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Entry
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- *607566 - EPM2A GLUCAN PHOSPHATASE, LAFORIN; EPM2A
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- OMIM
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*607566</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneStructure">Gene Structure</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#mapping">Mapping</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#genotypePhenotypeCorrelations">Genotype/Phenotype Correlations</a>
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<a href="#animalModel">Animal Model</a>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/607566">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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</ul>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000112425;t=ENST00000367519" class="mim-tip-hint" title="Genome databases for vertebrates and other eukaryotic species." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Ensembl', 'domain': 'ensembl.org'})">Ensembl</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/genome/gdv/browser/gene/?id=7957" class="mim-tip-hint" title="Detailed views of the complete genomes of selected organisms from vertebrates to protozoa." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Genome Viewer', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Genome Viewer</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&hgFind=omimGeneAcc&position=607566" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
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<span class="panel-title">
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<span class="small">
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<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
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</a>
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</span>
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</span>
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</div>
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<div id="mimDnaLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Transcript/Sequence_cDNA?db=core;g=ENSG00000112425;t=ENST00000367519" class="mim-tip-hint" title="Transcript-based views for coding and noncoding DNA." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Ensembl', 'domain': 'ensembl.org'})">Ensembl (MANE Select)</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_001018041,NM_001360057,NM_001360064,NM_001360071,NM_001368129,NM_001368130,NM_001368131,NM_001368132,NM_005670,NR_153398,XM_011536113,XM_011536116,XM_017011302,XM_024446550,XM_024446551,XM_047419363,XM_047419364" class="mim-tip-hint" title="A collection of genome, gene, and transcript sequence data from several sources, including GenBank, RefSeq." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI RefSeq', 'domain': 'ncbi.nlm.nih'})">NCBI RefSeq</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_005670" class="mim-tip-hint" title="A collection of genome, gene, and transcript sequence data from several sources, including GenBank, RefSeq." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI RefSeq (MANE)', 'domain': 'ncbi.nlm.nih'})">NCBI RefSeq (MANE Select)</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&hgFind=omimGeneAcc&position=607566" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimProtein">
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<span class="panel-title">
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<span class="small">
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<a href="#mimProteinLinksFold" id="mimProteinLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimProteinLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Protein
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</a>
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</span>
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</span>
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</div>
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<div id="mimProteinLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://hprd.org/summary?hprd_id=06345&isoform_id=06345_1&isoform_name=Isoform_1" class="mim-tip-hint" title="The Human Protein Reference Database; manually extracted and visually depicted information on human proteins." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HPRD', 'domain': 'hprd.org'})">HPRD</a></div>
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<div><a href="https://www.proteinatlas.org/search/EPM2A" class="mim-tip-hint" title="The Human Protein Atlas contains information for a large majority of all human protein-coding genes regarding the expression and localization of the corresponding proteins based on both RNA and protein data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HumanProteinAtlas', 'domain': 'proteinatlas.org'})">Human Protein Atlas</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/protein/3980309,3980311,6005986,10505185,11321613,13528990,27462632,27462634,27462636,27462638,47682971,50400258,66346728,119568227,119568228,119568229,193785672,194388874,380876884,767943546,767943553,1034651653,1334928394,1334928398,1334928400,1370508680,1370508682,1559191237,1559191242,1559191254,1559191259,2217363109,2217363114,2462610571,2462610573,2462610575,2462610577,2462610579,2462610581,2462610583,2462610585" class="mim-tip-hint" title="NCBI protein data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Protein', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Protein</a></div>
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<div><a href="https://www.uniprot.org/uniprotkb/O95278" class="mim-tip-hint" title="Comprehensive protein sequence and functional information, including supporting data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UniProt', 'domain': 'uniprot.org'})">UniProt</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGeneInfo">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGeneInfoLinksFold" id="mimGeneInfoLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimGeneInfoLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Gene Info</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimGeneInfoLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="http://biogps.org/#goto=genereport&id=7957" class="mim-tip-hint" title="The Gene Portal Hub; customizable portal of gene and protein function information." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'BioGPS', 'domain': 'biogps.org'})">BioGPS</a></div>
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<div><a href="https://www.ensembl.org/Homo_sapiens/Gene/Summary?db=core;g=ENSG00000112425;t=ENST00000367519" class="mim-tip-hint" title="Orthologs, paralogs, regulatory regions, and splice variants." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Ensembl', 'domain': 'ensembl.org'})">Ensembl</a></div>
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<div><a href="https://www.genecards.org/cgi-bin/carddisp.pl?gene=EPM2A" class="mim-tip-hint" title="The Human Genome Compendium; web-based cards integrating automatically mined information on human genes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GeneCards', 'domain': 'genecards.org'})">GeneCards</a></div>
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<div><a href="http://amigo.geneontology.org/amigo/search/annotation?q=EPM2A" class="mim-tip-hint" title="Terms, defined using controlled vocabulary, representing gene product properties (biologic process, cellular component, molecular function) across species." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GeneOntology', 'domain': 'amigo.geneontology.org'})">Gene Ontology</a></div>
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<div><a href="https://www.genome.jp/dbget-bin/www_bget?hsa+7957" class="mim-tip-hint" title="Kyoto Encyclopedia of Genes and Genomes; diagrams of signaling pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'KEGG', 'domain': 'genome.jp'})">KEGG</a></div>
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<dd><a href="http://v1.marrvel.org/search/gene/EPM2A" class="mim-tip-hint" title="Model organism Aggregated Resources for Rare Variant ExpLoration." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MARRVEL', 'domain': 'marrvel.org'})">MARRVEL</a></dd>
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<dd><a href="https://monarchinitiative.org/NCBIGene:7957" class="mim-tip-hint" title="Monarch Initiative." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Monarch', 'domain': 'monarchinitiative.org'})">Monarch</a></dd>
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<div><a href="https://www.ncbi.nlm.nih.gov/gene/7957" class="mim-tip-hint" title="Gene-specific map, sequence, expression, structure, function, citation, and homology data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Gene', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Gene</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgGene?db=hg38&hgg_chrom=chr6&hgg_gene=ENST00000367519.9&hgg_start=145383353&hgg_end=145736023&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/gene-dosage/HGNC:3413" class="mim-tip-hint" title="A ClinGen curated resource of genes and regions of the genome that are dosage sensitive and should be targeted on a cytogenomic array." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Dosage', 'domain': 'dosage.clinicalgenome.org'})">ClinGen Dosage</a></div>
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:3413" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://medlineplus.gov/genetics/gene/epm2a" class="mim-tip-hint" title="Consumer-friendly information about the effects of genetic variation on human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MedlinePlus Genetics', 'domain': 'medlineplus.gov'})">MedlinePlus Genetics</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=607566[mim]" class="mim-tip-hint" title="Genetic Testing Registry." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GTR', 'domain': 'ncbi.nlm.nih.gov'})">GTR</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimVariation">
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<span class="panel-title">
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<span class="small">
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<a href="#mimVariationLinksFold" id="mimVariationLinksToggle" class=" mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimVariationLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">▼</span> Variation
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</a>
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</span>
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</span>
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</div>
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<div id="mimVariationLinksFold" class="panel-collapse collapse in mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ncbi.nlm.nih.gov/clinvar?term=607566[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000112425" class="mim-tip-hint" title="The Genome Aggregation Database (gnomAD), Broad Institute." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'gnomAD', 'domain': 'gnomad.broadinstitute.org'})">gnomAD</a></div>
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<div><a href="https://www.ebi.ac.uk/gwas/search?query=EPM2A" class="mim-tip-hint" title="GWAS Catalog; NHGRI-EBI Catalog of published genome-wide association studies." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GWAS Catalog', 'domain': 'gwascatalog.org'})">GWAS Catalog </a></div>
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<div><a href="https://www.gwascentral.org/search?q=EPM2A" class="mim-tip-hint" title="GWAS Central; summary level genotype-to-phenotype information from genetic association studies." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GWAS Central', 'domain': 'gwascentral.org'})">GWAS Central </a></div>
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<div><a href="http://www.hgmd.cf.ac.uk/ac/gene.php?gene=EPM2A" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=EPM2A&upstreamSize=0&downstreamSize=0&x=0&y=0" class="mim-tip-hint" title="National Heart, Lung, and Blood Institute Exome Variant Server." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NHLBI EVS', 'domain': 'evs.gs.washington.edu'})">NHLBI EVS</a></div>
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<div><a href="https://www.pharmgkb.org/gene/PA27832" class="mim-tip-hint" title="Pharmacogenomics Knowledge Base; curated and annotated information regarding the effects of human genetic variations on drug response." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PharmGKB', 'domain': 'pharmgkb.org'})">PharmGKB</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimAnimalModels">
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<span class="panel-title">
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<span class="small">
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<a href="#mimAnimalModelsLinksFold" id="mimAnimalModelsLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimAnimalModelsLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Animal Models</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimAnimalModelsLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.alliancegenome.org/gene/HGNC:3413" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
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<div><a href="https://www.mousephenotype.org/data/genes/MGI:1341085" class="mim-tip-hint" title="International Mouse Phenotyping Consortium." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'IMPC', 'domain': 'knockoutmouse.org'})">IMPC</a></div>
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<div><a href="http://v1.marrvel.org/search/gene/EPM2A#HomologGenesPanel" class="mim-tip-hint" title="Model organism Aggregated Resources for Rare Variant ExpLoration." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MARRVEL', 'domain': 'marrvel.org'})">MARRVEL</a></div>
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<div><a href="http://www.informatics.jax.org/marker/MGI:1341085" class="mim-tip-hint" title="Mouse Genome Informatics; international database resource for the laboratory mouse, including integrated genetic, genomic, and biological data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MGI Mouse Gene', 'domain': 'informatics.jax.org'})">MGI Mouse Gene</a></div>
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<div><a href="https://www.mmrrc.org/catalog/StrainCatalogSearchForm.php?search_query=" class="mim-tip-hint" title="Mutant Mouse Resource & Research Centers." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MMRRC', 'domain': 'mmrrc.org'})">MMRRC</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gene/7957/ortholog/" class="mim-tip-hint" title="Orthologous genes at NCBI." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Orthologs', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Orthologs</a></div>
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<div><a href="https://www.orthodb.org/?ncbi=7957" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-100922-143" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
|
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<span class="panel-title">
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<span class="small">
|
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
|
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://reactome.org/content/query?q=EPM2A&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
|
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<span class="text-danger"><strong>*</strong></span>
|
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607566
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</span>
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</span>
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</div>
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</div>
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<div>
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<a id="preferredTitle" class="mim-anchor"></a>
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<h3>
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<span class="mim-font">
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EPM2A GLUCAN PHOSPHATASE, LAFORIN; EPM2A
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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LAFORIN
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="includedTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
|
|
Other entities represented in this entry:
|
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</span>
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</p>
|
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</div>
|
|
<div>
|
|
<span class="h3 mim-font">
|
|
EPM2A, ISOFORM A, INCLUDED
|
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</span>
|
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</div>
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<div>
|
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<span class="h4 mim-font">
|
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EPM2A, ISOFORM B, INCLUDED
|
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</span>
|
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</div>
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</div>
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<div>
|
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<br />
|
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</div>
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</div>
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<div>
|
|
<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
|
<p>
|
|
<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=EPM2A" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">EPM2A</a></em></strong>
|
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</span>
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</p>
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</div>
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<div>
|
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<a id="cytogeneticLocation" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
|
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<strong>
|
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<em>
|
|
Cytogenetic location: <a href="/geneMap/6/925?start=-3&limit=10&highlight=925">6q24.3</a>
|
|
|
|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr6:145383353-145736023&dgv=pack&knownGene=pack&omimGene=pack" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">6:145,383,353-145,736,023</a> </span>
|
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</em>
|
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</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
|
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</span>
|
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</p>
|
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</div>
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<div>
|
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<br />
|
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</div>
|
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<div>
|
|
<a id="geneMap" class="mim-anchor"></a>
|
|
<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
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<th>
|
|
Location
