume: 287 Pages: 8398-8406
  • Peer Reviewed
• [Journal Article] Absence of post-phosphoryl modification in dystroglycanopathy mouse models and wild-type tissues expressing a non-laminin binding form ofα-dystroglycan (2012)
  • Author(s): Kuga A, Kanagawa M, Sudo A, Chan YM, Tajiri M, Manya H, Kikkawa Y, Nomizu M, Kobayashi K, Endo T, Lu QL, Wada Y, Toda T
  • Journal Title: J Biol Chem Volume: 287 Pages: 9560-9567
  • Peer Reviewed
• [Journal Article] Absence of post-phosphoryl modification in dystroglycanopathy mouse models and wild-type tissues expressing a non-laminin binding form of α-dystroglycan (2012)
  • Author(s): Kuga A
  • Journal Title: J Biol Chem Volume: 287 Issue: 12 Pages: 9560-9567
  • DOI: 10.1074/jbc.m111.271767
  • Peer Reviewed
• [Journal Article] Pathogenic exon-trapping by SVA retrotransposon and rescue in Fukuyama muscular dystrophy (2011)
  • Author(s): Taniguchi-Ikeda M, Kobayashi K(equally contributed), Kanagawa M, Yu CC, Mori K, Oda T, Kuga A, Kurahashi H, Akman HO, Dimauro S, Kaji R, Yokota T, Takeda S, Toda T
  • Journal Title: Nature Volume: 478 Pages: 127-131
  • Peer Reviewed
• [Journal Article] Pathogenic exon-trapping by SVA retrotransposon and rescue in Fukuyama muscular dystrophy (2011)
  • Author(s): Taniguchi-Ikeda M, Kobayashi K, Kanagawa M, Yu CC, Mori K, Oda T, Kuga A, Kurahashi H, Akman HO, DiMauro S, Kaji R, Yokota T, Takeda S, Toda T
  • Journal Title: Nature Volume: 478 Issue: 7367 Pages: 127-131
  • DOI: 10.1038/nature10456
  • Peer Reviewed
• [Journal Article] Post-translational maturation of dystroglycan is necessary for pikachurin binding and ribbon synaptic localization (2010)
  • Author(s): Kanagawa M, Omori Y, Sato S, Kobayashi K, Miyagoe-Suzuki Y, Takeda S, Endo T, Furukawa T, Toda T
  • Journal Title: J Biol Chem Volume: 285 Pages: 31208-31216
  • Peer Reviewed
• [Journal Article] The dyslexia-associated KIAA0319 protein undergoes proteolytic processing with {gamma}-secretase-independent intramembrane cleavage. (2010)
  • Author(s): Velayos-Baeza A
  • Journal Title: J Biol Chem Volume: 285 Pages: 40148-40162
  • Peer Reviewed
• [Journal Article] Post-translational maturation of dystroglycan is necessary for pikachurin binding and ribbon synaptic localization. (2010)
  • Author(s): Kanagawa M
  • Journal Title: J Biol Chem Volume: 285 Pages: 31208-31216
  • Peer Reviewed
• [Journal Article] Fukutin gene retrotransposal insertion in a non-Japanese Fukuyama congenital muscular dystrophy(FCMD) patient (2009)
  • Author(s): Xiong H, Wang S, Kobayashi K, Jiang Y, Wang J, Chang X, Yuan Y, Liu J, Toda T, Fukuyama Y, Wu X
  • Journal Title: Am J Med Genet Volume: A149 Pages: 2403-2408
  • Peer Reviewed
• [Journal Article] Spinocerebellar ataxia type 31 is associated with "inserted" penta-nucleotide repeats containing (TGGAA)_n. (2009)
  • Author(s): Sato N
  • Journal Title: Am J Hum Genet 85 Pages: 544-557
  • Peer Reviewed
• [Journal Article] Fukutin gene retrotransposal insertion in a non-Japanese Fukuyama congenital muscular dystrophy (FCMD) patient. (2009)
  • Author(s): Xiong H
  • Journal Title: Am J Med Genet A 149 Pages: 2403-2408
  • Peer Reviewed
• [Journal Article] MET and autism susceptibility : family and case-control studies. (2009)
  • Author(s): Sousa I
  • Journal Title: Eur J Hum Genet 17 Pages: 749-758
