Abstract
GNE myopathy is an autosomal recessive disease, which is characterized by gradually progressive muscle atrophy and weakness, and preferentially involves the distal muscles of lower extremities, especially the tibialis anterior muscle. GNE myopathy is caused by mutations in the UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE) gene which encodes the bifunctional enzyme catalyzing the rate-limiting step in sialic acid biosynthesis. GNE myopathy model mouse, in which Gne is knocked out with human GNE transgene with D176V, recaptured the symptoms of human GNE myopathy. The supplementation of ManNAc, NeuAc, and sialyllactose prevented the onset of the disorder and also recovered the muscle function from symptomatic status, suggesting hyposialylation is one of key factors in the pathogenesis of this disorder. Based on the studies with GNE myopathy model, the clinical trials are conducted at the three places in the world (USA, Japan, and Israel). Expectedly GNE myopathy will be treatable in the near future.
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References
Nonaka I, Sunohara N, Ishiura S et al (1981) Familial distal myopathy with rimmed vacuole and lamellar (myeloid) body formation. J Neurol Sci 51:141–155
Argov Z, Yarom R (1984) “Rimmed vacuole myopathy” sparing the quadriceps. A unique disorder in Iranian Jews. J Neurol Sci 64:33–43
Eisenberg I, Avidan N, Potikha T et al (2001) The UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase gene is mutated in recessive hereditary inclusion body myopathy. Nat Genet 29:83–87
Cho A, Hayashi YK, Monma K (2013) Mutation profile of the GNE gene in Japanese patients with distal myopathy with rimmed vacuoles (GNE myopathy). J Neurol Neurosurg Psychiatry. doi:10.1136/jnnp-2013-305587
Celeste FV, Vilboux T, Ciccone C et al (2014) Mutation update for GNE gene variants associated with GNE myopathy. Hum Mutat 35:915–926
Noguchi S, Keira Y, Murayama K et al (2004) Reduction of UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase activity and sialylation in distal myopathy with rimmed vacuoles. J Biol Chem 279:11402–11407
Nishino I, Noguchi S, Murayama K (2002) Distal myopathy with rimmed vacuoles is allelic to hereditary inclusion body myopathy. Neurology 59:1689–1693
Huizing M, Carrillo-Carrasco N, Malicdan MC et al (2014) GNE myopathy: new name and new mutation nomenclature. Neuromuscul Disord 24:387–389
Mori-Yoshimura M, Oya Y, Yajima H (2014) GNE myopathy: a prospective natural history study of disease progression. Neuromuscul Disord 24:380–386
Mori-Yoshimura M, Oya Y, Hayashi YK (2013) Respiratory dysfunction in patients severely affected by GNE myopathy (distal myopathy with rimmed vacuoles). Neuromuscul Disord 23:84–88
Malicdan MC, Noguchi S, Nishino I (2007) Autophagy in a mouse model of distal myopathy with rimmed vacuoles or hereditary inclusion body myopathy. Autophagy 3:396–398
Shea L, Raben N (2009) Autophagy in skeletal muscle: implications for Pompe disease. Int J Clin Pharmacol Ther 47(Suppl 1):S42–S47
Malicdan MC, Noguchi S, Nonaka I et al (2008) Lysosomal myopathies: an excessive build-up in autophagosomes is too much to handle. Neuromuscul Disord 18:521–529
Mori-Yoshimura M, Monma K, Suzuki N et al (2012) Heterozygous UDP-GlcNAc 2-epimerase and N-acetylmannosamine kinase domain mutations in the GNE gene result in a less severe GNE myopathy phenotype compared to homozygous N-acetylmannosamine kinase domain mutations. J Neurol Sci 318:100–105
Malicdan MC, Noguchi S, Nishino I (2010) A preclinical trial of sialic acid metabolites on distal myopathy with rimmed vacuoles/hereditary inclusion body myopathy, a sugar-deficient myopathy: a review. Ther Adv Neurol Disord 3:127–135