|
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</th>
|
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<th>
|
|
Phenotype
|
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</th>
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<th>
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|
Phenotype <br /> MIM number
|
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</th>
|
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<th>
|
|
Inheritance
|
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</th>
|
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<th>
|
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Phenotype <br /> mapping key
|
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</th>
|
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</tr>
|
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</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="1">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/6/925?start=-3&limit=10&highlight=925">
|
|
6q24.3
|
|
</a>
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
Myoclonic epilepsy of Lafora 1
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
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<span class="mim-font">
|
|
|
|
<a href="/entry/254780"> 254780 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
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</span>
|
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</td>
|
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</tr>
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</tbody>
|
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</table>
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</div>
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</div>
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<div>
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<div class="btn-group">
|
|
<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
|
PheneGene Graphics <span class="caret"></span>
|
|
</button>
|
|
<ul class="dropdown-menu" style="width: 17em;">
|
|
<li><a href="/graph/linear/607566" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/607566" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
|
|
</ul>
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<p>The EPM2A gene encodes laforin, a dual-specificity protein phosphatase that hydrolyzes phosphotyrosine and phosphoserine/threonine substrates. Laforin also binds complex carbohydrates and plays a role in glycogen metabolism (<a href="#24" class="mim-tip-reference" title="Worby, C. A., Gentry, M. S., Dixon, J. E. <strong>Laforin, a dual specificity phosphatase that dephosphorylates complex carbohydrates.</strong> J. Biol. Chem. 281: 30412-30418, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16901901/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16901901</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16901901[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1074/jbc.M606117200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16901901">Worby et al., 2006</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16901901" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>Linkage studies in patients with myoclonic epilepsy of Lafora-1 (<a href="/entry/254780">254780</a>) demonstrated that the putative causative gene was located on chromosome 6q24. Using a positional cloning approach in this region, <a href="#19" class="mim-tip-reference" title="Minassian, B. A., Lee, J. R., Herbrick, J.-A., Huizenga, J., Soder, S., Mungall, A. J., Dunham, I., Gardner, R., Fong, C. G., Carpenter, S., Jardim, L., Satishchandra, P., Andermann, E., Snead, O. C., III, Lopes-Cendes, I., Tsui, L.-C., Delgado-Escueta, A. V., Rouleau, G. A., Scherer, S. W. <strong>Mutations in a gene encoding a novel protein tyrosine phosphatase cause progressive myoclonus epilepsy.</strong> Nature Genet. 20: 171-174, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9771710/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9771710</a>] [<a href="https://doi.org/10.1038/2470" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9771710">Minassian et al. (1998)</a> identified a novel gene, EPM2A, encoding a protein, termed laforin, with a consensus amino acid sequence indicative of a protein-tyrosine phosphatase (PTP). They found mRNA transcripts representing alternatively spliced forms of EPM2A in every tissue examined, including brain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9771710" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#21" class="mim-tip-reference" title="Serratosa, J. M., Gomez-Garre, P., Gallardo, M. E., Anta, B., Beltran-Valero de Bernabe, D., Lindhout, D., Augustijn, P. B., Tassinari, C. A., Michelucci, R., Malafosse, A., Topcu, M., Grid, D., Dravet, C., Berkovic, S. F., Rodriguez de Cordoba, S. <strong>A novel protein tyrosine phosphatase gene is mutated in progressive myoclonus epilepsy of the Lafora type (EPM2).</strong> Hum. Molec. Genet. 8: 345-352, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9931343/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9931343</a>] [<a href="https://doi.org/10.1093/hmg/8.2.345" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9931343">Serratosa et al. (1999)</a> independently reported the positional cloning of the EPM2 gene on 6q and identified alternative splicing in the 5-prime and 3-prime end regions. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9931343" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#19" class="mim-tip-reference" title="Minassian, B. A., Lee, J. R., Herbrick, J.-A., Huizenga, J., Soder, S., Mungall, A. J., Dunham, I., Gardner, R., Fong, C. G., Carpenter, S., Jardim, L., Satishchandra, P., Andermann, E., Snead, O. C., III, Lopes-Cendes, I., Tsui, L.-C., Delgado-Escueta, A. V., Rouleau, G. A., Scherer, S. W. <strong>Mutations in a gene encoding a novel protein tyrosine phosphatase cause progressive myoclonus epilepsy.</strong> Nature Genet. 20: 171-174, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9771710/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9771710</a>] [<a href="https://doi.org/10.1038/2470" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9771710">Minassian et al. (1998)</a> reported that the EPM2A gene encodes 2 isoforms of the laforin protein which have alternate C termini. The common segment consists of a carbohydrate-binding module and a dual-specificity protein phosphatase domain (<a href="#5" class="mim-tip-reference" title="Ganesh, S., Agarwala, K. L., Ueda, K., Akagi, T., Shoda, K., Usui, T., Hashikawa, T., Osada, H., Delgado-Escueta, A. V., Yamakawa, K. <strong>Laforin, defective in the progressive myoclonus epilepsy of Lafora type, is a dual-specificity phosphatase associated with polyribosomes.</strong> Hum. Molec. Genet. 9: 2251-2261, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11001928/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11001928</a>] [<a href="https://doi.org/10.1093/oxfordjournals.hmg.a018916" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11001928">Ganesh et al., 2000</a>). Isoform A localizes at the rough endoplasmic reticulum. Isoform B localizes to the nucleus. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9771710+11001928" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#13" class="mim-tip-reference" title="Gomez-Garre, P., Sanz, Y., Rodriguez de Cordoba, S., Serratosa, J. M. <strong>Mutational spectrum of the EPM2A gene in progressive myoclonus epilepsy of Lafora: high degree of allelic heterogeneity and prevalence of deletions.</strong> Europ. J. Hum. Genet. 8: 946-954, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11175283/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11175283</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200571" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11175283">Gomez-Garre et al. (2000)</a> reported the complete coding sequence of the EPM2A gene, including the ATG initiation codon region. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11175283" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#23" class="mim-tip-reference" title="Wang, J., Stuckey, J. A., Wishart, M. J., Dixon, J. E. <strong>A unique carbohydrate binding domain targets the Lafora disease phosphatase to glycogen.</strong> J. Biol. Chem. 277: 2377-2380, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11739371/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11739371</a>] [<a href="https://doi.org/10.1074/jbc.C100686200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11739371">Wang et al. (2002)</a> cloned EPM2A from a muscle cDNA library. Subcellular fractionation of human embryonic kidney cells showed that about half of overexpressed recombinant EPM2A sedimented with glycogen-microsomal complexes. Alpha-amylase treatment released EPM2A from the glycogen complexes. Molecular modeling predicted that 2 invariant trp residues and an invariant lys in the carbohydrate-binding domain (trp32, trp99, and lys87) interact directly with polysaccharides. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11739371" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By RT-PCR <a href="#9" class="mim-tip-reference" title="Ganesh, S., Suzuki, T., Yamakawa, K. <strong>Alternative splicing modulates subcellular localization of laforin.</strong> Biochem. Biophys. Res. Commun. 291: 1134-1137, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11883934/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11883934</a>] [<a href="https://doi.org/10.1006/bbrc.2002.6590" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11883934">Ganesh et al. (2002)</a> determined that human fetal brain expressed both splice variants of EPM2A. The variant encoding the 317-amino acid protein was expressed at a lower level than the variant encoding the 331-amino acid protein. Western blot analysis of transfected HeLa cells detected the shorter isoform at an apparent molecular mass of 37 kD. This variant accumulated in both the cytoplasm and the nucleus. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11883934" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#5" class="mim-tip-reference" title="Ganesh, S., Agarwala, K. L., Ueda, K., Akagi, T., Shoda, K., Usui, T., Hashikawa, T., Osada, H., Delgado-Escueta, A. V., Yamakawa, K. <strong>Laforin, defective in the progressive myoclonus epilepsy of Lafora type, is a dual-specificity phosphatase associated with polyribosomes.</strong> Hum. Molec. Genet. 9: 2251-2261, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11001928/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11001928</a>] [<a href="https://doi.org/10.1093/oxfordjournals.hmg.a018916" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11001928">Ganesh et al. (2000)</a> cloned and expressed the full-length 38-kD laforin protein in transfected cells. Recombinant laforin was able to hydrolyze phosphotyrosine as well as phosphoserine/threonine substrates, demonstrating that laforin is an active dual-specificity phosphatase. Biochemical, immunofluorescence, and ultrastructural studies on transfected HeLa cells revealed that laforin is a cytoplasmic protein associated with polyribosomes. Expression of 2 proteins with missense mutations seen in EPM2A patients resulted in ubiquitin-positive perinuclear aggregates, suggesting that these were misfolded proteins targeted for degradation. The authors suggested 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. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11001928" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#23" class="mim-tip-reference" title="Wang, J., Stuckey, J. A., Wishart, M. J., Dixon, J. E. <strong>A unique carbohydrate binding domain targets the Lafora disease phosphatase to glycogen.</strong> J. Biol. Chem. 277: 2377-2380, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11739371/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11739371</a>] [<a href="https://doi.org/10.1074/jbc.C100686200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11739371">Wang et al. (2002)</a> determined that wildtype EPM2A associated with glycogen complexes in vitro and in vivo, whereas EPM2A carrying the trp32-to-gly mutation (W32G; <a href="#0010">607566.0010</a>) did not. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11739371" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#10" class="mim-tip-reference" title="Ganesh, S., Tsurutani, N., Suzuki, T., Ueda, K., Agarwala, K. L., Osada, H., Delgado-Escueta, A. V., Yamakawa, K. <strong>The Lafora disease gene product laforin interacts with HIRIP5, a phylogenetically conserved protein containing a NifU-like domain.</strong> Hum. Molec. Genet. 12: 2359-2368, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12915448/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12915448</a>] [<a href="https://doi.org/10.1093/hmg/ddg253" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12915448">Ganesh et al. (2003)</a> used the yeast 2-hybrid system to screen for protein(s) that interact with laforin. The authors found a specific interaction between the N-terminal CBD4 domain of laforin and the C-terminal NifU-like domain of HIRIP5 (<a href="/entry/608100">608100</a>). They also determined that HIRIP5 is a substrate for the phosphatase activity of laforin. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12915448" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#4" class="mim-tip-reference" title="Fernandez-Sanchez, M. E., Criado-Garcia, O., Heath, K. E., Garcia-Fojeda, B., Medrano-Fernandez, I., Gomez-Garre, P., Sanz, P., Serratosa, J. M., Rodriguez de Cordoba, S. <strong>Laforin, the dual-phosphatase responsible for Lafora disease, interacts with R5 (PTG), a regulatory subunit of protein phosphatase-1 that enhances glycogen accumulation.</strong> Hum. Molec. Genet. 12: 3161-3171, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14532330/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14532330</a>] [<a href="https://doi.org/10.1093/hmg/ddg340" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14532330">Fernandez-Sanchez et al. (2003)</a> showed that laforin interacted with itself and with PPP1R3C (<a href="/entry/602999">602999</a>), a protein that acts as a molecular scaffold assembling protein phosphatase-1 (PP1; see <a href="/entry/176875">176875</a>) with glycogen synthase (GYS1; <a href="/entry/138570">138570</a>) at intracellular glycogen particles. Full-length laforin was required for the interaction with PPP1R3C. However, a minimal central region of PPP1R3C (amino acids 116 to 238), including the binding sites for glycogen and glycogen synthase, was sufficient to interact with laforin. Point mutagenesis of the glycogen synthase-binding site completely blocked interaction with laforin. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14532330" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By yeast 2-hybrid screen of a human brain cDNA library, <a href="#12" class="mim-tip-reference" title="Gentry, M. S., Worby, C. A., Dixon, J. E. <strong>Insights into Lafora disease: malin is an E3 ubiquitin ligase that ubiquitinates and promotes the degradation of laforin.</strong> Proc. Nat. Acad. Sci. 102: 8501-8506, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15930137/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15930137</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15930137[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0503285102" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15930137">Gentry et al. (2005)</a> found that malin (NHLRC1; <a href="/entry/608072">608072</a>) directly bound and interacted with laforin in HEK293T cells in vivo. Mutations in the NHLRC1 gene also result in Lafora disease. In normal cells, laforin is polyubiquitinated in a malin-dependent manner, which leads to laforin degradation. <a href="#12" class="mim-tip-reference" title="Gentry, M. S., Worby, C. A., Dixon, J. E. <strong>Insights into Lafora disease: malin is an E3 ubiquitin ligase that ubiquitinates and promotes the degradation of laforin.</strong> Proc. Nat. Acad. Sci. 102: 8501-8506, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15930137/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15930137</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15930137[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0503285102" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15930137">Gentry et al. (2005)</a> concluded that malin is a single-subunit E3 ligase, that laforin is a malin substrate, and that malin regulates laforin protein concentration. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15930137" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#17" class="mim-tip-reference" title="Lohi, H., Ianzano, L., Zhao, X.-C., Chan, E. M., Turnbull, J., Scherer, S. W., Ackerley, C. A., Minassian, B. A. <strong>Novel glycogen synthase kinase 3 and ubiquitination pathways in progressive myoclonus epilepsy.</strong> Hum. Molec. Genet. 14: 2727-2736, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16115820/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16115820</a>] [<a href="https://doi.org/10.1093/hmg/ddi306" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16115820">Lohi et al. (2005)</a> showed that laforin is a GSK3B (<a href="/entry/605004">605004</a>) ser9 phosphatase, and therefore capable of inactivating glycogen synthase. Laforin was also shown to interact with malin. The authors proposed that laforin, in response to appearance of polyglucosans, directs 2 negative feedback pathways: polyglucosan-laforin-GSK3-GYS1 to inhibit GYS1 activity, and polyglucosan-laforin-malin-GYS1 to remove GYS1 through proteasomal degradation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16115820" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#24" class="mim-tip-reference" title="Worby, C. A., Gentry, M. S., Dixon, J. E. <strong>Laforin, a dual specificity phosphatase that dephosphorylates complex carbohydrates.</strong> J. Biol. Chem. 281: 30412-30418, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16901901/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16901901</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16901901[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1074/jbc.M606117200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16901901">Worby et al. (2006)</a> demonstrated that laforin displayed robust phosphatase activity against a plant-derived complex carbohydrate, amylopectin, whereas several other active human phosphatases were unable to perform this function. The authors suggested that laforin may be necessary for the maintenance of normal cellular glycogen. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16901901" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#20" class="mim-tip-reference" title="Mittal, S., Dubey, D., Yamakawa, K., Ganesh, S. <strong>Lafora disease proteins malin and laforin are recruited to aggresomes in response to proteasomal impairment.</strong> Hum. Molec. Genet. 16: 753-762, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17337485/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17337485</a>] [<a href="https://doi.org/10.1093/hmg/ddm006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17337485">Mittal et al. (2007)</a> showed that laforin and malin were recruited to aggresomes upon proteasomal blockade, possibly to clear misfolded proteins through the ubiquitin-proteasome system (UPS). <a href="#11" class="mim-tip-reference" title="Garyali, P., Siwach, P., Singh, P. K., Puri, R., Mittal, S., Sengupta, S., Parihar, R., Ganesh, S. <strong>The malin-laforin complex suppresses the cellular toxicity of misfolded proteins by promoting their degradation through the ubiquitin-proteasome system.