Epm2a

Summary

Gene Symbol: Epm2a
Description: epilepsy, progressive myoclonic epilepsy, type 2 gene alpha
Alias: TG-B, Tg(TcraK,TcrbK)TG-BFlv, laforin, LAFPTPase, glucan phosphatase, lafora PTPase
Species: mouse
Products:     Epm2a

Top Publications

  1. Tagliabracci V, Turnbull J, Wang W, Girard J, Zhao X, Skurat A, et al. Laforin is a glycogen phosphatase, deficiency of which leads to elevated phosphorylation of glycogen in vivo. Proc Natl Acad Sci U S A. 2007;104:19262-6 pubmed
    ..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...
  2. Liu Y, Wang Y, Wu C, Liu Y, Zheng P. Dimerization of Laforin is required for its optimal phosphatase activity, regulation of GSK3beta phosphorylation, and Wnt signaling. J Biol Chem. 2006;281:34768-74 pubmed
    Epilepsy of progressive myoclonus type 2 gene A (EPM2A) encodes a dual specificity protein phosphatase called Laforin. Laforin is also a tumor suppressor that dephosphorylates GSK3beta at the critical Ser9 position and regulates Wnt ..
  3. Ganesh S, Delgado Escueta A, Sakamoto T, Avila M, Machado Salas J, Hoshii Y, et al. Targeted disruption of the Epm2a gene causes formation of Lafora inclusion bodies, neurodegeneration, ataxia, myoclonus epilepsy and impaired behavioral response in mice. Hum Mol Genet. 2002;11:1251-62 pubmed
    Mutations in the EPM2A gene encoding a dual-specificity phosphatase (laforin) cause Lafora disease (LD), a progressive and invariably fatal epilepsy with periodic acid-Schiff-positive (PAS+) cytoplasmic inclusions (Lafora bodies) in the ..
  4. Chan E, Ackerley C, Lohi H, Ianzano L, Cortez M, Shannon P, et al. Laforin preferentially binds the neurotoxic starch-like polyglucosans, which form in its absence in progressive myoclonus epilepsy. Hum Mol Genet. 2004;13:1117-29 pubmed
    ..The disease is caused by loss of function of the laforin dual-specificity phosphatase or the malin E3 ubiquitin ligase...
  5. Wang Y, Ma K, Wang P, Baba O, Zhang H, Parent J, et al. Laforin prevents stress-induced polyglucosan body formation and Lafora disease progression in neurons. Mol Neurobiol. 2013;48:49-61 pubmed publisher
    ..and metabolism, though progress is accruing through the neurodegenerative epilepsy Lafora disease (LD) proteins laforin and malin...
  6. Aguado C, Sarkar S, Korolchuk V, Criado O, Vernia S, Boya P, et al. Laforin, the most common protein mutated in Lafora disease, regulates autophagy. Hum Mol Genet. 2010;19:2867-76 pubmed publisher
    ..Here we describe that the major genetic lesion that causes LD, loss-of-function of the protein laforin, impairs autophagy...
  7. Puri R, Suzuki T, Yamakawa K, Ganesh S. Dysfunctions in endosomal-lysosomal and autophagy pathways underlie neuropathology in a mouse model for Lafora disease. Hum Mol Genet. 2012;21:175-84 pubmed publisher
    ..LD can be caused by defects in the laforin phosphatase or the malin ubiquitin ligase and the clinical symptoms resulting from these two defects are almost ..
  8. Singh P, Singh S, Ganesh S. The laforin-malin complex negatively regulates glycogen synthesis by modulating cellular glucose uptake via glucose transporters. Mol Cell Biol. 2012;32:652-63 pubmed publisher
    ..Therefore, laforin phosphatase and malin ubiquitin E3 ligase, the two proteins that are defective in LD, are thought to regulate ..
  9. DePaoli Roach A, Segvich D, Meyer C, Rahimi Y, Worby C, Gentry M, et al. Laforin and malin knockout mice have normal glucose disposal and insulin sensitivity. Hum Mol Genet. 2012;21:1604-10 pubmed publisher
    ..Garcia-Roves, P.M., Cansell, C., Denis, R., Luquet, S., Foufelle, F., Ferre, P. et al. (2011) Laforin, a dual-specificity phosphatase involved in Lafora disease, regulates insulin response and whole-body energy ..

