• Search Research Projects
  • Search Researchers
  • How to Use
  1. Back to project page

2003 Fiscal Year Final Research Report Summary

The elucidation of pathomechanism and the development of therapy of myopathies with autophagic abnormalities

Research Project

Project/Area Number 13470138
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Neurology
Research InstitutionNATIONAL INSTITUTE OF NEUROSCIENE, NATIONAL CENTER OF NEUROLOGY AND PSYCHIATRY (NCNP)

Principal Investigator

NISHINO Ichizo  NATIONAL INSTITUTE OF NEUROSCIENE, NATIONAL CENTER OF NEUROLOGY AND PSYCHIATRY (NCNP), DIRECTOR, 疾病研究第一部, 部長 (00332388)

Co-Investigator(Kenkyū-buntansha) MURAKAMI Nobuyuki  DOKKYO UNIVERSITY, SCHOOL OF MEDICINE, 越谷病院・小児科, 講師
Project Period (FY) 2001 – 2003
Keywordslysosome / myopathy / autophagic vacuole / Danon disease / rimmed vacuoles / distal myopathy
Research Abstract

We clinicopathologically characterized 38 patients from 13 distinct families with genetically confirmed Danon disease. Cardiomyopathy and myopathy were seen in all men but mental retardation was present in 70% of men. Serum CK level is elevated in all men but only in 63% of women. Men died at age 19±6 years while women died at age 40±7 years, both due to cardiac failure. All women developed lethal cardiomyopathy even though they had milder symptoms. We identified two new forms of autophagic vacuolar myopathy (AVM) which resembles Danon disease but are genetically distinct : adult-onset AVM with multi-organ involvement and X-linked AVM resembling congenital myopathy. The latter disease was mapped to Xq28. LC3,which is supposed to be degraded immediately after the fusion between autophagosomes and lysosomes, was not degraded in the X-linked AVM, suggesting an abnormality in the degradation process.
We identified that the GNE gene encoding UDP-GlcNAc 2-epimerase/ManNAc kinase (GNE/MNK) is the causative gene for distal myopathy with rimmed vacuoles (DMRV) just as in hereditary inclusion body myopathy. Recombinant proteins with mutations found in patients showed that those with mutations in GNE domain had decreased GNE activity while those with MNK mutations had decreased MNK activity.
Sialylation was decreased in patients' cells, which was recovered by adding ManNAc or NeuAc. Our results suggest a possibility of curative therapy for DMRV.

  • Research Products

    (27 results)

All Other

All Publications (27 results)

  • [Publications] Yamamoto A, et al.: "Infantile autophagic vacuolar myopathy is distinct from Danon disease."Neurology. 57. 903-905 (2001)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Nishino I, at al.: "Danon disease and related disorders."Acta Myologica. 20. 120-124 (2001)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 西野 一三: "過剰自己貧食を伴うX連鎖性ミオパチー"日本臨床. 36. 230-232 (2001)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 西野 一三: "Danon病"日本臨床. 36. 225-229 (2001)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Sugie K, et al.: "Clinicopathological features of genetically confirmed Danon disease."Neurology. 58. 1773-1778 (2002)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Takahashi M, et al.: "Germline mosaicism of a novel mutation in LAMP-2 deficiency (Danon disease)."Ann Neurol. 52. 122-125 (2002)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Michele DE, et al.: "Post-translational disruption of dystroglycan-ligand interactions in congenital muscular dystrophies."Nature. 418. 417-422 (2002)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Nishino, et al.: "Distal myopathy with rimmed vacuoles in allelic to hereditary inclusion body myopathy."Neurology. 59. 1689-1693 (2002)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Nishino I: "Autophagic vacuolar myopathies."Curr Neurol Neorosci Rep. 3. 64-69 (2003)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Noguchi S, at al.: "cDNA microarray analysis of individual Duchenne muscular dystrophy patients."Hum Mol Genet. 12. 595-600 (2003)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Kaneda D, at al.: "A novel form of autophagic vacuolar myopachy with late-onset and multiorgan involvement."Neurology. 61. 128-131 (2003)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Sugie K, et al.: "Characterization of Donon disease in a male patient and his affected mother."Neuromuscul Disord. 13. 708-711 (2003)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Noguchi S, et al.: "Reduction of UDP-GlcNAc 2-epimerase/ManNAc kinase activity and sialylation in distal myopathy with rimmed vacuoles."J Biol Chem. 279. 11402-11407 (2004)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 西野 一三: "縁取り空胞を伴う遠位型ミオパチーの原因遺伝子と分子病態"ゲノム医学. 4. 21-26 (2004)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Nishino I, et al.: "Structural and Molecular Basis of Skeletal Muscle Diseases.(Karpati C, ed.)"INS Neuropath Press, Basel, Switzerland. (2002)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Nishino I: "Lysosomal membrane disorders - LAMP-2 deficiency. The Molecular and genetic basis of neurologic and psychiatric disease"Butterwoth-Heinemamm, Boston, MA, USA. (2003)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Yamamoto A, et al.: "Infantile autophagic vacuolar myopathy is distinct from Danon disease."Neurology. 57. 903-905 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Nishino I, et al.: "Danon disease and related disorders."Acta Myologica. 20. 120-124 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Sugie K, et al.: "Clinicopathological features of genetically confirmed Danon disease."Neurology. 58. 1773-1778 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Takahashi M, et al.: "Germline mosaicism of a novel mutation in lysosome-associated membrane protein-2 deficiency (Danon disease)."Ann Neurol. 52. 122-125 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Michele DE, et al.: "Post-translational disruption of dystroglycan-ligand interactions in congenital mouscular dystrophies."Nature. 418. 417-422 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Nishino I, et al.: "Distal myopathy with rimmed vacuoles is allelic to hereditary inclusion body myopathy."Neurology. 59. 1689-1693 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Nishino I: "Autophagic Vacuolar Myopathies."Curre Neurol Neurosci Rep. 3. 64-69 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Noguchi S, et al.: "cDNA microarray analysis of individual Duchnne muscular dystrophy patients."Hum Mol Genet. 12. 595-600 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Kaneda D, et al.: "A novel form of autophagic vacuolar myopathy with late-onset and multiorgan Involvement."Neurology. 61. 128-131 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Sugie K, et al.: "Characterization of Danon disease in a male patient and his affected mother."Neuromuscul Disord. 13. 708-711 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Noguchi S, et al.: "Reduction of UDP-GlcNAc 2-epimerase/ManNAc kinase activity and sialylation in distal myopathy with rimmed vacuoles."J Biol Chem. 279. 11402-11407 (2004)

    • Description
      「研究成果報告書概要(欧文)」より

URL: 

Published: 2005-04-19  

Information User Guide FAQ News Terms of Use Attribution of KAKENHI

Powered by NII kakenhi