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Entry
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- *614191 - DEP DOMAIN-CONTAINING PROTEIN 5; DEPDC5
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- OMIM
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<p>
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<span class="h4">*614191</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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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="#geneStructure">Gene Structure</a>
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<a href="#biochemicalFeatures">Biochemical Features</a>
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<a href="#mapping">Mapping</a>
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<a href="#geneFunction">Gene Function</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#animalModel">Animal Model</a>
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/614191">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 role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</ul>
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<div id="mimFloatingLinksMenu">
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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 class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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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=ENSG00000100150;t=ENST00000651528" 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=9681" 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=614191" 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 class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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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=ENSG00000100150;t=ENST00000651528" 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_001007188,NM_001136029,NM_001242896,NM_001242897,NM_001363852,NM_001363854,NM_001364318,NM_001364319,NM_001364320,NM_001369901,NM_001369902,NM_001369903,NM_014662,NR_110988,NR_146296,NR_157125,NR_157126,NR_157128,XM_011530557,XM_011530561,XM_011530562,XM_011530563,XM_011530565,XM_011530569,XM_017029113,XM_017029114,XM_024452305,XM_047441625,XM_047441626,XM_047441627,XM_047441628,XM_047441629,XM_047441630,XM_047441631,XM_047441632,XM_047441633,XM_047441634,XM_047441635,XM_047441636,XM_047441637,XR_007067997" 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_001242896" 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=614191" 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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<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://www.proteinatlas.org/search/DEPDC5" 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/4156155,7662222,34365097,34785518,51476338,55749924,57283540,57283542,57283629,119580400,119580401,119580402,119580403,148921571,194377652,194379006,194389544,209862859,221043320,221046116,223459672,339276028,339276033,510120820,768026616,768026632,768026636,768026640,768026649,768026667,929654067,1034630010,1034630012,1370482742,1394533346,1394533388,1402623770,1402626124,1402626276,1624525553,1624525599,1624525609,2217340592,2217340596,2217340598,2217340600,2217340603,2217340605,2217340607,2217340610,2217340612,2217340614,2217340616,2217340618,2217340624,2462586018,2462586020,2462586022,2462586024,2462586026,2462586028,2462586030,2462586032,2462586035,2462586037,2462586039,2462586041,2462586043,2462586045,2462586047,2462586049,2462586051,2462586053,2462586055,2462586057,2462586059,2462586061" 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/O75140" 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=9681" 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=ENSG00000100150;t=ENST00000651528" 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=DEPDC5" 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=DEPDC5" 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+9681" 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/DEPDC5" 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:9681" 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/9681" 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=chr22&hgg_gene=ENST00000651528.2&hgg_start=31753968&hgg_end=31908033&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/genes/HGNC:18423" 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/depdc5" 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=614191[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=614191[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://www.deciphergenomics.org/gene/DEPDC5/overview/clinical-info" class="mim-tip-hint" title="DECIPHER" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'DECIPHER', 'domain': 'DECIPHER'})">DECIPHER</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000100150" 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=DEPDC5" 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=DEPDC5" 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=DEPDC5" 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=DEPDC5&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/PA134864958" 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:18423" 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://flybase.org/reports/FBgn0035227.html" class="mim-tip-hint" title="A Database of Drosophila Genes and Genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'FlyBase', 'domain': 'flybase.org'})">FlyBase</a></div>
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<div><a href="https://www.mousephenotype.org/data/genes/MGI:2141101" 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/DEPDC5#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:2141101" 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/9681/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=9681" 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://wormbase.org/db/gene/gene?name=WBGene00011604;class=Gene" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name'{'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">Wormbase Gene</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-091204-356" 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">
|
|
<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://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:9681" 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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<div><a href="https://reactome.org/content/query?q=DEPDC5&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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614191
|
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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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DEP DOMAIN-CONTAINING PROTEIN 5; DEPDC5
|
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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>
|
|
<span class="mim-font">
|
|
KIAA0645
|
|
</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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<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=DEPDC5" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">DEPDC5</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>
|
|
<span class="mim-text-font">
|
|
<strong>
|
|
<em>
|
|
Cytogenetic location: <a href="/geneMap/22/192?start=-3&limit=10&highlight=192">22q12.2-q12.3</a>
|
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|
|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr22:31753968-31908033&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'})">22:31,753,968-31,908,033</a> </span>
|
|
</em>
|
|
</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
|
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|
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|
|
</span>
|
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</p>
|
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</div>
|
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<div>
|
|
<br />
|
|
</div>
|
|
<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
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
|
|
<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=620504,604364" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
|
</a>
|
|
</span>
|
|
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="2">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/22/192?start=-3&limit=10&highlight=192">
|
|
22q12.2-q12.3
|
|
</a>
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
Developmental and epileptic encephalopathy 111
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/620504"> 620504 </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>
|
|
</td>
|
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</tr>
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PheneGene Graphics <span class="caret"></span>
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<p>The DEPDC5 gene encodes a GTPase that, together with NPRL2 (<a href="/entry/607072">607072</a>) and NPRL3 (<a href="/entry/600928">600928</a>), constitutes the GATOR1 complex, which inhibits RAG (see, e.g., RRAGA, <a href="/entry/612194">612194</a>)-dependent activation of the mTOR signaling pathway (see <a href="/entry/601231">601231</a>) that is involved in multiple biologic processes, including cell growth, proliferation, and protein synthesis (summary by <a href="#25" class="mim-tip-reference" title="van Kranenburg, M., Hoogeveen-Westerveld, M., Nellist, M. <strong>Preliminary functional assessment and classification of DEPDC5 variants associated with focal epilepsy.</strong> Hum. Mutat. 36: 200-209, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25366275/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25366275</a>] [<a href="https://doi.org/10.1002/humu.22723" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25366275">van Kranenburg et al., 2015</a>; <a href="#13" class="mim-tip-reference" title="Liu, L., Chen, Z.-R., Xu, H.-Q., Liu, D.-T., Mao, Y., Liu, H.-K., Liu, X.-R., Zhou, P., Lin, S.-M., Li, B., He, N., Su, T., Zhai, Q.-X., Meng, H., Liao, W.-P., Yi, Y.-H. <strong>DEPDC5 variants associated malformations of cortical development and focal epilepsy with febrile seizure plus/febrile seizures: the role of molecular sub-regional effect.</strong> Front. Neurosci. 14: 821, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32848577/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32848577</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=32848577[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/10.3389/fnins.2020.00821" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32848577">Liu et al., 2020</a>; <a href="#21" class="mim-tip-reference" title="Samanta, D. <strong>DEPDC5-related epilepsy: A comprehensive review.</strong> Epilepsy Behav. 130: 108678, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35429726/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35429726</a>] [<a href="https://doi.org/10.1016/j.yebeh.2022.108678" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="35429726">Samanta, 2022</a>; <a href="#26" class="mim-tip-reference" title="Ververi, A., Zagaglia, S., Menzies, L., Baptista, J., Caswell, R., Baulac, S., Ellard, S., Lynch, S., Genomics England Research Consortium, Jacques, T. S., Chawla, M. S., Heier, M., and 27 others. <strong>Germline homozygous missense DEPDC5 variants cause severe refractory early-onset epilepsy, macrocephaly and bilateral polymicrogyria.</strong> Hum. Molec. Genet. 32: 580-594, 2023.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/36067010/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">36067010</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=36067010[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/ddac225" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="36067010">Ververi et al., 2023</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=32848577+25366275+35429726+36067010" 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>By screening cDNA libraries for genes encoding large proteins expressed in brain, <a href="#11" class="mim-tip-reference" title="Ishikawa, K., Nagase, T., Suyama, M., Miyajima, N., Tanaka, A., Kotani, H., Nomura, N., Ohara, O. <strong>Prediction of the coding sequences of unidentified human genes. X. The complete sequences of 100 new cDNA clones from brain which can code for large proteins in vitro.</strong> DNA Res. 5: 169-176, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9734811/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9734811</a>] [<a href="https://doi.org/10.1093/dnares/5.3.169" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9734811">Ishikawa et al. (1998)</a> isolated DEPDC5, which they called KIAA0645. The predicted protein contains 1,572 amino acids. RT-PCR analysis detected ubiquitous expression in human tissues. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9734811" 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>Using RT-PCR, <a href="#6" class="mim-tip-reference" title="Dibbens, L. M., de Vries, B., Donatello, S., Heron, S. E., Hodgson, B. L., Chintawar, S., Crompton, D. E., Hughes, J. N., Bellows, S. T., Klein, K. M., Callenbach, P. M. C., Corbett, M. A., and 23 others. <strong>Mutations in DEPDC5 cause familial focal epilepsy with variable foci.</strong> Nature Genet. 45: 546-551, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23542697/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23542697</a>] [<a href="https://doi.org/10.1038/ng.2599" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23542697">Dibbens et al. (2013)</a> found expression of the Depdc5 gene at low levels in all mouse brain regions analyzed. Expression occurred throughout brain development, including in midgestation embryonic head, neonatal brain, and whole adult brain. Immunofluorescence studies showed that Depdc5 was expressed in neurons and GABAergic interneurons, but was absent in nonneuronal cells, including astrocytes. Immunofluorescence was localized to the cytosol of the neuronal cell body and was mostly perinuclear, with little or no extension into neuronal processes. This subcellular localization was confirmed in human neurospheres derived from induced pluripotent stem cells from control individuals and in human neuroblastoma cells. These results suggested a role for DEPDC5 in neuronal signal transduction. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23542697" 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="#16" class="mim-tip-reference" title="Miki, D., Ochi, H., Hayes, C. N., Abe, H., Yoshima, T., Aikata, H., Ikeda, K., Kumada, H., Toyota, J., Morizono, T., Tsunoda, T., Kubo, M., Nakamura, Y., Kamatani, N., Chayama, K. <strong>Variation in the DEPDC5 locus is associated with progression to hepatocellular carcinoma in chronic hepatitis C virus carriers.</strong> Nature Genet. 43: 797-800, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21725309/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21725309</a>] [<a href="https://doi.org/10.1038/ng.876" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21725309">Miki et al. (2011)</a> reported that the DEPDC5 gene contains 42 exons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21725309" 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="#24" class="mim-tip-reference" title="Shen, K., Huang, R. K., Brignole, E. J., Condon, K. J., Valenstein, M. L., Chantranupong, L., Bomaliyamu, A., Choe, A., Hong, C., Yu, Z., Sabatini, D. M. <strong>Architecture of the human GATOR1 and GATOR1-Rag GTPases complexes.</strong> Nature 556: 64-69, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29590090/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29590090</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29590090[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/10.1038/nature26158" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29590090">Shen et al. (2018)</a> used cryoelectron microscopy to solve structures of GATOR1 and GATOR1-RAG GTPases complexes. GATOR1 adopts an extended architecture with a cavity in the middle; NPRL2 (<a href="/entry/607072">607072</a>) links DEPDC5 and NPRL3 (<a href="/entry/600928">600928</a>), and DEPDC5 contacts the RAG GTPase heterodimer. Biochemical analyses revealed that this GATOR1-RAG GTPases structure is inhibitory, and that at least 2 binding modes must exist between the RAG GTPases and GATOR1. Direct interaction of DEPDC5 with RAGA (<a href="/entry/612194">612194</a>) inhibits GATOR1-mediated stimulation of GTP hydrolysis by RAGA, whereas weaker interactions between the NPRL2-NPRL3 heterodimer and RAGA execute GAP activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29590090" 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>By radiation hybrid analysis, <a href="#11" class="mim-tip-reference" title="Ishikawa, K., Nagase, T., Suyama, M., Miyajima, N., Tanaka, A., Kotani, H., Nomura, N., Ohara, O. <strong>Prediction of the coding sequences of unidentified human genes. X. The complete sequences of 100 new cDNA clones from brain which can code for large proteins in vitro.</strong> DNA Res. 5: 169-176, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9734811/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9734811</a>] [<a href="https://doi.org/10.1093/dnares/5.3.169" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9734811">Ishikawa et al. (1998)</a> mapped the KIAA0645 gene to chromosome 22. <a href="#16" class="mim-tip-reference" title="Miki, D., Ochi, H., Hayes, C. N., Abe, H., Yoshima, T., Aikata, H., Ikeda, K., Kumada, H., Toyota, J., Morizono, T., Tsunoda, T., Kubo, M., Nakamura, Y., Kamatani, N., Chayama, K. <strong>Variation in the DEPDC5 locus is associated with progression to hepatocellular carcinoma in chronic hepatitis C virus carriers.</strong> Nature Genet. 43: 797-800, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21725309/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21725309</a>] [<a href="https://doi.org/10.1038/ng.876" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21725309">Miki et al. (2011)</a> stated that the DEPDC5 gene maps to chromosome 22q12.2-q12.3 between the C22ORF30 and YWHAH (<a href="/entry/113508">113508</a>) genes. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=21725309+9734811" 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="#1" class="mim-tip-reference" title="Bar-Peled, L., Chantranupong, L., Cherniack, A. D., Chen, W. W., Ottina, K. A., Grabiner, B. C., Spear, E. D., Carter, S. L., Meyerson, M., Sabatini, D. M. <strong>A tumor suppressor complex with GAP activity for the Rag GTPases that signal amino acid sufficiency to mTORC1.