  • Peer Reviewed
• [Presentation] SVAレトロトランスポゾン挿入による病的exon-trappingと福山型筋ジストロフィーにおけるレスキュー (2011)
  • Author(s): 小林千浩
  • Organizer: 第34回日本分子生物学会年会
  • Place of Presentation: シフィコ横浜(神奈川)
  • Year and Date: 2011-12-14
• [Presentation] SVAレトロトランスポゾン挿入による病的exon-trappingと福山型筋ジストロフィーにおけるレスキュー (2011)
  • Author(s): 小林千浩
  • Organizer: 第34回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜(神奈川県)
  • Year and Date: 2011-12-14
• [Presentation] SVAレトロトランスポゾンによる病的エクソントラッピングと福山型筋ジストロフィーにおけるレスキュー (2011)
  • Author(s): 谷口(池田)真理子
  • Organizer: 日本人類遺伝学会第56回大会
  • Place of Presentation: 幕張メッセ(千葉)
  • Year and Date: 2011-11-12
• [Presentation] フクチン変異筋ジストロフィーにおけるミスセンス変異体局在異常とジストログリカン糖修飾活性、およびクルクミンによる局在補正 (2011)
  • Author(s): 立川雅司
  • Organizer: 日本人類遺伝学会第56回大会
  • Place of Presentation: 幕張メッセ(千葉)
  • Year and Date: 2011-11-11
• [Presentation] Pathogenic exon trapping by SVA retrotransposon and rescue in Fukuyama muscular dystrophy (2011)
  • Author(s): Taniguchi-Ikeda M
  • Organizer: 16th International Congress of the World Muscle Society
  • Place of Presentation: Ria Park Hotel Almancil(アルガルヴェ、ポルトガル)
  • Year and Date: 2011-10-22
• [Presentation] 認知能力の差が顕著な一卵性双生児のDNAメチル化解析 (2010)
  • Author(s): 小林千浩
  • Organizer: 第33回日本分子生物学会年会第83回日本生化学会大会合同大会
  • Place of Presentation: 神戸ポートアイランド(兵庫県)
  • Year and Date: 2010-12-07
• [Presentation] Genome-wide gene expression and DNA methylation analyses of significantly discordant monozygotic twins for cognitive ability. (2010)
  • Author(s): Kobayashi K
  • Organizer: American Society of Human Genetics 60th Annual Meeting
  • Place of Presentation: Washington Convention Center(Washington DC,米国)
  • Year and Date: 2010-11-03
• [Presentation] 認知能力の差が顕著な一卵性双生児の分子遺伝学的解析 (2010)
  • Author(s): 小林千浩
  • Organizer: 日本人類遺伝学会第55回大会
  • Place of Presentation: 大宮ソニックシティ(埼玉県)
  • Year and Date: 2010-10-30
• [Presentation] 認知能力の差が顕著な一卵性双生児の網羅的遺伝子発現・DNAメチル化解析 (2010)
  • Author(s): 小林千浩
  • Organizer: 日本パーソナリティ心理学会第19回大会
  • Place of Presentation: 慶應義塾大学三田キャンパス(東京都)(招待講演)
  • Year and Date: 2010-10-11
• [Presentation] 福山型先天性筋ジストロフィーはスプライシング異常症である (2010)
  • Author(s): 谷口真理子
  • Organizer: 日本人類遺伝学会第55回大会
  • Place of Presentation: 大宮(埼玉)
• [Presentation] Disruption of dystroglycan-pikachurin interaction underlies the molecular pathogenesis of eye abnormalities in dystroglycanopathy (2010)
  • Author(s): Kanagawa M
  • Organizer: The 15th International Congress of World Muscle Society
  • Place of Presentation: 熊本
• [Presentation] 骨格筋特異的fukutin KOマウスの表現型解析～福山型先天性筋ジストロフィーの病態解明に向けて～ (2009)
  • Author(s): 佐藤佳乃子
  • Organizer: 第32回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜(神奈川県)
  • Year and Date: 2009-12-10
• [Presentation] 骨格筋特異的fukutin KOマウスの表現型解析～福山型先天性筋ジストロフィーの病態解明に向けて～ (2009)
  • Author(s): 佐藤佳乃子
  • Organizer: 第32回日本分子生物学会年会
  • Place of Presentation: 横浜(神奈川)
• [Presentation] Residual laminin-binding activity and enhanced dystroglycan glycosylation by LARGE in novel model mice to dystroglycanopathy (2009)
  • Author(s): Taniguchi M
  • Organizer: The American society of human genetics, 59th annual meeting
  • Place of Presentation: ホノルル、アメリカ
• [Remarks]
  • URL: http://www.med.kobe-u.ac.jp/clgene/
• [Remarks]
  • URL: http://www.med.kobe-u.ac.jp/clgene/
• [Remarks]
  • URL: http://www.med.kobe-u.ac.jp/clgene/