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Gene Review

EPM2A  -  epilepsy, progressive myoclonus type 2A,...

Homo sapiens

Synonyms: EPM2, LD, LDE, MELF
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Disease relevance of EPM2A


Psychiatry related information on EPM2A

  • Lafora disease (LD) is an autosomal recessive inherited form of progressive myoclonic epilepsy with dementia and ataxia, usually presenting in the second decade of life and inexorably progressing until death [6].

High impact information on EPM2A

  • Six distinct DNA sequence variations in EPM2A in nine families, and one homozygous microdeletion in another family, have been found to cosegregate with LD [7].
  • Using a positional cloning approach, we have identified at chromosome 6q24 a novel gene, EPM2A, that encodes a protein with consensus amino acid sequence indicative of a protein tyrosine phosphatase (PTP). mRNA transcripts representing alternatively spliced forms of EPM2A were found in every tissue examined, including brain [7].
  • Lafora's disease (LD; OMIM 254780) is an autosomal recessive form of progressive myoclonus epilepsy characterized by seizures and cumulative neurological deterioration [7].
  • Additionally, malin interacts with and polyubiquitinates laforin, leading to its degradation [8].
  • Insights into Lafora disease: malin is an E3 ubiquitin ligase that ubiquitinates and promotes the degradation of laforin [8].

Chemical compound and disease context of EPM2A

  • We recently cloned the major gene for Lafora disease (EPM2A) and characterised the corresponding product, a putative protein tyrosine phosphatase (LAFPTPase) [9].
  • Our aim was to determine whether LDL cholesterol concentration plus LDE increased clearance occur in lymphomas [10].
  • METHODS: [(3)H]-etoposide oleate associated to LDE labeled with [(14)C]-cholesteryl oleate was intravenously injected into four ovarian carcinoma patients (50 +/- 8.7 years) 24 h before surgery [11].
  • Indeed, we subsequently showed that when carmustine is associated with LDE the toxicity of the drug is significantly reduced in patients with advanced cancers [12].
  • Five patients, four with EPM 1 (Unverricht-Lundborg disease) and one patient with EPM2 (Lafora body disease) were treated with 6 g/day of NAC [13].

Biological context of EPM2A


Anatomical context of EPM2A


Associations of EPM2A with chemical compounds


Other interactions of EPM2A

  • To date 43 different variations in EPM2A and 23 in NHLRC1 are known, including missense, nonsense, frameshift, and deletions [24].
  • A microdeletion within the EPM2 critical region, present inhomozygosis in an affected individual, was found to disrupt a novel gene encoding a putative protein tyrosine phosphatase (PTPase) [25].
  • Mice defective in the GAA gene encoding lysosomal alpha-glucosidase (acid maltase) overaccumulate glycogen in the lysosome but did not have elevated laforin [26].
  • Moreover, all of the naturally occurring Laforin mutations tested impaired laforin GSK3beta dephosphorylation at Ser(9) dimerization, and beta-catenin accumulation in nucleus [22].
  • NAC improved markedly and stabilized the neurological symptoms in patients with EPM 1 but had a doubtful effect in the patient with EPM 2 [13].

Analytical, diagnostic and therapeutic context of EPM2A

  • In addition, sequence analyses in the patient and control DNA samples identified 4 single nucleotide polymorphisms (SNPs) (75G/A, 120G/T, 159C/G, 171C/T) in the coding region and a novel insertion/deletion polymorphic site (-483[T](11/10)[A](2/3)) and a SNP (-547A/G) in the putative regulatory region of the EPM2A gene [17].
  • We identified large EPM2A and EPM2B deletions undetectable by PCR in the heterozygous state and describe simple methods for their routine detection [27].
  • Using immunogold electron microscopy, we show that laforin is found in close proximity to the ER surrounding the polyglucosan accumulations [21].
  • In this review, we summarise the available information on the genetic basis of LD, and correlate these advances with the rapidly expanding information about the mechanisms of LD gained from studies on both cell biological and animal models [19].
  • Gamma camera images obtained 6 h after the injection of 99mTc-label LDE into one patient with ALL showed biodistribution similar to that of LDL [28].