</strong> Science 340: 1100-1106, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23723238/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23723238</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23723238[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/10.1126/science.1232044" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23723238">Bar-Peled et al. (2013)</a> identified the octameric GATOR (GTPase-activating protein (GAP) activity toward RAGs) complex as a critical regulator of the pathway that signals amino acid sufficiency to mTORC1 (see <a href="/entry/601231">601231</a>). GATOR is composed of 2 subcomplexes, GATOR1 and GATOR2. Inhibition of the GATOR1 subunits DEPDC5, NPRL2 (<a href="/entry/607072">607072</a>), and NPRL3 (<a href="/entry/600928">600928</a>) makes mTORC1 signaling resistant to amino acid deprivation. In contrast, inhibition of the GATOR2 subunits MIOS (<a href="/entry/615359">615359</a>), WDR24 (<a href="/entry/620307">620307</a>), WDR59 (<a href="/entry/617418">617418</a>), SEH1L (<a href="/entry/609263">609263</a>), and SEC13 (<a href="/entry/600152">600152</a>) suppresses mTORC1 signaling, and epistasis analysis shows that GATOR2 negatively regulates DEPDC5. GATOR1 has GAP activity for RAGA (<a href="/entry/612194">612194</a>) and RAGB (<a href="/entry/300725">300725</a>), and its components are mutated in human cancer. In cancer cells with inactivating mutations in GATOR1, mTORC1 is hyperactive and insensitive to amino acid starvation, and such cells are hypersensitive to rapamycin, an mTORC1 inhibitor. Thus, <a href="#1" class="mim-tip-reference" title="Bar-Peled, L., Chantranupong, L., Cherniack, A. D., Chen, W. W., Ottina, K. A., Grabiner, B. C., Spear, E. D., Carter, S. L., Meyerson, M., Sabatini, D. M. <strong>A tumor suppressor complex with GAP activity for the Rag GTPases that signal amino acid sufficiency to mTORC1.</strong> Science 340: 1100-1106, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23723238/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23723238</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23723238[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/10.1126/science.1232044" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23723238">Bar-Peled et al. (2013)</a> concluded that they had identified a key negative regulator of the RAG GTPases and revealed that, like other mTORC1 regulators, RAG function can be deregulated in cancer. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23723238" 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>Using HEK293 cells, <a href="#8" class="mim-tip-reference" title="Gu, X., Orozco, J. M., Saxton, R. A., Condon, K. J., Liu, G. Y., Krawczyk, P. A., Scaria, S. M., Harper, J. W., Gygi, S. P., Sabatini, D. M. <strong>SAMTOR is an S-adenosylmethionine sensor for the mTORC1 pathway.</strong> Science 358: 813-818, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29123071/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29123071</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29123071[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/10.1126/science.aao3265" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29123071">Gu et al. (2017)</a> found that SAMTOR (BMT2; <a href="/entry/617855">617855</a>) bound the GATOR1-KICSTOR (see <a href="/entry/617420">617420</a>) supercomplex, and that SAMTOR-GATOR1-KICSTOR inhibited MTORC1 signaling at lysosomes. Binding of S-adenosylmethionine (SAM) to SAMTOR interfered with binding of SAMTOR to GATOR1-KICSTOR and permitted MTORC1 signaling. Methionine starvation reduced SAM levels, promoting association of SAMTOR with GATOR1-KICSTOR and inhibition of MTORC1 lysosomal signaling. The authors concluded that SAMTOR senses methionine availability via SAM binding and thereby links methionine availability with MTORC1 signaling. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29123071" 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="#5" class="mim-tip-reference" title="Chen, J., Ou, Y., Yang, Y., Li, W., Xu, Y., Xie, Y., Liu, Y. <strong>KLHL22 activates amino-acid-dependent mTORC1 signalling to promote tumorigenesis and ageing.</strong> Nature 557: 585-589, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29769719/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29769719</a>] [<a href="https://doi.org/10.1038/s41586-018-0128-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29769719">Chen et al. (2018)</a> found that DEPDC5 underwent proteasome-mediated degradation in response to amino acid stimulation. The authors identified CUL3 (<a href="/entry/603136">603136</a>)-RBX1 (<a href="/entry/603814">603814</a>)-KLHL22 (<a href="/entry/618020">618020</a>) as the E3 ubiquitin ligase that catalyzed lys48-linked polyubiquitination at multiple sites of DEPDC5, a key step in DEPDC5 degradation. During amino acid starvation, KLHL22 was trapped by 14-3-3 proteins (see <a href="/entry/601289">601289</a>) in the nucleus. Upon amino acid stimulation, KLHL22 was released and translocated to the cytosol, where it localized, at least in part, to the lysosome, where GATOR1 resides. KLHL22 played an essential role in amino acid-induced activation of mTORC1 and its downstream signaling events, and functional studies showed that this role was evolutionarily conserved from worms through mammals. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29769719" 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><strong><em>Familial Focal Epilepsy With Variable Foci 1</em></strong></p><p>
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In affected members of 7 of 8 families with autosomal dominant familial focal epilepsy with variable foci-1 (FFEVF1; <a href="/entry/604364">604364</a>), <a href="#6" class="mim-tip-reference" title="Dibbens, L. M., de Vries, B., Donatello, S., Heron, S. E., Hodgson, B. L., Chintawar, S., Crompton, D. E., Hughes, J. N., Bellows, S. T., Klein, K. M., Callenbach, P. M. C., Corbett, M. A., and 23 others. <strong>Mutations in DEPDC5 cause familial focal epilepsy with variable foci.</strong> Nature Genet. 45: 546-551, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23542697/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23542697</a>] [<a href="https://doi.org/10.1038/ng.2599" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23542697">Dibbens et al. (2013)</a> identified heterozygous mutations in the DEPDC5 gene (see, e.g., <a href="#0001">614191.0001</a>-<a href="#0004">614191.0004</a>). The first 2 mutations were found by exome sequencing, and mutations occurred throughout the gene. Screening of this gene in 82 probands with focal epilepsy and no detectable structural lesions identified pathogenic DEPDC5 mutations in 10 (12.2%), indicating that mutations in this gene are an important cause of the disorder. Most mutations caused premature termination of the protein, suggesting haploinsufficiency as the disease mechanism. Most patients had onset in the first or second decades of temporal or frontal lobe epilepsy. Parietal, occipital, and multifocal seizures were less common. All families showed some degree of incomplete penetrance. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23542697" 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 affected members of 6 (37%) of 16 families with autosomal dominant focal epilepsies, <a href="#10" class="mim-tip-reference" title="Ishida, S., Picard, F., Rudolf, G., Noe, E., Achaz, G., Thomas, P., Genton, P., Mundwiller, E., Wolff, M., Marescaux, C., Miles, R., Baulac, M., Hirsch, E., Leguern, E., Baulac, S. <strong>Mutations of DEPDC5 cause autosomal dominant focal epilepsies.</strong> Nature Genet. 45: 552-555, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23542701/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23542701</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23542701[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/10.1038/ng.2601" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23542701">Ishida et al. (2013)</a> identified 6 different heterozygous mutations in the DEPDC5 gene (see, e.g., <a href="#0005">614191.0005</a>-<a href="#0007">614191.0007</a>). Five of the mutations resulted in a truncated protein, indicating that haploinsufficiency is the disease mechanism. Four families had FFEVF1, 2 had features consistent with temporal lobe epilepsy, and 1 had features consistent with nocturnal frontal lobe epilepsy; all types of focal seizures. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23542701" 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 9 patients from 4 unrelated families of European descent with FFEVF1 presenting as autosomal dominant nocturnal frontal lobe epilepsy, <a href="#19" class="mim-tip-reference" title="Picard, F., Makrythanasis, P., Navarro, V., Ishida, S., de Bellescize, J., Ville, D., Weckhuysen, S., Fosselle, E., Suls, A., De Jonghe, P., Vasselon Raina, M., Lesca, G., and 13 others. <strong>DEPDC5 mutations in families presenting as autosomal dominant nocturnal frontal lobe epilepsy.</strong> Neurology 82: 2101-2106, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24814846/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24814846</a>] [<a href="https://doi.org/10.1212/WNL.0000000000000488" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24814846">Picard et al. (2014)</a> identified 4 different heterozygous mutations in the DEPDC5 gene (see, e.g., <a href="#0004">614191.0004</a>; <a href="#0008">614191.0008</a>-<a href="#0009">614191.0009</a>). Functional studies of the variants were not performed, but <a href="#19" class="mim-tip-reference" title="Picard, F., Makrythanasis, P., Navarro, V., Ishida, S., de Bellescize, J., Ville, D., Weckhuysen, S., Fosselle, E., Suls, A., De Jonghe, P., Vasselon Raina, M., Lesca, G., and 13 others. <strong>DEPDC5 mutations in families presenting as autosomal dominant nocturnal frontal lobe epilepsy.</strong> Neurology 82: 2101-2106, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24814846/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24814846</a>] [<a href="https://doi.org/10.1212/WNL.0000000000000488" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24814846">Picard et al. (2014)</a> postulated haploinsufficiency as a disease mechanism. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24814846" 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="Martin, C., Meloche, C., Rioux, M.-F., Nguyen, D. K., Carmant, L., Andermann, E., Gravel, M., Cossette, P. <strong>A recurrent mutation in DEPDC5 predisposes to focal epilepsies in the French-Canadian population.</strong> Clin. Genet. 86: 570-574, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24283814/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24283814</a>] [<a href="https://doi.org/10.1111/cge.12311" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24283814">Martin et al. (2014)</a> identified 2 different heterozygous mutations in the DEPDC5 gene (R843X, <a href="#0010">614191.0010</a> and T864M, <a href="#0011">614191.0011</a>) in 4 (5%) of 79 French Canadian probands with focal epilepsy. Haplotype analysis was consistent with a founder effect for the R843X mutation. Functional studies were not performed. <a href="#15" class="mim-tip-reference" title="Martin, C., Meloche, C., Rioux, M.-F., Nguyen, D. K., Carmant, L., Andermann, E., Gravel, M., Cossette, P. <strong>A recurrent mutation in DEPDC5 predisposes to focal epilepsies in the French-Canadian population.</strong> Clin. Genet. 86: 570-574, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24283814/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24283814</a>] [<a href="https://doi.org/10.1111/cge.12311" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24283814">Martin et al. (2014)</a> noted that <a href="#6" class="mim-tip-reference" title="Dibbens, L. M., de Vries, B., Donatello, S., Heron, S. E., Hodgson, B. L., Chintawar, S., Crompton, D. E., Hughes, J. N., Bellows, S. T., Klein, K. M., Callenbach, P. M. C., Corbett, M. A., and 23 others. <strong>Mutations in DEPDC5 cause familial focal epilepsy with variable foci.</strong> Nature Genet. 45: 546-551, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23542697/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23542697</a>] [<a href="https://doi.org/10.1038/ng.2599" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23542697">Dibbens et al. (2013)</a> had previously identified the R843X mutation in a French Canadian family with the disorder. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=24283814+23542697" 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="Baulac, S., Ishida, S., Marsan, E., Miquel, C., Biraben, A., Nguyen, D. K., Nordli, D., Cossette, P., Nguyen, S., Lambrecq, V., Vlaicu, M., Daniau, M., Bielle, F., Andermann, E., Andermann, F., Leguern, E., Chassoux, F., Picard, F. <strong>Familial focal epilepsy with focal cortical dysplasia due to DEPDC5 mutations.</strong> Ann. Neurol. 77: 675-683, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25623524/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25623524</a>] [<a href="https://doi.org/10.1002/ana.24368" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25623524">Baulac et al. (2015)</a> found that 1 of the patients in an FFEVF1 family reported by <a href="#10" class="mim-tip-reference" title="Ishida, S., Picard, F., Rudolf, G., Noe, E., Achaz, G., Thomas, P., Genton, P., Mundwiller, E., Wolff, M., Marescaux, C., Miles, R., Baulac, M., Hirsch, E., Leguern, E., Baulac, S. <strong>Mutations of DEPDC5 cause autosomal dominant focal epilepsies.</strong> Nature Genet. 45: 552-555, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23542701/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23542701</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23542701[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/10.1038/ng.2601" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23542701">Ishida et al. (2013)</a> who had a germline heterozygous R239X mutation in the DEPDC5 gene (<a href="#0006">614191.0006</a>) also carried a somatic heterozygous truncating mutation (R422X) in the DEPDC5 gene; the mutation was detected in a brain specimen examined after the patient underwent surgery for seizures. Histology of this brain sample was poor, but showed focal cortical dysplasia type I (FCD I) with a disturbance of cortical lamination. <a href="#2" class="mim-tip-reference" title="Baulac, S., Ishida, S., Marsan, E., Miquel, C., Biraben, A., Nguyen, D. K., Nordli, D., Cossette, P., Nguyen, S., Lambrecq, V., Vlaicu, M., Daniau, M., Bielle, F., Andermann, E., Andermann, F., Leguern, E., Chassoux, F., Picard, F. <strong>Familial focal epilepsy with focal cortical dysplasia due to DEPDC5 mutations.</strong> Ann. Neurol. 77: 675-683, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25623524/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25623524</a>] [<a href="https://doi.org/10.1002/ana.24368" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25623524">Baulac et al. (2015)</a> suggested that this second mutation in the DEPDC5 gene resulted in biallelic inactivation in this tissue, consistent with a 2-hit hypothesis. <a href="#2" class="mim-tip-reference" title="Baulac, S., Ishida, S., Marsan, E., Miquel, C., Biraben, A., Nguyen, D. K., Nordli, D., Cossette, P., Nguyen, S., Lambrecq, V., Vlaicu, M., Daniau, M., Bielle, F., Andermann, E., Andermann, F., Leguern, E., Chassoux, F., Picard, F. <strong>Familial focal epilepsy with focal cortical dysplasia due to DEPDC5 mutations.</strong> Ann. Neurol. 77: 675-683, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25623524/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25623524</a>] [<a href="https://doi.org/10.1002/ana.24368" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25623524">Baulac et al. (2015)</a> identified this individual as patient 1/IV-9. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=25623524+23542701" 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 6 affected members of a French-Canadian family with FFEVF1, <a href="#17" class="mim-tip-reference" title="Nascimento, F. A., Borlot, F., Cossette, P., Minassian, B. A., Andrade, D. M. <strong>Two definite cases of sudden unexpected death in epilepsy in a family with a DEPDC5 mutation.</strong> Neurol. Genet. 1: e28, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27066565/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27066565</a>] [<a href="https://doi.org/10.1212/NXG.0000000000000028" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27066565">Nascimento et al. (2015)</a> identified a heterozygous nonsense mutation in the DEPDC5 gene (Q216X; <a href="#0015">614191.0015</a>). The mutation segregated with the disorder in the family, although there was 1 asymptomatic carrier. Affected individuals had focal seizures, absence seizures, generalized tonic-clonic seizures, and febrile seizures. Of note, 2 family members who were not sequenced, died of sudden unexpected death in epilepsy (SUDEP) at 58 and 50 years of age. Functional studies of the variant and studies of patient cells were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27066565" 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 6-year-old child with FFEVF1 and focal cortical dysplasia type IIa, <a href="#20" class="mim-tip-reference" title="Ribierre, T., Deleuze, C., Bacq, A., Baldassari, S., Marsan, E., Chipaux, M., Muraca, G., Roussel, D., Navarro, V., Leguern, E., Miles, R., Baulac, S. <strong>Second-hit mosaic mutation in mTORC1 repressor DEPDC5 causes focal cortical dysplasia-associated epilepsy.</strong> J. Clin. Invest. 128: 2452-2458, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29708508/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29708508</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29708508[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/10.1172/JCI99384" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29708508">Ribierre et al. (2018)</a> identified a heterozygous germline nonsense mutation in the DEPDC5 gene (R286X; <a href="#0013">614191.0013</a>). The mutation, which was found sequencing of a gene panel and confirmed by Sanger sequencing, was inherited from the unaffected mother; it was not present in the gnomAD database. Analysis of resected brain tissue from the patient showed a somatic mosaic heterozygous nonsense mutation (Q289X) in the DEPDC5 that was in trans with the R286X mutation. The Q289X mutation was also absent from gnomAD. The somatic mosaic mutation was present in the cortical seizure-onset zone, but not in the surrounding cortical epileptic zone or in blood. These findings were consistent with biallelic inactivation of DEPDC5 in this patient. Neurons in the resected brain specimen showed increased phosphorylation of RPS6 (<a href="/entry/180460">180460</a>), consistent with increased mTOR (<a href="/entry/601231">601231</a>) activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29708508" 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 10 individuals from 7 unrelated Han Chinese families with FFEVF1, <a href="#13" class="mim-tip-reference" title="Liu, L., Chen, Z.-R., Xu, H.-Q., Liu, D.-T., Mao, Y., Liu, H.-K., Liu, X.-R., Zhou, P., Lin, S.-M., Li, B., He, N., Su, T., Zhai, Q.-X., Meng, H., Liao, W.-P., Yi, Y.-H. <strong>DEPDC5 variants associated malformations of cortical development and focal epilepsy with febrile seizure plus/febrile seizures: the role of molecular sub-regional effect.</strong> Front. Neurosci. 14: 821, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32848577/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32848577</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=32848577[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/10.3389/fnins.2020.00821" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32848577">Liu et al. (2020)</a> identified heterozygous mutations in the DEPDC5 gene (see, e.g., <a href="#0006">614191.0006</a> and <a href="#0014">614191.0014</a>). The mutations were found by sequencing of a targeted gene panel and confirmed by Sanger sequencing. Three families (families A-C) carried truncating mutations (2 nonsense and 1 frameshift), and family D carried a termination extension mutation, all of which were absent from gnomAD and predicted to result in functional haploinsufficiency. Studies of patient cells were not performed. Three families carried missense variants (Y7C, Y836C, and G1545S) that were present at low frequencies in public databases and were considered to be variants of uncertain significance (VUS). Of the whole cohort, 6 patients had focal epilepsy with febrile seizures-plus (FEFS+), 1 had febrile seizures, and 3 had focal or unclassified epilepsy. Four unaffected parents carried the variants, indicating incomplete penetrance. In addition, 8 individuals from 4 families (families G-J) with FEFS+, febrile seizures, or rolandic epilepsy, carried a heterozygous P1031H missense variant, and 1 patient (family K) with frontal lobe epilepsy with focal cortical dysplasia carried a homozygous P1031H variant. However, the authors noted that the pathogenicity of the P1031H variant is unclear, and has been classified as a VUS or likely benign. The 12 probands were ascertained from a cohort of 305 patients with focal epilepsy, with DEPDC5 variants accounting for 3.9%. The findings expanded the phenotype of FFEVF1 to include febrile seizures and FEFS+. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32848577" 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><strong><em>Developmental And Epileptic Encephalopathy 111</em></strong></p><p>