More Information

Publications50

  1. Wang Y, Liu Y, Wu C, Zhang H, Zheng X, Zheng Z, et al. Epm2a suppresses tumor growth in an immunocompromised host by inhibiting Wnt signaling. Cancer Cell. 2006;10:179-90 pubmed
    ..Downregulation of Epm2a expression is widespread among mouse and human lymphoma cell lines. Epm2a-encoded laforin is a phosphatase for GSK-3beta and an important repressor in the Wnt signaling pathway...
  2. Wang Y, Liu Y, Wu C, McNally B, Liu Y, Zheng P. Laforin confers cancer resistance to energy deprivation-induced apoptosis. Cancer Res. 2008;68:4039-44 pubmed publisher
    ..we show that the hexose kinase inhibitor 2-deoxyglucose (2-dG) preferentially kills cancer cells with defective laforin expression and significantly increases the survival of mice with aggressive lymphoma due to a genetic defect of ..
  3. Tagliabracci V, Girard J, Segvich D, Meyer C, Turnbull J, Zhao X, et al. Abnormal metabolism of glycogen phosphate as a cause for Lafora disease. J Biol Chem. 2008;283:33816-25 pubmed publisher
    ..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 is able to release the small amount of covalent ..
  4. Vernia S, Rubio T, Heredia M, Rodriguez de Cordoba S, Sanz P. Increased endoplasmic reticulum stress and decreased proteasomal function in lafora disease models lacking the phosphatase laforin. PLoS ONE. 2009;4:e5907 pubmed publisher
    ..disorder caused by loss-of-function mutations in either the EPM2A gene, encoding the dual specificity phosphatase laforin, or the EPM2B gene, encoding the E3-ubiquitin ligase malin...
  5. Turnbull J, DePaoli Roach A, Zhao X, Cortez M, Pencea N, Tiberia E, et al. PTG depletion removes Lafora bodies and rescues the fatal epilepsy of Lafora disease. PLoS Genet. 2011;7:e1002037 pubmed publisher
    ..This results in near-complete disappearance of polyglucosans and in resolution of neurodegeneration and myoclonic epilepsy. This work discloses an entryway to treating this fatal epilepsy and potentially other glycogen storage diseases. ..
  6. Criado O, Aguado C, Gayarre J, Durán Trío L, Garcia Cabrero A, Vernia S, et al. Lafora bodies and neurological defects in malin-deficient mice correlate with impaired autophagy. Hum Mol Genet. 2012;21:1521-33 pubmed publisher
    ..the presence of intracellular inclusions called Lafora bodies (LBs), is caused by loss-of-function mutations in laforin or malin...
  7. Cheng A, Zhang M, Gentry M, Worby C, Dixon J, Saltiel A. A role for AGL ubiquitination in the glycogen storage disorders of Lafora and Cori's disease. Genes Dev. 2007;21:2399-409 pubmed
    ..Taken together, these results indicate that binding to glycogen crucially regulates the stability of AGL and, further, that its ubiquitination may play an important role in the pathophysiology of both Lafora and Cori's disease. ..
  8. Vilchez D, Ros S, Cifuentes D, Pujadas L, Valles J, Garcia Fojeda B, et al. Mechanism suppressing glycogen synthesis in neurons and its demise in progressive myoclonus epilepsy. Nat Neurosci. 2007;10:1407-13 pubmed
    ..This suppression was further ensured by a complex of laforin and malin, which are the two proteins whose mutations cause Lafora disease...
  9. Puri R, Suzuki T, Yamakawa K, Ganesh S. Hyperphosphorylation and aggregation of Tau in laforin-deficient mice, an animal model for Lafora disease. J Biol Chem. 2009;284:22657-63 pubmed publisher
    ..disease; LD) is caused by mutations in the EPM2A gene encoding a dual specificity protein phosphatase named laforin. Our analyses on the Epm2a gene knock-out mice, which developed most of the symptoms of LD, reveal the presence ..
  10. Garyali P, Siwach P, Singh P, Puri R, Mittal S, Sengupta S, et al. The malin-laforin complex suppresses the cellular toxicity of misfolded proteins by promoting their degradation through the ubiquitin-proteasome system. Hum Mol Genet. 2009;18:688-700 pubmed publisher
    ..b>Laforin, a protein phosphatase, and malin, an E3 ubiquitin ligase, are two of the proteins that are defective in LD...