</strong> Hum. Molec. Genet. 18: 688-700, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19036738/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19036738</a>] [<a href="https://doi.org/10.1093/hmg/ddn398" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19036738">Garyali et al. (2009)</a> tested this possibility using a variety of cytotoxic misfolded proteins, including the expanded polyglutamine protein, as potential substrates. Laforin and malin, together with Hsp70 (HSPA1A; <a href="/entry/140550">140550</a>) as a functional complex, suppressed the cellular toxicity of misfolded proteins; all 3 members of the complex were required for this function. Laforin and malin interacted with misfolded proteins and promoted their degradation through the UPS, and they were recruited to the polyglutamine aggregates and reduced the frequency of aggregate-positive cells. <a href="#11" class="mim-tip-reference" title="Garyali, P., Siwach, P., Singh, P. K., Puri, R., Mittal, S., Sengupta, S., Parihar, R., Ganesh, S. <strong>The malin-laforin complex suppresses the cellular toxicity of misfolded proteins by promoting their degradation through the ubiquitin-proteasome system.</strong> Hum. Molec. Genet. 18: 688-700, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19036738/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19036738</a>] [<a href="https://doi.org/10.1093/hmg/ddn398" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19036738">Garyali et al. (2009)</a> suggested that the malin-laforin complex is a novel player in the neuronal response to misfolded proteins. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=17337485+19036738" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#1" class="mim-tip-reference" title="Aguado, C., Sarkar, S., Korolchuk, V. I., Criado, O., Vernia, S., Boya, P., Sanz, P., Rodriguez de Cordoba, S., Knecht, E., Rubinsztein, D. C. <strong>Laforin, the most common protein mutated in Lafora disease, regulates autophagy.</strong> Hum. Molec. Genet. 19: 2867-2876, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20453062/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20453062</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20453062[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddq190" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20453062">Aguado et al. (2010)</a> reported that loss of function of laforin impairs autophagy in patient cell lines, in embryonic fibroblasts from laforin knockout mice, and in tissues from such mice. Conversely, laforin overexpression stimulated autophagy. Laforin regulates autophagy through the mammalian target of rapamycin (MTOR; <a href="/entry/601231">601231</a>) kinase-dependent pathway, demonstrated by correlation of increased mTOR activity with starvation of human fibroblasts and of wildtype mice. The authors suggested that laforin-mediated changes in autophagy may regulate the balance of diverse substrates expected to impact Lafora body accumulation and the cell stress associated with Lafora disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20453062" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#9" class="mim-tip-reference" title="Ganesh, S., Suzuki, T., Yamakawa, K. <strong>Alternative splicing modulates subcellular localization of laforin.</strong> Biochem. Biophys. Res. Commun. 291: 1134-1137, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11883934/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11883934</a>] [<a href="https://doi.org/10.1006/bbrc.2002.6590" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11883934">Ganesh et al. (2002)</a> determined that the EPM2A gene contains 5 exons that are alternatively spliced to form 2 major EPM2A transcripts. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11883934" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>The EPM2A gene maps to chromosome 6q24 (<a href="#19" class="mim-tip-reference" title="Minassian, B. A., Lee, J. R., Herbrick, J.-A., Huizenga, J., Soder, S., Mungall, A. J., Dunham, I., Gardner, R., Fong, C. G., Carpenter, S., Jardim, L., Satishchandra, P., Andermann, E., Snead, O. C., III, Lopes-Cendes, I., Tsui, L.-C., Delgado-Escueta, A. V., Rouleau, G. A., Scherer, S. W. <strong>Mutations in a gene encoding a novel protein tyrosine phosphatase cause progressive myoclonus epilepsy.</strong> Nature Genet. 20: 171-174, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9771710/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9771710</a>] [<a href="https://doi.org/10.1038/2470" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9771710">Minassian et al., 1998</a>). <a href="#6" class="mim-tip-reference" title="Ganesh, S., Amano, K., Delgado-Escueta, A. V., Yamakawa, K. <strong>Isolation and characterization of mouse homologue for the human epilepsy gene, EPM2A.</strong> Biochem. Biophys. Res. Commun. 257: 24-28, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10092504/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10092504</a>] [<a href="https://doi.org/10.1006/bbrc.1999.0402" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10092504">Ganesh et al. (1999)</a> mapped the mouse Epm2a gene to a region of mouse chromosome 10A that shows homology of synteny to human chromosome 6q24. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9771710+10092504" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In 10 families with myoclonic epilepsy of Lafora, <a href="#19" class="mim-tip-reference" title="Minassian, B. A., Lee, J. R., Herbrick, J.-A., Huizenga, J., Soder, S., Mungall, A. J., Dunham, I., Gardner, R., Fong, C. G., Carpenter, S., Jardim, L., Satishchandra, P., Andermann, E., Snead, O. C., III, Lopes-Cendes, I., Tsui, L.-C., Delgado-Escueta, A. V., Rouleau, G. A., Scherer, S. W. <strong>Mutations in a gene encoding a novel protein tyrosine phosphatase cause progressive myoclonus epilepsy.</strong> Nature Genet. 20: 171-174, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9771710/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9771710</a>] [<a href="https://doi.org/10.1038/2470" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9771710">Minassian et al. (1998)</a> identified 6 distinct DNA sequence variations in the EPM2A gene and 1 homozygous microdeletion (see Lafora disease-1, <a href="/entry/254780">254780</a>), each segregating with the disorder (see, e.g., <a href="#0001">607566.0001</a>-<a href="#0003">607566.0003</a>). These mutations were predicted to cause deleterious effects in the laforin protein, resulting in the disorder. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9771710" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In patients with Lafora disease-1, <a href="#21" class="mim-tip-reference" title="Serratosa, J. M., Gomez-Garre, P., Gallardo, M. E., Anta, B., Beltran-Valero de Bernabe, D., Lindhout, D., Augustijn, P. B., Tassinari, C. A., Michelucci, R., Malafosse, A., Topcu, M., Grid, D., Dravet, C., Berkovic, S. F., Rodriguez de Cordoba, S. <strong>A novel protein tyrosine phosphatase gene is mutated in progressive myoclonus epilepsy of the Lafora type (EPM2).</strong> Hum. Molec. Genet. 8: 345-352, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9931343/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9931343</a>] [<a href="https://doi.org/10.1093/hmg/8.2.345" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9931343">Serratosa et al. (1999)</a> identified 8 loss-of-function mutations in the EPM2A gene: a microdeletion, a frameshift, an insertion, 4 missense mutations, and a nonsense mutation (see, e.g., <a href="#0004">607566.0004</a> and <a href="#0007">607566.0007</a>). The authors suggested that the gene may be important in the control of glycogen metabolism, thus accounting for the glycogen-like intracellular inclusion bodies (Lafora bodies). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9931343" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#13" class="mim-tip-reference" title="Gomez-Garre, P., Sanz, Y., Rodriguez de Cordoba, S., Serratosa, J. M. <strong>Mutational spectrum of the EPM2A gene in progressive myoclonus epilepsy of Lafora: high degree of allelic heterogeneity and prevalence of deletions.</strong> Europ. J. Hum. Genet. 8: 946-954, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11175283/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11175283</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200571" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11175283">Gomez-Garre et al. (2000)</a> used SSCP analysis of the 4 exons of the EPM2A gene in 34 unrelated patients with Lafora disease and identified mutations in 27 (79%) of them (49 of 68 chromosomes, or 72%). The patients originated from Spain, Italy, Australia, Holland, the US, North Africa, Turkey, and France. A total of 20 different EPM2A mutations, 11 of them novel, were characterized. The authors summarized 25 EPM2A mutations distributed throughout the gene in 44 unrelated Lafora disease patients. The mutations included 10 deletions of different sizes, 9 missense mutations, 3 nonsense mutations, and 3 frameshift mutations. The R241X mutation (<a href="#0001">607566.0001</a>) was encountered in almost 40% of the probands. In 5 Lafora disease families (13% of the families studied), <a href="#13" class="mim-tip-reference" title="Gomez-Garre, P., Sanz, Y., Rodriguez de Cordoba, S., Serratosa, J. M. <strong>Mutational spectrum of the EPM2A gene in progressive myoclonus epilepsy of Lafora: high degree of allelic heterogeneity and prevalence of deletions.</strong> Europ. J. Hum. Genet. 8: 946-954, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11175283/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11175283</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200571" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11175283">Gomez-Garre et al. (2000)</a> excluded linkage to the EPM2A gene region, suggesting genetic heterogeneity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11175283" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 8 patients with Lafora disease, <a href="#14" class="mim-tip-reference" title="Ianzano, L., Young, E. J., Zhao, X. C., Chan, E. M., Rodriguez, M. T., Torrado, M. V., Scherer, S. W., Minassian, B. A. <strong>Loss of function of the cytoplasmic isoform of the protein laforin (EPM2A) causes Lafora progressive myoclonus epilepsy.</strong> Hum. Mutat. 23: 170-176, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14722920/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14722920</a>] [<a href="https://doi.org/10.1002/humu.10306" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14722920">Ianzano et al. (2004)</a> identified 11 different mutations in the EPM2A gene, 6 of which were novel. One of the novel mutations, a 1-bp insertion resulting in a frameshift (<a href="#0009">607566.0009</a>), was specific to the cytoplasmic laforin isoform. Previously, all documented disease mutations, including the knockout mouse model deletion, had been located in the segment of the protein common to both isoforms. <a href="#14" class="mim-tip-reference" title="Ianzano, L., Young, E. J., Zhao, X. C., Chan, E. M., Rodriguez, M. T., Torrado, M. V., Scherer, S. W., Minassian, B. A. <strong>Loss of function of the cytoplasmic isoform of the protein laforin (EPM2A) causes Lafora progressive myoclonus epilepsy.</strong> Hum. Mutat. 23: 170-176, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14722920/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14722920</a>] [<a href="https://doi.org/10.1002/humu.10306" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14722920">Ianzano et al. (2004)</a> demonstrated a drastic reduction in the phosphatase activity of the mutant laforin, despite maintenance of its location at the endoplasmic reticulum. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14722920" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#4" class="mim-tip-reference" title="Fernandez-Sanchez, M. E., Criado-Garcia, O., Heath, K. E., Garcia-Fojeda, B., Medrano-Fernandez, I., Gomez-Garre, P., Sanz, P., Serratosa, J. M., Rodriguez de Cordoba, S. <strong>Laforin, the dual-phosphatase responsible for Lafora disease, interacts with R5 (PTG), a regulatory subunit of protein phosphatase-1 that enhances glycogen accumulation.</strong> Hum. Molec. Genet. 12: 3161-3171, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14532330/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14532330</a>] [<a href="https://doi.org/10.1093/hmg/ddg340" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14532330">Fernandez-Sanchez et al. (2003)</a> found that the majority of EPM2A missense mutations in Lafora disease-1 patients resulted in lack of phosphatase activity, absence of binding to glycogen, and lack of interaction with PPP1R3C. They identified an EPM2A missense mutation that had no effect on the phosphatase or glycogen-binding activities of laforin but disrupted interaction with PPP1R3C, suggesting that binding to PPP1R3C may be critical for laforin function. <a href="#4" class="mim-tip-reference" title="Fernandez-Sanchez, M. E., Criado-Garcia, O., Heath, K. E., Garcia-Fojeda, B., Medrano-Fernandez, I., Gomez-Garre, P., Sanz, P., Serratosa, J. M., Rodriguez de Cordoba, S. <strong>Laforin, the dual-phosphatase responsible for Lafora disease, interacts with R5 (PTG), a regulatory subunit of protein phosphatase-1 that enhances glycogen accumulation.</strong> Hum. Molec. Genet. 12: 3161-3171, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14532330/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14532330</a>] [<a href="https://doi.org/10.1093/hmg/ddg340" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14532330">Fernandez-Sanchez et al. (2003)</a> suggested that laforin may function in the multiprotein complex associated with intracellular glycogen particles, reinforcing the concept that laforin may be involved in the regulation of glycogen metabolism. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14532330" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#16" class="mim-tip-reference" title="Liu, Y., Wang, Y., Wu, C., Liu, Y., Zheng, P. <strong>Deletions and missense mutations of EPM2A exacerbate unfolded protein response and apoptosis of neuronal cells induced by endoplasm reticulum stress.</strong> Hum. Molec. Genet. 18: 2622-2631, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19403557/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19403557</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19403557[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddp196" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19403557">Liu et al. (2009)</a> reported that the mutant EPM2A proteins encoded by all missense mutations and most deletions tested were unstable, insoluble, and ubiquitinated, and were accumulated in aggresome-like structures. The effect of apparent gain-of-function mutations could be corrected by cotransfection with wildtype EPM2A cDNA, which is consistent with the recessive nature of these mutations in Lafora disease patients. In mouse neuroblastoma cells, these mutant aggregates exacerbated endoplasm reticulum (ER) stress and made the cells susceptible to the apoptosis induced by the ER stressor thapsigargin. The chemical chaperone 4-phenylbutyrate increased the mutant solubility, reduced ER stress, and dulled the sensitivity of mutant mouse neuroblastoma cells to apoptosis induced by thapsigargin and the mutant laforin proteins. <a href="#16" class="mim-tip-reference" title="Liu, Y., Wang, Y., Wu, C., Liu, Y., Zheng, P. <strong>Deletions and missense mutations of EPM2A exacerbate unfolded protein response and apoptosis of neuronal cells induced by endoplasm reticulum stress.</strong> Hum. Molec. Genet. 18: 2622-2631, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19403557/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19403557</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19403557[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddp196" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19403557">Liu et al. (2009)</a> proposed that increased sensitivity to ER stress-induced apoptosis may contribute to Lafora disease pathogenesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19403557" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#15" class="mim-tip-reference" title="Ianzano, L., Zhang, J., Chan, E. M., Zhao, X.-C., Lohi, H., Scherer, S. W., Minassian, B. A. <strong>Lafora progressive myoclonus epilepsy mutation database-EPM2A and NHLRC1 (EPM2B) genes.</strong> Hum. Mutat. 26: 397 only, 2005. Note: Full article online.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16134145/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16134145</a>] [<a href="https://doi.org/10.1002/humu.9376" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16134145">Ianzano et al. (2005)</a> reported the creation of a Lafora progressive myoclonus epilepsy mutation database. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16134145" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#8" class="mim-tip-reference" title="Ganesh, S., Delgado-Escueta, A. V., Suzuki, T., Francheschetti, S., Riggio, C., Avanzini, G., Rabinowicz, A., Bohlega, S., Bailey, J., Alonso, M. E., Rasmussen, A., Thomson, A. E., Ochoa, A., Prado, A. J., Medina, M. T., Yamakawa, K. <strong>Genotype-phenotype correlations for EPM2A mutations in Lafora's progressive myoclonus epilepsy: exon 1 mutations associate with an early-onset cognitive deficit subphenotype.</strong> Hum. Molec. Genet. 11: 1263-1271, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12019207/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12019207</a>] [<a href="https://doi.org/10.1093/hmg/11.11.1263" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12019207">Ganesh et al. (2002)</a> related mutations in EPM2A with phenotypes of 22 patients (14 families) and identified 2 subsyndromes: (1) classic Lafora disease with adolescent-onset stimulus-sensitive grand mal, absence, and myoclonic seizures followed by dementia and neurologic deterioration, and associated mainly with mutations in exon 4 (p = 0.0007); (2) atypical Lafora disease with childhood-onset dyslexia and learning disorder followed by epilepsy and neurologic deterioration, and associated mainly with mutations in exon 1 (p = 0.0015). The authors further investigated the effect of 5 missense mutations in the carbohydrate-binding domain (CBD4; coded by exon 1) and 3 missense mutations in the dual phosphatase domain (DSPD; coded by exons 3 and 4) on laforin's intracellular localization in transfected HeLa cells. Expression of 3 mutant proteins in DSPD formed ubiquitin-positive cytoplasmic aggregates, suggesting that they were folding mutants set for degradation. In contrast, none of the 3 CBD4 mutants showed cytoplasmic clumping. However, 2 of the CBD4 mutants targeted both cytoplasm and nucleus, suggesting that laforin had diminished its usual affinity for polysomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12019207" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#7" class="mim-tip-reference" title="Ganesh, S., Delgado-Escueta, A. V., Sakamoto, T., Avila, M. R., Machado-Salas, J., Hoshii, Y., Akagi, T., Gomi, H., Suzuki, T., Amano, K., Agarwala, K. L., Hasegawa, Y., Bai, D.