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Laforin is a glycogen phosphatase, deficiency of which leads to elevated phosphorylation of glycogen in vivo
- Source :
- Proceedings of the National Academy of Sciences. 104:19262-19266
- Publication Year :
- 2007
- Publisher :
- Proceedings of the National Academy of Sciences, 2007.
-
Abstract
- Lafora disease is a progressive myoclonus epilepsy with onset typically in the second decade of life and death within 10 years. Lafora bodies, deposits of abnormally branched, insoluble glycogen-like polymers, form in neurons, muscle, liver, and other tissues. Approximately half of the cases of Lafora disease result from mutations in the EPM2A gene, which encodes laforin, a member of the dual-specificity protein phosphatase family that additionally contains a glycogen binding domain. The molecular basis for the formation of Lafora bodies is completely unknown. Glycogen, a branched polymer of glucose, contains a small amount of covalently linked phosphate whose origin and function are obscure. We report here that recombinant laforin is able to release this phosphate in vitro , in a time-dependent reaction with an apparent K m for glycogen of 4.5 mg/ml. Mutations of laforin that disable the glycogen binding domain also eliminate its ability to dephosphorylate glycogen. We have also analyzed glycogen from a mouse model of Lafora disease, Epm2a −/− mice, which develop Lafora bodies in several tissues. Glycogen isolated from these mice had a 40% increase in the covalent phosphate content in liver and a 4-fold elevation in muscle. We propose that excessive phosphorylation of glycogen leads to aberrant branching and Lafora body formation. This study provides a molecular link between an observed biochemical property of laforin and the phenotype of a mouse model of Lafora disease. The results also have important implications for glycogen metabolism generally.
- Subjects :
- Male
congenital, hereditary, and neonatal diseases and abnormalities
Progressive myoclonus epilepsy
Lafora disease
Glycogen debranching enzyme
Mice
chemistry.chemical_compound
Glycogen branching enzyme
medicine
Animals
Phosphorylation
Glycogen synthase
Mice, Knockout
Glycogen binding
Multidisciplinary
biology
Glycogen
Biological Sciences
Protein Tyrosine Phosphatases, Non-Receptor
medicine.disease
Recombinant Proteins
Disease Models, Animal
Glycogen Synthase
Lafora Disease
chemistry
Biochemistry
Mutation
biology.protein
Dual-Specificity Phosphatases
Rabbits
Laforin
Subjects
Details
- ISSN :
- 10916490 and 00278424
- Volume :
- 104
- Database :
- OpenAIRE
- Journal :
- Proceedings of the National Academy of Sciences
- Accession number :
- edsair.doi.dedup.....c19211c60134c4d28ce5c24980a87ec6