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Entry
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- *114204 - CALCIUM CHANNEL, VOLTAGE-DEPENDENT, ALPHA-2/DELTA SUBUNIT 1; CACNA2D1
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- OMIM
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<p>
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<span class="h4">*114204</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneStructure">Gene Structure</a>
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<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<a href="#cytogenetics">Cytogenetics</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#animalModel">Animal Model</a>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/114204">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 class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000153956;t=ENST00000356860" 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=781" 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=114204" 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="mimDna">
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<span class="panel-title">
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<span class="small">
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<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
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</a>
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</span>
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</span>
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</div>
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<div id="mimDnaLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Transcript/Sequence_cDNA?db=core;g=ENSG00000153956;t=ENST00000356860" 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_000722,NM_001302890,NM_001366867,XM_005250572,XM_005250573,XM_005250574,XM_006716118,XM_006716120,XM_006716121,XM_011516570,XM_011516571,XM_011516572,XM_047420819,XM_047420820,XM_047420821,XM_047420822,XR_001744873" 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_000722" 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=114204" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimProtein">
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<span class="panel-title">
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<span class="small">
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<a href="#mimProteinLinksFold" id="mimProteinLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimProteinLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Protein
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</a>
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</span>
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</span>
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</div>
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<div id="mimProteinLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://hprd.org/summary?hprd_id=00245&isoform_id=00245_1&isoform_name=Isoform_1" class="mim-tip-hint" title="The Human Protein Reference Database; manually extracted and visually depicted information on human proteins." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HPRD', 'domain': 'hprd.org'})">HPRD</a></div>
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<div><a href="https://www.proteinatlas.org/search/CACNA2D1" 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/179762,3900852,4454526,5788107,6090615,6624059,54112390,109658756,109659118,119597396,221042934,262527579,530386381,530386383,530386385,578814598,578814602,578814604,726965402,767948720,767948722,767948724,1495460181,2217368439,2217368443,2217368446,2217368449,2462616036,2462616038,2462616040,2462616042,2462616044,2462616046,2462616048,2462616050,2462616052,2462616054,2462616056,2462616058,2462616060,2462616063" 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/P54289" 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=781" 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=ENSG00000153956;t=ENST00000356860" 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=CACNA2D1" 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=CACNA2D1" 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+781" 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/CACNA2D1" 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:781" 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/781" 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=chr7&hgg_gene=ENST00000819119.1&hgg_start=81946444&hgg_end=82443956&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:1399" 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://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=114204[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=114204[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000153956" 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=CACNA2D1" 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=CACNA2D1" 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=CACNA2D1" 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=CACNA2D1&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/PA86" 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:1399" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
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<div><a href="https://www.mousephenotype.org/data/genes/MGI:88295" 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/CACNA2D1#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:88295" 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/781/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=781" 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="mim#WormbaseGeneFold" id="mimWormbaseGeneToggle" data-toggle="collapse" class="mim-tip-hint mimTriangleToggle" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes."><span id="mimWormbaseGeneToggleTriangle" class="small" style="margin-left: -0.8em;">►</span>Wormbase Gene</div>
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<div id="mimWormbaseGeneFold" class="collapse">
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<div style="margin-left: 0.5em;"><a href="https://wormbase.org/db/gene/gene?name=WBGene00006772;class=Gene" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">WBGene00006772 </a></div><div style="margin-left: 0.5em;"><a href="https://wormbase.org/db/gene/gene?name=WBGene00007041;class=Gene" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">WBGene00007041 </a></div>
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</div>
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<div><a href="https://zfin.org/ZDB-GENE-041210-215" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:781" 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=CACNA2D1&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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114204
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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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CALCIUM CHANNEL, VOLTAGE-DEPENDENT, ALPHA-2/DELTA SUBUNIT 1; CACNA2D1
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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CALCIUM CHANNEL, L TYPE, ALPHA-2 POLYPEPTIDE; CACNL2A<br />
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CALCIUM CHANNEL, ALPHA-2/DELTA SUBUNIT
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
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<p>
|