-S., Ishihara, T., Hashikawa, T., Itohara, S., Cornford, E. M., Niki, H., Yamakawa, K. <strong>Targeted disruption of the Epm2a gene causes formation of Lafora inclusion bodies, neurodegeneration, ataxia, myoclonus epilepsy and impaired behavioral response in mice.</strong> Hum. Molec. Genet. 11: 1251-1262, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12019206/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12019206</a>] [<a href="https://doi.org/10.1093/hmg/11.11.1251" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12019206">Ganesh et al. (2002)</a> disrupted the Epm2a gene in mice. At 2 months of age, homozygous null mutants developed widespread degeneration of neurons, most of which occurred in the absence of Lafora bodies. Dying neurons characteristically exhibited swelling in the endoplasmic reticulum, Golgi networks, and mitochondria in the absence of apoptotic bodies or fragmentation of DNA. As Lafora bodies became more prominent at 4 to 12 months, organelles and nuclei were disrupted. The Lafora bodies, present both in neuronal and nonneural tissues, were positive for ubiquitin and advanced glycation end products only in neurons, suggesting a different pathologic consequence for Lafora inclusions in neuronal tissues. Neuronal degeneration and Lafora inclusion bodies predated the onset of impaired behavioral responses, ataxia, spontaneous myoclonic seizures, and EEG epileptiform activity. The authors hypothesized that Lafora disease is a primary neurodegenerative disorder that may utilize a nonapoptotic mechanism of cell death. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12019206" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#2" class="mim-tip-reference" title="Chan, E. M., Ackerley, C. A., Lohi, H., Ianzano, L., Cortez, M. A., Shannon, P., Scherer, S. W., Minassian, B. A. <strong>Laforin preferentially binds the neurotoxic starch-like polyglucosans, which form in its absence in progressive myoclonus epilepsy.</strong> Hum. Molec. Genet. 13: 1117-1129, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15102711/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15102711</a>] [<a href="https://doi.org/10.1093/hmg/ddh130" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15102711">Chan et al. (2004)</a> generated a transgenic mouse overexpressing inactivated laforin to trap laforin's substrate. Lafora bodies formed in liver, muscle, neuronal perikarya, and dendrites. By immunogold electron microscopy, laforin was found in close proximity to the endoplasmic reticulum surrounding the polyglucosan accumulations. In neurons, it compartmentalized to perikaryon and dendrites, but not to axons. It bound polyglucosans, establishing a direct association between the disease-defining storage product and disease protein. It preferentially bound polyglucosans over glycogen in vivo and starch over glycogen in vitro. The laforin-interacting protein EPM2AIP1 (<a href="/entry/607911">607911</a>) also localized on the polyglucosan masses, and laforin bound intensely to Lafora bodies in human Lafora disease biopsy material. <a href="#2" class="mim-tip-reference" title="Chan, E. M., Ackerley, C. A., Lohi, H., Ianzano, L., Cortez, M. A., Shannon, P., Scherer, S. W., Minassian, B. A. <strong>Laforin preferentially binds the neurotoxic starch-like polyglucosans, which form in its absence in progressive myoclonus epilepsy.</strong> Hum. Molec. Genet. 13: 1117-1129, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15102711/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15102711</a>] [<a href="https://doi.org/10.1093/hmg/ddh130" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15102711">Chan et al. (2004)</a> proposed that laforin's role may begin after the appearance of polyglucosans, and that the laforin pathway may be involved in monitoring for and then preventing the formation of polyglucosans. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15102711" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#22" class="mim-tip-reference" title="Vernia, S., Heredia, M., Criado, O., Rodriguez de Cordoba, S., Garcia-Roves, P. M., Cansell, C., Denis, R., Luquet, S., Foufelle, F., Ferre, P., Sanz, P. <strong>Laforin, a dual specificity phosphatase involved in Lafora disease, regulates insulin response and whole-body energy balance in mice.</strong> Hum. Molec. Genet. 20: 2571-2584, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21493628/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21493628</a>] [<a href="https://doi.org/10.1093/hmg/ddr157" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21493628">Vernia et al. (2011)</a> found that Epm2a -/- mice had increased body weight and increased food intake. Metabolic analysis showed higher levels of triglycerides and cholesterol in plasma, correlating with a higher adiposity, in Epm2a -/- mice. High levels of triglycerides and cholesterol were due to increased lipid biosynthesis in liver. Epm2a -/- mice had enhanced glucose disposal with increased energy expenditure, but similar spontaneous locomotor activity, compared with controls. Enhanced glucose disposal was due to increased insulin response in Epm2a -/- mice. The insulin signaling response was also enhanced in heart and liver of Epm2a -/- mice. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21493628" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#3" class="mim-tip-reference" title="DePaoli-Roach, A. A., Segvich, D. M., Meyer, C. M., Rahimi, Y., Worby, C. A., Gentry, M. S., Roach, P. J. <strong>Laforin and malin knockout mice have normal glucose disposal and insulin sensitivity.</strong> Hum. Molec. Genet. 21: 1604-1610, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22186021/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22186021</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22186021[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddr598" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22186021">DePaoli-Roach et al. (2012)</a> found that Epm2a -/- and wildtype mice had statistically identical body weights and composition, with indistinguishable whole-body metabolism. Deletion of Epm2a in mice did not change insulin signaling pathways, insulin sensitivity, glucose disposal, or cardiac function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22186021" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=607566[MIM]" class="btn btn-default mim-tip-hint" role="button" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs104893950 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104893950;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs104893950?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs104893950" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs104893950" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000003244 OR RCV000187394 OR RCV000703218 OR RCV002371755 OR RCV004576870 OR RCV004757945" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003244, RCV000187394, RCV000703218, RCV002371755, RCV004576870, RCV004757945" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003244...</a>
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<p><a href="#13" class="mim-tip-reference" title="Gomez-Garre, P., Sanz, Y., Rodriguez de Cordoba, S., Serratosa, J. M. <strong>Mutational spectrum of the EPM2A gene in progressive myoclonus epilepsy of Lafora: high degree of allelic heterogeneity and prevalence of deletions.</strong> Europ. J. Hum. Genet. 8: 946-954, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11175283/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11175283</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200571" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11175283">Gomez-Garre et al. (2000)</a> noted that a 721C-T transition in exon 4 of the EPM2A gene, resulting in an arg241-to-ter mutation, is a prevalent mutation in patients with Lafora disease-1 (MELF1, EPM2A; <a href="/entry/254780">254780</a>), having been reported in 16 of 68 chromosomes (23.5%). Haplotype analysis using 7 polymorphic markers within or near the EPM2A gene showed that the mutation was associated with 5 different haplotypes, one of them present in 10 of the 16 disease chromosomes. The authors concluded that the high prevalence of this mutation, originally described by <a href="#19" class="mim-tip-reference" title="Minassian, B. A., Lee, J. R., Herbrick, J.-A., Huizenga, J., Soder, S., Mungall, A. J., Dunham, I., Gardner, R., Fong, C. G., Carpenter, S., Jardim, L., Satishchandra, P., Andermann, E., Snead, O. C., III, Lopes-Cendes, I., Tsui, L.-C., Delgado-Escueta, A. V., Rouleau, G. A., Scherer, S. W. <strong>Mutations in a gene encoding a novel protein tyrosine phosphatase cause progressive myoclonus epilepsy.</strong> Nature Genet. 20: 171-174, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9771710/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9771710</a>] [<a href="https://doi.org/10.1038/2470" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9771710">Minassian et al. (1998)</a>, was a consequence of both a founder effect and of recurrence. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9771710+11175283" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#19" class="mim-tip-reference" title="Minassian, B. A., Lee, J. R., Herbrick, J.-A., Huizenga, J., Soder, S., Mungall, A. J., Dunham, I., Gardner, R., Fong, C. G., Carpenter, S., Jardim, L., Satishchandra, P., Andermann, E., Snead, O. C., III, Lopes-Cendes, I., Tsui, L.-C., Delgado-Escueta, A. V., Rouleau, G. A., Scherer, S. W. <strong>Mutations in a gene encoding a novel protein tyrosine phosphatase cause progressive myoclonus epilepsy.</strong> Nature Genet. 20: 171-174, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9771710/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9771710</a>] [<a href="https://doi.org/10.1038/2470" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9771710">Minassian et al. (1998)</a> found homozygosity for the nonsense mutation, which they stated was an arg168-to-ter (ARG168TER) substitution, in 4 consanguineous Spanish families with Lafora disease and on one allele of another consanguineous Spanish family (family L6) in which the other chromosome in affected individuals had a G-to-A change (see <a href="#0002">607566.0002</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9771710" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a patient (S109) with Lafora-type myoclonic epilepsy, <a href="#21" class="mim-tip-reference" title="Serratosa, J. M., Gomez-Garre, P., Gallardo, M. E., Anta, B., Beltran-Valero de Bernabe, D., Lindhout, D., Augustijn, P. B., Tassinari, C. A., Michelucci, R., Malafosse, A., Topcu, M., Grid, D., Dravet, C., Berkovic, S. F., Rodriguez de Cordoba, S. <strong>A novel protein tyrosine phosphatase gene is mutated in progressive myoclonus epilepsy of the Lafora type (EPM2).</strong> Hum. Molec. Genet. 8: 345-352, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9931343/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9931343</a>] [<a href="https://doi.org/10.1093/hmg/8.2.345" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9931343">Serratosa et al. (1999)</a> identified this mutation, which they stated was a 480C-T transition in exon 4a the EPM2A cDNA, resulting in substitution of a stop codon for arg160 (ARG160TER). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9931343" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs137852917 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137852917;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs137852917?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs137852917" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs137852917" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000675700 OR RCV003746498 OR RCV004576871" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000675700, RCV003746498, RCV004576871" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000675700...</a>
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<p><a href="#15" class="mim-tip-reference" title="Ianzano, L., Zhang, J., Chan, E. M., Zhao, X.-C., Lohi, H., Scherer, S. W., Minassian, B. A. <strong>Lafora progressive myoclonus epilepsy mutation database-EPM2A and NHLRC1 (EPM2B) genes.</strong> Hum. Mutat. 26: 397 only, 2005. Note: Full article online.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16134145/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16134145</a>] [<a href="https://doi.org/10.1002/humu.9376" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16134145">Ianzano et al. (2005)</a> stated that an 835G-A transition in exon 4 of the EPM2A gene, resulting in a gly279-to-ser (G279S) substitution, had been identified in 5 unrelated families segregating Lafora myoclonic epilepsy (MELF1; <a href="/entry/254780">254780</a>). They noted that 1 of the families had been reported by <a href="#19" class="mim-tip-reference" title="Minassian, B. A., Lee, J. R., Herbrick, J.-A., Huizenga, J., Soder, S., Mungall, A. J., Dunham, I., Gardner, R., Fong, C. G., Carpenter, S., Jardim, L., Satishchandra, P., Andermann, E., Snead, O. C., III, Lopes-Cendes, I., Tsui, L.-C., Delgado-Escueta, A. V., Rouleau, G. A., Scherer, S. W. <strong>Mutations in a gene encoding a novel protein tyrosine phosphatase cause progressive myoclonus epilepsy.</strong> Nature Genet. 20: 171-174, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9771710/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9771710</a>] [<a href="https://doi.org/10.1038/2470" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9771710">Minassian et al. (1998)</a> and 3 others by <a href="#21" class="mim-tip-reference" title="Serratosa, J. M., Gomez-Garre, P., Gallardo, M. E., Anta, B., Beltran-Valero de Bernabe, D., Lindhout, D., Augustijn, P. B., Tassinari, C. A., Michelucci, R., Malafosse, A., Topcu, M., Grid, D., Dravet, C., Berkovic, S. F., Rodriguez de Cordoba, S. <strong>A novel protein tyrosine phosphatase gene is mutated in progressive myoclonus epilepsy of the Lafora type (EPM2).</strong> Hum. Molec. Genet. 8: 345-352, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9931343/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9931343</a>] [<a href="https://doi.org/10.1093/hmg/8.2.345" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9931343">Serratosa et al. (1999)</a>. <a href="#19" class="mim-tip-reference" title="Minassian, B. A., Lee, J. R., Herbrick, J.-A., Huizenga, J., Soder, S., Mungall, A. J., Dunham, I., Gardner, R., Fong, C. G., Carpenter, S., Jardim, L., Satishchandra, P., Andermann, E., Snead, O. C., III, Lopes-Cendes, I., Tsui, L.-C., Delgado-Escueta, A. V., Rouleau, G. A., Scherer, S. W. <strong>Mutations in a gene encoding a novel protein tyrosine phosphatase cause progressive myoclonus epilepsy.</strong> Nature Genet. 20: 171-174, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9771710/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9771710</a>] [<a href="https://doi.org/10.1038/2470" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9771710">Minassian et al. (1998)</a> found the mutation, which they designated GLY216SER, in compound heterozygous state with a nonsense mutation (<a href="#0001">607566.0001</a>) in a consanguineous Spanish family. <a href="#21" class="mim-tip-reference" title="Serratosa, J. M., Gomez-Garre, P., Gallardo, M. E., Anta, B., Beltran-Valero de Bernabe, D., Lindhout, D., Augustijn, P. B., Tassinari, C. A., Michelucci, R., Malafosse, A., Topcu, M., Grid, D., Dravet, C., Berkovic, S. F., Rodriguez de Cordoba, S. <strong>A novel protein tyrosine phosphatase gene is mutated in progressive myoclonus epilepsy of the Lafora type (EPM2).</strong> Hum. Molec. Genet. 8: 345-352, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9931343/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9931343</a>] [<a href="https://doi.org/10.1093/hmg/8.2.345" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9931343">Serratosa et al. (1999)</a> found the mutation, which they designated GLY198SER, in 3 unrelated patients with Lafora disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9771710+9931343+16134145" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs137852915 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137852915;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs137852915?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs137852915" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs137852915" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV001851604 OR RCV004576872" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001851604, RCV004576872" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001851604...</a>
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<p><a href="#15" class="mim-tip-reference" title="Ianzano, L., Zhang, J., Chan, E. M., Zhao, X.-C., Lohi, H., Scherer, S. W., Minassian, B. A. <strong>Lafora progressive myoclonus epilepsy mutation database-EPM2A and NHLRC1 (EPM2B) genes.</strong> Hum. Mutat. 26: 397 only, 2005. Note: Full article online.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16134145/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16134145</a>] [<a href="https://doi.org/10.1002/humu.9376" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16134145">Ianzano et al. (2005)</a> stated that a 322C-T transition in exon 2 of the EPM2A gene, resulting in an arg108-to-cys (R108C) substitution, had been identified in 6 unrelated families segregating Lafora myoclonic epilepsy (MELF1; <a href="/entry/254780">254780</a>). They noted that one of the families had been reported by <a href="#19" class="mim-tip-reference" title="Minassian, B. A., Lee, J. R., Herbrick, J.-A., Huizenga, J., Soder, S., Mungall, A. J., Dunham, I., Gardner, R., Fong, C. G., Carpenter, S., Jardim, L., Satishchandra, P., Andermann, E., Snead, O. C., III, Lopes-Cendes, I., Tsui, L.-C., Delgado-Escueta, A. V., Rouleau, G. A., Scherer, S. W. <strong>Mutations in a gene encoding a novel protein tyrosine phosphatase cause progressive myoclonus epilepsy.</strong> Nature Genet. 20: 171-174, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9771710/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9771710</a>] [<a href="https://doi.org/10.1038/2470" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9771710">Minassian et al. (1998)</a>. <a href="#19" class="mim-tip-reference" title="Minassian, B. A., Lee, J. R., Herbrick, J.-A., Huizenga, J., Soder, S., Mungall, A. J., Dunham, I., Gardner, R., Fong, C. G., Carpenter, S., Jardim, L., Satishchandra, P., Andermann, E., Snead, O. C., III, Lopes-Cendes, I., Tsui, L.-C., Delgado-Escueta, A. V., Rouleau, G. A., Scherer, S. W. <strong>Mutations in a gene encoding a novel protein tyrosine phosphatase cause progressive myoclonus epilepsy.</strong> Nature Genet. 20: 171-174, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9771710/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9771710</a>] [<a href="https://doi.org/10.1038/2470" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9771710">Minassian et al. (1998)</a> found that affected members in a consanguineous family with progressive myoclonic epilepsy-2 (family LD-5) had homozygosity for a 134C-T transition at nucleotide 134 of the EPM2A gene resulting in an arg45-to-cys (ARG45CYS) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9771710+16134145" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV004576873" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV004576873" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV004576873</a>
