Abstract | BACKGROUND: 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.
|
Authors | Katherine A Patzel, Tal Yardeni, Erell Le Poëc-Celic, Petcharat Leoyklang, Heidi Dorward, Dominic S Alonzi, Nikolay V Kukushkin, Bixue Xu, Yongmin Zhang, Matthieu Sollogoub, Yves Blériot, William A Gahl, Marjan Huizing, Terry D Butters |
Journal | Journal of inherited metabolic disease
(J Inherit Metab Dis)
Vol. 37
Issue 2
Pg. 297-308
(Mar 2014)
ISSN: 1573-2665 [Electronic] United States |
PMID | 24136589
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
|
Chemical References |
- Glycosphingolipids
- Hexosamines
- Multienzyme Complexes
- UDP-N-acetylglucosamine 2-epimerase - N-acetylmannosamine kinase
- N-Acetylneuraminic Acid
- N-acetylmannosamine
|
Topics |
- Animals
- Case-Control Studies
- Cells, Cultured
- Female
- Fibroblasts
(metabolism)
- Glycosphingolipids
(blood, genetics, metabolism)
- Hexosamines
(blood, genetics, metabolism)
- Humans
- Mice
- Mice, Inbred C57BL
- Multienzyme Complexes
(blood, genetics, metabolism)
- Muscles
(metabolism)
- Muscular Diseases
(blood, genetics, metabolism)
- Mutation
- N-Acetylneuraminic Acid
(blood, genetics, metabolism)
|