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=CACNA2D1" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">CACNA2D1</a></em></strong>
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</span>
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</p>
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</div>
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<div>
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<a id="cytogeneticLocation" class="mim-anchor"></a>
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<p>
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<span class="mim-text-font">
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<strong>
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<em>
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Cytogenetic location: <a href="/geneMap/7/377?start=-3&limit=10&highlight=377">7q21.11</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr7:81946444-82443956&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'})">7:81,946,444-82,443,956</a> </span>
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</em>
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</strong>
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<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
|
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<a id="geneMap" class="mim-anchor"></a>
|
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<div style="margin-bottom: 10px;">
|
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<span class="h4 mim-font">
|
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</div>
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<div>
|
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<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
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<thead>
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<tr class="active">
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<th>
|
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Location
|
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
|
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<td rowspan="1">
|
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<span class="mim-font">
|
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<a href="/geneMap/7/377?start=-3&limit=10&highlight=377">
|
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7q21.11
|
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</a>
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</span>
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</td>
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<td>
|
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<span class="mim-font">
|
|
Developmental and epileptic encephalopathy 110
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
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<a href="/entry/620149"> 620149 </a>
|
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</span>
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</td>
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<td>
|
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<span class="mim-font">
|
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<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
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</span>
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</td>
|
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<td>
|
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<span class="mim-font">
|
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<div class="btn-group">
|
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<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
|
PheneGene Graphics <span class="caret"></span>
|
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</button>
|
|
<ul class="dropdown-menu" style="width: 17em;">
|
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<li><a href="/graph/linear/114204" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
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<li><a href="/graph/radial/114204" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
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</ul>
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</div>
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<p>The CACNA2D1 gene encodes the alpha-2/delta subunit of skeletal muscle and brain voltage-dependent calcium channels, which are heteromultimer complexes comprising 4 subunits: alpha-1 (see, e.g., CACNA1A; <a href="/entry/601011">601011</a>), alpha-2/delta, beta-1 (CACNB1; <a href="/entry/114207">114207</a>), and gamma (CACNG1; <a href="/entry/114209">114209</a>) (<a href="#7" class="mim-tip-reference" title="Powers, P. A., Scherer, S. W., Tsui, L.-C., Gregg, R. G., Hogan, K. <strong>Localization of the gene encoding the alpha-2/delta subunit (CACNL2A) of the human skeletal muscle voltage-dependent Ca(2+) channel to chromosome 7q21-q22 by somatic cell hybrid analysis.</strong> Genomics 19: 192-193, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8188232/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8188232</a>] [<a href="https://doi.org/10.1006/geno.1994.1044" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8188232">Powers et al., 1994</a>). CACNA2D1 alters the properties of pore-forming alpha-1 subunits of voltage-gated calcium channels, and it is posttranslationally processed into 2 peptides, an alpha-2 subunit and a delta subunit, that are held together by a disulfide bond. The alpha-2/delta protein is encoded by at least 4 different genes: CACNA2D1, CACNA2D2 (<a href="/entry/607082">607082</a>), CACNA2D3 (<a href="/entry/606399">606399</a>), and CACNA2D4 (<a href="/entry/608171">608171</a>) (<a href="#8" class="mim-tip-reference" title="Schleithoff, L., Mehrke, G., Reutlinger, B., Lehmann-Horn, F. <strong>Genomic structure and functional expression of a human alpha-2/delta calcium channel subunit gene (CACNA2).</strong> Genomics 61: 201-209, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10534405/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10534405</a>] [<a href="https://doi.org/10.1006/geno.1999.5941" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10534405">Schleithoff et al., 1999</a>; <a href="#2" class="mim-tip-reference" title="Field, M. J., Cox, P. J., Stott, E., Melrose, H., Offord, J., Su, T.-Z., Bramwell, S., Corradini, L., England, S., Winks, J., Kinloch, R. A., Hendrich, J., Dolphin, A. C., Webb, T., Williams, D. <strong>Identification of the alpha-2-delta-1 subunit of voltage-dependent calcium channels as a molecular target for pain mediating the analgesic actions of pregabalin.</strong> Proc. Nat. Acad. Sci. 103: 17537-17542, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17088553/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17088553</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17088553[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0409066103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17088553">Field et al., 2006</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=17088553+8188232+10534405" 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="#12" class="mim-tip-reference" title="Williams, M. E., Feldman, D. H., McCue, A. F., Brenner, R., Velicelebi, G., Ellis, S. B., Harpold, M. M. <strong>Structure and functional expression of alpha-1, alpha-2, and beta subunits of a novel human neuronal calcium channel subtype.