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<p><a href="#15" class="mim-tip-reference" title="Ianzano, L., Zhang, J., Chan, E. M., Zhao, X.-C., Lohi, H., Scherer, S. W., Minassian, B. A. <strong>Lafora progressive myoclonus epilepsy mutation database-EPM2A and NHLRC1 (EPM2B) genes.</strong> Hum. Mutat. 26: 397 only, 2005. Note: Full article online.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16134145/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16134145</a>] [<a href="https://doi.org/10.1002/humu.9376" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16134145">Ianzano et al. (2005)</a> stated that a 1-bp insertion in exon 2 of the EPM2A gene (335_336insA), resulting in a frameshift and premature termination (Tyr112fs), had been identified in 2 unrelated families with Lafora myoclonic epilepsy (MELF1; <a href="/entry/254780">254780</a>). They noted that one of the families had been reported by <a href="#21" class="mim-tip-reference" title="Serratosa, J. M., Gomez-Garre, P., Gallardo, M. E., Anta, B., Beltran-Valero de Bernabe, D., Lindhout, D., Augustijn, P. B., Tassinari, C. A., Michelucci, R., Malafosse, A., Topcu, M., Grid, D., Dravet, C., Berkovic, S. F., Rodriguez de Cordoba, S. <strong>A novel protein tyrosine phosphatase gene is mutated in progressive myoclonus epilepsy of the Lafora type (EPM2).</strong> Hum. Molec. Genet. 8: 345-352, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9931343/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9931343</a>] [<a href="https://doi.org/10.1093/hmg/8.2.345" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9931343">Serratosa et al. (1999)</a>. In the report by <a href="#21" class="mim-tip-reference" title="Serratosa, J. M., Gomez-Garre, P., Gallardo, M. E., Anta, B., Beltran-Valero de Bernabe, D., Lindhout, D., Augustijn, P. B., Tassinari, C. A., Michelucci, R., Malafosse, A., Topcu, M., Grid, D., Dravet, C., Berkovic, S. F., Rodriguez de Cordoba, S. <strong>A novel protein tyrosine phosphatase gene is mutated in progressive myoclonus epilepsy of the Lafora type (EPM2).</strong> Hum. Molec. Genet. 8: 345-352, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9931343/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9931343</a>] [<a href="https://doi.org/10.1093/hmg/8.2.345" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9931343">Serratosa et al. (1999)</a>, a family (S114) with Lafora-type myoclonic epilepsy was found to have an insertion of an adenine after nucleotide 94 of the EPM2A cDNA (94_95insA), causing a frameshift and truncation of the gene product after tyr31. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9931343+16134145" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs137852916 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137852916;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs137852916?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs137852916" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs137852916" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000003248 OR RCV000469417 OR RCV004566675 OR RCV004576874" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003248, RCV000469417, RCV004566675, RCV004576874" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003248...</a>
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<p><a href="#15" class="mim-tip-reference" title="Ianzano, L., Zhang, J., Chan, E. M., Zhao, X.-C., Lohi, H., Scherer, S. W., Minassian, B. A. <strong>Lafora progressive myoclonus epilepsy mutation database-EPM2A and NHLRC1 (EPM2B) genes.</strong> Hum. Mutat. 26: 397 only, 2005. Note: Full article online.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16134145/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16134145</a>] [<a href="https://doi.org/10.1002/humu.9376" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16134145">Ianzano et al. (2005)</a> stated that a 512G-A transition in exon 3 of the EPM2A gene, resulting in an arg171-to-cys (R171C) substitution, had been identified in 7 unrelated families segregating Lafora myoclonic epilepsy (MELF1; <a href="/entry/254780">254780</a>). They noted that one of the families had been reported by <a href="#21" class="mim-tip-reference" title="Serratosa, J. M., Gomez-Garre, P., Gallardo, M. E., Anta, B., Beltran-Valero de Bernabe, D., Lindhout, D., Augustijn, P. B., Tassinari, C. A., Michelucci, R., Malafosse, A., Topcu, M., Grid, D., Dravet, C., Berkovic, S. F., Rodriguez de Cordoba, S. <strong>A novel protein tyrosine phosphatase gene is mutated in progressive myoclonus epilepsy of the Lafora type (EPM2).</strong> Hum. Molec. Genet. 8: 345-352, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9931343/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9931343</a>] [<a href="https://doi.org/10.1093/hmg/8.2.345" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9931343">Serratosa et al. (1999)</a>. In the report by <a href="#21" class="mim-tip-reference" title="Serratosa, J. M., Gomez-Garre, P., Gallardo, M. E., Anta, B., Beltran-Valero de Bernabe, D., Lindhout, D., Augustijn, P. B., Tassinari, C. A., Michelucci, R., Malafosse, A., Topcu, M., Grid, D., Dravet, C., Berkovic, S. F., Rodriguez de Cordoba, S. <strong>A novel protein tyrosine phosphatase gene is mutated in progressive myoclonus epilepsy of the Lafora type (EPM2).</strong> Hum. Molec. Genet. 8: 345-352, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9931343/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9931343</a>] [<a href="https://doi.org/10.1093/hmg/8.2.345" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9931343">Serratosa et al. (1999)</a>, a patient (S2) with Lafora-type myoclonic epilepsy was found to have an arg90-to-his (ARG90HIS) mutation due to a 271G-A transition in the EPM2A cDNA. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9931343+16134145" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs587776554 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587776554;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs587776554" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs587776554" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV004576875" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV004576875" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV004576875</a>
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<p><a href="#14" class="mim-tip-reference" title="Ianzano, L., Young, E. J., Zhao, X. C., Chan, E. M., Rodriguez, M. T., Torrado, M. V., Scherer, S. W., Minassian, B. A. <strong>Loss of function of the cytoplasmic isoform of the protein laforin (EPM2A) causes Lafora progressive myoclonus epilepsy.</strong> Hum. Mutat. 23: 170-176, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14722920/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14722920</a>] [<a href="https://doi.org/10.1002/humu.10306" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14722920">Ianzano et al. (2004)</a> described the first case of Lafora myoclonic epilepsy (MELF1; <a href="/entry/254780">254780</a>) in which the mutation was specific to the cytoplasmic laforin isoform (isoform A). They identified a 1-bp insertion in the EPM2A gene, 950insT, which resulted in a frameshift after codon 319 (Q319fs). The patient developed normally with average school performance and an uneventful childhood. At age 14 years, she exhibited personality changes, became more anxious, and developed severe learning difficulties. At age 15 years, she had several generalized tonic-clonic seizures, and myoclonus appeared. EEG background was slow, with frequent paroxysmal generalized irregular spike-wave discharges. At age 22 years, she was bedridden, with continuous myoclonia, frequent generalized seizures, and dementia. She died at age 24 years. Muscle biopsy showed polyglucosan accumulations, and an axillary skin biopsy showed pathognomonic periodic acid-Schiff-positive inclusions (Lafora bodies) in myoepithelial cells of apocrine glands. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14722920" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#15" class="mim-tip-reference" title="Ianzano, L., Zhang, J., Chan, E. M., Zhao, X.-C., Lohi, H., Scherer, S. W., Minassian, B. A. <strong>Lafora progressive myoclonus epilepsy mutation database-EPM2A and NHLRC1 (EPM2B) genes.</strong> Hum. Mutat. 26: 397 only, 2005. Note: Full article online.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16134145/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16134145</a>] [<a href="https://doi.org/10.1002/humu.9376" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16134145">Ianzano et al. (2005)</a> stated that this insertion occurs at nucleotide 953 (953_954insT) in exon 4 of the laforin gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16134145" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs104893955 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104893955;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs104893955" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs104893955" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a Brazilian patient with myoclonic epilepsy of Lafora-1 (MELF1; <a href="/entry/254780">254780</a>), <a href="#18" class="mim-tip-reference" title="Minassian, B. A., Ianzano, L., Meloche, M., Andermann, E., Rouleau, G. A., Delgado-Escueta, A. V., Scherer, S. W. <strong>Mutation spectrum and predicted function of laforin in Lafora's progressive myoclonus epilepsy.</strong> Neurology 55: 341-346, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10932264/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10932264</a>] [<a href="https://doi.org/10.1212/wnl.55.3.341" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10932264">Minassian et al. (2000)</a> identified a homozygous T-to-G transversion at nucleotide 94 in exon 1 of the EPM2A gene, resulting in a trp32-to-gly (W32G) substitution in the carbohydrate-binding domain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10932264" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#23" class="mim-tip-reference" title="Wang, J., Stuckey, J. A., Wishart, M. J., Dixon, J. E. <strong>A unique carbohydrate binding domain targets the Lafora disease phosphatase to glycogen.</strong> J. Biol. Chem. 277: 2377-2380, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11739371/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11739371</a>] [<a href="https://doi.org/10.1074/jbc.C100686200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11739371">Wang et al. (2002)</a> predicted that the W32G mutation would disrupt the polysaccharide-binding pocket of EPM2A and potentially unfold the region immediately adjacent to the binding pocket. They determined that the W32G mutation reduced the phosphatase activity of EPM2A by about 50%. Furthermore, while wildtype EPM2A associated with glycogen complexes in vitro and in vivo, EPM2A carrying the W32G mutation did not. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11739371" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>REFERENCES</strong>
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<a id="Aguado2010" class="mim-anchor"></a>
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<div class="">
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Aguado, C., Sarkar, S., Korolchuk, V. I., Criado, O., Vernia, S., Boya, P., Sanz, P., Rodriguez de Cordoba, S., Knecht, E., Rubinsztein, D. C.
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[<a href="https://doi.org/10.1093/hmg/ddq190" target="_blank">Full Text</a>]
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<a id="Chan2004" class="mim-anchor"></a>
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Chan, E. M., Ackerley, C. A., Lohi, H., Ianzano, L., Cortez, M. A., Shannon, P., Scherer, S. W., Minassian, B. A.
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<strong>Laforin preferentially binds the neurotoxic starch-like polyglucosans, which form in its absence in progressive myoclonus epilepsy.</strong>
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Hum. Molec. Genet. 13: 1117-1129, 2004.
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[<a href="https://doi.org/10.1093/hmg/ddh130" target="_blank">Full Text</a>]
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<a id="DePaoli-Roach2012" class="mim-anchor"></a>
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<div class="">
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DePaoli-Roach, A. A., Segvich, D. M., Meyer, C. M., Rahimi, Y., Worby, C. A., Gentry, M. S., Roach, P. J.
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<strong>Laforin and malin knockout mice have normal glucose disposal and insulin sensitivity.</strong>
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Hum. Molec. Genet. 21: 1604-1610, 2012.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22186021/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22186021</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22186021[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22186021" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/ddr598" target="_blank">Full Text</a>]
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<a id="Fernandez-Sanchez2003" class="mim-anchor"></a>
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Fernandez-Sanchez, M. E., Criado-Garcia, O., Heath, K. E., Garcia-Fojeda, B., Medrano-Fernandez, I., Gomez-Garre, P., Sanz, P., Serratosa, J. M., Rodriguez de Cordoba, S.
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<strong>Laforin, the dual-phosphatase responsible for Lafora disease, interacts with R5 (PTG), a regulatory subunit of protein phosphatase-1 that enhances glycogen accumulation.</strong>
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Hum. Molec. Genet. 12: 3161-3171, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14532330/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14532330</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14532330" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/ddg340" target="_blank">Full Text</a>]
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<a id="Ganesh2000" class="mim-anchor"></a>
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<div class="">
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Ganesh, S., Agarwala, K. L., Ueda, K., Akagi, T., Shoda, K., Usui, T., Hashikawa, T., Osada, H., Delgado-Escueta, A. V., Yamakawa, K.
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<strong>Laforin, defective in the progressive myoclonus epilepsy of Lafora type, is a dual-specificity phosphatase associated with polyribosomes.</strong>
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Hum. Molec. Genet. 9: 2251-2261, 2000.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11001928/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11001928</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11001928" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/oxfordjournals.hmg.a018916" target="_blank">Full Text</a>]
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<a id="6" class="mim-anchor"></a>
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<a id="Ganesh1999" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Ganesh, S., Amano, K., Delgado-Escueta, A. V., Yamakawa, K.
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<strong>Isolation and characterization of mouse homologue for the human epilepsy gene, EPM2A.</strong>
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[<a href="https://doi.org/10.1006/bbrc.1999.0402" target="_blank">Full Text</a>]
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<a id="7" class="mim-anchor"></a>
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<a id="Ganesh2002" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Ganesh, S., Delgado-Escueta, A. V., Sakamoto, T., Avila, M. R., Machado-Salas, J., Hoshii, Y., Akagi, T., Gomi, H., Suzuki, T., Amano, K., Agarwala, K. L., Hasegawa, Y., Bai, D.-S., Ishihara, T., Hashikawa, T., Itohara, S., Cornford, E. M., Niki, H., Yamakawa, K.
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<strong>Targeted disruption of the Epm2a gene causes formation of Lafora inclusion bodies, neurodegeneration, ataxia, myoclonus epilepsy and impaired behavioral response in mice.</strong>
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Hum. Molec. Genet. 11: 1251-1262, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12019206/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12019206</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12019206" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/11.11.1251" target="_blank">Full Text</a>]
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<a id="Ganesh2002" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Ganesh, S., Delgado-Escueta, A. V., Suzuki, T., Francheschetti, S., Riggio, C., Avanzini, G., Rabinowicz, A., Bohlega, S., Bailey, J., Alonso, M. E., Rasmussen, A., Thomson, A. E., Ochoa, A., Prado, A. J., Medina, M. T., Yamakawa, K.
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<strong>Genotype-phenotype correlations for EPM2A mutations in Lafora's progressive myoclonus epilepsy: exon 1 mutations associate with an early-onset cognitive deficit subphenotype.</strong>
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Hum. Molec. Genet. 11: 1263-1271, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12019207/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12019207</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12019207" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/11.11.1263" target="_blank">Full Text</a>]
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<a id="9" class="mim-anchor"></a>
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<a id="Ganesh2002" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Ganesh, S., Suzuki, T., Yamakawa, K.
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<strong>Alternative splicing modulates subcellular localization of laforin.</strong>
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Biochem. Biophys. Res. Commun. 291: 1134-1137, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11883934/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11883934</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11883934" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1006/bbrc.2002.6590" target="_blank">Full Text</a>]
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<a id="10" class="mim-anchor"></a>
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<a id="Ganesh2003" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Ganesh, S., Tsurutani, N., Suzuki, T., Ueda, K., Agarwala, K. L., Osada, H., Delgado-Escueta, A. V., Yamakawa, K.
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<strong>The Lafora disease gene product laforin interacts with HIRIP5, a phylogenetically conserved protein containing a NifU-like domain.</strong>
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Hum. Molec. Genet. 12: 2359-2368, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12915448/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12915448</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12915448" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/ddg253" target="_blank">Full Text</a>]
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<a id="11" class="mim-anchor"></a>
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<a id="Garyali2009" class="mim-anchor"></a>
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<div class="">
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Garyali, P., Siwach, P., Singh, P. K., Puri, R., Mittal, S., Sengupta, S., Parihar, R., Ganesh, S.