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In 9 patients from 5 unrelated families with developmental and epileptic encephalopathy-111 (DEE111; <a href="/entry/620504">620504</a>), <a href="#26" class="mim-tip-reference" title="Ververi, A., Zagaglia, S., Menzies, L., Baptista, J., Caswell, R., Baulac, S., Ellard, S., Lynch, S., Genomics England Research Consortium, Jacques, T. S., Chawla, M. S., Heier, M., and 27 others. <strong>Germline homozygous missense DEPDC5 variants cause severe refractory early-onset epilepsy, macrocephaly and bilateral polymicrogyria.</strong> Hum. Molec. Genet. 32: 580-594, 2023.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/36067010/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">36067010</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=36067010[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/ddac225" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="36067010">Ververi et al. (2023)</a> identified homozygous missense mutations in the DEPDC5 gene: T337R (<a href="#0016">614191.0016</a>) and R806C (<a href="#0017">614191.0017</a>). The mutations, which were found by whole-exome sequencing, segregated with the disorder in the families and were not present in the gnomAD database. Molecular modeling predicted that the mutations would result in a loss of protein stability and adversely affect protein function. Functional studies of the variants were not performed, but immunohistochemical studies of a skin sample from 1 of the patients with the T337R mutation was consistent with an overall increase in mTOR (<a href="/entry/601231">601231</a>) activity. Since heterozygous carriers in the families were unaffected, <a href="#26" class="mim-tip-reference" title="Ververi, A., Zagaglia, S., Menzies, L., Baptista, J., Caswell, R., Baulac, S., Ellard, S., Lynch, S., Genomics England Research Consortium, Jacques, T. S., Chawla, M. S., Heier, M., and 27 others. <strong>Germline homozygous missense DEPDC5 variants cause severe refractory early-onset epilepsy, macrocephaly and bilateral polymicrogyria.</strong> Hum. Molec. Genet. 32: 580-594, 2023.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/36067010/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">36067010</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=36067010[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/ddac225" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="36067010">Ververi et al. (2023)</a> postulated that these missense mutations resulted in a partial loss of function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=36067010" 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><strong><em>Hepatitis C Infection</em></strong></p><p>
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Using a genomewide-association study of 212 Japanese individuals with chronic hepatitis C virus (HCV; see <a href="/entry/609532">609532</a>) infection and hepatocellular carcinoma (HCC; <a href="/entry/114550">114550</a>) and 765 Japanese individuals with chronic HCV infection without HCC, <a href="#16" class="mim-tip-reference" title="Miki, D., Ochi, H., Hayes, C. N., Abe, H., Yoshima, T., Aikata, H., Ikeda, K., Kumada, H., Toyota, J., Morizono, T., Tsunoda, T., Kubo, M., Nakamura, Y., Kamatani, N., Chayama, K. <strong>Variation in the DEPDC5 locus is associated with progression to hepatocellular carcinoma in chronic hepatitis C virus carriers.</strong> Nature Genet. 43: 797-800, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21725309/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21725309</a>] [<a href="https://doi.org/10.1038/ng.876" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21725309">Miki et al. (2011)</a> identified an intronic SNP in the DEPDC5 gene, <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1012068;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs1012068</a>, that was associated with HCC risk. They confirmed the association using an independent case-control study of 710 cases and 1,625 controls. The association was significant when the 2 stages were analyzed separately as well as together (P combined = 1.27 x 10(-13); odds ratio = 1.75), and the significance level increased further after adjusting for gender, age, and platelet count (P = 1.35 x 10(-14); odds ratio = 1.96). The risk associated with the SNP was weaker in females and those over age 65. RT-PCR analysis of 43 individuals with HCV and HCC revealed higher DEPDC5 expression in tumor than in nontumor tissue, regardless of SNP genotype. <a href="#16" class="mim-tip-reference" title="Miki, D., Ochi, H., Hayes, C. N., Abe, H., Yoshima, T., Aikata, H., Ikeda, K., Kumada, H., Toyota, J., Morizono, T., Tsunoda, T., Kubo, M., Nakamura, Y., Kamatani, N., Chayama, K. <strong>Variation in the DEPDC5 locus is associated with progression to hepatocellular carcinoma in chronic hepatitis C virus carriers.</strong> Nature Genet. 43: 797-800, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21725309/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21725309</a>] [<a href="https://doi.org/10.1038/ng.876" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21725309">Miki et al. (2011)</a> concluded that the intronic SNP <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1012068;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs1012068</a> is associated with a 2-fold increased risk in HCV-related HCC development. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21725309" 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 a study of 1,751 knockout alleles created by the International Mouse Phenotyping Consortium (IMPC), <a href="#7" class="mim-tip-reference" title="Dickinson, M. E., Flenniken, A. M., Ji, X., Teboul, L., Wong, M. D., White, J. K., Meehan, T. F., Weninger, W. J., Westerberg, H., Adissu, H., Baker, C. N., Bower, L., and 73 others. <strong>High-throughput discovery of novel developmental phenotypes.</strong> Nature 537: 508-514, 2016. Note: Erratum: Nature 551: 398 only, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27626380/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27626380</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27626380[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/10.1038/nature19356" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27626380">Dickinson et al. (2016)</a> found that knockout of the mouse homolog of human DEPDC5 is homozygous-lethal (defined as absence of homozygous mice after screening of at least 28 pups before weaning). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27626380" 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="#14" class="mim-tip-reference" title="Marsan, E., Ishida, S., Schramm, A., Weckhuysen, S., Muraca, G., Lecas, S., Liang, N., Treins, C., Pende, M., Roussel, D., Le Van Quyen, M., Mashimo, T., Kaneko, T., Yamamoto, T., Sakuma, T., Mahon, S., Miles, R., Leguern, E., Charpier, S., Baulac, S. <strong>Depdc5 knockout rat: A novel model of mTORopathy.</strong> Neurobiol. Dis 89: 180-189, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26873552/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26873552</a>] [<a href="https://doi.org/10.1016/j.nbd.2016.02.010" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26873552">Marsan et al. (2016)</a> found that Depdc5 -/- rats underwent embryonic lethality that was preceded by global growth delay. Livers of Depdc5 -/- rats contained apoptotic cells, and the cerebral neocortex showed structural defects. Growth delay and embryonic lethality were rescued by prenatal administration of the mTorc1 inhibitor rapamycin. Western blot analysis showed constitutive activation of mTorc1 in brains of Depdc5 -/- embryos. Amino acid starvation in cultured Depdc5 -/- primary rat embryonic fibroblasts led to mTorc1 upregulation, suggesting that DEPDC5 is necessary to control cell growth by repressing the mTORC1 pathway during amino acid starvation. Depdc5 +/- rats displayed no differences in gross anatomy, fertility, and rate of weight gain compared with wildtype, but they had enhanced cell size and dysmorphy of neurons, which were prevented by rapamycin treatment. Moreover, Depdc5 +/- rats showed changes in pyramidal cell electrophysiology, as Depdc5 deficiency impacted both the overall intrinsic properties and excitability of cortical pyramidal neurons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26873552" 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="#9" class="mim-tip-reference" title="Hu, S., Knowlton, R. C., Watson, B. O., Glanowska, K. M., Murphy, G. G., Parent, J. M., Wang, Y. <strong>Somatic Depdc5 deletion recapitulates electroclinical features of human focal cortical dysplasia type IIA.</strong> Ann. Neurol. 84: 140-146, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30080265/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30080265</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30080265[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/10.1002/ana.25272" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30080265">Hu et al. (2018)</a> found that deletion of Depdc5 in rat brain led to focal cortical mTor hyperactivation. Mutant rats developed spontaneous seizures with focal pathologic and electroclinical features clinically relevant to human FCD IIA (<a href="/entry/607341">607341</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30080265" 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 affected members of a large Australian family with autosomal dominant familial focal epilepsy with variable foci-1 (FFEVF1; <a href="/entry/604364">604364</a>), originally reported by <a href="#23" class="mim-tip-reference" title="Scheffer, I. E., Phillips, H. A., O'Brien, C. E., Saling, M. M., Wrennall, J. A., Wallace, R. H., Mulley, J. C., Berkovic, S. F. <strong>Familial partial epilepsy with variable foci: a new partial epilepsy syndrome with suggestion of linkage to chromosome 2.</strong> Ann. Neurol. 44: 890-899, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9851433/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9851433</a>] [<a href="https://doi.org/10.1002/ana.410440607" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9851433">Scheffer et al. (1998)</a> and later by <a href="#12" class="mim-tip-reference" title="Klein, K. M., O'Brien, T. J., Praveen, K., Heron, S. E., Mulley, J. C., Foote, S., Berkovic, S. F., Scheffer, I. E. <strong>Familial focal epilepsy with variable foci mapped to chromosome 22q12: expansion of the phenotypic spectrum.</strong> Epilepsia 53: e151-155, 2012. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22780917/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22780917</a>] [<a href="https://doi.org/10.1111/j.1528-1167.2012.03585.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22780917">Klein et al. (2012)</a>, <a href="#6" class="mim-tip-reference" title="Dibbens, L. M., de Vries, B., Donatello, S., Heron, S. E., Hodgson, B. L., Chintawar, S., Crompton, D. E., Hughes, J. N., Bellows, S. T., Klein, K. M., Callenbach, P. M. C., Corbett, M. A., and 23 others. <strong>Mutations in DEPDC5 cause familial focal epilepsy with variable foci.</strong> Nature Genet. 45: 546-551, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23542697/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23542697</a>] [<a href="https://doi.org/10.1038/ng.2599" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23542697">Dibbens et al. (2013)</a> identified a heterozygous c.21C-G transversion in the DEPDC5 gene, resulting in a tyr7-to-ter (Y7X) substitution. The mutation, which was found by exome sequencing, segregated with the disorder and was not found in a large exome database or in 710 control chromosomes. However, there was evidence of incomplete penetrance. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9851433+22780917+23542697" 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> rs587776973 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587776973;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/rs587776973?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=rs587776973" 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=rs587776973" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In affected members of a Dutch family with familial focal epilepsy with variable foci-1 (FFEVF1; <a href="/entry/604364">604364</a>), originally reported by <a href="#4" class="mim-tip-reference" title="Callenbach, P. M. C., van den Maagdenberg, A. M. J. M., Hottenga, J. J., van den Boogerd, E. H., de Coo, R. F. M., Lindhout, D., Frants, R. R., Sandkuijl, L. A., Brouwer, O. F. <strong>Familial partial epilepsy with variable foci in a Dutch family: clinical characteristics and confirmation of linkage to chromosome 22q.</strong> Epilepsia 44: 1298-1305, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14510823/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14510823</a>] [<a href="https://doi.org/10.1046/j.1528-1157.2003.62302.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14510823">Callenbach et al. (2003)</a>, <a href="#6" class="mim-tip-reference" title="Dibbens, L. M., de Vries, B., Donatello, S., Heron, S. E., Hodgson, B. L., Chintawar, S., Crompton, D. E., Hughes, J. N., Bellows, S. T., Klein, K. M., Callenbach, P. M. C., Corbett, M. A., and 23 others. <strong>Mutations in DEPDC5 cause familial focal epilepsy with variable foci.</strong> Nature Genet. 45: 546-551, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23542697/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23542697</a>] [<a href="https://doi.org/10.1038/ng.2599" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23542697">Dibbens et al. (2013)</a> identified a heterozygous c.1663C-T transition in the DEPDC5 gene, resulting in an arg555-to-ter (R555X) substitution. The mutation, which was found by exome sequencing, segregated with the disorder and was not found in a large exome database or in 710 control chromosomes. However, there was evidence of incomplete penetrance. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=23542697+14510823" 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">rs587776974 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587776974;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=rs587776974" 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=rs587776974" 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=RCV000043581 OR RCV003156221" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000043581, RCV003156221" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000043581...</a>
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<p>In affected members of 3 large French Canadian families with familial focal epilepsy with variable foci-1 (FFEVF1; <a href="/entry/604364">604364</a>), originally reported by <a href="#27" class="mim-tip-reference" title="Xiong, L., Labuda, M., Li, D.-S., Hudson, T. J., Desbiens, R., Patry, G., Verret, S., Langevin, P., Mercho, S., Seni, M.-H., Scheffer, I., Dubeau, F., Berkovic, S. F., Andermann, F., Andermann, E., Pandolfo, M. <strong>Mapping of a gene determining familial partial epilepsy with variable foci to chromosome 22q11-q12.</strong> Am. J. Hum. Genet. 65: 1698-1710, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10577924/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10577924</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10577924[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/10.1086/302649" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10577924">Xiong et al. (1999)</a> and <a href="#3" class="mim-tip-reference" title="Berkovic, S. F., Serratosa, J. M., Phillips, H. A., Xiong, L., Andermann, E., Diaz-Otero, F., Gomez-Garre, P., Martin, M., Fernandez-Bullido, Y., Andermann, F., Lopes-Cendes, I., Dubeau, F., Desbiens, R., Scheffer, I. E., Wallace, R. H., Mulley, J. C., Pandolfo, M. <strong>Familial partial epilepsy with variable foci: clinical features and linkage to chromosome 22q12.</strong> Epilepsia 45: 1054-1060, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15329069/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15329069</a>] [<a href="https://doi.org/10.1111/j.0013-9580.2004.30502.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15329069">Berkovic et al. (2004)</a>, <a href="#6" class="mim-tip-reference" title="Dibbens, L. M., de Vries, B., Donatello, S., Heron, S. E., Hodgson, B. L., Chintawar, S., Crompton, D. E., Hughes, J. N., Bellows, S. T., Klein, K. M., Callenbach, P. M. C., Corbett, M. A., and 23 others. <strong>Mutations in DEPDC5 cause familial focal epilepsy with variable foci.</strong> Nature Genet. 45: 546-551, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23542697/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23542697</a>] [<a href="https://doi.org/10.1038/ng.2599" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23542697">Dibbens et al. (2013)</a> identified a heterozygous 3-bp in-frame deletion (c.488_490delTGT), resulting in the deletion of phe164 (phe164del). Haplotype analysis indicated a founder effect. The mutation segregated with the disorder and was not found in a large exome database or in 710 control chromosomes. However, there was evidence of incomplete penetrance. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=23542697+15329069+10577924" 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">rs587776975 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587776975;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=rs587776975" 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=rs587776975" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In affected members of a large Spanish family with familial focal epilepsy with variable foci-1 (FFEVF1; <a href="/entry/604364">604364</a>) reported by <a href="#3" class="mim-tip-reference" title="Berkovic, S. F., Serratosa, J. M., Phillips, H. A., Xiong, L., Andermann, E., Diaz-Otero, F., Gomez-Garre, P., Martin, M., Fernandez-Bullido, Y., Andermann, F., Lopes-Cendes, I., Dubeau, F., Desbiens, R., Scheffer, I. E., Wallace, R. H., Mulley, J. C., Pandolfo, M. <strong>Familial partial epilepsy with variable foci: clinical features and linkage to chromosome 22q12.</strong> Epilepsia 45: 1054-1060, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15329069/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15329069</a>] [<a href="https://doi.org/10.1111/j.0013-9580.2004.30502.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15329069">Berkovic et al. (2004)</a>, <a href="#6" class="mim-tip-reference" title="Dibbens, L. M., de Vries, B., Donatello, S., Heron, S. E., Hodgson, B. L., Chintawar, S., Crompton, D. E., Hughes, J. N., Bellows, S. T., Klein, K. M., Callenbach, P. M. C., Corbett, M. A., and 23 others. <strong>Mutations in DEPDC5 cause familial focal epilepsy with variable foci.</strong> Nature Genet. 45: 546-551, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23542697/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23542697</a>] [<a href="https://doi.org/10.1038/ng.2599" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23542697">Dibbens et al. (2013)</a> identified a heterozygous c.4107G-A transition in the DEPDC5 gene, resulting in a trp1369-to-ter (W1369X) substitution. The mutation segregated with the disorder and was not found in a large exome database or in 710 control chromosomes. However, there was evidence of incomplete penetrance. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=23542697+15329069" 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="Picard, F., Makrythanasis, P., Navarro, V., Ishida, S., de Bellescize, J., Ville, D., Weckhuysen, S., Fosselle, E., Suls, A., De Jonghe, P., Vasselon Raina, M., Lesca, G., and 13 others. <strong>DEPDC5 mutations in families presenting as autosomal dominant nocturnal frontal lobe epilepsy.</strong> Neurology 82: 2101-2106, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24814846/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24814846</a>] [<a href="https://doi.org/10.1212/WNL.0000000000000488" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24814846">Picard et al. (2014)</a> identified the W1369X mutation in 3 members of a family of European descent with FFEVF1 presenting as nocturnal frontal lobe epilepsy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24814846" 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 affected members of a large French family with familial focal epilepsy with variable foci-1 (FFEVF1; <a href="/entry/604364">604364</a>), reported as 'family N' by <a href="#18" class="mim-tip-reference" title="Picard, F., Baulac, S., Kahane, P., Hirsch, E., Sebastianelli, R., Thomas, P., Vigevano, F., Genton, P., Guerrini, R., Gericke, C. A., An, I., Rudolf, G., Herman, A., Brice, A., Marescaux, C., LeGuern, E. <strong>Dominant partial epilepsies: a clinical, electrophysiological and genetic study of 19 European families.</strong> Brain 123: 1247-1262, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10825362/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10825362</a>] [<a href="https://doi.org/10.1093/brain/123.6.1247" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10825362">Picard et al. (2000)</a>, <a href="#10" class="mim-tip-reference" title="Ishida, S., Picard, F., Rudolf, G., Noe, E., Achaz, G., Thomas, P., Genton, P., Mundwiller, E., Wolff, M., Marescaux, C., Miles, R., Baulac, M., Hirsch, E., Leguern, E., Baulac, S. <strong>Mutations of DEPDC5 cause autosomal dominant focal epilepsies.</strong> Nature Genet. 45: 552-555, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23542701/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23542701</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23542701[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/10.1038/ng.2601" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23542701">Ishida et al. (2013)</a> identified a heterozygous 1-bp deletion (c.1122delA) in exon 16 of the DEPDC5 gene, resulting in a frameshift and premature termination (Leu374PhefsTer30). The mutation, which was found by exome sequencing and segregated with the disorder, was not found in several large control databases. Disease penetrance was incomplete. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10825362+23542701" 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">rs587776976 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587776976;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=rs587776976" 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=rs587776976" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In affected members of a large French family with familial focal epilepsy with variable foci-1 (FFEVF1; <a href="/entry/604364">604364</a>), reported as 'family S' by <a href="#18" class="mim-tip-reference" title="Picard, F., Baulac, S., Kahane, P., Hirsch, E., Sebastianelli, R., Thomas, P., Vigevano, F., Genton, P., Guerrini, R., Gericke, C. A., An, I., Rudolf, G., Herman, A., Brice, A., Marescaux, C., LeGuern, E. <strong>Dominant partial epilepsies: a clinical, electrophysiological and genetic study of 19 European families.</strong> Brain 123: 1247-1262, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10825362/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10825362</a>] [<a href="https://doi.org/10.1093/brain/123.6.1247" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10825362">Picard et al. (2000)</a>, <a href="#10" class="mim-tip-reference" title="Ishida, S., Picard, F., Rudolf, G., Noe, E., Achaz, G., Thomas, P., Genton, P., Mundwiller, E., Wolff, M., Marescaux, C., Miles, R., Baulac, M., Hirsch, E., Leguern, E., Baulac, S. <strong>Mutations of DEPDC5 cause autosomal dominant focal epilepsies.</strong> Nature Genet. 45: 552-555, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23542701/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23542701</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23542701[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/10.1038/ng.2601" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23542701">Ishida et al. (2013)</a> identified a heterozygous c.715C-T transition in exon 12 of the DEPDC5 gene, resulting in an arg239-to-ter (R239X) substitution. The mutation was not found in several large control databases. The mutation was shown to cause nonsense-mediated mRNA decay, indicating that haploinsufficiency is the disease mechanism. Disease penetrance was incomplete. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10825362+23542701" 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="Baulac, S., Ishida, S., Marsan, E., Miquel, C., Biraben, A., Nguyen, D. K., Nordli, D., Cossette, P., Nguyen, S., Lambrecq, V., Vlaicu, M., Daniau, M., Bielle, F., Andermann, E., Andermann, F., Leguern, E., Chassoux, F., Picard, F. <strong>Familial focal epilepsy with focal cortical dysplasia due to DEPDC5 mutations.</strong> Ann. Neurol. 77: 675-683, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25623524/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25623524</a>] [<a href="https://doi.org/10.1002/ana.24368" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25623524">Baulac et al. (2015)</a> found that 1 of the patients in the family reported by <a href="#10" class="mim-tip-reference" title="Ishida, S., Picard, F., Rudolf, G., Noe, E., Achaz, G., Thomas, P., Genton, P., Mundwiller, E., Wolff, M., Marescaux, C., Miles, R., Baulac, M., Hirsch, E., Leguern, E., Baulac, S. <strong>Mutations of DEPDC5 cause autosomal dominant focal epilepsies.</strong> Nature Genet. 45: 552-555, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23542701/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23542701</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23542701[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/10.1038/ng.2601" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23542701">Ishida et al. (2013)</a> who had a germline R239X mutation in the DEPDC5 gene also carried a somatic heterozygous truncating mutation (R422X) in the DEPDC5 gene; the mutation was detected in a brain specimen examined after the patient underwent surgery for seizures. Histology of this brain sample was poor, but showed focal cortical dysplasia type I (FCD I) with a disturbance of cortical lamination. <a href="#2" class="mim-tip-reference" title="Baulac, S., Ishida, S., Marsan, E., Miquel, C., Biraben, A., Nguyen, D. K., Nordli, D., Cossette, P., Nguyen, S., Lambrecq, V., Vlaicu, M., Daniau, M., Bielle, F., Andermann, E., Andermann, F., Leguern, E., Chassoux, F., Picard, F. <strong>Familial focal epilepsy with focal cortical dysplasia due to DEPDC5 mutations.</strong> Ann. Neurol. 77: 675-683, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25623524/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25623524</a>] [<a href="https://doi.org/10.1002/ana.24368" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25623524">Baulac et al. (2015)</a> suggested that this second mutation in the DEPDC5 gene resulted in biallelic inactivation in this tissue, consistent with a 2-hit hypothesis. <a href="#2" class="mim-tip-reference" title="Baulac, S., Ishida, S., Marsan, E., Miquel, C., Biraben, A., Nguyen, D. K., Nordli, D., Cossette, P., Nguyen, S., Lambrecq, V., Vlaicu, M., Daniau, M., Bielle, F., Andermann, E., Andermann, F., Leguern, E., Chassoux, F., Picard, F. <strong>Familial focal epilepsy with focal cortical dysplasia due to DEPDC5 mutations.</strong> Ann. Neurol. 77: 675-683, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25623524/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25623524</a>] [<a href="https://doi.org/10.1002/ana.24368" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25623524">Baulac et al. (2015)</a> identified this individual as patient 1/IV-9. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=25623524+23542701" 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 17-year-old Han Chinese boy (family B) with FFEVF1, <a href="#13" class="mim-tip-reference" title="Liu, L., Chen, Z.-R., Xu, H.-Q., Liu, D.-T., Mao, Y., Liu, H.-K., Liu, X.-R., Zhou, P., Lin, S.-M., Li, B., He, N., Su, T., Zhai, Q.-X., Meng, H., Liao, W.-P., Yi, Y.-H. <strong>DEPDC5 variants associated malformations of cortical development and focal epilepsy with febrile seizure plus/febrile seizures: the role of molecular sub-regional effect.</strong> Front. Neurosci. 14: 821, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32848577/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32848577</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=32848577[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/10.3389/fnins.2020.00821" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32848577">Liu et al. (2020)</a> identified a de novo heterozygous R239X mutation in the DEPDC5 gene. The mutation, which was found by targeted sequencing of a gene panel and confirmed by Sanger sequencing, was not present in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed, but it was predicted to result in functional haploinsufficiency. The patient had onset of febrile and afebrile generalized tonic-clonic seizures at 15 years of age. Brain imaging was not performed. He became seizure-free on medication. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32848577" 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 affected members of a family with familial focal epilepsy with variable foci-1 (FFEVF1; <a href="/entry/604364">604364</a>), <a href="#10" class="mim-tip-reference" title="Ishida, S., Picard, F., Rudolf, G., Noe, E., Achaz, G., Thomas, P., Genton, P., Mundwiller, E., Wolff, M., Marescaux, C., Miles, R., Baulac, M., Hirsch, E., Leguern, E., Baulac, S. <strong>Mutations of DEPDC5 cause autosomal dominant focal epilepsies.</strong> Nature Genet. 45: 552-555, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23542701/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23542701</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23542701[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/10.1038/ng.2601" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23542701">Ishida et al. (2013)</a> identified a heterozygous c.982C-T transition in exon 15 of the DEPDC5 gene, resulting in an arg328-to-ter (R328X) substitution. The mutation was not found in several large control databases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23542701" 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 2 affected members of a family of European descent with familial focal epilepsy with variable foci-1 (FFEVF1; <a href="/entry/604364">604364</a>), <a href="#19" class="mim-tip-reference" title="Picard, F., Makrythanasis, P., Navarro, V., Ishida, S., de Bellescize, J., Ville, D., Weckhuysen, S., Fosselle, E., Suls, A., De Jonghe, P., Vasselon Raina, M., Lesca, G., and 13 others. <strong>DEPDC5 mutations in families presenting as autosomal dominant nocturnal frontal lobe epilepsy.</strong> Neurology 82: 2101-2106, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24814846/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24814846</a>] [<a href="https://doi.org/10.1212/WNL.0000000000000488" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24814846">Picard et al. (2014)</a> identified a heterozygous c.3259C-T transition in the DEPDC5 gene, resulting in an arg1087-to-ter (R1087X) substitution. The mutation, which was found by direct sequencing, was not present in the dbSNP (build 135), 1000 Genomes Project, or Exome Variant Server databases. Patient lymphoblasts showed no mutant mRNA, suggesting nonsense-mediated mRNA decay. One mutation carrier was unaffected, consistent with incomplete penetrance. The patients had onset of drug-resistant nocturnal frontal lobe epilepsy and rare diurnal seizures in their teenage years. Functional studies of the variant were not performed, but <a href="#19" class="mim-tip-reference" title="Picard, F., Makrythanasis, P., Navarro, V., Ishida, S., de Bellescize, J., Ville, D., Weckhuysen, S., Fosselle, E., Suls, A., De Jonghe, P., Vasselon Raina, M., Lesca, G., and 13 others. <strong>DEPDC5 mutations in families presenting as autosomal dominant nocturnal frontal lobe epilepsy.</strong> Neurology 82: 2101-2106, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24814846/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24814846</a>] [<a href="https://doi.org/10.1212/WNL.0000000000000488" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24814846">Picard et al. (2014)</a> postulated haploinsufficiency as a disease mechanism. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24814846" 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>.0009 EPILEPSY, FAMILIAL FOCAL, WITH VARIABLE FOCI 1</strong>
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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> rs587777459 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587777459;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/rs587777459?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=rs587777459" 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=rs587777459" 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=RCV000128401 OR RCV001008659 OR RCV002514701" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000128401, RCV001008659, RCV002514701" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000128401...</a>
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<p>In 2 affected members of a family with familial focal epilepsy with variable foci-1 (FFEVF1; <a href="/entry/604364">604364</a>), <a href="#19" class="mim-tip-reference" title="Picard, F., Makrythanasis, P., Navarro, V., Ishida, S., de Bellescize, J., Ville, D., Weckhuysen, S., Fosselle, E., Suls, A., De Jonghe, P., Vasselon Raina, M., Lesca, G., and 13 others. <strong>DEPDC5 mutations in families presenting as autosomal dominant nocturnal frontal lobe epilepsy.</strong> Neurology 82: 2101-2106, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24814846/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24814846</a>] [<a href="https://doi.org/10.1212/WNL.0000000000000488" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24814846">Picard et al. (2014)</a> identified a heterozygous c.1459C-T transition in the DEPDC5 gene, resulting in an arg487-to-ter (R487X) substitution. The mutation, which was found by direct sequencing, was not present in the dbSNP (build 135), 1000 Genomes Project, or Exome Variant Server databases. Patient lymphoblasts showed no mutant mRNA, suggesting nonsense-mediated mRNA decay. One mutation carrier was unaffected, consistent with incomplete penetrance. The patients had onset of drug-resistant nocturnal frontal lobe epilepsy in early childhood; both also had rare diurnal seizures and intellectual disability. Functional studies of the variant were not performed, but <a href="#19" class="mim-tip-reference" title="Picard, F., Makrythanasis, P., Navarro, V., Ishida, S., de Bellescize, J., Ville, D., Weckhuysen, S., Fosselle, E., Suls, A., De Jonghe, P., Vasselon Raina, M., Lesca, G., and 13 others. <strong>DEPDC5 mutations in families presenting as autosomal dominant nocturnal frontal lobe epilepsy.</strong> Neurology 82: 2101-2106, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24814846/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24814846</a>] [<a href="https://doi.org/10.1212/WNL.0000000000000488" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24814846">Picard et al. (2014)</a> postulated haploinsufficiency as a disease mechanism. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24814846" 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>.0010 EPILEPSY, FAMILIAL FOCAL, WITH VARIABLE FOCI 1</strong>
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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> rs541024038 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs541024038;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/rs541024038?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=rs541024038" 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=rs541024038" 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=RCV000157606 OR RCV001571065 OR RCV003407588 OR RCV003593921" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000157606, RCV001571065, RCV003407588, RCV003593921" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000157606...</a>