</strong> Neuron 8: 71-84, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1309651/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1309651</a>] [<a href="https://doi.org/10.1016/0896-6273(92)90109-q" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1309651">Williams et al. (1992)</a> isolated a clone corresponding to a human voltage-dependent calcium channel alpha-2 subunit from human basal ganglia and human brainstem cDNA libraries. The deduced 1,091-amino acid protein has a calculated molecular mass of 123 kD. Various transcripts were identified in the brain, skeletal muscle, and aortic tissue. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1309651" 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="Iles, D. E., Lehmann-Horn, F., Scherer, S. W., Tsui, L.-C., Olde Weghuis, D., Suijkerbuijk, R. F., Heytens, L., Mikala, G., Schwartz, A., Ellis, F. R., Stewart, A. D., Deufel, T., Wieringa, B. <strong>Localization of the gene encoding the alpha-2/delta-subunits of the L-type voltage-dependent calcium channel to chromosome 7q and analysis of the segregation of flanking markers in malignant hyperthermia susceptible families.</strong> Hum. Molec. Genet. 3: 969-975, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7951247/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7951247</a>] [<a href="https://doi.org/10.1093/hmg/3.6.969" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7951247">Iles et al. (1994)</a> cloned and partially sequenced the CACNL2A gene. The CACNL2A is expressed in many tissues, including skeletal muscle, brain, heart, and lung. A comparison of sequences of cDNAs representing the skeletal muscle and brain isoforms showed that they are encoded by a single gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7951247" 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="#8" class="mim-tip-reference" title="Schleithoff, L., Mehrke, G., Reutlinger, B., Lehmann-Horn, F. <strong>Genomic structure and functional expression of a human alpha-2/delta calcium channel subunit gene (CACNA2).</strong> Genomics 61: 201-209, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10534405/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10534405</a>] [<a href="https://doi.org/10.1006/geno.1999.5941" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10534405">Schleithoff et al. (1999)</a> isolated overlapping cDNAs corresponding to the CACNA2D1 gene from a human phage library. The 'delta' portion, encoded by exons 37 to 40, is posttranscriptionally cleaved from the C-terminal 'alpha' portion of the protein. The membrane-spanning region of the delta portion is encoded by exon 40. Cotransfection of the full cDNA clone with alpha-1a and beta-4 (<a href="/entry/601949">601949</a>) subunits enhanced Q-type calcium currents 18-fold. The CACNA2D1 gene undergoes alternative splicing at exons 19 and 24, corresponding to muscle and brain isoforms, respectively. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10534405" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#8" class="mim-tip-reference" title="Schleithoff, L., Mehrke, G., Reutlinger, B., Lehmann-Horn, F. <strong>Genomic structure and functional expression of a human alpha-2/delta calcium channel subunit gene (CACNA2).</strong> Genomics 61: 201-209, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10534405/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10534405</a>] [<a href="https://doi.org/10.1006/geno.1999.5941" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10534405">Schleithoff et al. (1999)</a> determined that the CACNA2D1 gene spans over 150 kb and contains 40 exons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10534405" 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 PCR assay of Chinese hamster/human somatic cell hybrid DNAs, <a href="#7" class="mim-tip-reference" title="Powers, P. A., Scherer, S. W., Tsui, L.-C., Gregg, R. G., Hogan, K. <strong>Localization of the gene encoding the alpha-2/delta subunit (CACNL2A) of the human skeletal muscle voltage-dependent Ca(2+) channel to chromosome 7q21-q22 by somatic cell hybrid analysis.</strong> Genomics 19: 192-193, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8188232/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8188232</a>] [<a href="https://doi.org/10.1006/geno.1994.1044" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8188232">Powers et al. (1994)</a> assigned the CACNL2A gene to chromosome 7. They refined the localization to 7q21-q22 by analysis of a panel of human/rodent somatic cell hybrids containing defined regions of human chromosome 7. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8188232" 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="Iles, D. E., Lehmann-Horn, F., Scherer, S. W., Tsui, L.-C., Olde Weghuis, D., Suijkerbuijk, R. F., Heytens, L., Mikala, G., Schwartz, A., Ellis, F. R., Stewart, A. D., Deufel, T., Wieringa, B. <strong>Localization of the gene encoding the alpha-2/delta-subunits of the L-type voltage-dependent calcium channel to chromosome 7q and analysis of the segregation of flanking markers in malignant hyperthermia susceptible families.</strong> Hum. Molec. Genet. 3: 969-975, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7951247/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7951247</a>] [<a href="https://doi.org/10.1093/hmg/3.6.969" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7951247">Iles et al. (1994)</a> found that the CACNL2A gene and a neighboring polymorphic dinucleotide repeat marker, D7S849, were linked to the hepatocyte growth factor gene (HGF; <a href="/entry/142409">142409</a>). Using a human chromosome 7-specific YAC library, they found that HGF was within approximately 110 to 380 kb of CACNL2A. They also mapped CACNL2A to 7q11.23-q21.1 by fluorescence in situ hybridization, the same location where D7S849 had been placed by analysis of human/hamster somatic cell hybrids. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7951247" 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 studies in Xenopus oocytes, <a href="#12" class="mim-tip-reference" title="Williams, M. E., Feldman, D. H., McCue, A. F., Brenner, R., Velicelebi, G., Ellis, S. B., Harpold, M. M. <strong>Structure and functional expression of alpha-1, alpha-2, and beta subunits of a novel human neuronal calcium channel subtype.</strong> Neuron 8: 71-84, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1309651/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1309651</a>] [<a href="https://doi.org/10.1016/0896-6273(92)90109-q" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1309651">Williams et al. (1992)</a> found that the alpha-2 subunit enhanced activity of a dihydropyrimidine (DHP)-sensitive, high voltage-activated, long-lasting calcium channel when coexpressed with an alpha-1D (CACNA1D; <a href="/entry/114206">114206</a>) and beta-2 (CACNB2; <a href="/entry/600003">600003</a>) subunits. The results suggested that the alpha-2 subunit plays an accessory role. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1309651" 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>Self-biting and other self-injurious behaviors occur in a number of By expression studies in Xenopus oocytes, <a href="#13" class="mim-tip-reference" title="Yamaguchi, H., Okuda, M., Mikala, G., Fukasawa, K., Varadi, G. <strong>Cloning of the beta-2a subunit of the voltage-dependent calcium channel from human heart: cooperative effect of alpha-2/delta and beta-2a on the membrane expression of the alpha-1c subunit.