Salama I, Hinderlich S, Shlomai Z et al (2005) No overall hyposialylation in hereditary inclusion body myopathy myoblasts carrying the homozygous M712T GNE mutation. Biochem Biophys Res Commun 328:221–226
Hinderlich S, Salama I, Eisenberg I (2004) The homozygous M712T mutation of UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase results in reduced enzyme activities but not in altered overall cellular sialylation in hereditary inclusion body myopathy. FEBS Lett 566:105–109
Kakani S, Yardeni T, Poling J et al (2012) The Gne M712T mouse as a model for human glomerulopathy. Am J Pathol 180:1431–1440
Ito M, Sugihara K, Asaka T (2012) Glycoprotein hyposialylation gives rise to a nephrotic-like syndrome that is prevented by sialic acid administration in GNE V572L point-mutant mice. PLoS One 7:e29873
Daya A, Vatine GD, Becker-Cohen M et al (2014) Gne depletion during zebrafish development impairs skeletal muscle structure and function. Hum Mol Genet 23:3349–3361
Malicdan MC, Noguchi S, Nonaka I et al (2007) A Gne knockout mouse expressing human GNE D176V mutation develops features similar to distal myopathy with rimmed vacuoles or hereditary inclusion body myopathy. Hum Mol Genet 16:2669–2682
Malicdan MC, Noguchi S, Hayashi YK (2008) Muscle weakness correlates with muscle atrophy and precedes the development of inclusion body or rimmed vacuoles in the mouse model of DMRV/hIBM. Physiol Genomics 35:106–115
North KN, Laing NG, Wallgren-Pettersson C (1997) Nemaline myopathy: current concepts. The ENMC International Consortium and Nemaline Myopathy. J Med Genet 34:705–713
D’Antona G, Brocca L, Pansarasa O et al (2007) Structural and functional alterations of muscle fibres in the novel mouse model of facioscapulohumeral muscular dystrophy. J Physiol 584:997–1009
Yeung EW, Head SI, Allen DG (2003) Gadolinium reduces short-term stretch-induced muscle damage in isolated mdx mouse muscle fibres. J Physiol 552:449–458
Sugarman MC, Kitazawa M, Baker M (2006) Pathogenic accumulation of APP in fast twitch muscle of IBM patients and a transgenic model. Neurobiol Aging 27:423–432
Schwarzkopf M, Knobeloch KP, Rohde E et al (2002) Sialylation is essential for early development in mice. Proc Natl Acad Sci U S A 99:5267–5270
Malicdan MC, Noguchi S, Hayashi YK et al (2009) Prophylactic treatment with sialic acid metabolites precludes the development of the myopathic phenotype in the DMRV-hIBM mouse model. Nat Med 15:690–695
Malicdan MC, Noguchi S, Tokutomi T (2012) Peracetylated N-acetylmannosamine, a synthetic sugar molecule, efficiently rescues muscle phenotype and biochemical defects in mouse model of sialic acid-deficient myopathy. J Biol Chem 287:2689–2705
Yonekawa T, Malicdan MC, Cho A et al (2014) Sialyllactose ameliorates myopathic phenotypes in symptomatic GNE myopathy model mice. Brain 137:2670–2679
Nishino I, Carrillo-Carrasco N, Argov Z (2014) GNE myopathy: current update and future therapy. J Neurol Neurosurg Psychiatry 86:385–392
Sparks S, Rakocevic G, Joe G (2007) Intravenous immune globulin in hereditary inclusion body myopathy: a pilot study. BMC Neurol 29(7):3
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Nishimura, H., Noguchi, S. (2016). Molecular Pathogenesis and Therapeutic Strategy in GNE Myopathy. In: Takeda, S., Miyagoe-Suzuki, Y., Mori-Yoshimura, M. (eds) Translational Research in Muscular Dystrophy. Springer, Tokyo. https://doi.org/10.1007/978-4-431-55678-7_4
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DOI: https://doi.org/10.1007/978-4-431-55678-7_4
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