11. Function and Mutations of the GNE Gene Leading to Distal Myopathy with Rimmed Vacuoles/Hereditary Inclusion-Body Myopathy, Animal Models, and Potential Treatment

  1. Valerie Askanas MD, PhD and
  2. W. King Engel MD
  1. May Christine V. Malicdan MD,
  2. Satoru Noguchi PhD and
  3. Ichizo Nishino MD, PhD

Published Online: 19 DEC 2011

DOI: 10.1002/9781444398311.ch11

Muscle Aging, Inclusion-Body Myositis and Myopathies

Muscle Aging, Inclusion-Body Myositis and Myopathies

How to Cite

Malicdan, M. C. V., Noguchi, S. and Nishino, I. (2012) Function and Mutations of the GNE Gene Leading to Distal Myopathy with Rimmed Vacuoles/Hereditary Inclusion-Body Myopathy, Animal Models, and Potential Treatment, in Muscle Aging, Inclusion-Body Myositis and Myopathies (eds V. Askanas and W. K. Engel), Wiley-Blackwell, Oxford, UK. doi: 10.1002/9781444398311.ch11

Editor Information

  1. Departments of Neurology and Pathology, University of Southern California Neuromuscular Center, University of Southern California Keck School of Medicine, Good Samaritan Hospital, Los Angeles, CA, USA

Author Information

  1. Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan

Publication History

  1. Published Online: 19 DEC 2011
  2. Published Print: 27 JAN 2012

ISBN Information

Print ISBN: 9781405196468

Online ISBN: 9781444398311

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Keywords:

  • distal myopathy;
  • gene therapy;
  • GNE;
  • inclusion-body myopathy;
  • mannosamine;
  • rimmed vacuoles;
  • sialic acid

Summary

The GNE gene encodes a bifunctional enzyme that is critical for the synthesis of sialic acids, which are negatively charged monosaccharides found at the termini of glycoproteins and glycolipids, and important in biologic processes for regulating cell adhesion and signal transduction. In humans, two diseases are caused by mutations in GNE: first, distal myopathy with rimmed vacuoles (DMRV)/hereditary inclusion-body myopathy (h-IBM) is due to mutations in the epimerase and kinase domains of the gene which result to partial loss of enzymatic activities; second, sialuria is due to mutations in the allosteric region of the gene, resulting in the loss of feedback inhibition of sialic acid synthesis, thus leading to uncontrolled sialic acid production. Partial loss of GNE enzymatic activities suggests that DMRV/h-IBM is a metabolic disease, but it has been controversial whether the proposed hyposialylation defect would lead to myopathy. Recent years have witnessed increased efforts to understand this concept. This chapter provides a review of the existing theories on how GNE mutations lead to the development of myopathy in DMRV/h-IBM, and concepts which provide the basis for potential therapeutic strategies.