  1. The Lafora disease gene product laforin interacts with HIRIP5, a phylogenetically conserved protein containing a NifU-like domain. Ganesh, S., Tsurutani, N., Suzuki, T., Ueda, K., Agarwala, K.L., Osada, H., Delgado-Escueta, A.V., Yamakawa, K. Hum. Mol. Genet. (2003) [Pubmed]
  2. A unique carbohydrate binding domain targets the lafora disease phosphatase to glycogen. Wang, J., Stuckey, J.A., Wishart, M.J., Dixon, J.E. J. Biol. Chem. (2002) [Pubmed]
  3. Novel NHLRC1 mutations and genotype-phenotype correlations in patients with Lafora's progressive myoclonic epilepsy. Singh, S., Sethi, I., Francheschetti, S., Riggio, C., Avanzini, G., Yamakawa, K., Delgado-Escueta, A.V., Ganesh, S. J. Med. Genet. (2006) [Pubmed]
  4. Mutations in the NHLRC1 gene are the common cause for Lafora disease in the Japanese population. Singh, S., Suzuki, T., Uchiyama, A., Kumada, S., Moriyama, N., Hirose, S., Takahashi, Y., Sugie, H., Mizoguchi, K., Inoue, Y., Kimura, K., Sawaishi, Y., Yamakawa, K., Ganesh, S. J. Hum. Genet. (2005) [Pubmed]
  5. Lafora disease. Madhavan, D., Kuzniecky, R.I. Reviews in neurological diseases. (2006) [Pubmed]
  6. Bioptically demonstrated Lafora disease without EPM2A mutation: a clinical and neurophysiological study of two sisters. Boccella, P., Striano, P., Zara, F., Barbieri, F., Sarappa, C., Vacca, G., de Falco, F.A., Striano, S. Clinical neurology and neurosurgery. (2003) [Pubmed]
  7. Mutations in a gene encoding a novel protein tyrosine phosphatase cause progressive myoclonus epilepsy. Minassian, B.A., Lee, J.R., Herbrick, J.A., Huizenga, J., Soder, S., Mungall, A.J., Dunham, I., Gardner, R., Fong, C.Y., Carpenter, S., Jardim, L., Satishchandra, P., Andermann, E., Snead, O.C., Lopes-Cendes, I., Tsui, L.C., Delgado-Escueta, A.V., Rouleau, G.A., Scherer, S.W. Nat. Genet. (1998) [Pubmed]
  8. Insights into Lafora disease: malin is an E3 ubiquitin ligase that ubiquitinates and promotes the degradation of laforin. Gentry, M.S., Worby, C.A., Dixon, J.E. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  9. Mutational spectrum of the EPM2A gene in progressive myoclonus epilepsy of Lafora: high degree of allelic heterogeneity and prevalence of deletions. Gómez-Garre, P., Sanz, Y., Rodríguez De Córdoba, S.R., Serratosa, J.M. Eur. J. Hum. Genet. (2000) [Pubmed]
  10. Plasma kinetics of a cholesterol-rich microemulsion (LDE) in patients with Hodgkin's and non-Hodgkin's lymphoma and a preliminary study on the toxicity of etoposide associated with LDE. Pinheiro, K.V., Hungria, V.T., Ficker, E.S., Valduga, C.J., Mesquita, C.H., Maranhão, R.C. Cancer Chemother. Pharmacol. (2006) [Pubmed]
  11. Plasma kinetics and uptake by the tumor of a cholesterol-rich microemulsion (LDE) associated to etoposide oleate in patients with ovarian carcinoma. Azevedo, C.H., Carvalho, J.P., Valduga, C.J., Maranhão, R.C. Gynecol. Oncol. (2005) [Pubmed]
  12. Metabolism of a cholesterol-rich microemulsion (LDE) in patients with multiple myeloma and a preliminary clinical study of LDE as a drug vehicle for the treatment of the disease. Hungria, V.T., Latrilha, M.C., Rodrigues, D.G., Bydlowski, S.P., Chiattone, C.S., Maranhão, R.C. Cancer Chemother. Pharmacol. (2004) [Pubmed]
  13. Superoxide dismutase and glutathione peroxidase function in progressive myoclonus epilepsies. Ben-Menachem, E., Kyllerman, M., Marklund, S. Epilepsy Res. (2000) [Pubmed]
  14. Identification of a novel protein interacting with laforin, the EPM2a progressive myoclonus epilepsy gene product. Ianzano, L., Zhao, X.C., Minassian, B.A., Scherer, S.W. Genomics (2003) [Pubmed]