</strong> Biochem. Biophys. Res. Commun. 267: 156-163, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10623591/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10623591</a>] [<a href="https://doi.org/10.1006/bbrc.1999.1926" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10623591">Yamaguchi et al. (2000)</a> showed that the beta-2a (CACNB2) and alpha-2/delta subunits cooperatively increased membrane expression of the alpha-1c subunit, whereas their effects on voltage-dependence of the channel complex were additive. Furthermore, the beta-2a subunit, but not the alpha-2/delta subunit, enhanced channel opening. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10623591" 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="#6" class="mim-tip-reference" title="Marais, E., Klugbauer, N., Hofmann, F. <strong>Calcium channel alpha(2)delta subunits: structure and gabapentin binding.</strong> Molec. Pharm. 59: 1243-1248, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11306709/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11306709</a>] [<a href="https://doi.org/10.1124/mol.59.5.1243" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11306709">Marais et al. (2001)</a> found that the alpha-2/delta subunit binds the antiepileptic drug gabapentin. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11306709" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#4" class="mim-tip-reference" title="Hoppa, M. B., Lana, B., Margas, W., Dolphin, A. C., Ryan, T. A. <strong>Alpha-2-delta expression sets presynaptic calcium channel abundance and release probability.</strong> Nature 486: 122-125, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22678293/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22678293</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22678293[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/nature11033" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22678293">Hoppa et al. (2012)</a> showed that a trafficking step probably sets synaptic voltage-gated calcium channel (VGCC) levels in rats, because overexpression of the pore-forming alpha-1A VGCC subunit (CACNA1A; <a href="/entry/601011">601011</a>) fails to change synaptic VGCC abundance or function. Alpha-2-deltas are a family of glycosylphosphatidylinositol (GPI)-anchored VGCC-associated subunits that, in addition to being the target of the potent neuropathic analgesics gabapentin and pregabalin (alpha-2-delta-1 (CACNA2D1) and alpha-2-delta-2 (CACNA2D2)), were also identified in a forward genetic screen for pain genes (alpha-2-delta-3 (CACNA2D3)). <a href="#4" class="mim-tip-reference" title="Hoppa, M. B., Lana, B., Margas, W., Dolphin, A. C., Ryan, T. A. <strong>Alpha-2-delta expression sets presynaptic calcium channel abundance and release probability.</strong> Nature 486: 122-125, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22678293/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22678293</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22678293[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/nature11033" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22678293">Hoppa et al. (2012)</a> showed that these proteins confer powerful modulation of presynaptic function through 2 distinct molecular mechanisms. First, alpha-2-delta subunits set synaptic VGCC abundance, as predicted from their chaperone-like function when expressed in nonneuronal cells. Second, alpha-2-deltas configure synaptic VGCCs to drive exocytosis through an extracellular metal ion-dependent adhesion site (MIDAS), a conserved set of amino acids within the predicted von Willebrand A domain of alpha-2-delta. Expression of alpha-2-delta with an intact MIDAS motif leads to an 80% increase in release probability, while simultaneously protecting exocytosis from blockade by an intracellular calcium chelator. Alpha-2-deltas harboring MIDAS site mutations still drive synaptic accumulation of VGCCs; however, they no longer change release probability or sensitivity to intracellular calcium chelators. <a href="#4" class="mim-tip-reference" title="Hoppa, M. B., Lana, B., Margas, W., Dolphin, A. C., Ryan, T. A. <strong>Alpha-2-delta expression sets presynaptic calcium channel abundance and release probability.</strong> Nature 486: 122-125, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22678293/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22678293</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22678293[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/nature11033" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22678293">Hoppa et al. (2012)</a> concluded that their data revealed dual functionality of these clinically important VGCC subunits, allowing synapses to make more efficient use of calcium entry to drive neurotransmitter release. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22678293" 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="#10" class="mim-tip-reference" title="Vergult, S., Dheedene, A., Meurs, A., Faes, F., Isidor, B., Janssens, S., Gautier, A., Le Caignec, C., Menten, B. <strong>Genomic aberrations of the CACNA2D1 gene in three patients with epilepsy and intellectual disability.</strong> Europ. J. Hum. Genet. 23: 628-632, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25074461/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25074461</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25074461[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/ejhg.2014.141" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25074461">Vergult et al. (2015)</a> reported 3 unrelated girls with intellectual disability and epilepsy associated with a heterozygous genomic alteration that disrupted the CACNA2D1 gene. One female patient had a de novo apparently balanced reciprocal translocation 46,X,t(X;7)(p10;q21.2). There was 100% skewing of X-chromosome inactivation in favor of the abnormal chromosome. The second patient had a de novo 7.5-Mb deletion on 7q21.11-q21.12 including 14 genes, as well as a maternally inherited 150-kb deletion on chromosome 16q24.1. This patient also had obesity with hyperinsulinism, which may have been caused by deletion of the CD36 gene (<a href="/entry/173510">173510</a>). The third patient had a 2.72-Mb deletion on 7q21.11 containing 5 genes; the deletion was inherited from her mother who had mild intellectual disability and was illiterate. The smallest region of overlap in the 2 patients with deletions encompassed 5 genes, including CACNA2D1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25074461" 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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In 2 unrelated boys with developmental and epileptic encephalopathy-110 (DEE110; <a href="/entry/620149">620149</a>), <a href="#1" class="mim-tip-reference" title="Dahimene, S., von Elsner, L., Holling, T., Mattas, L. S., Pickard, J., Lessel, D., Pilch, K. S., Kadurin, I., Pratt, W. S., Zhulin, I. B., Dai, H., Hempel, M., Ruzhnikov, M. R. Z., Kutsche, K., Dolphin, A. C. <strong>Biallelic CACNA2D1 loss-of-function variants cause early-onset developmental epileptic encephalopathy.</strong> Brain 145: 2721-2729, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35293990/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35293990</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=35293990[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/brain/awac081" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="35293990">Dahimene et al. (2022)</a> identified homozygous or compound heterozygous mutations in the CACNA2D1 gene (<a href="#0001">114204.0001</a>-<a href="#0003">114204.0003</a>). The mutations, which were found by trio-based exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in both families. Patient 1 was homozygous for a frameshift allele, and patient 2 was compound heterozygous for a frameshift and a missense allele. Studies of patient fibroblasts and in vitro functional studies of cells transfected with the missense variant (G209D; <a href="#0003">114204.0003</a>) indicated that the variants resulted in a loss-of-function effect on calcium channel function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=35293990" 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>Associations Pending Confirmation</em></strong></p><p>