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<p>In affected members from 3 families with familial focal epilepsy with variable foci-1 (FFEVF1; <a href="/entry/604364">604364</a>), <a href="#15" class="mim-tip-reference" title="Martin, C., Meloche, C., Rioux, M.-F., Nguyen, D. K., Carmant, L., Andermann, E., Gravel, M., Cossette, P. <strong>A recurrent mutation in DEPDC5 predisposes to focal epilepsies in the French-Canadian population.</strong> Clin. Genet. 86: 570-574, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24283814/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24283814</a>] [<a href="https://doi.org/10.1111/cge.12311" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24283814">Martin et al. (2014)</a> identified a heterozygous c.2527C-T transition in exon 28 of the DEPDC5 gene, resulting in an arg843-to-ter (R843X) substitution. One large family contained 11 mutation carriers, including 5 affected, 1 with febrile seizures, and 5 asymptomatic, consistent with incomplete penetrance. All 3 families originated from the same region in Quebec, Canada, and haplotype analysis indicated a founder effect. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24283814" 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>.0011 EPILEPSY, FAMILIAL FOCAL, WITH VARIABLE FOCI 1</strong>
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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> rs564667614 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs564667614;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/rs564667614?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=rs564667614" 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=rs564667614" 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=RCV000157607 OR RCV001034645 OR RCV001564151 OR RCV002313009 OR RCV003233475" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000157607, RCV001034645, RCV001564151, RCV002313009, RCV003233475" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000157607...</a>
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<p>In a French Canadian patient with familial focal epilepsy with variable foci-1 (FFEVF1; <a href="/entry/604364">604364</a>), <a href="#15" class="mim-tip-reference" title="Martin, C., Meloche, C., Rioux, M.-F., Nguyen, D. K., Carmant, L., Andermann, E., Gravel, M., Cossette, P. <strong>A recurrent mutation in DEPDC5 predisposes to focal epilepsies in the French-Canadian population.</strong> Clin. Genet. 86: 570-574, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24283814/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24283814</a>] [<a href="https://doi.org/10.1111/cge.12311" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24283814">Martin et al. (2014)</a> identified a heterozygous c.2591C-T transition in exon 28 of the DEPDC5 gene, resulting in a thr864-to-met (T864M) substitution at a highly conserved residue. The variant was not found in the dbSNP (build 137), 1000 Genomes Project, or Exome Variant Server databases. The only family member available for study was the patient's father, who did not carry the variant. Functional studies were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24283814" 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>.0012 EPILEPSY, FAMILIAL FOCAL, WITH VARIABLE FOCI 1</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs786205703 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs786205703;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=rs786205703" 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=rs786205703" 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=RCV000170597 OR RCV001201380" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000170597, RCV001201380" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000170597...</a>
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<p>In 6 affected members of an Australian family (family A) with familial focal epilepsy with variable foci-1 (FFEVF1; <a href="/entry/604364">604364</a>), <a href="#22" class="mim-tip-reference" title="Scheffer, I. E., Heron, S. E., Regan, B. M., Mandelstam, S., Crompton, D. E., Hodgson, B. L., Licchetta, L., Provini, F., Bisulli, F., Vadlamudi, L., Gecz, J., Connelly, A., Tinuper, P., Ricos, M. G., Berkovic, S. F., Dibbens, L. M. <strong>Mutations in mammalian target of rapamycin regulator DEPDC5 cause focal epilepsy with brain malformations.</strong> Ann. Neurol. 75: 782-787, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24585383/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24585383</a>] [<a href="https://doi.org/10.1002/ana.24126" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24585383">Scheffer et al. (2014)</a> identified a heterozygous c.418C-T transition in the DEPDC5 gene, resulting in a gln140-to-ter (Q140X) substitution, predicted to result in a loss of function and thus haploinsufficiency. The mutation, which was found by whole-exome sequencing, was not present in the dbSNP or Exome Variant Server databases. There were 4 unaffected mutation carriers, consistent with incomplete penetrance. The patients had onset of frontal lobe epilepsy in the first 2 decades; brain imaging in 2 patients showed cortical thickening and loss of gray-white differentiation at the bottom of an abnormal sulcus, suggesting cortical dysplasia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24585383" 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>.0013 EPILEPSY, FAMILIAL FOCAL, WITH VARIABLE FOCI 1</strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV003329185 OR RCV003329484 OR RCV003329485 OR RCV005003057" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV003329185, RCV003329484, RCV003329485, RCV005003057" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV003329185...</a>
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<p>In a 6-year-old child with familial focal epilepsy with variable foci-1 (FFEVF1; <a href="/entry/604364">604364</a>) and focal cortical dysplasia type IIa, <a href="#20" class="mim-tip-reference" title="Ribierre, T., Deleuze, C., Bacq, A., Baldassari, S., Marsan, E., Chipaux, M., Muraca, G., Roussel, D., Navarro, V., Leguern, E., Miles, R., Baulac, S. <strong>Second-hit mosaic mutation in mTORC1 repressor DEPDC5 causes focal cortical dysplasia-associated epilepsy.</strong> J. Clin. Invest. 128: 2452-2458, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29708508/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29708508</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29708508[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/10.1172/JCI99384" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29708508">Ribierre et al. (2018)</a> identified a heterozygous germline c.856C-T transition (c.856C-T, NM_001242896) in the DEPDC5 gene, resulting in an arg286-to-ter (R286X) substitution. The mutation, which was found sequencing of a gene panel and confirmed by Sanger sequencing, was inherited from the unaffected mother; it was not present in the gnomAD database. Analysis of resected brain tissue from the patient showed a somatic mosaic heterozygous c.865C-T transition in the DEPDC5 gene, resulting in a gln289-to-ter (Q289X) substitution that was in trans with the R286X mutation. The Q289X mutation was also absent from gnomAD. The somatic mosaic mutation was present in the cortical seizure-onset zone, but not in the surrounding cortical epileptic zone or in blood. These findings were consistent with biallelic inactivation of DEPDC5 in this patient. Neurons in the resected brain specimen showed increased phosphorylation of RPS6 (<a href="/entry/180460">180460</a>), consistent with increased mTOR (<a href="/entry/601231">601231</a>) activity. <a href="#20" class="mim-tip-reference" title="Ribierre, T., Deleuze, C., Bacq, A., Baldassari, S., Marsan, E., Chipaux, M., Muraca, G., Roussel, D., Navarro, V., Leguern, E., Miles, R., Baulac, S. <strong>Second-hit mosaic mutation in mTORC1 repressor DEPDC5 causes focal cortical dysplasia-associated epilepsy.</strong> J. Clin. Invest. 128: 2452-2458, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29708508/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29708508</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29708508[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/10.1172/JCI99384" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29708508">Ribierre et al. (2018)</a> found that mouse embryos with focal mosaic knockdown of the Depdc5 gene in postmitotic neurons, generated by in utero electrocorporation and CRISPR/Cas9 gene editing, demonstrated impaired neuronal radial migration to the cortical plate. The mutant neurons were round and balloon-like, similar to dysmorphic neurons found in focal cortical dysplasia IIa. These abnormalities were associated with increased mTOR activity, and the neuronal migration defects could be prevented by treatment with the mTOR inhibitor rapamycin. Focal mosaic mutant mice showed increased susceptibility to focal seizures, and some showed seizure-related death, reminiscent of sudden expected death in epilepsy (SUDEP). Pyramidal cells from mutant mice showed increased complexity of dendritic branching, hypertrophy of dendritic spins, and enhanced excitatory synaptic activity compared to controls. These findings indicated that complete inactivation of Depdc5 during brain development causes epilepsy with focal cortical malformations, and that biallelic DEPDC5 mutations, germline and brain somatic mosaic (representing Knudson's 2-hit hypothesis of disease mechanism), underlie the focal cortical dysplasia that is sometimes observed in this disorder. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29708508" 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 a 24-year-old Han Chinese woman (family A) with familial focal epilepsy with variable foci-1 (FFEVF1; <a href="/entry/604364">604364</a>), <a href="#13" class="mim-tip-reference" title="Liu, L., Chen, Z.-R., Xu, H.-Q., Liu, D.-T., Mao, Y., Liu, H.-K., Liu, X.-R., Zhou, P., Lin, S.-M., Li, B., He, N., Su, T., Zhai, Q.-X., Meng, H., Liao, W.-P., Yi, Y.-H. <strong>DEPDC5 variants associated malformations of cortical development and focal epilepsy with febrile seizure plus/febrile seizures: the role of molecular sub-regional effect.</strong> Front. Neurosci. 14: 821, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32848577/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32848577</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=32848577[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/10.3389/fnins.2020.00821" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32848577">Liu et al. (2020)</a> identified a heterozygous 1-bp deletion (c.450delG, NM_001242896.1) in the DEPDC5 gene, resulting in a frameshift and premature termination (Val151SerfsTer27). The mutation, which was found by targeted sequencing of a gene panel and confirmed by Sanger sequencing, was not present in the gnomAD database. The mutation was inherited from the unaffected father, indicating incomplete penetrance. Functional studies of the variant and studies of patient cells were not performed, but it was predicted to result in functional haploinsufficiency. The patient had onset of seizures at 4 years of age; she had both febrile generalized tonic-clonic seizures and simple partial seizures. EEG showed focal spikes and waves, and brain imaging was normal. She became seizure-free on medication. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32848577" 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">rs886039253 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs886039253;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=rs886039253" 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=rs886039253" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In 6 affected members of a French-Canadian family with familial focal epilepsy with variable foci-1 (FFEVF1; <a href="/entry/604364">604364</a>), <a href="#17" class="mim-tip-reference" title="Nascimento, F. A., Borlot, F., Cossette, P., Minassian, B. A., Andrade, D. M. <strong>Two definite cases of sudden unexpected death in epilepsy in a family with a DEPDC5 mutation.</strong> Neurol. Genet. 1: e28, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27066565/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27066565</a>] [<a href="https://doi.org/10.1212/NXG.0000000000000028" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27066565">Nascimento et al. (2015)</a> identified a heterozygous c.646C-T transition (c.646C-T, ENST00000536766) in the DEPDC5 gene, resulting in a gln216-to-ter (Q216X) substitution. The mutation segregated with the disorder in the family, although there was 1 asymptomatic carrier. Affected individuals had focal seizures, absence seizures, generalized tonic-clonic seizures, and febrile seizures. Of note, 2 family members who were not sequenced died of sudden unexpected death in epilepsy (SUDEP) at 58 and 50 years of age. Functional studies of the variant and studies of patient cells were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27066565" 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> rs1037878155 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1037878155;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/rs1037878155?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=rs1037878155" 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=rs1037878155" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In 6 patients from 3 unrelated families (families 1-3), all of Irish Traveller origin, with developmental and epileptic encephalopathy-111 (DEE111; <a href="/entry/620504">620504</a>), <a href="#26" class="mim-tip-reference" title="Ververi, A., Zagaglia, S., Menzies, L., Baptista, J., Caswell, R., Baulac, S., Ellard, S., Lynch, S., Genomics England Research Consortium, Jacques, T. S., Chawla, M. S., Heier, M., and 27 others. <strong>Germline homozygous missense DEPDC5 variants cause severe refractory early-onset epilepsy, macrocephaly and bilateral polymicrogyria.</strong> Hum. Molec. Genet. 32: 580-594, 2023.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/36067010/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">36067010</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=36067010[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/ddac225" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="36067010">Ververi et al. (2023)</a> identified a homozygous c.1010C-G transversion (c.1010C-G, NM_001242896.3) in the DEPDC5 gene, resulting in a thr337-to-arg (T337R) substitution. The mutation, which was found by whole-exome sequencing, segregated with the disorder in the families and was not present in the gnomAD database. Molecular modeling predicted that the mutation would result in a loss of protein stability and adversely affect protein function. Functional studies of the variant were not performed, but immunohistochemical studies of a skin sample from 1 of the patients was consistent with an overall increase in mTOR (<a href="/entry/601231">601231</a>) activity. Since heterozygous carriers in the families were unaffected, <a href="#26" class="mim-tip-reference" title="Ververi, A., Zagaglia, S., Menzies, L., Baptista, J., Caswell, R., Baulac, S., Ellard, S., Lynch, S., Genomics England Research Consortium, Jacques, T. S., Chawla, M. S., Heier, M., and 27 others. <strong>Germline homozygous missense DEPDC5 variants cause severe refractory early-onset epilepsy, macrocephaly and bilateral polymicrogyria.</strong> Hum. Molec. Genet. 32: 580-594, 2023.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/36067010/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">36067010</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=36067010[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/ddac225" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="36067010">Ververi et al. (2023)</a> postulated that the T337R mutation results in a partial loss of function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=36067010" 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 3 patients from 2 unrelated consanguineous families (family 4 of Tunisian descent and family 5 of Lebanese descent), with developmental and epileptic encephalopathy-111 (DEE111; <a href="/entry/620504">620504</a>), <a href="#26" class="mim-tip-reference" title="Ververi, A., Zagaglia, S., Menzies, L., Baptista, J., Caswell, R., Baulac, S., Ellard, S., Lynch, S., Genomics England Research Consortium, Jacques, T. S., Chawla, M. S., Heier, M., and 27 others. <strong>Germline homozygous missense DEPDC5 variants cause severe refractory early-onset epilepsy, macrocephaly and bilateral polymicrogyria.</strong> Hum. Molec. Genet. 32: 580-594, 2023.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/36067010/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">36067010</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=36067010[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/ddac225" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="36067010">Ververi et al. (2023)</a> identified a homozygous c.2416C-T transition (c.2416C-T, NM_001242896.3) in the DEPDC5 gene, resulting in an arg806-to-cys (R806C) substitution. The mutation, which was found by whole-exome sequencing, segregated with the disorder in the families and was not present in the gnomAD database. Molecular modeling predicted that the mutation would result in a loss of protein stability and adversely affect protein function. Since heterozygous carriers in the families were unaffected, <a href="#26" class="mim-tip-reference" title="Ververi, A., Zagaglia, S., Menzies, L., Baptista, J., Caswell, R., Baulac, S., Ellard, S., Lynch, S., Genomics England Research Consortium, Jacques, T. S., Chawla, M. S., Heier, M., and 27 others. <strong>Germline homozygous missense DEPDC5 variants cause severe refractory early-onset epilepsy, macrocephaly and bilateral polymicrogyria.</strong> Hum. Molec. Genet. 32: 580-594, 2023.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/36067010/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">36067010</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=36067010[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/ddac225" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="36067010">Ververi et al. (2023)</a> postulated that the R806C mutation results in a partial loss of function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=36067010" 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://doi.org/10.1046/j.1528-1157.2003.62302.x" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/ng.2601" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/dnares/5.3.169" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22780917/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22780917</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22780917" 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/10.1111/j.1528-1167.2012.03585.x" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.3389/fnins.2020.00821" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/j.nbd.2016.02.010" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/ng.876" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/brain/123.6.1247" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1212/WNL.0000000000000488" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/j.yebeh.2022.108678" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/humu.22723" target="_blank">Full Text</a>]
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Ververi, A., Zagaglia, S., Menzies, L., Baptista, J., Caswell, R., Baulac, S., Ellard, S., Lynch, S., Genomics England Research Consortium, Jacques, T. S., Chawla, M. S., Heier, M., and 27 others.
