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Non-specific accumulation of glycosphingolipids in GNE myopathy
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Non-specific accumulation of glycosphingolipids in GNE myopathy
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Journal Article
Non-specific accumulation of glycosphingolipids in GNE myopathy
2014
Overview
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.
Conclusion
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.
Publisher
Springer Netherlands,Blackwell Publishing Ltd,Springer Verlag
Subject
/ Endocrinology and metabolism
/ Female
/ Glycosphingolipids - genetics
/ Glycosphingolipids - metabolism
/ Humans
/ Medicine
/ Mice
/ Multienzyme Complexes - blood
/ Multienzyme Complexes - genetics
/ Multienzyme Complexes - metabolism
/ Muscular Diseases - genetics
/ Muscular Diseases - metabolism
/ Mutation
/ N-Acetylneuraminic Acid - blood
/ N-Acetylneuraminic Acid - genetics