  11. Garcia Cabrero A, Marinas A, Guerrero R, de Cordoba S, Serratosa J, Sanchez M. Laforin and malin deletions in mice produce similar neurologic impairments. J Neuropathol Exp Neurol. 2012;71:413-21 pubmed publisher
    Lafora disease is a progressive myoclonus epilepsy caused by mutations in the EPM2A gene encoding laforin or in the EPM2B gene encoding malin...
  12. Tiberia E, Turnbull J, Wang T, Ruggieri A, Zhao X, Pencea N, et al. Increased laforin and laforin binding to glycogen underlie Lafora body formation in malin-deficient Lafora disease. J Biol Chem. 2012;287:25650-9 pubmed publisher
    ..LD is caused by loss-of-function mutations in the EPM2A or EPM2B gene, encoding the interacting laforin phosphatase and malin E3 ubiquitin ligase enzymes, respectively...
  13. Klug F, Prakash H, Huber P, Seibel T, Bender N, Halama N, et al. Low-dose irradiation programs macrophage differentiation to an iNOS?/M1 phenotype that orchestrates effective T cell immunotherapy. Cancer Cell. 2013;24:589-602 pubmed publisher
  14. Muñoz Ballester C, Berthier A, Viana R, Sanz P. Homeostasis of the astrocytic glutamate transporter GLT-1 is altered in mouse models of Lafora disease. Biochim Biophys Acta. 2016;1862:1074-83 pubmed publisher
    ..On the other hand, the overexpression in cellular models of laforin and malin, the two proteins related to LD, results in an accumulation of GLT-1 (EAAT2) at the plasma membrane and ..
  15. Zheng X, Gao J, Zhang H, Geiger T, Liu Y, Zheng P. Clonal deletion of simian virus 40 large T antigen-specific T cells in the transgenic adenocarcinoma of mouse prostate mice: an important role for clonal deletion in shaping the repertoire of T cells specific for antigens overexpressed in solid tumor. J Immunol. 2002;169:4761-9 pubmed
  16. Ganesh S, Amano K, Delgado Escueta A, Yamakawa K. Isolation and characterization of mouse homologue for the human epilepsy gene, EPM2A. Biochem Biophys Res Commun. 1999;257:24-8 pubmed
    Mutations in the novel gene, EPM2A, have been shown recently to cause the progressive myoclonus epilepsy of Lafora type...
  17. Zhou P, Fang X, McNally B, Yu P, Zhu M, Fu Y, et al. Targeting lymphotoxin-mediated negative selection to prevent prostate cancer in mice with genetic predisposition. Proc Natl Acad Sci U S A. 2009;106:17134-9 pubmed publisher
    ..Our data demonstrated the value of non-antigen-based immune prevention for those with a genetic predisposition to cancer. ..
  18. Ganesh S, Tsurutani N, Amano K, Mittal S, Uchikawa C, Delgado Escueta A, et al. Transcriptional profiling of a mouse model for Lafora disease reveals dysregulation of genes involved in the expression and modification of proteins. Neurosci Lett. 2005;387:62-7 pubmed
    Lafora's progressive myoclonus epilepsy (Lafora disease: LD) is caused by mutations in the EPM2A or NHLRC1 gene, but cellular mechanisms of the pathogenesis remain unclear...
  19. Nitschke F, Wang P, Schmieder P, Girard J, Awrey D, Wang T, et al. Hyperphosphorylation of glucosyl C6 carbons and altered structure of glycogen in the neurodegenerative epilepsy Lafora disease. Cell Metab. 2013;17:756-67 pubmed publisher
    b>Laforin or malin deficiency causes Lafora disease, characterized by altered glycogen metabolism and teenage-onset neurodegeneration with intractable and invariably fatal epilepsy...
  20. Ganesh S, Tsurutani N, Suzuki T, Ueda K, Agarwala K, Osada H, et al. The Lafora disease gene product laforin interacts with HIRIP5, a phylogenetically conserved protein containing a NifU-like domain. Hum Mol Genet. 2003;12:2359-68 pubmed
    ..The EPM2A gene-encoded protein laforin is a dual-specificity phosphatase that associates with polyribosomes...