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[<a href="https://doi.org/10.1086/302649" target="_blank">Full Text</a>]
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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 : 12/08/2023
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Cassandra L. Kniffin - updated : 09/15/2023<br>Ada Hamosh - updated : 08/27/2018<br>Bao Lige - updated : 06/21/2018<br>Patricia A. Hartz - updated : 01/29/2018<br>Ada Hamosh - updated : 02/16/2017<br>Cassandra L. Kniffin - updated : 5/20/2015<br>Cassandra L. Kniffin - updated : 2/2/2015<br>Ada Hamosh - updated : 7/7/2014<br>Cassandra L. Kniffin - updated : 6/16/2014<br>Cassandra L. Kniffin - updated : 5/28/2013
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Paul J. Converse : 8/25/2011
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mgross : 12/08/2023
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alopez : 09/20/2023<br>ckniffin : 09/18/2023<br>ckniffin : 09/15/2023<br>mgross : 03/30/2023<br>alopez : 08/27/2018<br>mgross : 06/21/2018<br>carol : 02/14/2018<br>carol : 02/13/2018<br>mgross : 01/29/2018<br>mgross : 03/30/2017<br>alopez : 02/16/2017<br>carol : 09/21/2016<br>ckniffin : 09/20/2016<br>alopez : 05/20/2015<br>mcolton : 5/20/2015<br>ckniffin : 5/20/2015<br>carol : 2/5/2015<br>mcolton : 2/2/2015<br>ckniffin : 2/2/2015<br>alopez : 7/7/2014<br>carol : 6/18/2014<br>mcolton : 6/18/2014<br>ckniffin : 6/16/2014<br>carol : 2/19/2014<br>carol : 9/6/2013<br>carol : 6/4/2013<br>ckniffin : 5/28/2013<br>ckniffin : 5/28/2013<br>mgross : 8/25/2011
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<strong>*</strong> 614191
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DEP DOMAIN-CONTAINING PROTEIN 5; DEPDC5
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KIAA0645
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<strong><em>HGNC Approved Gene Symbol: DEPDC5</em></strong>
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Cytogenetic location: 22q12.2-q12.3
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Genomic coordinates <span class="small">(GRCh38)</span> : 22:31,753,968-31,908,033 </span>
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<span class="small">(from NCBI)</span>
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<strong>Gene-Phenotype Relationships</strong>
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Phenotype
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Phenotype <br /> MIM number
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Inheritance
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22q12.2-q12.3
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Developmental and epileptic encephalopathy 111
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620504
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Autosomal recessive
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3
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Epilepsy, familial focal, with variable foci 1
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604364
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Autosomal dominant
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3
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<strong>TEXT</strong>
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<p>The DEPDC5 gene encodes a GTPase that, together with NPRL2 (607072) and NPRL3 (600928), constitutes the GATOR1 complex, which inhibits RAG (see, e.g., RRAGA, 612194)-dependent activation of the mTOR signaling pathway (see 601231) that is involved in multiple biologic processes, including cell growth, proliferation, and protein synthesis (summary by van Kranenburg et al., 2015; Liu et al., 2020; Samanta, 2022; Ververi et al., 2023). </p>
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<strong>Cloning and Expression</strong>
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<p>By screening cDNA libraries for genes encoding large proteins expressed in brain, Ishikawa et al. (1998) isolated DEPDC5, which they called KIAA0645. The predicted protein contains 1,572 amino acids. RT-PCR analysis detected ubiquitous expression in human tissues. </p><p>Using RT-PCR, Dibbens et al. (2013) found expression of the Depdc5 gene at low levels in all mouse brain regions analyzed. Expression occurred throughout brain development, including in midgestation embryonic head, neonatal brain, and whole adult brain. Immunofluorescence studies showed that Depdc5 was expressed in neurons and GABAergic interneurons, but was absent in nonneuronal cells, including astrocytes. Immunofluorescence was localized to the cytosol of the neuronal cell body and was mostly perinuclear, with little or no extension into neuronal processes. This subcellular localization was confirmed in human neurospheres derived from induced pluripotent stem cells from control individuals and in human neuroblastoma cells. These results suggested a role for DEPDC5 in neuronal signal transduction. </p>
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<strong>Gene Structure</strong>
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<p>Miki et al. (2011) reported that the DEPDC5 gene contains 42 exons. </p>
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<strong>Biochemical Features</strong>
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<p><strong><em>Cryoelectron Microscopy</em></strong></p><p>
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Shen et al. (2018) used cryoelectron microscopy to solve structures of GATOR1 and GATOR1-RAG GTPases complexes. GATOR1 adopts an extended architecture with a cavity in the middle; NPRL2 (607072) links DEPDC5 and NPRL3 (600928), and DEPDC5 contacts the RAG GTPase heterodimer. Biochemical analyses revealed that this GATOR1-RAG GTPases structure is inhibitory, and that at least 2 binding modes must exist between the RAG GTPases and GATOR1. Direct interaction of DEPDC5 with RAGA (612194) inhibits GATOR1-mediated stimulation of GTP hydrolysis by RAGA, whereas weaker interactions between the NPRL2-NPRL3 heterodimer and RAGA execute GAP activity. </p>
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<strong>Mapping</strong>
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<p>By radiation hybrid analysis, Ishikawa et al. (1998) mapped the KIAA0645 gene to chromosome 22. Miki et al. (2011) stated that the DEPDC5 gene maps to chromosome 22q12.2-q12.3 between the C22ORF30 and YWHAH (113508) genes. </p>
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<strong>Gene Function</strong>
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<p>Bar-Peled et al. (2013) identified the octameric GATOR (GTPase-activating protein (GAP) activity toward RAGs) complex as a critical regulator of the pathway that signals amino acid sufficiency to mTORC1 (see 601231). GATOR is composed of 2 subcomplexes, GATOR1 and GATOR2. Inhibition of the GATOR1 subunits DEPDC5, NPRL2 (607072), and NPRL3 (600928) makes mTORC1 signaling resistant to amino acid deprivation. In contrast, inhibition of the GATOR2 subunits MIOS (615359), WDR24 (620307), WDR59 (617418), SEH1L (609263), and SEC13 (600152) suppresses mTORC1 signaling, and epistasis analysis shows that GATOR2 negatively regulates DEPDC5. GATOR1 has GAP activity for RAGA (612194) and RAGB (300725), and its components are mutated in human cancer. In cancer cells with inactivating mutations in GATOR1, mTORC1 is hyperactive and insensitive to amino acid starvation, and such cells are hypersensitive to rapamycin, an mTORC1 inhibitor. Thus, Bar-Peled et al. (2013) concluded that they had identified a key negative regulator of the RAG GTPases and revealed that, like other mTORC1 regulators, RAG function can be deregulated in cancer. </p><p>Using HEK293 cells, Gu et al. (2017) found that SAMTOR (BMT2; 617855) bound the GATOR1-KICSTOR (see 617420) supercomplex, and that SAMTOR-GATOR1-KICSTOR inhibited MTORC1 signaling at lysosomes. Binding of S-adenosylmethionine (SAM) to SAMTOR interfered with binding of SAMTOR to GATOR1-KICSTOR and permitted MTORC1 signaling. Methionine starvation reduced SAM levels, promoting association of SAMTOR with GATOR1-KICSTOR and inhibition of MTORC1 lysosomal signaling. The authors concluded that SAMTOR senses methionine availability via SAM binding and thereby links methionine availability with MTORC1 signaling. </p><p>Chen et al. (2018) found that DEPDC5 underwent proteasome-mediated degradation in response to amino acid stimulation. The authors identified CUL3 (603136)-RBX1 (603814)-KLHL22 (618020) as the E3 ubiquitin ligase that catalyzed lys48-linked polyubiquitination at multiple sites of DEPDC5, a key step in DEPDC5 degradation. During amino acid starvation, KLHL22 was trapped by 14-3-3 proteins (see 601289) in the nucleus. Upon amino acid stimulation, KLHL22 was released and translocated to the cytosol, where it localized, at least in part, to the lysosome, where GATOR1 resides. KLHL22 played an essential role in amino acid-induced activation of mTORC1 and its downstream signaling events, and functional studies showed that this role was evolutionarily conserved from worms through mammals. </p>
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<strong>Molecular Genetics</strong>
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<p><strong><em>Familial Focal Epilepsy With Variable Foci 1</em></strong></p><p>
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In affected members of 7 of 8 families with autosomal dominant familial focal epilepsy with variable foci-1 (FFEVF1; 604364), Dibbens et al. (2013) identified heterozygous mutations in the DEPDC5 gene (see, e.g., 614191.0001-614191.0004). The first 2 mutations were found by exome sequencing, and mutations occurred throughout the gene. Screening of this gene in 82 probands with focal epilepsy and no detectable structural lesions identified pathogenic DEPDC5 mutations in 10 (12.2%), indicating that mutations in this gene are an important cause of the disorder. Most mutations caused premature termination of the protein, suggesting haploinsufficiency as the disease mechanism. Most patients had onset in the first or second decades of temporal or frontal lobe epilepsy. Parietal, occipital, and multifocal seizures were less common. All families showed some degree of incomplete penetrance. </p><p>In affected members of 6 (37%) of 16 families with autosomal dominant focal epilepsies, Ishida et al. (2013) identified 6 different heterozygous mutations in the DEPDC5 gene (see, e.g., 614191.0005-614191.0007). Five of the mutations resulted in a truncated protein, indicating that haploinsufficiency is the disease mechanism. Four families had FFEVF1, 2 had features consistent with temporal lobe epilepsy, and 1 had features consistent with nocturnal frontal lobe epilepsy; all types of focal seizures. </p><p>In 9 patients from 4 unrelated families of European descent with FFEVF1 presenting as autosomal dominant nocturnal frontal lobe epilepsy, Picard et al. (2014) identified 4 different heterozygous mutations in the DEPDC5 gene (see, e.g., 614191.0004; 614191.0008-614191.0009). Functional studies of the variants were not performed, but Picard et al. (2014) postulated haploinsufficiency as a disease mechanism. </p><p>Martin et al. (2014) identified 2 different heterozygous mutations in the DEPDC5 gene (R843X, 614191.0010 and T864M, 614191.0011) in 4 (5%) of 79 French Canadian probands with focal epilepsy. Haplotype analysis was consistent with a founder effect for the R843X mutation. Functional studies were not performed. Martin et al. (2014) noted that Dibbens et al. (2013) had previously identified the R843X mutation in a French Canadian family with the disorder. </p><p>Baulac et al. (2015) found that 1 of the patients in an FFEVF1 family reported by Ishida et al. (2013) who had a germline heterozygous R239X mutation in the DEPDC5 gene (614191.0006) also carried a somatic heterozygous truncating mutation (R422X) in the DEPDC5 gene; the mutation was detected in a brain specimen examined after the patient underwent surgery for seizures. Histology of this brain sample was poor, but showed focal cortical dysplasia type I (FCD I) with a disturbance of cortical lamination. Baulac et al. (2015) suggested that this second mutation in the DEPDC5 gene resulted in biallelic inactivation in this tissue, consistent with a 2-hit hypothesis. Baulac et al. (2015) identified this individual as patient 1/IV-9. </p><p>In 6 affected members of a French-Canadian family with FFEVF1, Nascimento et al. (2015) identified a heterozygous nonsense mutation in the DEPDC5 gene (Q216X; 614191.0015). The mutation segregated with the disorder in the family, although there was 1 asymptomatic carrier. Affected individuals had focal seizures, absence seizures, generalized tonic-clonic seizures, and febrile seizures. Of note, 2 family members who were not sequenced, died of sudden unexpected death in epilepsy (SUDEP) at 58 and 50 years of age. Functional studies of the variant and studies of patient cells were not performed. </p><p>In a 6-year-old child with FFEVF1 and focal cortical dysplasia type IIa, Ribierre et al. (2018) identified a heterozygous germline nonsense mutation in the DEPDC5 gene (R286X; 614191.0013). The mutation, which was found sequencing of a gene panel and confirmed by Sanger sequencing, was inherited from the unaffected mother; it was not present in the gnomAD database. Analysis of resected brain tissue from the patient showed a somatic mosaic heterozygous nonsense mutation (Q289X) in the DEPDC5 that was in trans with the R286X mutation. The Q289X mutation was also absent from gnomAD. The somatic mosaic mutation was present in the cortical seizure-onset zone, but not in the surrounding cortical epileptic zone or in blood. These findings were consistent with biallelic inactivation of DEPDC5 in this patient. Neurons in the resected brain specimen showed increased phosphorylation of RPS6 (180460), consistent with increased mTOR (601231) activity. </p><p>In 10 individuals from 7 unrelated Han Chinese families with FFEVF1, Liu et al. (2020) identified heterozygous mutations in the DEPDC5 gene (see, e.g., 614191.0006 and 614191.0014). The mutations were found by sequencing of a targeted gene panel and confirmed by Sanger sequencing. Three families (families A-C) carried truncating mutations (2 nonsense and 1 frameshift), and family D carried a termination extension mutation, all of which were absent from gnomAD and predicted to result in functional haploinsufficiency. Studies of patient cells were not performed. Three families carried missense variants (Y7C, Y836C, and G1545S) that were present at low frequencies in public databases and were considered to be variants of uncertain significance (VUS). Of the whole cohort, 6 patients had focal epilepsy with febrile seizures-plus (FEFS+), 1 had febrile seizures, and 3 had focal or unclassified epilepsy. Four unaffected parents carried the variants, indicating incomplete penetrance. In addition, 8 individuals from 4 families (families G-J) with FEFS+, febrile seizures, or rolandic epilepsy, carried a heterozygous P1031H missense variant, and 1 patient (family K) with frontal lobe epilepsy with focal cortical dysplasia carried a homozygous P1031H variant. However, the authors noted that the pathogenicity of the P1031H variant is unclear, and has been classified as a VUS or likely benign. The 12 probands were ascertained from a cohort of 305 patients with focal epilepsy, with DEPDC5 variants accounting for 3.9%. The findings expanded the phenotype of FFEVF1 to include febrile seizures and FEFS+. </p><p><strong><em>Developmental And Epileptic Encephalopathy 111</em></strong></p><p>
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In 9 patients from 5 unrelated families with developmental and epileptic encephalopathy-111 (DEE111; 620504), Ververi et al. (2023) identified homozygous missense mutations in the DEPDC5 gene: T337R (614191.0016) and R806C (614191.0017). The mutations, which were found by whole-exome sequencing, segregated with the disorder in the families and were not present in the gnomAD database. Molecular modeling predicted that the mutations would result in a loss of protein stability and adversely affect protein function. Functional studies of the variants were not performed, but immunohistochemical studies of a skin sample from 1 of the patients with the T337R mutation was consistent with an overall increase in mTOR (601231) activity. Since heterozygous carriers in the families were unaffected, Ververi et al. (2023) postulated that these missense mutations resulted in a partial loss of function. </p><p><strong><em>Hepatitis C Infection</em></strong></p><p>