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<strong>The malin-laforin complex suppresses the cellular toxicity of misfolded proteins by promoting their degradation through the ubiquitin-proteasome system.</strong>
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Hum. Molec. Genet. 18: 688-700, 2009.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19036738/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19036738</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19036738" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/ddn398" target="_blank">Full Text</a>]
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<a id="Gentry2005" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Gentry, M. S., Worby, C. A., Dixon, J. E.
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<strong>Insights into Lafora disease: malin is an E3 ubiquitin ligase that ubiquitinates and promotes the degradation of laforin.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15930137/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15930137</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15930137[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15930137" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1073/pnas.0503285102" target="_blank">Full Text</a>]
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<a id="13" class="mim-anchor"></a>
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<a id="Gomez-Garre2000" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Gomez-Garre, P., Sanz, Y., Rodriguez de Cordoba, S., Serratosa, J. M.
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<strong>Mutational spectrum of the EPM2A gene in progressive myoclonus epilepsy of Lafora: high degree of allelic heterogeneity and prevalence of deletions.</strong>
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Europ. J. Hum. Genet. 8: 946-954, 2000.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11175283/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11175283</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11175283" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/sj.ejhg.5200571" target="_blank">Full Text</a>]
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<a id="14" class="mim-anchor"></a>
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<a id="Ianzano2004" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Ianzano, L., Young, E. J., Zhao, X. C., Chan, E. M., Rodriguez, M. T., Torrado, M. V., Scherer, S. W., Minassian, B. A.
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<strong>Loss of function of the cytoplasmic isoform of the protein laforin (EPM2A) causes Lafora progressive myoclonus epilepsy.</strong>
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Hum. Mutat. 23: 170-176, 2004.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14722920/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14722920</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14722920" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/humu.10306" target="_blank">Full Text</a>]
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<a id="Ianzano2005" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Ianzano, L., Zhang, J., Chan, E. M., Zhao, X.-C., Lohi, H., Scherer, S. W., Minassian, B. A.
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<strong>Lafora progressive myoclonus epilepsy mutation database-EPM2A and NHLRC1 (EPM2B) genes.</strong>
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Hum. Mutat. 26: 397 only, 2005. Note: Full article online.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16134145/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16134145</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16134145" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/humu.9376" target="_blank">Full Text</a>]
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</p>
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<a id="16" class="mim-anchor"></a>
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<a id="Liu2009" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Liu, Y., Wang, Y., Wu, C., Liu, Y., Zheng, P.
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<strong>Deletions and missense mutations of EPM2A exacerbate unfolded protein response and apoptosis of neuronal cells induced by endoplasm reticulum stress.</strong>
|
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Hum. Molec. Genet. 18: 2622-2631, 2009.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19403557/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19403557</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19403557[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19403557" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/ddp196" target="_blank">Full Text</a>]
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</p>
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<a id="17" class="mim-anchor"></a>
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<a id="Lohi2005" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Lohi, H., Ianzano, L., Zhao, X.-C., Chan, E. M., Turnbull, J., Scherer, S. W., Ackerley, C. A., Minassian, B. A.
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<strong>Novel glycogen synthase kinase 3 and ubiquitination pathways in progressive myoclonus epilepsy.</strong>
|
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Hum. Molec. Genet. 14: 2727-2736, 2005.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16115820/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16115820</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16115820" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/ddi306" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="18" class="mim-anchor"></a>
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<a id="Minassian2000" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Minassian, B. A., Ianzano, L., Meloche, M., Andermann, E., Rouleau, G. A., Delgado-Escueta, A. V., Scherer, S. W.
|
|
<strong>Mutation spectrum and predicted function of laforin in Lafora's progressive myoclonus epilepsy.</strong>
|
|
Neurology 55: 341-346, 2000.
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|
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10932264/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10932264</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10932264" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1212/wnl.55.3.341" target="_blank">Full Text</a>]
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</p>
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</div>
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<li>
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<a id="19" class="mim-anchor"></a>
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<a id="Minassian1998" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Minassian, B. A., Lee, J. R., Herbrick, J.-A., Huizenga, J., Soder, S., Mungall, A. J., Dunham, I., Gardner, R., Fong, C. G., Carpenter, S., Jardim, L., Satishchandra, P., Andermann, E., Snead, O. C., III, Lopes-Cendes, I., Tsui, L.-C., Delgado-Escueta, A. V., Rouleau, G. A., Scherer, S. W.
|
|
<strong>Mutations in a gene encoding a novel protein tyrosine phosphatase cause progressive myoclonus epilepsy.</strong>
|
|
Nature Genet. 20: 171-174, 1998.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9771710/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9771710</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9771710" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/2470" target="_blank">Full Text</a>]
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</p>
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</div>
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<li>
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<a id="20" class="mim-anchor"></a>
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<a id="Mittal2007" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Mittal, S., Dubey, D., Yamakawa, K., Ganesh, S.
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<strong>Lafora disease proteins malin and laforin are recruited to aggresomes in response to proteasomal impairment.</strong>
|
|
Hum. Molec. Genet. 16: 753-762, 2007.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17337485/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17337485</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17337485" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/ddm006" target="_blank">Full Text</a>]
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</div>
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<li>
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<a id="21" class="mim-anchor"></a>
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<a id="Serratosa1999" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Serratosa, J. M., Gomez-Garre, P., Gallardo, M. E., Anta, B., Beltran-Valero de Bernabe, D., Lindhout, D., Augustijn, P. B., Tassinari, C. A., Michelucci, R., Malafosse, A., Topcu, M., Grid, D., Dravet, C., Berkovic, S. F., Rodriguez de Cordoba, S.
|
|
<strong>A novel protein tyrosine phosphatase gene is mutated in progressive myoclonus epilepsy of the Lafora type (EPM2).</strong>
|
|
Hum. Molec. Genet. 8: 345-352, 1999.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9931343/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9931343</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9931343" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/8.2.345" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="22" class="mim-anchor"></a>
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<a id="Vernia2011" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Vernia, S., Heredia, M., Criado, O., Rodriguez de Cordoba, S., Garcia-Roves, P. M., Cansell, C., Denis, R., Luquet, S., Foufelle, F., Ferre, P., Sanz, P.
|
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<strong>Laforin, a dual specificity phosphatase involved in Lafora disease, regulates insulin response and whole-body energy balance in mice.</strong>
|
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Hum. Molec. Genet. 20: 2571-2584, 2011.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21493628/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21493628</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21493628" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/ddr157" target="_blank">Full Text</a>]
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<li>
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<a id="23" class="mim-anchor"></a>
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<a id="Wang2002" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Wang, J., Stuckey, J. A., Wishart, M. J., Dixon, J. E.
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<strong>A unique carbohydrate binding domain targets the Lafora disease phosphatase to glycogen.</strong>
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J. Biol. Chem. 277: 2377-2380, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11739371/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11739371</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11739371" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1074/jbc.C100686200" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="24" class="mim-anchor"></a>
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<a id="Worby2006" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Worby, C. A., Gentry, M. S., Dixon, J. E.
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<strong>Laforin, a dual specificity phosphatase that dephosphorylates complex carbohydrates.</strong>
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J. Biol. Chem. 281: 30412-30418, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16901901/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16901901</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16901901[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16901901" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1074/jbc.M606117200" target="_blank">Full Text</a>]
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</ol>
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<div>
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<br />
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</div>
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</div>
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<div>
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<a id="contributors" class="mim-anchor"></a>
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<div class="row">
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<span class="mim-text-font">
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Bao Lige - updated : 05/12/2022
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseContributors">
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<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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George E. Tiller - updated : 8/22/2013<br>George E. Tiller - updated : 3/31/2010<br>George E. Tiller - updated : 8/10/2009<br>George E. Tiller - updated : 12/10/2008<br>Cassandra L. Kniffin - updated : 2/15/2007<br>George E. Tiller - updated : 9/7/2006<br>George E. Tiller - updated : 1/11/2006<br>George E. Tiller - updated : 9/9/2005<br>Patricia A. Hartz - updated : 5/10/2004<br>Victor A. McKusick - updated : 2/26/2004<br>Victor A. McKusick - updated : 12/29/2003
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="creationDate" class="mim-anchor"></a>
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Cassandra L. Kniffin : 2/13/2003
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</span>
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</div>
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</div>
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</div>
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<a id="editHistory" class="mim-anchor"></a>
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<span class="text-nowrap mim-text-font">
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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</span>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 01/25/2024
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</span>
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</div>
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<div class="row collapse" id="mimCollapseEditHistory">
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 01/24/2024<br>alopez : 11/03/2022<br>mgross : 05/12/2022<br>carol : 12/16/2019<br>carol : 08/04/2016<br>mcolton : 01/20/2015<br>carol : 1/20/2015<br>carol : 3/6/2014<br>carol : 3/6/2014<br>carol : 2/20/2014<br>tpirozzi : 8/22/2013<br>alopez : 3/8/2013<br>wwang : 4/14/2010<br>terry : 3/31/2010<br>wwang : 8/20/2009<br>terry : 8/10/2009<br>wwang : 12/10/2008<br>wwang : 2/20/2007<br>ckniffin : 2/15/2007<br>alopez : 9/7/2006<br>wwang : 2/7/2006<br>wwang : 1/27/2006<br>terry : 1/11/2006<br>alopez : 10/19/2005<br>alopez : 10/19/2005<br>terry : 9/9/2005<br>mgross : 5/10/2004<br>terry : 5/10/2004<br>tkritzer : 3/1/2004<br>tkritzer : 2/27/2004<br>terry : 2/26/2004<br>tkritzer : 2/6/2004<br>tkritzer : 1/15/2004<br>terry : 12/29/2003<br>carol : 2/27/2003<br>ckniffin : 2/14/2003
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</span>
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</div>
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</div>
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</div>
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<div class="container visible-print-block">
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<div class="row">
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<div class="col-md-8 col-md-offset-1">
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<div>
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<div>
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<h3>
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<span class="mim-font">
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<strong>*</strong> 607566
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</span>
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</h3>
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</div>
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<div>
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<h3>
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<span class="mim-font">
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EPM2A GLUCAN PHOSPHATASE, LAFORIN; EPM2A
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</span>
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</h3>
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</div>
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<div>
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<br />
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<div>
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<div >
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
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<span class="mim-font">
|
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LAFORIN
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
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<div>
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<p>
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<span class="mim-font">
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Other entities represented in this entry:
|
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</span>
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</p>
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</div>
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<div>
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<span class="h3 mim-font">
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EPM2A, ISOFORM A, INCLUDED
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</span>
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</div>
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<div>
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<span class="h4 mim-font">
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EPM2A, ISOFORM B, INCLUDED
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</span>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: EPM2A</em></strong>
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</span>
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</p>
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong>
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<em>
|
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Cytogenetic location: 6q24.3
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Genomic coordinates <span class="small">(GRCh38)</span> : 6:145,383,353-145,736,023 </span>
|
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</em>
|
|
</strong>
|
|
<span class="small">(from NCBI)</span>
|
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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<strong>Gene-Phenotype Relationships</strong>
|
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</span>
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</h4>
|
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<div>
|
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<table class="table table-bordered table-condensed small mim-table-padding">
|
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<thead>
|
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<tr class="active">
|
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<th>
|
|
Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
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<td rowspan="1">
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<span class="mim-font">
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6q24.3
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</span>
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</td>
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<td>
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<span class="mim-font">
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Myoclonic epilepsy of Lafora 1
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</span>
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</td>
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<td>
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<span class="mim-font">
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254780
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal recessive
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
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</span>