  15. Laforin, the dual-phosphatase responsible for Lafora disease, interacts with R5 (PTG), a regulatory subunit of protein phosphatase-1 that enhances glycogen accumulation. Fernández-Sánchez, M.E., Criado-García, O., Heath, K.E., García-Fojeda, B., Medraño-Fernández, I., Gomez-Garre, P., Sanz, P., Serratosa, J.M., Rodríguez de Córdoba, S. Hum. Mol. Genet. (2003) [Pubmed]
  16. Laforin, defective in the progressive myoclonus epilepsy of Lafora type, is a dual-specificity phosphatase associated with polyribosomes. Ganesh, S., Agarwala, K.L., Ueda, K., Akagi, T., Shoda, K., Usui, T., Hashikawa, T., Osada, H., Delgado-Escueta, A.V., Yamakawa, K. Hum. Mol. Genet. (2000) [Pubmed]
  17. Mutation screening for Japanese Lafora's disease patients: identification of novel sequence variants in the coding and upstream regulatory regions of EPM2A gene. Ganesh, S., Shoda, K., Amano, K., Uchiyama, A., Kumada, S., Moriyama, N., Hirose, S., Yamakawa, K. Mol. Cell. Probes (2001) [Pubmed]
  18. Laforin is a cell membrane and endoplasmic reticulum-associated protein tyrosine phosphatase. Minassian, B.A., Andrade, D.M., Ianzano, L., Young, E.J., Chan, E., Ackerley, C.A., Scherer, S.W. Ann. Neurol. (2001) [Pubmed]
  19. Recent advances in the molecular basis of Lafora's progressive myoclonus epilepsy. Ganesh, S., Puri, R., Singh, S., Mittal, S., Dubey, D. J. Hum. Genet. (2006) [Pubmed]
  20. Lafora's disease: towards a clinical, pathologic, and molecular synthesis. Minassian, B.A. Pediatric neurology. (2001) [Pubmed]
  21. Laforin preferentially binds the neurotoxic starch-like polyglucosans, which form in its absence in progressive myoclonus epilepsy. Chan, E.M., Ackerley, C.A., Lohi, H., Ianzano, L., Cortez, M.A., Shannon, P., Scherer, S.W., Minassian, B.A. Hum. Mol. Genet. (2004) [Pubmed]
  22. Dimerization of Laforin Is Required for Its Optimal Phosphatase Activity, Regulation of GSK3beta Phosphorylation, and Wnt Signaling. Liu, Y., Wang, Y., Wu, C., Liu, Y., Zheng, P. J. Biol. Chem. (2006) [Pubmed]
  23. Plasma kinetics of a cholesterol-rich emulsion in subjects with or without coronary artery disease. Santos, R.D., Hueb, W., Oliveira, A.A., Ramires, J.A., Maranhão, R.C. J. Lipid Res. (2003) [Pubmed]
  24. Lafora progressive Myoclonus Epilepsy mutation database-EPM2A and NHLRC1 (EMP2B) genes. Ianzano, L., Zhang, J., Chan, E.M., Zhao, X.C., Lohi, H., Scherer, S.W., Minassian, B.A. Hum. Mutat. (2005) [Pubmed]
  25. A novel protein tyrosine phosphatase gene is mutated in progressive myoclonus epilepsy of the Lafora type (EPM2). Serratosa, J.M., Gómez-Garre, P., Gallardo, M.E., Anta, B., de Bernabé, D.B., Lindhout, D., Augustijn, P.B., Tassinari, C.A., Malafosse, R.M., Topcu, M., Grid, D., Dravet, C., Berkovic, S.F., de Córdoba, S.R. Hum. Mol. Genet. (1999) [Pubmed]
  26. Relationship between glycogen accumulation and the laforin dual specificity phosphatase. Wang, W., Parker, G.E., Skurat, A.V., Raben, N., Depaoli-Roach, A.A., Roach, P.J. Biochem. Biophys. Res. Commun. (2006) [Pubmed]
  27. Genetic diagnosis in Lafora disease: genotype-phenotype correlations and diagnostic pitfalls. Lohi, H., Turnbull, J., Zhao, X.C., Pullenayegum, S., Ianzano, L., Yahyaoui, M., Mikati, M.A., Franceschetti, S., Zara, F., Minassian, B.A. Neurology (2007) [Pubmed]
  28. Plasma kinetics and biodistribution of a lipid emulsion resembling low-density lipoprotein in patients with acute leukemia. Maranhão, R.C., Garicochea, B., Silva, E.L., Dorlhiac-Llacer, P., Cadena, S.M., Coelho, I.J., Meneghetti, J.C., Pileggi, F.J., Chamone, D.A. Cancer Res. (1994) [Pubmed]
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