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A close association is formed at the skeletal muscle triadic junctions between the ryanodine receptor (RYR1; <a href="/entry/180901">180901</a>) and the L-type voltage-dependent calcium channel, also referred to as the dihydropyridine receptor (DHPR), and the 2 channel complexes appear to function together in excitation-contraction coupling (<a href="#5" class="mim-tip-reference" title="Iles, D. E., Lehmann-Horn, F., Scherer, S. W., Tsui, L.-C., Olde Weghuis, D., Suijkerbuijk, R. F., Heytens, L., Mikala, G., Schwartz, A., Ellis, F. R., Stewart, A. D., Deufel, T., Wieringa, B. <strong>Localization of the gene encoding the alpha-2/delta-subunits of the L-type voltage-dependent calcium channel to chromosome 7q and analysis of the segregation of flanking markers in malignant hyperthermia susceptible families.</strong> Hum. Molec. Genet. 3: 969-975, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7951247/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7951247</a>] [<a href="https://doi.org/10.1093/hmg/3.6.969" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7951247">Iles et al., 1994</a>). Because of the association with the ryanodine receptor, other subunits of the L-type voltage-dependent calcium channel have been considered as possible sites of a mutation causing malignant hyperthermia susceptibility (MHS). In 6 families with susceptibility to malignant hyperthermia (MHS3; <a href="/entry/154276">154276</a>) that were not linked to the RYR1 locus on chromosome 19, <a href="#5" class="mim-tip-reference" title="Iles, D. E., Lehmann-Horn, F., Scherer, S. W., Tsui, L.-C., Olde Weghuis, D., Suijkerbuijk, R. F., Heytens, L., Mikala, G., Schwartz, A., Ellis, F. R., Stewart, A. D., Deufel, T., Wieringa, B. <strong>Localization of the gene encoding the alpha-2/delta-subunits of the L-type voltage-dependent calcium channel to chromosome 7q and analysis of the segregation of flanking markers in malignant hyperthermia susceptible families.</strong> Hum. Molec. Genet. 3: 969-975, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7951247/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7951247</a>] [<a href="https://doi.org/10.1093/hmg/3.6.969" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7951247">Iles et al. (1994)</a> found linkage to D7S849. No recombination was observed between MHS and D7S849 and 2 other markers through 11 meioses in 1 well-characterized 3-generation pedigree. In affected members of a family linked to the MHS3 locus by <a href="#5" class="mim-tip-reference" title="Iles, D. E., Lehmann-Horn, F., Scherer, S. W., Tsui, L.-C., Olde Weghuis, D., Suijkerbuijk, R. F., Heytens, L., Mikala, G., Schwartz, A., Ellis, F. R., Stewart, A. D., Deufel, T., Wieringa, B. <strong>Localization of the gene encoding the alpha-2/delta-subunits of the L-type voltage-dependent calcium channel to chromosome 7q and analysis of the segregation of flanking markers in malignant hyperthermia susceptible families.</strong> Hum. Molec. Genet. 3: 969-975, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7951247/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7951247</a>] [<a href="https://doi.org/10.1093/hmg/3.6.969" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7951247">Iles et al. (1994)</a>, <a href="#8" class="mim-tip-reference" title="Schleithoff, L., Mehrke, G., Reutlinger, B., Lehmann-Horn, F. <strong>Genomic structure and functional expression of a human alpha-2/delta calcium channel subunit gene (CACNA2).</strong> Genomics 61: 201-209, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10534405/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10534405</a>] [<a href="https://doi.org/10.1006/geno.1999.5941" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10534405">Schleithoff et al. (1999)</a> did not identify any pathogenic mutations in the coding region of the CACNA2D1 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7951247+10534405" 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="Templin, C., Ghadri, J. R., Rougier, J. S., Baumer, A., Kaplan, V., Albesa, M., Sticht, H., Rauch, A., Puleo, C., Hu, D., Barajas-Martinez, H., Antzelevitch, C., Luscher, T. F., Abriel, H., Duru, F. <strong>Identification of a novel loss-of-function calcium channel gene mutation in short QT syndrome (SQTS6).</strong> Europ. Heart J. 32: 1077-1088, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21383000/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21383000</a>] [<a href="https://doi.org/10.1093/eurheartj/ehr076" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21383000">Templin et al. (2011)</a> reported a single patient, a 17-year-old Caucasian girl, with short QT syndrome, which they designated SQTS6, manifesting as ventricular fibrillation and QTc of 329 ms, with a missense variant (c.2264G-C, ser755 to thr, S755T) in CACNA2D1. Her father and paternal grandmother also carried the variant, but her father had borderline short QTc interval (362 ms) and the grandmother's QTc interval was normal. Neither had any symptoms. Expression studies comparing wildtype and variant CACNA2D1 with other L-type calcium channel subunits in HEK293 cells showed that the mutant protein was expressed at levels comparable to wildtype protein, but that barium ion currents were reduced by 70% when the mutant channel was introduced, compared with wildtype CACNA2D1. <a href="#3" class="mim-tip-reference" title="Hamosh, A. <strong>Personal Communication.</strong> Baltimore, Md. 02/08/2023."None>Hamosh (2023)</a> reported that the S755T variant was present in 1% of Ashkenazi Jews in gnomad (109/10,324, MAF of 0.01056), present in homozygosity in 2 individuals, and reported as benign by 4 independent clinical laboratories in ClinVar; it was present in a total of 241 of 281,304 individuals in gnomAD for an overall MAF of 8.57 x 10(-4) (February 8, 2023). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21383000" 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 porcine brain, <a href="#11" class="mim-tip-reference" title="Wang, M., Offord, J., Oxender, D. L., Su, T.-Z. <strong>Structural requirement of the calcium-channel subunit alpha-2-delta for gabapentin binding.</strong> Biochem. J. 342: 313-320, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10455017/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10455017</a>]" pmid="10455017">Wang et al. (1999)</a> identified putative gabapentin-bindings sites within the alpha-2/delta subunit and showed that an arg217-to-ala (R217A) substitution within the Cacna2d1 gene disrupted gabapentin binding. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10455017" 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 mutant mouse line with the Cacna2d1 R217A substitution, <a href="#2" class="mim-tip-reference" title="Field, M. J., Cox, P. J., Stott, E., Melrose, H., Offord, J., Su, T.-Z., Bramwell, S., Corradini, L., England, S., Winks, J., Kinloch, R. A., Hendrich, J., Dolphin, A. C., Webb, T., Williams, D. <strong>Identification of the alpha-2-delta-1 subunit of voltage-dependent calcium channels as a molecular target for pain mediating the analgesic actions of pregabalin.</strong> Proc. Nat. Acad. Sci. 103: 17537-17542, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17088553/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17088553</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17088553[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0409066103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17088553">Field et al. (2006)</a> found significantly decreased binding of the analgesic pregabalin in multiple brain areas, including cortex, hippocampus, caudate putamen, lumbar dorsal horn, and cerebellum compared to wildtype controls. Pregabalin had no effect against chemically induced tonic pain or nerve injury-induced chronic pain in the mutant mice, whereas wildtype mice showed dose-dependent analgesia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17088553" 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 4-year-old boy (patient 1), born of consanguineous Afghan parents, with developmental and epileptic encephalopathy-110 (DEE110; <a href="/entry/620149">620149</a>), <a href="#1" class="mim-tip-reference" title="Dahimene, S., von Elsner, L., Holling, T., Mattas, L. S., Pickard, J., Lessel, D., Pilch, K. S., Kadurin, I., Pratt, W. S., Zhulin, I. B., Dai, H., Hempel, M., Ruzhnikov, M. R. Z., Kutsche, K., Dolphin, A. C. <strong>Biallelic CACNA2D1 loss-of-function variants cause early-onset developmental epileptic encephalopathy.</strong> Brain 145: 2721-2729, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35293990/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35293990</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=35293990[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/brain/awac081" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="35293990">Dahimene et al. (2022)</a> identified a homozygous 4-bp duplication (c.818_821dupGAAC, NM_000722.3) in the CACNA2D1 gene, resulting in a frameshift and premature termination (Ser275AsnfsTer13). The mutation, which was found by trio-based exome sequencing and confirmed by Sanger sequencing, was present in each unaffected parent in the heterozygous state. It was not present in the gnomAD database. Patient fibroblasts showed reduced levels of CACNA2D1 mRNA (6 to 9% compared to controls) and decreased levels of the full-length protein (10 to 12% compared to controls). These findings were consistent with nonsense-mediated mRNA decay and a loss-of-function effect of the mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=35293990" 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>.0002 DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 110</strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV002464993" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV002464993" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV002464993</a>
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<p>In a 4-year-old boy (patient 2), born of unrelated parents, with developmental and epileptic encephalopathy-110 (DEE110; <a href="/entry/620149">620149</a>), <a href="#1" class="mim-tip-reference" title="Dahimene, S., von Elsner, L., Holling, T., Mattas, L. S., Pickard, J., Lessel, D., Pilch, K. S., Kadurin, I., Pratt, W. S., Zhulin, I. B., Dai, H., Hempel, M., Ruzhnikov, M. R. Z., Kutsche, K., Dolphin, A. C. <strong>Biallelic CACNA2D1 loss-of-function variants cause early-onset developmental epileptic encephalopathy.</strong> Brain 145: 2721-2729, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35293990/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35293990</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=35293990[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/brain/awac081" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="35293990">Dahimene et al. (2022)</a> identified compound heterozygous mutations in the CACNA2D1 gene: an 11-bp duplication (c.13_23dupTGCCTGCTGGC, NM_000722.3), predicted to result in a frameshift and premature termination (Leu9AlafsTer5), and a c.626G-A transition in exon 7, resulting in a gly209-to-asp (G209D; <a href="#0003">114204.0003</a>) substitution at a highly conserved residue that is important for protein structure. The mutations, which were found by trio-based exome sequencing and confirmed by Sanger sequencing, showed parental segregation. The 11-bp duplication was present at a low frequency in the gnomAD database (0.003%), whereas G209D was absent from gnomAD. Patient fibroblasts showed normal levels of CACNA2D1 mRNA, but mildly decreased amounts of the full-length protein (31 to 38% compared to controls), suggesting that the frameshift allele resulted in a loss of function. In vitro cellular studies showed that the G209D mutation disrupted plasma expression of the protein, as it was reduced by about 80% at the cell membrane compared to controls. The G209D variant abolished the ability of CACNA2D1 to promote calcium currents in cells transfected with the mutation. The mutation also disrupted trafficking of calcium channels into hippocampal neurites and reduced complex formation with Ca(V)2.2 (see CACNA1B, <a href="/entry/601012">601012</a>). The G209D mutant protein remained largely in the uncleaved immature form, suggesting it is likely retained in the endoplasmic reticulum. These data indicated that G209D is a loss-of-function allele. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=35293990" 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>For discussion of the c.626G-A transition (c.626G-A, NM_000722.3) in exon 7 in the CACNA2D1 gene, resulting in gly209-to-asp (G209D) substitution, that was found in compound heterozygous state in a patient with developmental and epileptic encephalopathy-110 (DEE110; <a href="/entry/620149">620149</a>) by <a href="#1" class="mim-tip-reference" title="Dahimene, S., von Elsner, L., Holling, T., Mattas, L. S., Pickard, J., Lessel, D., Pilch, K. S., Kadurin, I., Pratt, W. S., Zhulin, I. B., Dai, H., Hempel, M., Ruzhnikov, M. R. Z., Kutsche, K., Dolphin, A. C. <strong>Biallelic CACNA2D1 loss-of-function variants cause early-onset developmental epileptic encephalopathy.</strong> Brain 145: 2721-2729, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35293990/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35293990</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=35293990[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/brain/awac081" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="35293990">Dahimene et al. (2022)</a>, see <a href="#0002">114204.0002</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=35293990" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>REFERENCES</strong>
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<a id="Dahimene2022" class="mim-anchor"></a>
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Dahimene, S., von Elsner, L., Holling, T., Mattas, L. S., Pickard, J., Lessel, D., Pilch, K. S., Kadurin, I., Pratt, W. S., Zhulin, I. B., Dai, H., Hempel, M., Ruzhnikov, M. R. Z., Kutsche, K., Dolphin, A. C.
