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The Metabolic Map into the Pathomechanism and Treatment of PGM1-CDG.
- Source :
-
American journal of human genetics [Am J Hum Genet] 2019 May 02; Vol. 104 (5), pp. 835-846. Date of Electronic Publication: 2019 Apr 11. - Publication Year :
- 2019
-
Abstract
- 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.<br /> (Copyright © 2019 American Society of Human Genetics. All rights reserved.)
- Subjects :
- Cells, Cultured
Cohort Studies
Congenital Disorders of Glycosylation drug therapy
Congenital Disorders of Glycosylation pathology
Fibroblasts drug effects
Fibroblasts pathology
Glycosylation
Humans
Congenital Disorders of Glycosylation metabolism
Fibroblasts metabolism
Galactose administration & dosage
Phosphoglucomutase deficiency
Uridine Diphosphate Galactose metabolism
Uridine Diphosphate Glucose metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1537-6605
- Volume :
- 104
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- American journal of human genetics
- Publication Type :
- Academic Journal
- Accession number :
- 30982613
- Full Text :
- https://doi.org/10.1016/j.ajhg.2019.03.003