Non-specific accumulation of glycosphingolipids in GNE myopathy

• Published in: Journal of inherited metabolic disease Vol. 37; no. 2; pp. 297 - 308
• Main Authors: Patzel, Katherine A., Yardeni, Tal, Le Poëc-Celic, Erell, Leoyklang, Petcharat, Dorward, Heidi, Alonzi, Dominic S., Kukushkin, Nikolay V., Xu, Bixue, Zhang, Yongmin, Sollogoub, Matthieu, Blériot, Yves, Gahl, William A., Huizing, Marjan, Butters, Terry D.
• Format: Journal Article
• Language: English
• Published: Dordrecht Springer Netherlands 01.03.2014; Blackwell Publishing Ltd; Springer Verlag
• Subjects: Animals; Biochemistry; Case-Control Studies; Cells, Cultured; Endocrinology and metabolism; Female; Fibroblasts - metabolism; Glycosphingolipids - blood; Glycosphingolipids - genetics; Glycosphingolipids - metabolism; Hexosamines - blood; Hexosamines - genetics; Hexosamines - metabolism; Human Genetics; Human health and pathology; Humans; Internal Medicine; Life Sciences; Medicine; Medicine & Public Health; Metabolic Diseases; Mice; Mice, Inbred C57BL; Multienzyme Complexes - blood; Multienzyme Complexes - genetics; Multienzyme Complexes - metabolism; Muscles - metabolism; Muscular Diseases - blood; Muscular Diseases - genetics; Muscular Diseases - metabolism; Mutation; N-Acetylneuraminic Acid - blood; N-Acetylneuraminic Acid - genetics; N-Acetylneuraminic Acid - metabolism; Original Article; Pediatrics; Sialic Acid; Hereditary Inclusion Body Myopathy; Control Fibroblast; National Human Genome Research Institute; Kinase Domain Mutation
• ISSN: 0141-8955; 1573-2665
• DOI: 10.1007/s10545-013-9655-6

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.