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The Metabolic Map into the Pathomechanism and Treatment of PGM1-CDG
S. Radenkovic, MJ. Bird, TL. Emmerzaal, SY. Wong, C. Felgueira, KM. Stiers, L. Sabbagh, N. Himmelreich, G. Poschet, P. Windmolders, J. Verheijen, P. Witters, R. Altassan, T. Honzik, TF. Eminoglu, PM. James, AC. Edmondson, J. Hertecant, T. Kozicz,...
Language English Country United States
Document type Journal Article, Research Support, Non-U.S. Gov't
Grant support
T32 GM008638
NIGMS NIH HHS - United States
NV16-31932A
MZ0
CEP Register
Digital library NLK
Full text - Article
NLK
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- MeSH
- Fibroblasts drug effects metabolism pathology MeSH
- Phosphoglucomutase deficiency MeSH
- Galactose administration & dosage MeSH
- Glycosylation MeSH
- Cohort Studies MeSH
- Cells, Cultured MeSH
- Humans MeSH
- Uridine Diphosphate Galactose metabolism MeSH
- Uridine Diphosphate Glucose metabolism MeSH
- Congenital Disorders of Glycosylation drug therapy metabolism pathology MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
Phosphoglucomutase 1 (PGM1) encodes the metabolic enzyme that interconverts glucose-6-P and glucose-1-P. Mutations in PGM1 cause impairment in glycogen metabolism and glycosylation, the latter manifesting as a congenital disorder of glycosylation (CDG). This unique metabolic defect leads to abnormal N-glycan synthesis in the endoplasmic reticulum (ER) and the Golgi apparatus (GA). On the basis of the decreased galactosylation in glycan chains, galactose was administered to individuals with PGM1-CDG and was shown to markedly reverse most disease-related laboratory abnormalities. The disease and treatment mechanisms, however, have remained largely elusive. Here, we confirm the clinical benefit of galactose supplementation in PGM1-CDG-affected individuals and obtain significant insights into the functional and biochemical regulation of glycosylation. We report here that, by using tracer-based metabolomics, we found that galactose treatment of PGM1-CDG fibroblasts metabolically re-wires their sugar metabolism, and as such replenishes the depleted levels of galactose-1-P, as well as the levels of UDP-glucose and UDP-galactose, the nucleotide sugars that are required for ER- and GA-linked glycosylation, respectively. To this end, we further show that the galactose in UDP-galactose is incorporated into mature, de novo glycans. Our results also allude to the potential of monosaccharide therapy for several other CDG.
Biochemistry Department University of Missouri Columbia MO 65211 USA
Center of Individualized Medicine Department of Clinical Genomics Mayo Clinic Rochester MN 55905 USA
Centre for Organismal Studies University of Heidelberg 69120 Heidelberg Germany
Clinical Department of Laboratory Medicine University Hospitals Leuven 3000 Leuven Belgium
Department of Cardiovascular Sciences Katholieke Universiteit Leuven 3000 Leuven Belgium
Department of Pediatrics United Arab Emirates University Al Ain United Arab Emirates
Hayward Genetics Center Tulane University School of Medicine New Orleans LA 70112 LA USA
Medical Genetics Department Montréal Children's Hospital McGill University Montreal QC H4A3J1 Canada
Metabolic Center University Hospitals Leuven 3000 Leuven Belgium
References provided by Crossref.org
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