Disease relevance of EPM2A

• Lafora disease is an autosomal recessive type of progressive myoclonus epilepsy caused by mutations in the EPM2A gene [1].
• Lafora disease (progressive myoclonus epilepsy of Lafora type) is an autosomal recessive neurodegenerative disorder resulting from defects in the EPM2A gene [2].
• CONCLUSIONS: Patients with NHLRC1 mutations have a slower rate of disease progression than those with EPM2A mutations [3].
• Lafora disease (LD) is a rare autosomal recessive genetic disorder characterized by epilepsy, myoclonus, and progressive neurological deterioration [4].
• LD is a member of the family of progressive myoclonic epilepsies, which are a heterogeneous group of disorders characterized by myoclonic epilepsy, developmental regression, and associated neurologic symptoms [5].

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

• Because genetic heterogeneity in Lafora disease has been described, mutational analysis of the EPM2AIP1 gene was performed on non-EPM2A patients, but no mutations were found [14].
• Linkage analysis and homozygosity mapping localized EPM2A, a major gene for LD, to chromosome 6q24 [15].
• Our results suggest that laforin is involved in translational regulation and that protein misfolding may be one of the molecular bases of the Lafora disease phenotype caused by missense mutations in the EPM2A gene [16].
• EPM2A encodes a 331-amino acid protein containing a carboxyl-terminal phosphatase catalytic domain [2].
• Mutation screening for Japanese Lafora's disease patients: identification of novel sequence variants in the coding and upstream regulatory regions of EPM2A gene [17].

Anatomical context of EPM2A

• The EPM2A gene-encoded protein laforin is a dual-specificity phosphatase that associates with polyribosomes [1].
• Here we report that the protein encoded by the EPM2A gene, which is mutated in LD, localizes at the plasma membrane and the endoplasmic reticulum and that it is a functional protein tyrosine phosphatase [18].
• Analyses of the structure and function of these gene products suggest defects in post-translational modification of proteins as the common mechanism that leads to the formation of Lafora inclusion bodies, neurodegeneration and the epileptic phenotype of LD [19].
• The EPM2A gene codes for the protein laforin, which localizes at the plasma membrane and the rough endoplasmic reticulum and functions as a dual-specificity phosphatase [20].
• Biochemical, immunofluorescence and electron microscopic studies on the full-length laforin expressed in HeLa cells revealed that laforin is a cytoplasmic protein associated with polyribosomes, possibly through a conformation-dependent protein-protein interaction [16].

Associations of EPM2A with chemical compounds

• Laforin preferentially binds the neurotoxic starch-like polyglucosans, which form in its absence in progressive myoclonus epilepsy [21].
• Recombinant laforin was able to hydrolyze phosphotyrosine as well as phosphoserine/threonine substrates, demonstrating that laforin is an active dual-specificity phosphatase [16].
• Dimerization of Laforin Is Required for Its Optimal Phosphatase Activity, Regulation of GSK3beta Phosphorylation, and Wnt Signaling [22].
• In this study, LDE was labeled with [14C]cholesteryl oleate and [3H]cholesterol and injected into 19 patients with coronary artery disease (CAD) and into 14 subjects without CAD to verify whether the kinetic behavior of the radioactive lipids is different in CAD [23].
• A cholesterol-rich emulsion (LDE) that resembles the LDL lipidic structure is taken-up by LDL receptors after intravenous injection by means of apolipoprotein E it acquires in the circulation and can be used to probe LDL metabolism [23].

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].

References