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<strong>Biallelic CACNA2D1 loss-of-function variants cause early-onset developmental epileptic encephalopathy.</strong>
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Brain 145: 2721-2729, 2022.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35293990/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35293990</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=35293990[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=35293990" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/brain/awac081" target="_blank">Full Text</a>]
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Field, M. J., Cox, P. J., Stott, E., Melrose, H., Offord, J., Su, T.-Z., Bramwell, S., Corradini, L., England, S., Winks, J., Kinloch, R. A., Hendrich, J., Dolphin, A. C., Webb, T., Williams, D.
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<strong>Identification of the alpha-2-delta-1 subunit of voltage-dependent calcium channels as a molecular target for pain mediating the analgesic actions of pregabalin.</strong>
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[<a href="https://doi.org/10.1073/pnas.0409066103" target="_blank">Full Text</a>]
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Hamosh, A.
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<strong>Personal Communication.</strong>
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Baltimore, Md. 02/08/2023.
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Hoppa, M. B., Lana, B., Margas, W., Dolphin, A. C., Ryan, T. A.
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<strong>Alpha-2-delta expression sets presynaptic calcium channel abundance and release probability.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22678293/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22678293</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22678293[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22678293" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/nature11033" target="_blank">Full Text</a>]
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Iles, D. E., Lehmann-Horn, F., Scherer, S. W., Tsui, L.-C., Olde Weghuis, D., Suijkerbuijk, R. F., Heytens, L., Mikala, G., Schwartz, A., Ellis, F. R., Stewart, A. D., Deufel, T., Wieringa, B.
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<strong>Localization of the gene encoding the alpha-2/delta-subunits of the L-type voltage-dependent calcium channel to chromosome 7q and analysis of the segregation of flanking markers in malignant hyperthermia susceptible families.</strong>
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Hum. Molec. Genet. 3: 969-975, 1994.
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[<a href="https://doi.org/10.1093/hmg/3.6.969" target="_blank">Full Text</a>]
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Marais, E., Klugbauer, N., Hofmann, F.
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<strong>Calcium channel alpha(2)delta subunits: structure and gabapentin binding.</strong>
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Powers, P. A., Scherer, S. W., Tsui, L.-C., Gregg, R. G., Hogan, K.
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<strong>Localization of the gene encoding the alpha-2/delta subunit (CACNL2A) of the human skeletal muscle voltage-dependent Ca(2+) channel to chromosome 7q21-q22 by somatic cell hybrid analysis.</strong>
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Genomics 19: 192-193, 1994.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8188232/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8188232</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8188232" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1006/geno.1994.1044" target="_blank">Full Text</a>]
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Schleithoff, L., Mehrke, G., Reutlinger, B., Lehmann-Horn, F.
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<strong>Genomic structure and functional expression of a human alpha-2/delta calcium channel subunit gene (CACNA2).</strong>
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Genomics 61: 201-209, 1999.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10534405/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10534405</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10534405" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1006/geno.1999.5941" target="_blank">Full Text</a>]
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Templin, C., Ghadri, J. R., Rougier, J. S., Baumer, A., Kaplan, V., Albesa, M., Sticht, H., Rauch, A., Puleo, C., Hu, D., Barajas-Martinez, H., Antzelevitch, C., Luscher, T. F., Abriel, H., Duru, F.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21383000/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21383000</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21383000" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/eurheartj/ehr076" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="10" class="mim-anchor"></a>
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<a id="Vergult2015" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Vergult, S., Dheedene, A., Meurs, A., Faes, F., Isidor, B., Janssens, S., Gautier, A., Le Caignec, C., Menten, B.
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<strong>Genomic aberrations of the CACNA2D1 gene in three patients with epilepsy and intellectual disability.</strong>
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Europ. J. Hum. Genet. 23: 628-632, 2015.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25074461/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25074461</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25074461[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25074461" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/ejhg.2014.141" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="11" class="mim-anchor"></a>
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<a id="Wang1999" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Wang, M., Offord, J., Oxender, D. L., Su, T.-Z.
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<strong>Structural requirement of the calcium-channel subunit alpha-2-delta for gabapentin binding.</strong>
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Biochem. J. 342: 313-320, 1999.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10455017/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10455017</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10455017" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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</p>
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<li>
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<a id="12" class="mim-anchor"></a>
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<a id="Williams1992" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Williams, M. E., Feldman, D. H., McCue, A. F., Brenner, R., Velicelebi, G., Ellis, S. B., Harpold, M. M.
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<strong>Structure and functional expression of alpha-1, alpha-2, and beta subunits of a novel human neuronal calcium channel subtype.</strong>
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Neuron 8: 71-84, 1992.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1309651/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1309651</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1309651" 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/10.1016/0896-6273(92)90109-q" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="13" class="mim-anchor"></a>
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<a id="Yamaguchi2000" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Yamaguchi, H., Okuda, M., Mikala, G., Fukasawa, K., Varadi, G.
