title: Ganglioside GM3 levels are altered in a mouse model of HIBM: GM3 as a cellular marker of the disease.
abstract: OBJECTIVE
  HIBM (Hereditary Inclusion Body Myopathy) is a recessive hereditary disease characterized by adult-onset, slowly progressive muscle weakness sparing the quadriceps. It is caused by a single missense mutation of each allele of the UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE) gene, a bifunctional enzyme catalyzing the first two steps of sialic acid synthesis in mammals. However, the mechanisms and cellular pathways affected by the GNE mutation and causing the muscle weakness could not be identified so far. Based on recent evidence in literature, we investigated a new hypothesis, i.e. the involvement in the disease of the GM3 ganglioside, a specific glycolipid implicated in muscle cell proliferation and differentiation.
  
  
  METHODS
  qRT-PCR analysis of St3gal5 (GM3 synthase) gene expression and HPLC quantification of GM3 ganglioside were conducted on muscle tissue from a mouse model of HIBM harboring the M712T mutation of GNE (Gne(M712T/M712T) mouse) vs control mice (Gne(+/+) mouse).
  
  
  RESULTS
  St3gal5 mRNA levels were significantly lower in Gne(M712T/M712T) mouse muscles vs Gne(+/+) mouse muscles (64.41%+/-10% of Gne(+/+) levels). GM3 ganglioside levels showed also a significant decrease in Gne(M712T/M712T) mouse muscle compared to Gne(+/+) mouse muscle (18.09%+/-5.33% of Gne(+/+) levels). Although these Gne(M712T/M712T) mice were described to suffer severe glomerular proteinuria, no GM3 alterations were noted in kidneys, highlighting a tissue specific alteration of gangliosides.
  
  
  CONCLUSIONS
  The M712T mutation of GNE hampers the muscle ability to synthesize normal levels of GM3. This is the first time that a mutation of GNE can be related to the molecular pathological mechanism of HIBM.
authors.affiliation: Centre de Recherche du Centre Hospitalier Universitaire de Québec-Unité de Génétique Humaine, Université Laval, Québec, Canada.
authors.forename: Thomas
authors.initials: T
authors.lastname: Paccalet
authors.forename: Zoé
authors.initials: Z
authors.lastname: Coulombe
authors.forename: Jacques P
authors.initials: JP
authors.lastname: Tremblay
mesh_terms: D000818:Animals; D015415:Biomarkers; D002238:Carbohydrate Epimerases / Q000235:genetics; D004195:Disease Models, Animal; D005679:G(M3) Ganglioside / Q000032:analysis* / Q000096:biosynthesis; D051379:Mice; D009097:Multienzyme Complexes / Q000235:genetics*; D018482:Muscle, Skeletal / Q000737:chemistry; D020125:Mutation, Missense; D018979:Myositis, Inclusion Body / Q000209:etiology / Q000235:genetics / Q000378:metabolism*; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics*; D012333:RNA, Messenger / Q000032:analysis; D012799:Sialyltransferases / Q000032:analysis / Q000235:genetics
chemical_list: D015415:Biomarkers; D005679:G(M3) Ganglioside; D009097:Multienzyme Complexes; D012333:RNA, Messenger; C482901:UDP-N-acetylglucosamine 2-epimerase - N-acetylmannosamine kinase; D012799:Sialyltransferases; C021343:haematoside synthetase; D017853:Phosphotransferases (Alcohol Group Acceptor); C018765:N-acylmannosamine kinase; D002238:Carbohydrate Epimerases; C100033:UDP acetylglucosamine-2-epimerase
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