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Using a genomewide-association study of 212 Japanese individuals with chronic hepatitis C virus (HCV; see 609532) infection and hepatocellular carcinoma (HCC; 114550) and 765 Japanese individuals with chronic HCV infection without HCC, Miki et al. (2011) identified an intronic SNP in the DEPDC5 gene, rs1012068, that was associated with HCC risk. They confirmed the association using an independent case-control study of 710 cases and 1,625 controls. The association was significant when the 2 stages were analyzed separately as well as together (P combined = 1.27 x 10(-13); odds ratio = 1.75), and the significance level increased further after adjusting for gender, age, and platelet count (P = 1.35 x 10(-14); odds ratio = 1.96). The risk associated with the SNP was weaker in females and those over age 65. RT-PCR analysis of 43 individuals with HCV and HCC revealed higher DEPDC5 expression in tumor than in nontumor tissue, regardless of SNP genotype. Miki et al. (2011) concluded that the intronic SNP rs1012068 is associated with a 2-fold increased risk in HCV-related HCC development. </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>In a study of 1,751 knockout alleles created by the International Mouse Phenotyping Consortium (IMPC), Dickinson et al. (2016) found that knockout of the mouse homolog of human DEPDC5 is homozygous-lethal (defined as absence of homozygous mice after screening of at least 28 pups before weaning). </p><p>Marsan et al. (2016) found that Depdc5 -/- rats underwent embryonic lethality that was preceded by global growth delay. Livers of Depdc5 -/- rats contained apoptotic cells, and the cerebral neocortex showed structural defects. Growth delay and embryonic lethality were rescued by prenatal administration of the mTorc1 inhibitor rapamycin. Western blot analysis showed constitutive activation of mTorc1 in brains of Depdc5 -/- embryos. Amino acid starvation in cultured Depdc5 -/- primary rat embryonic fibroblasts led to mTorc1 upregulation, suggesting that DEPDC5 is necessary to control cell growth by repressing the mTORC1 pathway during amino acid starvation. Depdc5 +/- rats displayed no differences in gross anatomy, fertility, and rate of weight gain compared with wildtype, but they had enhanced cell size and dysmorphy of neurons, which were prevented by rapamycin treatment. Moreover, Depdc5 +/- rats showed changes in pyramidal cell electrophysiology, as Depdc5 deficiency impacted both the overall intrinsic properties and excitability of cortical pyramidal neurons. </p><p>Hu et al. (2018) found that deletion of Depdc5 in rat brain led to focal cortical mTor hyperactivation. Mutant rats developed spontaneous seizures with focal pathologic and electroclinical features clinically relevant to human FCD IIA (607341). </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>17 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 EPILEPSY, FAMILIAL FOCAL, WITH VARIABLE FOCI 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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DEPDC5, TYR7TER
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<br />
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SNP: rs768241563,
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gnomAD: rs768241563,
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ClinVar: RCV000043579, RCV001034641, RCV001562282, RCV002426590
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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 affected members of a large Australian family with autosomal dominant familial focal epilepsy with variable foci-1 (FFEVF1; 604364), originally reported by Scheffer et al. (1998) and later by Klein et al. (2012), Dibbens et al. (2013) identified a heterozygous c.21C-G transversion in the DEPDC5 gene, resulting in a tyr7-to-ter (Y7X) substitution. The mutation, which was found by exome sequencing, segregated with the disorder and was not found in a large exome database or in 710 control chromosomes. However, there was evidence of incomplete penetrance. </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 EPILEPSY, FAMILIAL FOCAL, WITH VARIABLE FOCI 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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DEPDC5, ARG555TER
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<br />
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SNP: rs587776973,
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gnomAD: rs587776973,
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ClinVar: RCV000043580, RCV001034675, RCV001091571, RCV002316206
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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 affected members of a Dutch family with familial focal epilepsy with variable foci-1 (FFEVF1; 604364), originally reported by Callenbach et al. (2003), Dibbens et al. (2013) identified a heterozygous c.1663C-T transition in the DEPDC5 gene, resulting in an arg555-to-ter (R555X) substitution. The mutation, which was found by exome sequencing, segregated with the disorder and was not found in a large exome database or in 710 control chromosomes. However, there was evidence of incomplete penetrance. </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 EPILEPSY, FAMILIAL FOCAL, WITH VARIABLE FOCI 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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DEPDC5, 3-BP DEL, 488TGT
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<br />
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SNP: rs587776974,
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ClinVar: RCV000043581, RCV003156221
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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 affected members of 3 large French Canadian families with familial focal epilepsy with variable foci-1 (FFEVF1; 604364), originally reported by Xiong et al. (1999) and Berkovic et al. (2004), Dibbens et al. (2013) identified a heterozygous 3-bp in-frame deletion (c.488_490delTGT), resulting in the deletion of phe164 (phe164del). Haplotype analysis indicated a founder effect. The mutation segregated with the disorder and was not found in a large exome database or in 710 control chromosomes. However, there was evidence of incomplete penetrance. </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>.0004 EPILEPSY, FAMILIAL FOCAL, WITH VARIABLE FOCI 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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DEPDC5, TRP1369TER
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<br />
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SNP: rs587776975,
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ClinVar: RCV000043582, RCV003156068
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In affected members of a large Spanish family with familial focal epilepsy with variable foci-1 (FFEVF1; 604364) reported by Berkovic et al. (2004), Dibbens et al. (2013) identified a heterozygous c.4107G-A transition in the DEPDC5 gene, resulting in a trp1369-to-ter (W1369X) substitution. The mutation segregated with the disorder and was not found in a large exome database or in 710 control chromosomes. However, there was evidence of incomplete penetrance. </p><p>Picard et al. (2014) identified the W1369X mutation in 3 members of a family of European descent with FFEVF1 presenting as nocturnal frontal lobe epilepsy. </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>.0005 EPILEPSY, FAMILIAL FOCAL, WITH VARIABLE FOCI 1</strong>
|
|
</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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|
|
DEPDC5, 1-BP DEL, 1122A
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<br />
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|
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SNP: rs879255234,
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|
|
ClinVar: RCV000043583
|
|
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|
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</span>
|
|
</div>
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|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members of a large French family with familial focal epilepsy with variable foci-1 (FFEVF1; 604364), reported as 'family N' by Picard et al. (2000), Ishida et al. (2013) identified a heterozygous 1-bp deletion (c.1122delA) in exon 16 of the DEPDC5 gene, resulting in a frameshift and premature termination (Leu374PhefsTer30). The mutation, which was found by exome sequencing and segregated with the disorder, was not found in several large control databases. Disease penetrance was incomplete. </p>
|
|
</span>
|
|
</div>
|
|
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|
<div>
|
|
<br />
|
|
</div>
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|
|
</div>
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<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0006 EPILEPSY, FAMILIAL FOCAL, WITH VARIABLE FOCI 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
DEPDC5, ARG239TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs587776976,
|
|
|
|
|
|
|
|
ClinVar: RCV000043584, RCV000498718, RCV001387791, RCV002274906
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members of a large French family with familial focal epilepsy with variable foci-1 (FFEVF1; 604364), reported as 'family S' by Picard et al. (2000), Ishida et al. (2013) identified a heterozygous c.715C-T transition in exon 12 of the DEPDC5 gene, resulting in an arg239-to-ter (R239X) substitution. The mutation was not found in several large control databases. The mutation was shown to cause nonsense-mediated mRNA decay, indicating that haploinsufficiency is the disease mechanism. Disease penetrance was incomplete. </p><p>Baulac et al. (2015) found that 1 of the patients in the family reported by Ishida et al. (2013) who had a germline R239X mutation in the DEPDC5 gene also carried a somatic heterozygous truncating mutation (R422X) in the DEPDC5 gene; the mutation was detected in a brain specimen examined after the patient underwent surgery for seizures. Histology of this brain sample was poor, but showed focal cortical dysplasia type I (FCD I) with a disturbance of cortical lamination. Baulac et al. (2015) suggested that this second mutation in the DEPDC5 gene resulted in biallelic inactivation in this tissue, consistent with a 2-hit hypothesis. Baulac et al. (2015) identified this individual as patient 1/IV-9. </p><p>In a 17-year-old Han Chinese boy (family B) with FFEVF1, Liu et al. (2020) identified a de novo heterozygous R239X mutation in the DEPDC5 gene. The mutation, which was found by targeted sequencing of a gene panel and confirmed by Sanger sequencing, was not present in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed, but it was predicted to result in functional haploinsufficiency. The patient had onset of febrile and afebrile generalized tonic-clonic seizures at 15 years of age. Brain imaging was not performed. He became seizure-free on medication. </p>
|
|
</span>
|
|
</div>
|
|
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<div>
|
|
<br />
|
|
</div>
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|
|
|
</div>
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|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 EPILEPSY, FAMILIAL FOCAL, WITH VARIABLE FOCI 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
|
|
|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
DEPDC5, ARG328TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs587776977,
|
|
|
|
|
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|
|
ClinVar: RCV000043585, RCV001387793, RCV003162360, RCV004545741
|
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|
|
|
|
</span>
|
|
</div>
|
|
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|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members of a family with familial focal epilepsy with variable foci-1 (FFEVF1; 604364), Ishida et al. (2013) identified a heterozygous c.982C-T transition in exon 15 of the DEPDC5 gene, resulting in an arg328-to-ter (R328X) substitution. The mutation was not found in several large control databases. </p>
|
|
</span>
|
|
</div>
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|
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<div>
|
|
<br />
|
|
</div>
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</div>
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|
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|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0008 EPILEPSY, FAMILIAL FOCAL, WITH VARIABLE FOCI 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
DEPDC5, ARG1087TER
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|
|
|
|
<br />
|
|
|
|
SNP: rs587777458,
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|
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|
|
|
gnomAD: rs587777458,
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|
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|
|
|
ClinVar: RCV000128400, RCV001034630, RCV001091574
|
|
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|
|
</span>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 affected members of a family of European descent with familial focal epilepsy with variable foci-1 (FFEVF1; 604364), Picard et al. (2014) identified a heterozygous c.3259C-T transition in the DEPDC5 gene, resulting in an arg1087-to-ter (R1087X) substitution. The mutation, which was found by direct sequencing, was not present in the dbSNP (build 135), 1000 Genomes Project, or Exome Variant Server databases. Patient lymphoblasts showed no mutant mRNA, suggesting nonsense-mediated mRNA decay. One mutation carrier was unaffected, consistent with incomplete penetrance. The patients had onset of drug-resistant nocturnal frontal lobe epilepsy and rare diurnal seizures in their teenage years. Functional studies of the variant were not performed, but Picard et al. (2014) postulated haploinsufficiency as a disease mechanism. </p>
|
|
</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>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0009 EPILEPSY, FAMILIAL FOCAL, WITH VARIABLE FOCI 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
DEPDC5, ARG487TER
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<br />
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|
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SNP: rs587777459,
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gnomAD: rs587777459,
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ClinVar: RCV000128401, RCV001008659, RCV002514701
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In 2 affected members of a family with familial focal epilepsy with variable foci-1 (FFEVF1; 604364), Picard et al. (2014) identified a heterozygous c.1459C-T transition in the DEPDC5 gene, resulting in an arg487-to-ter (R487X) substitution. The mutation, which was found by direct sequencing, was not present in the dbSNP (build 135), 1000 Genomes Project, or Exome Variant Server databases. Patient lymphoblasts showed no mutant mRNA, suggesting nonsense-mediated mRNA decay. One mutation carrier was unaffected, consistent with incomplete penetrance. The patients had onset of drug-resistant nocturnal frontal lobe epilepsy in early childhood; both also had rare diurnal seizures and intellectual disability. Functional studies of the variant were not performed, but Picard et al. (2014) postulated haploinsufficiency as a disease mechanism. </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>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 EPILEPSY, FAMILIAL FOCAL, WITH VARIABLE FOCI 1</strong>
|
|
</span>
|
|
</h4>
|
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</div>
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<div>
|
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<span class="mim-text-font">
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DEPDC5, ARG843TER
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<br />
|
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SNP: rs541024038,
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gnomAD: rs541024038,
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ClinVar: RCV000157606, RCV001571065, RCV003407588, RCV003593921
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</span>
|
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members from 3 families with familial focal epilepsy with variable foci-1 (FFEVF1; 604364), Martin et al. (2014) identified a heterozygous c.2527C-T transition in exon 28 of the DEPDC5 gene, resulting in an arg843-to-ter (R843X) substitution. One large family contained 11 mutation carriers, including 5 affected, 1 with febrile seizures, and 5 asymptomatic, consistent with incomplete penetrance. All 3 families originated from the same region in Quebec, Canada, and haplotype analysis indicated a founder effect. </p>
|
|
</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>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0011 EPILEPSY, FAMILIAL FOCAL, WITH VARIABLE FOCI 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
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<span class="mim-text-font">
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DEPDC5, THR864MET
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<br />
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SNP: rs564667614,
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gnomAD: rs564667614,
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ClinVar: RCV000157607, RCV001034645, RCV001564151, RCV002313009, RCV003233475
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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 French Canadian patient with familial focal epilepsy with variable foci-1 (FFEVF1; 604364), Martin et al. (2014) identified a heterozygous c.2591C-T transition in exon 28 of the DEPDC5 gene, resulting in a thr864-to-met (T864M) substitution at a highly conserved residue. The variant was not found in the dbSNP (build 137), 1000 Genomes Project, or Exome Variant Server databases. The only family member available for study was the patient's father, who did not carry the variant. Functional studies were not performed. </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>.0012 EPILEPSY, FAMILIAL FOCAL, WITH VARIABLE FOCI 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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DEPDC5, GLN140TER
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<br />
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SNP: rs786205703,
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ClinVar: RCV000170597, RCV001201380
