title: Non-specific accumulation of glycosphingolipids in GNE myopathy.
abstract: BACKGROUND
  UDP-GlcNAc 2-epimerase/ManNAc 6-kinase (GNE) is a bifunctional enzyme responsible for the first committed steps in the synthesis of sialic acid, a common terminal monosaccharide in both protein and lipid glycosylation. GNE mutations are responsible for a rare autosomal recessive neuromuscular disorder, GNE myopathy (also called hereditary inclusion body myopathy). The connection between the impairment of sialic acid synthesis and muscle pathology in GNE myopathy remains poorly understood.
  
  
  METHODS
  Glycosphingolipid (GSL) analysis was performed by HPLC in multiple models of GNE myopathy, including patients' fibroblasts and plasma, control fibroblasts with inhibited GNE epimerase activity through a novel imino sugar, and tissues of Gne(M712T/M712T) knock-in mice.
  
  
  RESULTS
  Not only neutral GSLs, but also sialylated GSLs, were significantly increased compared to controls in all tested models of GNE myopathy. Treatment of GNE myopathy fibroblasts with N-acetylmannosamine (ManNAc), a sialic acid precursor downstream of GNE epimerase activity, ameliorated the increased total GSL concentrations.
  
  
  CONCLUSIONS
  GNE myopathy models have increased total GSL concentrations. ManNAc supplementation results in decrease of GSL levels, linking abnormal increase of total GSLs in GNE myopathy to defects in the sialic acid biosynthetic pathway. These data advocate for further exploring GSL concentrations as an informative biomarker, not only for GNE myopathy, but also for other disorders of sialic acid metabolism.
authors.affiliation: Oxford Glycobiology Institute, Department of Biochemistry, University of Oxford, Oxford, OX1 3QU, UK.
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Patzel
authors.forename: Tal
authors.initials: T
authors.lastname: Yardeni
authors.forename: Erell
authors.initials: E
authors.lastname: Le Poëc-Celic
authors.forename: Petcharat
authors.initials: P
authors.lastname: Leoyklang
authors.forename: Heidi
authors.initials: H
authors.lastname: Dorward
authors.forename: Dominic S
authors.initials: DS
authors.lastname: Alonzi
authors.forename: Nikolay V
authors.initials: NV
authors.lastname: Kukushkin
authors.forename: Bixue
authors.initials: B
authors.lastname: Xu
authors.forename: Yongmin
authors.initials: Y
authors.lastname: Zhang
authors.forename: Matthieu
authors.initials: M
authors.lastname: Sollogoub
authors.forename: Yves
authors.initials: Y
authors.lastname: Blériot
authors.forename: William A
authors.initials: WA
authors.lastname: Gahl
authors.forename: Marjan
authors.initials: M
authors.lastname: Huizing
authors.forename: Terry D
authors.initials: TD
authors.lastname: Butters
mesh_terms: D000818:Animals; D016022:Case-Control Studies; D002478:Cells, Cultured; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D006028:Glycosphingolipids / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D006595:Hexosamines / Q000097:blood / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009097:Multienzyme Complexes / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D009132:Muscles / Q000378:metabolism; D009135:Muscular Diseases / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D019158:N-Acetylneuraminic Acid / Q000097:blood / Q000235:genetics / Q000378:metabolism
chemical_list: D006028:Glycosphingolipids; D006595:Hexosamines; D009097:Multienzyme Complexes; C482901:UDP-N-acetylglucosamine 2-epimerase - N-acetylmannosamine kinase; D019158:N-Acetylneuraminic Acid; C002022:N-acetylmannosamine