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</h4>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Description</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>The EPM2A gene encodes laforin, a dual-specificity protein phosphatase that hydrolyzes phosphotyrosine and phosphoserine/threonine substrates. Laforin also binds complex carbohydrates and plays a role in glycogen metabolism (Worby et al., 2006). </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Linkage studies in patients with myoclonic epilepsy of Lafora-1 (254780) demonstrated that the putative causative gene was located on chromosome 6q24. Using a positional cloning approach in this region, Minassian et al. (1998) identified a novel gene, EPM2A, encoding a protein, termed laforin, with a consensus amino acid sequence indicative of a protein-tyrosine phosphatase (PTP). They found mRNA transcripts representing alternatively spliced forms of EPM2A in every tissue examined, including brain. </p><p>Serratosa et al. (1999) independently reported the positional cloning of the EPM2 gene on 6q and identified alternative splicing in the 5-prime and 3-prime end regions. </p><p>Minassian et al. (1998) reported that the EPM2A gene encodes 2 isoforms of the laforin protein which have alternate C termini. The common segment consists of a carbohydrate-binding module and a dual-specificity protein phosphatase domain (Ganesh et al., 2000). Isoform A localizes at the rough endoplasmic reticulum. Isoform B localizes to the nucleus. </p><p>Gomez-Garre et al. (2000) reported the complete coding sequence of the EPM2A gene, including the ATG initiation codon region. </p><p>Wang et al. (2002) cloned EPM2A from a muscle cDNA library. Subcellular fractionation of human embryonic kidney cells showed that about half of overexpressed recombinant EPM2A sedimented with glycogen-microsomal complexes. Alpha-amylase treatment released EPM2A from the glycogen complexes. Molecular modeling predicted that 2 invariant trp residues and an invariant lys in the carbohydrate-binding domain (trp32, trp99, and lys87) interact directly with polysaccharides. </p><p>By RT-PCR Ganesh et al. (2002) determined that human fetal brain expressed both splice variants of EPM2A. The variant encoding the 317-amino acid protein was expressed at a lower level than the variant encoding the 331-amino acid protein. Western blot analysis of transfected HeLa cells detected the shorter isoform at an apparent molecular mass of 37 kD. This variant accumulated in both the cytoplasm and the nucleus. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Function</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Ganesh et al. (2000) cloned and expressed the full-length 38-kD laforin protein in transfected cells. Recombinant laforin was able to hydrolyze phosphotyrosine as well as phosphoserine/threonine substrates, demonstrating that laforin is an active dual-specificity phosphatase. Biochemical, immunofluorescence, and ultrastructural studies on transfected HeLa cells revealed that laforin is a cytoplasmic protein associated with polyribosomes. Expression of 2 proteins with missense mutations seen in EPM2A patients resulted in ubiquitin-positive perinuclear aggregates, suggesting that these were misfolded proteins targeted for degradation. The authors suggested 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. </p><p>Wang et al. (2002) determined that wildtype EPM2A associated with glycogen complexes in vitro and in vivo, whereas EPM2A carrying the trp32-to-gly mutation (W32G; 607566.0010) did not. </p><p>Ganesh et al. (2003) used the yeast 2-hybrid system to screen for protein(s) that interact with laforin. The authors found a specific interaction between the N-terminal CBD4 domain of laforin and the C-terminal NifU-like domain of HIRIP5 (608100). They also determined that HIRIP5 is a substrate for the phosphatase activity of laforin. </p><p>Fernandez-Sanchez et al. (2003) showed that laforin interacted with itself and with PPP1R3C (602999), a protein that acts as a molecular scaffold assembling protein phosphatase-1 (PP1; see 176875) with glycogen synthase (GYS1; 138570) at intracellular glycogen particles. Full-length laforin was required for the interaction with PPP1R3C. However, a minimal central region of PPP1R3C (amino acids 116 to 238), including the binding sites for glycogen and glycogen synthase, was sufficient to interact with laforin. Point mutagenesis of the glycogen synthase-binding site completely blocked interaction with laforin. </p><p>By yeast 2-hybrid screen of a human brain cDNA library, Gentry et al. (2005) found that malin (NHLRC1; 608072) directly bound and interacted with laforin in HEK293T cells in vivo. Mutations in the NHLRC1 gene also result in Lafora disease. In normal cells, laforin is polyubiquitinated in a malin-dependent manner, which leads to laforin degradation. Gentry et al. (2005) concluded that malin is a single-subunit E3 ligase, that laforin is a malin substrate, and that malin regulates laforin protein concentration. </p><p>Lohi et al. (2005) showed that laforin is a GSK3B (605004) ser9 phosphatase, and therefore capable of inactivating glycogen synthase. Laforin was also shown to interact with malin. The authors proposed that laforin, in response to appearance of polyglucosans, directs 2 negative feedback pathways: polyglucosan-laforin-GSK3-GYS1 to inhibit GYS1 activity, and polyglucosan-laforin-malin-GYS1 to remove GYS1 through proteasomal degradation. </p><p>Worby et al. (2006) demonstrated that laforin displayed robust phosphatase activity against a plant-derived complex carbohydrate, amylopectin, whereas several other active human phosphatases were unable to perform this function. The authors suggested that laforin may be necessary for the maintenance of normal cellular glycogen. </p><p>Mittal et al. (2007) showed that laforin and malin were recruited to aggresomes upon proteasomal blockade, possibly to clear misfolded proteins through the ubiquitin-proteasome system (UPS). Garyali et al. (2009) tested this possibility using a variety of cytotoxic misfolded proteins, including the expanded polyglutamine protein, as potential substrates. Laforin and malin, together with Hsp70 (HSPA1A; 140550) as a functional complex, suppressed the cellular toxicity of misfolded proteins; all 3 members of the complex were required for this function. Laforin and malin interacted with misfolded proteins and promoted their degradation through the UPS, and they were recruited to the polyglutamine aggregates and reduced the frequency of aggregate-positive cells. Garyali et al. (2009) suggested that the malin-laforin complex is a novel player in the neuronal response to misfolded proteins. </p><p>Aguado et al. (2010) reported that loss of function of laforin impairs autophagy in patient cell lines, in embryonic fibroblasts from laforin knockout mice, and in tissues from such mice. Conversely, laforin overexpression stimulated autophagy. Laforin regulates autophagy through the mammalian target of rapamycin (MTOR; 601231) kinase-dependent pathway, demonstrated by correlation of increased mTOR activity with starvation of human fibroblasts and of wildtype mice. The authors suggested that laforin-mediated changes in autophagy may regulate the balance of diverse substrates expected to impact Lafora body accumulation and the cell stress associated with Lafora disease. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>Gene Structure</strong>
|
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</span>
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</h4>
|
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</div>
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<span class="mim-text-font">
|
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<p>Ganesh et al. (2002) determined that the EPM2A gene contains 5 exons that are alternatively spliced to form 2 major EPM2A transcripts. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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<strong>Mapping</strong>
|
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>The EPM2A gene maps to chromosome 6q24 (Minassian et al., 1998). Ganesh et al. (1999) mapped the mouse Epm2a gene to a region of mouse chromosome 10A that shows homology of synteny to human chromosome 6q24. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>Molecular Genetics</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>In 10 families with myoclonic epilepsy of Lafora, Minassian et al. (1998) identified 6 distinct DNA sequence variations in the EPM2A gene and 1 homozygous microdeletion (see Lafora disease-1, 254780), each segregating with the disorder (see, e.g., 607566.0001-607566.0003). These mutations were predicted to cause deleterious effects in the laforin protein, resulting in the disorder. </p><p>In patients with Lafora disease-1, Serratosa et al. (1999) identified 8 loss-of-function mutations in the EPM2A gene: a microdeletion, a frameshift, an insertion, 4 missense mutations, and a nonsense mutation (see, e.g., 607566.0004 and 607566.0007). The authors suggested that the gene may be important in the control of glycogen metabolism, thus accounting for the glycogen-like intracellular inclusion bodies (Lafora bodies). </p><p>Gomez-Garre et al. (2000) used SSCP analysis of the 4 exons of the EPM2A gene in 34 unrelated patients with Lafora disease and identified mutations in 27 (79%) of them (49 of 68 chromosomes, or 72%). The patients originated from Spain, Italy, Australia, Holland, the US, North Africa, Turkey, and France. A total of 20 different EPM2A mutations, 11 of them novel, were characterized. The authors summarized 25 EPM2A mutations distributed throughout the gene in 44 unrelated Lafora disease patients. The mutations included 10 deletions of different sizes, 9 missense mutations, 3 nonsense mutations, and 3 frameshift mutations. The R241X mutation (607566.0001) was encountered in almost 40% of the probands. In 5 Lafora disease families (13% of the families studied), Gomez-Garre et al. (2000) excluded linkage to the EPM2A gene region, suggesting genetic heterogeneity. </p><p>In 8 patients with Lafora disease, Ianzano et al. (2004) identified 11 different mutations in the EPM2A gene, 6 of which were novel. One of the novel mutations, a 1-bp insertion resulting in a frameshift (607566.0009), was specific to the cytoplasmic laforin isoform. Previously, all documented disease mutations, including the knockout mouse model deletion, had been located in the segment of the protein common to both isoforms. Ianzano et al. (2004) demonstrated a drastic reduction in the phosphatase activity of the mutant laforin, despite maintenance of its location at the endoplasmic reticulum. </p><p>Fernandez-Sanchez et al. (2003) found that the majority of EPM2A missense mutations in Lafora disease-1 patients resulted in lack of phosphatase activity, absence of binding to glycogen, and lack of interaction with PPP1R3C. They identified an EPM2A missense mutation that had no effect on the phosphatase or glycogen-binding activities of laforin but disrupted interaction with PPP1R3C, suggesting that binding to PPP1R3C may be critical for laforin function. Fernandez-Sanchez et al. (2003) suggested that laforin may function in the multiprotein complex associated with intracellular glycogen particles, reinforcing the concept that laforin may be involved in the regulation of glycogen metabolism. </p><p>Liu et al. (2009) reported that the mutant EPM2A proteins encoded by all missense mutations and most deletions tested were unstable, insoluble, and ubiquitinated, and were accumulated in aggresome-like structures. The effect of apparent gain-of-function mutations could be corrected by cotransfection with wildtype EPM2A cDNA, which is consistent with the recessive nature of these mutations in Lafora disease patients. In mouse neuroblastoma cells, these mutant aggregates exacerbated endoplasm reticulum (ER) stress and made the cells susceptible to the apoptosis induced by the ER stressor thapsigargin. The chemical chaperone 4-phenylbutyrate increased the mutant solubility, reduced ER stress, and dulled the sensitivity of mutant mouse neuroblastoma cells to apoptosis induced by thapsigargin and the mutant laforin proteins. Liu et al. (2009) proposed that increased sensitivity to ER stress-induced apoptosis may contribute to Lafora disease pathogenesis. </p><p>Ianzano et al. (2005) reported the creation of a Lafora progressive myoclonus epilepsy mutation database. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>Genotype/Phenotype Correlations</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Ganesh et al. (2002) related mutations in EPM2A with phenotypes of 22 patients (14 families) and identified 2 subsyndromes: (1) classic Lafora disease with adolescent-onset stimulus-sensitive grand mal, absence, and myoclonic seizures followed by dementia and neurologic deterioration, and associated mainly with mutations in exon 4 (p = 0.0007); (2) atypical Lafora disease with childhood-onset dyslexia and learning disorder followed by epilepsy and neurologic deterioration, and associated mainly with mutations in exon 1 (p = 0.0015). The authors further investigated the effect of 5 missense mutations in the carbohydrate-binding domain (CBD4; coded by exon 1) and 3 missense mutations in the dual phosphatase domain (DSPD; coded by exons 3 and 4) on laforin's intracellular localization in transfected HeLa cells. Expression of 3 mutant proteins in DSPD formed ubiquitin-positive cytoplasmic aggregates, suggesting that they were folding mutants set for degradation. In contrast, none of the 3 CBD4 mutants showed cytoplasmic clumping. However, 2 of the CBD4 mutants targeted both cytoplasm and nucleus, suggesting that laforin had diminished its usual affinity for polysomes. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Animal Model</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Ganesh et al. (2002) disrupted the Epm2a gene in mice. At 2 months of age, homozygous null mutants developed widespread degeneration of neurons, most of which occurred in the absence of Lafora bodies. Dying neurons characteristically exhibited swelling in the endoplasmic reticulum, Golgi networks, and mitochondria in the absence of apoptotic bodies or fragmentation of DNA. As Lafora bodies became more prominent at 4 to 12 months, organelles and nuclei were disrupted. The Lafora bodies, present both in neuronal and nonneural tissues, were positive for ubiquitin and advanced glycation end products only in neurons, suggesting a different pathologic consequence for Lafora inclusions in neuronal tissues. Neuronal degeneration and Lafora inclusion bodies predated the onset of impaired behavioral responses, ataxia, spontaneous myoclonic seizures, and EEG epileptiform activity. The authors hypothesized that Lafora disease is a primary neurodegenerative disorder that may utilize a nonapoptotic mechanism of cell death. </p><p>Chan et al. (2004) generated a transgenic mouse overexpressing inactivated laforin to trap laforin's substrate. Lafora bodies formed in liver, muscle, neuronal perikarya, and dendrites. By immunogold electron microscopy, laforin was found in close proximity to the endoplasmic reticulum surrounding the polyglucosan accumulations. In neurons, it compartmentalized to perikaryon and dendrites, but not to axons. It bound polyglucosans, establishing a direct association between the disease-defining storage product and disease protein. It preferentially bound polyglucosans over glycogen in vivo and starch over glycogen in vitro. The laforin-interacting protein EPM2AIP1 (607911) also localized on the polyglucosan masses, and laforin bound intensely to Lafora bodies in human Lafora disease biopsy material. Chan et al. (2004) proposed that laforin's role may begin after the appearance of polyglucosans, and that the laforin pathway may be involved in monitoring for and then preventing the formation of polyglucosans. </p><p>Vernia et al. (2011) found that Epm2a -/- mice had increased body weight and increased food intake. Metabolic analysis showed higher levels of triglycerides and cholesterol in plasma, correlating with a higher adiposity, in Epm2a -/- mice. High levels of triglycerides and cholesterol were due to increased lipid biosynthesis in liver. Epm2a -/- mice had enhanced glucose disposal with increased energy expenditure, but similar spontaneous locomotor activity, compared with controls. Enhanced glucose disposal was due to increased insulin response in Epm2a -/- mice. The insulin signaling response was also enhanced in heart and liver of Epm2a -/- mice. </p><p>DePaoli-Roach et al. (2012) found that Epm2a -/- and wildtype mice had statistically identical body weights and composition, with indistinguishable whole-body metabolism. Deletion of Epm2a in mice did not change insulin signaling pathways, insulin sensitivity, glucose disposal, or cardiac function. </p>
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</span>
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<div>
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<br />
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>10 Selected Examples):</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0001 MYOCLONIC EPILEPSY OF LAFORA 1</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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EPM2A, ARG241TER
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<br />
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SNP: rs104893950,
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gnomAD: rs104893950,
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ClinVar: RCV000003244, RCV000187394, RCV000703218, RCV002371755, RCV004576870, RCV004757945
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>Gomez-Garre et al. (2000) noted that a 721C-T transition in exon 4 of the EPM2A gene, resulting in an arg241-to-ter mutation, is a prevalent mutation in patients with Lafora disease-1 (MELF1, EPM2A; 254780), having been reported in 16 of 68 chromosomes (23.5%). Haplotype analysis using 7 polymorphic markers within or near the EPM2A gene showed that the mutation was associated with 5 different haplotypes, one of them present in 10 of the 16 disease chromosomes. The authors concluded that the high prevalence of this mutation, originally described by Minassian et al. (1998), was a consequence of both a founder effect and of recurrence. </p><p>Minassian et al. (1998) found homozygosity for the nonsense mutation, which they stated was an arg168-to-ter (ARG168TER) substitution, in 4 consanguineous Spanish families with Lafora disease and on one allele of another consanguineous Spanish family (family L6) in which the other chromosome in affected individuals had a G-to-A change (see 607566.0002). </p><p>In a patient (S109) with Lafora-type myoclonic epilepsy, Serratosa et al. (1999) identified this mutation, which they stated was a 480C-T transition in exon 4a the EPM2A cDNA, resulting in substitution of a stop codon for arg160 (ARG160TER). </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0002 MYOCLONIC EPILEPSY OF LAFORA 1</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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EPM2A, GLY279SER
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<br />
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SNP: rs137852917,
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gnomAD: rs137852917,
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ClinVar: RCV000675700, RCV003746498, RCV004576871
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>Ianzano et al. (2005) stated that an 835G-A transition in exon 4 of the EPM2A gene, resulting in a gly279-to-ser (G279S) substitution, had been identified in 5 unrelated families segregating Lafora myoclonic epilepsy (MELF1; 254780). They noted that 1 of the families had been reported by Minassian et al. (1998) and 3 others by Serratosa et al. (1999). Minassian et al. (1998) found the mutation, which they designated GLY216SER, in compound heterozygous state with a nonsense mutation (607566.0001) in a consanguineous Spanish family. Serratosa et al. (1999) found the mutation, which they designated GLY198SER, in 3 unrelated patients with Lafora disease. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0003 MYOCLONIC EPILEPSY OF LAFORA 1</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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EPM2A, ARG108CYS
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<br />
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SNP: rs137852915,
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gnomAD: rs137852915,
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ClinVar: RCV001851604, RCV004576872
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>Ianzano et al. (2005) stated that a 322C-T transition in exon 2 of the EPM2A gene, resulting in an arg108-to-cys (R108C) substitution, had been identified in 6 unrelated families segregating Lafora myoclonic epilepsy (MELF1; 254780). They noted that one of the families had been reported by Minassian et al. (1998). Minassian et al. (1998) found that affected members in a consanguineous family with progressive myoclonic epilepsy-2 (family LD-5) had homozygosity for a 134C-T transition at nucleotide 134 of the EPM2A gene resulting in an arg45-to-cys (ARG45CYS) substitution. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0004 MYOCLONIC EPILEPSY OF LAFORA 1</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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EPM2A, 1-BP INS, 335A
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<br />
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SNP: rs587776553,
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ClinVar: RCV004576873
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>Ianzano et al. (2005) stated that a 1-bp insertion in exon 2 of the EPM2A gene (335_336insA), resulting in a frameshift and premature termination (Tyr112fs), had been identified in 2 unrelated families with Lafora myoclonic epilepsy (MELF1; 254780). They noted that one of the families had been reported by Serratosa et al. (1999). In the report by Serratosa et al. (1999), a family (S114) with Lafora-type myoclonic epilepsy was found to have an insertion of an adenine after nucleotide 94 of the EPM2A cDNA (94_95insA), causing a frameshift and truncation of the gene product after tyr31. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0005 MYOCLONIC EPILEPSY OF LAFORA 1</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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EPM2A, ARG171HIS
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<br />
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SNP: rs137852916,
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gnomAD: rs137852916,
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ClinVar: RCV000003248, RCV000469417, RCV004566675, RCV004576874
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>Ianzano et al. (2005) stated that a 512G-A transition in exon 3 of the EPM2A gene, resulting in an arg171-to-cys (R171C) substitution, had been identified in 7 unrelated families segregating Lafora myoclonic epilepsy (MELF1; 254780). They noted that one of the families had been reported by Serratosa et al. (1999). In the report by Serratosa et al. (1999), a patient (S2) with Lafora-type myoclonic epilepsy was found to have an arg90-to-his (ARG90HIS) mutation due to a 271G-A transition in the EPM2A cDNA. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-text-font">
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<strong>.0006 MOVED TO 607566.0001</strong>
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</span>
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</h4>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-text-font">
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<strong>.0007 MOVED TO 607566.0002</strong>
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</span>
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</h4>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-text-font">
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<strong>.0008 MOVED TO 607566.0001</strong>
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</span>
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</h4>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>.0009 MYOCLONIC EPILEPSY OF LAFORA 1</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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EPM2A, 1-BP INS, 953T
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<br />
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SNP: rs587776554,
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ClinVar: RCV004576875
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>Ianzano et al. (2004) described the first case of Lafora myoclonic epilepsy (MELF1; 254780) in which the mutation was specific to the cytoplasmic laforin isoform (isoform A). They identified a 1-bp insertion in the EPM2A gene, 950insT, which resulted in a frameshift after codon 319 (Q319fs). The patient developed normally with average school performance and an uneventful childhood. At age 14 years, she exhibited personality changes, became more anxious, and developed severe learning difficulties. At age 15 years, she had several generalized tonic-clonic seizures, and myoclonus appeared. EEG background was slow, with frequent paroxysmal generalized irregular spike-wave discharges. At age 22 years, she was bedridden, with continuous myoclonia, frequent generalized seizures, and dementia. She died at age 24 years. Muscle biopsy showed polyglucosan accumulations, and an axillary skin biopsy showed pathognomonic periodic acid-Schiff-positive inclusions (Lafora bodies) in myoepithelial cells of apocrine glands. </p><p>Ianzano et al. (2005) stated that this insertion occurs at nucleotide 953 (953_954insT) in exon 4 of the laforin gene. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0010 MYOCLONIC EPILEPSY OF LAFORA 1</strong>
|
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</span>
|
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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EPM2A, TRP32GLY
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<br />
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SNP: rs104893955,
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ClinVar: RCV000494425, RCV002512695, RCV004576876
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a Brazilian patient with myoclonic epilepsy of Lafora-1 (MELF1; 254780), Minassian et al. (2000) identified a homozygous T-to-G transversion at nucleotide 94 in exon 1 of the EPM2A gene, resulting in a trp32-to-gly (W32G) substitution in the carbohydrate-binding domain. </p><p>Wang et al. (2002) predicted that the W32G mutation would disrupt the polysaccharide-binding pocket of EPM2A and potentially unfold the region immediately adjacent to the binding pocket. They determined that the W32G mutation reduced the phosphatase activity of EPM2A by about 50%. Furthermore, while wildtype EPM2A associated with glycogen complexes in vitro and in vivo, EPM2A carrying the W32G mutation did not. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
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</h4>
|
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<div>
|
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<p />
|
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</div>
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<div>
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<ol>
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<li>
|
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<p class="mim-text-font">
|
|
Aguado, C., Sarkar, S., Korolchuk, V. I., Criado, O., Vernia, S., Boya, P., Sanz, P., Rodriguez de Cordoba, S., Knecht, E., Rubinsztein, D. C.