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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 6 affected members of an Australian family (family A) with familial focal epilepsy with variable foci-1 (FFEVF1; 604364), Scheffer et al. (2014) identified a heterozygous c.418C-T transition in the DEPDC5 gene, resulting in a gln140-to-ter (Q140X) substitution, predicted to result in a loss of function and thus haploinsufficiency. The mutation, which was found by whole-exome sequencing, was not present in the dbSNP or Exome Variant Server databases. There were 4 unaffected mutation carriers, consistent with incomplete penetrance. The patients had onset of frontal lobe epilepsy in the first 2 decades; brain imaging in 2 patients showed cortical thickening and loss of gray-white differentiation at the bottom of an abnormal sulcus, suggesting cortical dysplasia. </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>.0013 EPILEPSY, FAMILIAL FOCAL, WITH VARIABLE FOCI 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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DEPDC5, ARG286TER
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<br />
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SNP: rs886039255,
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ClinVar: RCV003329185, RCV003329484, RCV003329485, RCV005003057
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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 6-year-old child with familial focal epilepsy with variable foci-1 (FFEVF1; 604364) and focal cortical dysplasia type IIa, Ribierre et al. (2018) identified a heterozygous germline c.856C-T transition (c.856C-T, NM_001242896) in the DEPDC5 gene, resulting in an arg286-to-ter (R286X) substitution. The mutation, which was found sequencing of a gene panel and confirmed by Sanger sequencing, was inherited from the unaffected mother; it was not present in the gnomAD database. Analysis of resected brain tissue from the patient showed a somatic mosaic heterozygous c.865C-T transition in the DEPDC5 gene, resulting in a gln289-to-ter (Q289X) substitution that was in trans with the R286X mutation. The Q289X mutation was also absent from gnomAD. The somatic mosaic mutation was present in the cortical seizure-onset zone, but not in the surrounding cortical epileptic zone or in blood. These findings were consistent with biallelic inactivation of DEPDC5 in this patient. Neurons in the resected brain specimen showed increased phosphorylation of RPS6 (180460), consistent with increased mTOR (601231) activity. Ribierre et al. (2018) found that mouse embryos with focal mosaic knockdown of the Depdc5 gene in postmitotic neurons, generated by in utero electrocorporation and CRISPR/Cas9 gene editing, demonstrated impaired neuronal radial migration to the cortical plate. The mutant neurons were round and balloon-like, similar to dysmorphic neurons found in focal cortical dysplasia IIa. These abnormalities were associated with increased mTOR activity, and the neuronal migration defects could be prevented by treatment with the mTOR inhibitor rapamycin. Focal mosaic mutant mice showed increased susceptibility to focal seizures, and some showed seizure-related death, reminiscent of sudden expected death in epilepsy (SUDEP). Pyramidal cells from mutant mice showed increased complexity of dendritic branching, hypertrophy of dendritic spins, and enhanced excitatory synaptic activity compared to controls. These findings indicated that complete inactivation of Depdc5 during brain development causes epilepsy with focal cortical malformations, and that biallelic DEPDC5 mutations, germline and brain somatic mosaic (representing Knudson's 2-hit hypothesis of disease mechanism), underlie the focal cortical dysplasia that is sometimes observed in this disorder. </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>.0014 EPILEPSY, FAMILIAL FOCAL, WITH VARIABLE FOCI 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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DEPDC5, 1-BP DEL, 450G
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<br />
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ClinVar: RCV003329186
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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 24-year-old Han Chinese woman (family A) with familial focal epilepsy with variable foci-1 (FFEVF1; 604364), Liu et al. (2020) identified a heterozygous 1-bp deletion (c.450delG, NM_001242896.1) in the DEPDC5 gene, resulting in a frameshift and premature termination (Val151SerfsTer27). The mutation, which was found by targeted sequencing of a gene panel and confirmed by Sanger sequencing, was not present in the gnomAD database. The mutation was inherited from the unaffected father, indicating incomplete penetrance. Functional studies of the variant and studies of patient cells were not performed, but it was predicted to result in functional haploinsufficiency. The patient had onset of seizures at 4 years of age; she had both febrile generalized tonic-clonic seizures and simple partial seizures. EEG showed focal spikes and waves, and brain imaging was normal. She became seizure-free on medication. </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>.0015 EPILEPSY, FAMILIAL FOCAL, WITH VARIABLE FOCI 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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DEPDC5, GLN216TER
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<br />
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SNP: rs886039253,
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ClinVar: RCV000254600
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In 6 affected members of a French-Canadian family with familial focal epilepsy with variable foci-1 (FFEVF1; 604364), Nascimento et al. (2015) identified a heterozygous c.646C-T transition (c.646C-T, ENST00000536766) in the DEPDC5 gene, resulting in a gln216-to-ter (Q216X) substitution. The mutation segregated with the disorder in the family, although there was 1 asymptomatic carrier. Affected individuals had focal seizures, absence seizures, generalized tonic-clonic seizures, and febrile seizures. Of note, 2 family members who were not sequenced died of sudden unexpected death in epilepsy (SUDEP) at 58 and 50 years of age. Functional studies of the variant and studies of patient cells were not performed. </p>
|
|
</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>.0016 DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 111</strong>
|
|
</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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DEPDC5, THR337ARG
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<br />
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SNP: rs1037878155,
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gnomAD: rs1037878155,
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|
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ClinVar: RCV000811133, RCV003329169
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|
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</span>
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</div>
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<div>
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|
<span class="mim-text-font">
|
|
<p>In 6 patients from 3 unrelated families (families 1-3), all of Irish Traveller origin, with developmental and epileptic encephalopathy-111 (DEE111; 620504), Ververi et al. (2023) identified a homozygous c.1010C-G transversion (c.1010C-G, NM_001242896.3) in the DEPDC5 gene, resulting in a thr337-to-arg (T337R) substitution. The mutation, which was found by whole-exome sequencing, segregated with the disorder in the families and was not present in the gnomAD database. Molecular modeling predicted that the mutation would result in a loss of protein stability and adversely affect protein function. Functional studies of the variant were not performed, but immunohistochemical studies of a skin sample from 1 of the patients was consistent with an overall increase in mTOR (601231) activity. Since heterozygous carriers in the families were unaffected, Ververi et al. (2023) postulated that the T337R mutation results in a partial loss of function. </p>
|
|
</span>
|
|
</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>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0017 DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 111</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
DEPDC5, ARG806CYS
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|
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|
|
<br />
|
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|
|
SNP: rs953743301,
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|
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|
|
|
|
ClinVar: RCV000517054, RCV000997906, RCV002231197, RCV003329165
|
|
|
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|
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</span>
|
|
</div>
|
|
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|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 3 patients from 2 unrelated consanguineous families (family 4 of Tunisian descent and family 5 of Lebanese descent), with developmental and epileptic encephalopathy-111 (DEE111; 620504), Ververi et al. (2023) identified a homozygous c.2416C-T transition (c.2416C-T, NM_001242896.3) in the DEPDC5 gene, resulting in an arg806-to-cys (R806C) substitution. The mutation, which was found by whole-exome sequencing, segregated with the disorder in the families and was not present in the gnomAD database. Molecular modeling predicted that the mutation would result in a loss of protein stability and adversely affect protein function. Since heterozygous carriers in the families were unaffected, Ververi et al. (2023) postulated that the R806C mutation results in a partial loss of function. </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>
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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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<ol>
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<li>
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Bar-Peled, L., Chantranupong, L., Cherniack, A. D., Chen, W. W., Ottina, K. A., Grabiner, B. C., Spear, E. D., Carter, S. L., Meyerson, M., Sabatini, D. M.
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<strong>A tumor suppressor complex with GAP activity for the Rag GTPases that signal amino acid sufficiency to mTORC1.</strong>
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Science 340: 1100-1106, 2013.
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[Full Text: https://doi.org/10.1126/science.1232044]
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Baulac, S., Ishida, S., Marsan, E., Miquel, C., Biraben, A., Nguyen, D. K., Nordli, D., Cossette, P., Nguyen, S., Lambrecq, V., Vlaicu, M., Daniau, M., Bielle, F., Andermann, E., Andermann, F., Leguern, E., Chassoux, F., Picard, F.
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<strong>Familial focal epilepsy with focal cortical dysplasia due to DEPDC5 mutations.</strong>
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<p class="mim-text-font">
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Berkovic, S. F., Serratosa, J. M., Phillips, H. A., Xiong, L., Andermann, E., Diaz-Otero, F., Gomez-Garre, P., Martin, M., Fernandez-Bullido, Y., Andermann, F., Lopes-Cendes, I., Dubeau, F., Desbiens, R., Scheffer, I. E., Wallace, R. H., Mulley, J. C., Pandolfo, M.
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<strong>Familial partial epilepsy with variable foci: clinical features and linkage to chromosome 22q12.</strong>
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Epilepsia 45: 1054-1060, 2004.
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Callenbach, P. M. C., van den Maagdenberg, A. M. J. M., Hottenga, J. J., van den Boogerd, E. H., de Coo, R. F. M., Lindhout, D., Frants, R. R., Sandkuijl, L. A., Brouwer, O. F.
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<strong>Familial partial epilepsy with variable foci in a Dutch family: clinical characteristics and confirmation of linkage to chromosome 22q.</strong>
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Epilepsia 44: 1298-1305, 2003.
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[PubMed: 14510823]
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[Full Text: https://doi.org/10.1046/j.1528-1157.2003.62302.x]
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<p class="mim-text-font">
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Chen, J., Ou, Y., Yang, Y., Li, W., Xu, Y., Xie, Y., Liu, Y.
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<strong>KLHL22 activates amino-acid-dependent mTORC1 signalling to promote tumorigenesis and ageing.</strong>
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Nature 557: 585-589, 2018.
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[PubMed: 29769719]
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[Full Text: https://doi.org/10.1038/s41586-018-0128-9]
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<p class="mim-text-font">
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Dibbens, L. M., de Vries, B., Donatello, S., Heron, S. E., Hodgson, B. L., Chintawar, S., Crompton, D. E., Hughes, J. N., Bellows, S. T., Klein, K. M., Callenbach, P. M. C., Corbett, M. A., and 23 others.
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<strong>Mutations in DEPDC5 cause familial focal epilepsy with variable foci.</strong>
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Nature Genet. 45: 546-551, 2013.
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[PubMed: 23542697]
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[Full Text: https://doi.org/10.1038/ng.2599]
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</p>
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<p class="mim-text-font">
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Dickinson, M. E., Flenniken, A. M., Ji, X., Teboul, L., Wong, M. D., White, J. K., Meehan, T. F., Weninger, W. J., Westerberg, H., Adissu, H., Baker, C. N., Bower, L., and 73 others.
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<strong>High-throughput discovery of novel developmental phenotypes.</strong>
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Nature 537: 508-514, 2016. Note: Erratum: Nature 551: 398 only, 2017.
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[PubMed: 27626380]
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[Full Text: https://doi.org/10.1038/nature19356]
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<p class="mim-text-font">
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Gu, X., Orozco, J. M., Saxton, R. A., Condon, K. J., Liu, G. Y., Krawczyk, P. A., Scaria, S. M., Harper, J. W., Gygi, S. P., Sabatini, D. M.
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<strong>SAMTOR is an S-adenosylmethionine sensor for the mTORC1 pathway.</strong>
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Science 358: 813-818, 2017.
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[PubMed: 29123071]
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[Full Text: https://doi.org/10.1126/science.aao3265]
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<p class="mim-text-font">
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Hu, S., Knowlton, R. C., Watson, B. O., Glanowska, K. M., Murphy, G. G., Parent, J. M., Wang, Y.
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<strong>Somatic Depdc5 deletion recapitulates electroclinical features of human focal cortical dysplasia type IIA.</strong>
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Ann. Neurol. 84: 140-146, 2018.
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[PubMed: 30080265]
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[Full Text: https://doi.org/10.1002/ana.25272]
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<p class="mim-text-font">
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Ishida, S., Picard, F., Rudolf, G., Noe, E., Achaz, G., Thomas, P., Genton, P., Mundwiller, E., Wolff, M., Marescaux, C., Miles, R., Baulac, M., Hirsch, E., Leguern, E., Baulac, S.
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<strong>Mutations of DEPDC5 cause autosomal dominant focal epilepsies.</strong>
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Nature Genet. 45: 552-555, 2013.
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[PubMed: 23542701]
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[Full Text: https://doi.org/10.1038/ng.2601]
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<li>
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<p class="mim-text-font">
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Ishikawa, K., Nagase, T., Suyama, M., Miyajima, N., Tanaka, A., Kotani, H., Nomura, N., Ohara, O.
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<strong>Prediction of the coding sequences of unidentified human genes. X. The complete sequences of 100 new cDNA clones from brain which can code for large proteins in vitro.</strong>
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DNA Res. 5: 169-176, 1998.
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[PubMed: 9734811]
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[Full Text: https://doi.org/10.1093/dnares/5.3.169]
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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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