  21. Jain N, Rai A, Mishra R, Ganesh S. Loss of malin, but not laforin, results in compromised autophagic flux and proteasomal dysfunction in cells exposed to heat shock. Cell Stress Chaperones. 2017;22:307-315 pubmed publisher
    ..b>Laforin phosphatase and malin E3 ubiquitin ligase, the two proteins defective in Lafora neurodegenerative disorder, are ..
  22. DePaoli Roach A, Contreras C, Segvich D, Heiss C, Ishihara M, Azadi P, et al. Glycogen phosphomonoester distribution in mouse models of the progressive myoclonic epilepsy, Lafora disease. J Biol Chem. 2015;290:841-50 pubmed publisher
    ..Some 90% of Lafora cases are attributed to mutations of the EPM2A or EPM2B genes, and mice with either gene disrupted accumulate hyperphosphorylated glycogen...
  23. Geiger T, Gooding L, Flavell R. T-cell responsiveness to an oncogenic peripheral protein and spontaneous autoimmunity in transgenic mice. Proc Natl Acad Sci U S A. 1992;89:2985-9 pubmed
    ..This result argues that T cells may become spontaneously autoreactive to certain postnatally expressed peripheral proteins and that this reactivity may lead to autoimmune disease. ..
  24. Rai A, Mishra R, Ganesh S. Suppression of leptin signaling reduces polyglucosan inclusions and seizure susceptibility in a mouse model for Lafora disease. Hum Mol Genet. 2017;26:4778-4785 pubmed publisher
    ..The disease is caused by defects in the EPM2A gene coding for a protein phosphatase (laforin) or the NHLRC1 gene coding for an ubiquitin ligase (malin)...
  25. Guerder S, Carding S, Flavell R. B7 costimulation is necessary for the activation of the lytic function in cytotoxic T lymphocyte precursors. J Immunol. 1995;155:5167-74 pubmed
    ..The production of IFN-gamma by CD8 T cells, however, does not appear to require costimulation. ..
  26. Machado Salas J, Avila Costa M, Guevara P, Guevara J, Duron R, Bai D, et al. Ontogeny of Lafora bodies and neurocytoskeleton changes in Laforin-deficient mice. Exp Neurol. 2012;236:131-40 pubmed publisher
    ..Therefore, we undertook a detailed microscopic analysis of the neuropile of a Laforin-deficient (epm2a-/-) mouse model...
  27. Vernia S, Heredia M, Criado O, Rodriguez de Cordoba S, Garcia Roves P, Cansell C, et al. Laforin, a dual specificity phosphatase involved in Lafora disease, regulates insulin response and whole-body energy balance in mice. Hum Mol Genet. 2011;20:2571-84 pubmed publisher
    b>Laforin is a dual specificity protein phosphatase involved in Lafora disease (LD), a fatal form of progressive myoclonus epilepsy characterized by neurodegeneration and the presence of intracellular polyglucosan inclusions (Lafora bodies)..
  28. Ganesh S, Agarwala K, Amano K, Suzuki T, Delgado Escueta A, Yamakawa K. Regional and developmental expression of Epm2a gene and its evolutionary conservation. Biochem Biophys Res Commun. 2001;283:1046-53 pubmed
    ..myoclonus epilepsy, is caused by mutations in the EPM2A gene encoding a dual-specificity phosphatase (DSP) named laforin. Here, we analyzed the developmental and regional expression of murine Epm2a and discussed its evolutionary ..
  29. Zeng L, Wang Y, Baba O, Zheng P, Liu Y, Liu Y. Laforin is required for the functional activation of malin in endoplasmic reticulum stress resistance in neuronal cells. FEBS J. 2012;279:2467-78 pubmed publisher
    Mutations in either EPM2A, the gene encoding a dual-specificity phosphatase named laforin, or NHLRC1, the gene encoding an E3 ubiquitin ligase named malin, cause Lafora disease in humans...
  30. Dervovic D, Liang H, Cannons J, Elford A, Mohtashami M, Ohashi P, et al. Cellular and molecular requirements for the selection of in vitro-generated CD8 T cells reveal a role for Notch. J Immunol. 2013;191:1704-15 pubmed publisher
    ..Our findings further establish the requirement for Notch receptor-ligand interactions throughout T cell differentiation, including the final step of CD8 SP selection. ..