|
|
<strong>Laforin, the most common protein mutated in Lafora disease, regulates autophagy.</strong>
|
|
Hum. Molec. Genet. 19: 2867-2876, 2010.
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[PubMed: 20453062]
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[Full Text: https://doi.org/10.1093/hmg/ddq190]
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</p>
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</li>
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<li>
|
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<p class="mim-text-font">
|
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Chan, E. M., Ackerley, C. A., Lohi, H., Ianzano, L., Cortez, M. A., Shannon, P., Scherer, S. W., Minassian, B. A.
|
|
<strong>Laforin preferentially binds the neurotoxic starch-like polyglucosans, which form in its absence in progressive myoclonus epilepsy.</strong>
|
|
Hum. Molec. Genet. 13: 1117-1129, 2004.
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[PubMed: 15102711]
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[Full Text: https://doi.org/10.1093/hmg/ddh130]
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</p>
|
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
DePaoli-Roach, A. A., Segvich, D. M., Meyer, C. M., Rahimi, Y., Worby, C. A., Gentry, M. S., Roach, P. J.
|
|
<strong>Laforin and malin knockout mice have normal glucose disposal and insulin sensitivity.</strong>
|
|
Hum. Molec. Genet. 21: 1604-1610, 2012.
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[PubMed: 22186021]
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[Full Text: https://doi.org/10.1093/hmg/ddr598]
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</p>
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Fernandez-Sanchez, M. E., Criado-Garcia, O., Heath, K. E., Garcia-Fojeda, B., Medrano-Fernandez, I., Gomez-Garre, P., Sanz, P., Serratosa, J. M., Rodriguez de Cordoba, S.
|
|
<strong>Laforin, the dual-phosphatase responsible for Lafora disease, interacts with R5 (PTG), a regulatory subunit of protein phosphatase-1 that enhances glycogen accumulation.</strong>
|
|
Hum. Molec. Genet. 12: 3161-3171, 2003.
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[PubMed: 14532330]
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[Full Text: https://doi.org/10.1093/hmg/ddg340]
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</p>
|
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</li>
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<li>
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<p class="mim-text-font">
|
|
Ganesh, S., Agarwala, K. L., Ueda, K., Akagi, T., Shoda, K., Usui, T., Hashikawa, T., Osada, H., Delgado-Escueta, A. V., Yamakawa, K.
|
|
<strong>Laforin, defective in the progressive myoclonus epilepsy of Lafora type, is a dual-specificity phosphatase associated with polyribosomes.</strong>
|
|
Hum. Molec. Genet. 9: 2251-2261, 2000.
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[PubMed: 11001928]
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[Full Text: https://doi.org/10.1093/oxfordjournals.hmg.a018916]
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</p>
|
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Ganesh, S., Amano, K., Delgado-Escueta, A. V., Yamakawa, K.
|
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<strong>Isolation and characterization of mouse homologue for the human epilepsy gene, EPM2A.</strong>
|
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Biochem. Biophys. Res. Commun. 257: 24-28, 1999.
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[PubMed: 10092504]
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[Full Text: https://doi.org/10.1006/bbrc.1999.0402]
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</p>
|
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Ganesh, S., Delgado-Escueta, A. V., Sakamoto, T., Avila, M. R., Machado-Salas, J., Hoshii, Y., Akagi, T., Gomi, H., Suzuki, T., Amano, K., Agarwala, K. L., Hasegawa, Y., Bai, D.-S., Ishihara, T., Hashikawa, T., Itohara, S., Cornford, E. M., Niki, H., Yamakawa, K.
|
|
<strong>Targeted disruption of the Epm2a gene causes formation of Lafora inclusion bodies, neurodegeneration, ataxia, myoclonus epilepsy and impaired behavioral response in mice.</strong>
|
|
Hum. Molec. Genet. 11: 1251-1262, 2002.
|
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|
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[PubMed: 12019206]
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|
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[Full Text: https://doi.org/10.1093/hmg/11.11.1251]
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</p>
|
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Ganesh, S., Delgado-Escueta, A. V., Suzuki, T., Francheschetti, S., Riggio, C., Avanzini, G., Rabinowicz, A., Bohlega, S., Bailey, J., Alonso, M. E., Rasmussen, A., Thomson, A. E., Ochoa, A., Prado, A. J., Medina, M. T., Yamakawa, K.
|
|
<strong>Genotype-phenotype correlations for EPM2A mutations in Lafora's progressive myoclonus epilepsy: exon 1 mutations associate with an early-onset cognitive deficit subphenotype.</strong>
|
|
Hum. Molec. Genet. 11: 1263-1271, 2002.
|
|
|
|
|
|
[PubMed: 12019207]
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[Full Text: https://doi.org/10.1093/hmg/11.11.1263]
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</p>
|
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</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Ganesh, S., Suzuki, T., Yamakawa, K.
|
|
<strong>Alternative splicing modulates subcellular localization of laforin.</strong>
|
|
Biochem. Biophys. Res. Commun. 291: 1134-1137, 2002.
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|
|
|
|
[PubMed: 11883934]
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|
|
[Full Text: https://doi.org/10.1006/bbrc.2002.6590]
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</p>
|
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Ganesh, S., Tsurutani, N., Suzuki, T., Ueda, K., Agarwala, K. L., Osada, H., Delgado-Escueta, A. V., Yamakawa, K.
|
|
<strong>The Lafora disease gene product laforin interacts with HIRIP5, a phylogenetically conserved protein containing a NifU-like domain.</strong>
|
|
Hum. Molec. Genet. 12: 2359-2368, 2003.
|
|
|
|
|
|
[PubMed: 12915448]
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|
|
[Full Text: https://doi.org/10.1093/hmg/ddg253]
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</p>
|
|
</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Garyali, P., Siwach, P., Singh, P. K., Puri, R., Mittal, S., Sengupta, S., Parihar, R., Ganesh, S.
|
|
<strong>The malin-laforin complex suppresses the cellular toxicity of misfolded proteins by promoting their degradation through the ubiquitin-proteasome system.</strong>
|
|
Hum. Molec. Genet. 18: 688-700, 2009.
|
|
|
|
|
|
[PubMed: 19036738]
|
|
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|
|
[Full Text: https://doi.org/10.1093/hmg/ddn398]
|
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|
|
</p>
|
|
</li>
|
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|
|
<li>
|
|
<p class="mim-text-font">
|
|
Gentry, M. S., Worby, C. A., Dixon, J. E.
|
|
<strong>Insights into Lafora disease: malin is an E3 ubiquitin ligase that ubiquitinates and promotes the degradation of laforin.</strong>
|
|
Proc. Nat. Acad. Sci. 102: 8501-8506, 2005.
|
|
|
|
|
|
[PubMed: 15930137]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1073/pnas.0503285102]
|
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|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Gomez-Garre, P., Sanz, Y., Rodriguez de Cordoba, S., Serratosa, J. M.
|
|
<strong>Mutational spectrum of the EPM2A gene in progressive myoclonus epilepsy of Lafora: high degree of allelic heterogeneity and prevalence of deletions.</strong>
|
|
Europ. J. Hum. Genet. 8: 946-954, 2000.
|
|
|
|
|
|
[PubMed: 11175283]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/sj.ejhg.5200571]
|
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|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Ianzano, L., Young, E. J., Zhao, X. C., Chan, E. M., Rodriguez, M. T., Torrado, M. V., Scherer, S. W., Minassian, B. A.
|
|
<strong>Loss of function of the cytoplasmic isoform of the protein laforin (EPM2A) causes Lafora progressive myoclonus epilepsy.</strong>
|
|
Hum. Mutat. 23: 170-176, 2004.
|
|
|
|
|
|
[PubMed: 14722920]
|
|
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|
|
[Full Text: https://doi.org/10.1002/humu.10306]
|
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</p>
|
|
</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Ianzano, L., Zhang, J., Chan, E. M., Zhao, X.-C., Lohi, H., Scherer, S. W., Minassian, B. A.
|
|
<strong>Lafora progressive myoclonus epilepsy mutation database-EPM2A and NHLRC1 (EPM2B) genes.</strong>
|
|
Hum. Mutat. 26: 397 only, 2005. Note: Full article online.
|
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|
|
|
[PubMed: 16134145]
|
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[Full Text: https://doi.org/10.1002/humu.9376]
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</p>
|
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Liu, Y., Wang, Y., Wu, C., Liu, Y., Zheng, P.
|
|
<strong>Deletions and missense mutations of EPM2A exacerbate unfolded protein response and apoptosis of neuronal cells induced by endoplasm reticulum stress.</strong>
|
|
Hum. Molec. Genet. 18: 2622-2631, 2009.
|
|
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|
|
[PubMed: 19403557]
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|
|
[Full Text: https://doi.org/10.1093/hmg/ddp196]
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</p>
|
|
</li>
|
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<li>
|
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<p class="mim-text-font">
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Minassian, B. A., Ianzano, L., Meloche, M., Andermann, E., Rouleau, G. A., Delgado-Escueta, A. V., Scherer, S. W.
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Minassian, B. A., Lee, J. R., Herbrick, J.-A., Huizenga, J., Soder, S., Mungall, A. J., Dunham, I., Gardner, R., Fong, C. G., Carpenter, S., Jardim, L., Satishchandra, P., Andermann, E., Snead, O. C., III, Lopes-Cendes, I., Tsui, L.-C., Delgado-Escueta, A. V., Rouleau, G. A., Scherer, S. W.
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<strong>Mutations in a gene encoding a novel protein tyrosine phosphatase cause progressive myoclonus epilepsy.</strong>
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Mittal, S., Dubey, D., Yamakawa, K., Ganesh, S.
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<strong>Lafora disease proteins malin and laforin are recruited to aggresomes in response to proteasomal impairment.</strong>
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Serratosa, J. M., Gomez-Garre, P., Gallardo, M. E., Anta, B., Beltran-Valero de Bernabe, D., Lindhout, D., Augustijn, P. B., Tassinari, C. A., Michelucci, R., Malafosse, A., Topcu, M., Grid, D., Dravet, C., Berkovic, S. F., Rodriguez de Cordoba, S.
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<strong>A novel protein tyrosine phosphatase gene is mutated in progressive myoclonus epilepsy of the Lafora type (EPM2).</strong>
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Vernia, S., Heredia, M., Criado, O., Rodriguez de Cordoba, S., Garcia-Roves, P. M., Cansell, C., Denis, R., Luquet, S., Foufelle, F., Ferre, P., Sanz, P.
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<strong>Laforin, a dual specificity phosphatase involved in Lafora disease, regulates insulin response and whole-body energy balance in mice.</strong>
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Wang, J., Stuckey, J. A., Wishart, M. J., Dixon, J. E.
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<strong>A unique carbohydrate binding domain targets the Lafora disease phosphatase to glycogen.</strong>
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Worby, C. A., Gentry, M. S., Dixon, J. E.
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Bao Lige - updated : 05/12/2022<br>George E. Tiller - updated : 8/22/2013<br>George E. Tiller - updated : 3/31/2010<br>George E. Tiller - updated : 8/10/2009<br>George E. Tiller - updated : 12/10/2008<br>Cassandra L. Kniffin - updated : 2/15/2007<br>George E. Tiller - updated : 9/7/2006<br>George E. Tiller - updated : 1/11/2006<br>George E. Tiller - updated : 9/9/2005<br>Patricia A. Hartz - updated : 5/10/2004<br>Victor A. McKusick - updated : 2/26/2004<br>Victor A. McKusick - updated : 12/29/2003
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