  31. Upadhyay M, Agarwal S, Bhadauriya P, Ganesh S. Loss of laforin or malin results in increased Drp1 level and concomitant mitochondrial fragmentation in Lafora disease mouse models. Neurobiol Dis. 2017;100:39-51 pubmed publisher
    ..LD can be caused by defects either in the laforin phosphatase coded by the EPM2A gene or in the malin E3 ubiquitin ligase coded by the NHLRC1 gene...
  32. Liu R, Wang L, Chen C, Liu Y, Zhou P, Wang Y, et al. Laforin negatively regulates cell cycle progression through glycogen synthase kinase 3beta-dependent mechanisms. Mol Cell Biol. 2008;28:7236-44 pubmed publisher
    ..Recently, we reported that the Epm2a-encoded laforin is a GSK-3beta phosphatase and a tumor suppressor...
  33. Garyali P, Segvich D, DePaoli Roach A, Roach P. Protein degradation and quality control in cells from laforin and malin knockout mice. J Biol Chem. 2014;289:20606-14 pubmed
    ..myoclonus epilepsy caused by mutations in the EPM2A or EPM2B genes that encode a glycogen phosphatase, laforin, and an E3 ubiquitin ligase, malin, respectively...
  34. Wang W, Roach P. Glycogen and related polysaccharides inhibit the laforin dual-specificity protein phosphatase. Biochem Biophys Res Commun. 2004;325:726-30 pubmed
    ..80% of cases by mutation of the EPM2A gene, which encodes a dual specificity protein phosphatase called laforin. In addition to its phosphatase domain, laforin contains an N-terminal carbohydrate-binding domain (CBD)...
  35. Garbi N, Arnold B, Gordon S, Hämmerling G, Ganss R. CpG motifs as proinflammatory factors render autochthonous tumors permissive for infiltration and destruction. J Immunol. 2004;172:5861-9 pubmed
  36. Lopez Gonzalez I, Viana R, Sanz P, Ferrer I. Inflammation in Lafora Disease: Evolution with Disease Progression in Laforin and Malin Knock-out Mouse Models. Mol Neurobiol. 2017;54:3119-3130 pubmed publisher
    ..the cytoplasm of neurons, which is most commonly associated with mutations in two genes: EPM2A, encoding the glucan phosphatase laforin, and EPM2B, encoding the E3-ubiquitin ligase malin...
  37. Newman B, Liu Y, Lee H, Sun D, Wang Y. HSP90 inhibitor 17-AAG selectively eradicates lymphoma stem cells. Cancer Res. 2012;72:4551-61 pubmed publisher
    ..This study supports the use of 17-AAG as a CSC targeting agent and, in addition, shows that HSF1 is an important target for elimination of both CSCs and non-CSCs in cancer...
  38. Singh P, Singh S, Ganesh S. Activation of serum/glucocorticoid-induced kinase 1 (SGK1) underlies increased glycogen levels, mTOR activation, and autophagy defects in Lafora disease. Mol Biol Cell. 2013;24:3776-86 pubmed publisher
    ..Therefore the two defective proteins in LD-laforin phosphatase and malin ubiquitin ligase-are believed to be involved in glycogen metabolism...
  39. Turnbull J, Girard J, Lohi H, Chan E, Wang P, Tiberia E, et al. Early-onset Lafora body disease. Brain. 2012;135:2684-98 pubmed publisher
    ..Lafora disease is caused by mutations in the EPM2A or EPM2B genes, encoding the laforin phosphatase and the malin ubiquitin ligase, respectively, two cytoplasmically active enzymes that regulate ..
  40. Jain N, Mishra R, Ganesh S. FoxO3a-mediated autophagy is down-regulated in the laforin deficient mice, an animal model for Lafora progressive myoclonus epilepsy. Biochem Biophys Res Commun. 2016;474:321-327 pubmed publisher
    ..neurodegeneration and accumulation of polyglucosan bodies (Lafora bodies), arising due to defects in either the laforin protein phosphatase or the malin ubiquitin ligase...
  41. Gayarre J, Durán Trío L, Criado Garcia O, Aguado C, Juana López L, Crespo I, et al. The phosphatase activity of laforin is dispensable to rescue Epm2a-/- mice from Lafora disease. Brain. 2014;137:806-18 pubmed publisher
    ..The vast majority of patients carry mutations in either the EPM2A or EPM2B genes, encoding laforin, a glucan phosphatase, and malin, an E3 ubiquitin ligase, respectively...