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<strong>Cloning of the beta-2a subunit of the voltage-dependent calcium channel from human heart: cooperative effect of alpha-2/delta and beta-2a on the membrane expression of the alpha-1c subunit.</strong>
|
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Biochem. Biophys. Res. Commun. 267: 156-163, 2000.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10623591/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10623591</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10623591" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1006/bbrc.1999.1926" target="_blank">Full Text</a>]
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</p>
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</ol>
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<br />
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</div>
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<div>
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<a id="contributors" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="mim-text-font">
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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<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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Ada Hamosh - updated : 02/08/2023
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseContributors">
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<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Cassandra L. Kniffin - updated : 12/3/2015<br>Ada Hamosh - updated : 7/17/2012<br>Cassandra L. Kniffin - updated : 2/7/2008<br>Cassandra L. Kniffin - updated : 12/12/2006<br>Patricia A. Hartz - updated : 11/11/2004<br>Victor A. McKusick - edited : 6/23/1997<br>Victor A. McKusick - updated : 6/17/1997
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</span>
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</div>
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<div>
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<a id="creationDate" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Victor A. McKusick : 2/9/1994
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="editHistory" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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alopez : 02/08/2023
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</span>
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</div>
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<div class="row collapse" id="mimCollapseEditHistory">
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 12/08/2022<br>alopez : 12/07/2022<br>ckniffin : 12/06/2022<br>carol : 06/22/2017<br>carol : 12/08/2015<br>ckniffin : 12/3/2015<br>alopez : 7/17/2012<br>terry : 7/17/2012<br>wwang : 2/21/2008<br>ckniffin : 2/7/2008<br>terry : 9/19/2007<br>terry : 9/18/2007<br>wwang : 12/21/2006<br>ckniffin : 12/12/2006<br>mgross : 11/11/2004<br>mgross : 10/18/2001<br>alopez : 6/18/1999<br>terry : 6/23/1997<br>terry : 6/17/1997<br>jason : 7/27/1994<br>mimadm : 5/18/1994<br>carol : 2/9/1994
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</span>
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</div>
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<div class="container visible-print-block">
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<h3>
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<span class="mim-font">
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<strong>*</strong> 114204
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</h3>
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</div>
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<div>
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<h3>
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<span class="mim-font">
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CALCIUM CHANNEL, VOLTAGE-DEPENDENT, ALPHA-2/DELTA SUBUNIT 1; CACNA2D1
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</span>
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</h3>
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</div>
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<div>
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<br />
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<div>
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<div >
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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CALCIUM CHANNEL, L TYPE, ALPHA-2 POLYPEPTIDE; CACNL2A<br />
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CALCIUM CHANNEL, ALPHA-2/DELTA SUBUNIT
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: CACNA2D1</em></strong>
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</span>
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</p>
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong>
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<em>
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Cytogenetic location: 7q21.11
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Genomic coordinates <span class="small">(GRCh38)</span> : 7:81,946,444-82,443,956 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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</span>
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</p>
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</div>
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<div>
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<br />
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</h4>
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<div>
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
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<td rowspan="1">
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<span class="mim-font">
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7q21.11
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</span>
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</td>
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<td>
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<span class="mim-font">
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Developmental and epileptic encephalopathy 110
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</span>
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</td>
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<td>
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<span class="mim-font">
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620149
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal recessive
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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<div>
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<br />
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<div>
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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
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</span>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Description</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>The CACNA2D1 gene encodes the alpha-2/delta subunit of skeletal muscle and brain voltage-dependent calcium channels, which are heteromultimer complexes comprising 4 subunits: alpha-1 (see, e.g., CACNA1A; 601011), alpha-2/delta, beta-1 (CACNB1; 114207), and gamma (CACNG1; 114209) (Powers et al., 1994). CACNA2D1 alters the properties of pore-forming alpha-1 subunits of voltage-gated calcium channels, and it is posttranslationally processed into 2 peptides, an alpha-2 subunit and a delta subunit, that are held together by a disulfide bond. The alpha-2/delta protein is encoded by at least 4 different genes: CACNA2D1, CACNA2D2 (607082), CACNA2D3 (606399), and CACNA2D4 (608171) (Schleithoff et al., 1999; Field et al., 2006). </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Williams et al. (1992) isolated a clone corresponding to a human voltage-dependent calcium channel alpha-2 subunit from human basal ganglia and human brainstem cDNA libraries. The deduced 1,091-amino acid protein has a calculated molecular mass of 123 kD. Various transcripts were identified in the brain, skeletal muscle, and aortic tissue. </p><p>Iles et al. (1994) cloned and partially sequenced the CACNL2A gene. The CACNL2A is expressed in many tissues, including skeletal muscle, brain, heart, and lung. A comparison of sequences of cDNAs representing the skeletal muscle and brain isoforms showed that they are encoded by a single gene. </p><p>Schleithoff et al. (1999) isolated overlapping cDNAs corresponding to the CACNA2D1 gene from a human phage library. The 'delta' portion, encoded by exons 37 to 40, is posttranscriptionally cleaved from the C-terminal 'alpha' portion of the protein. The membrane-spanning region of the delta portion is encoded by exon 40. Cotransfection of the full cDNA clone with alpha-1a and beta-4 (601949) subunits enhanced Q-type calcium currents 18-fold. The CACNA2D1 gene undergoes alternative splicing at exons 19 and 24, corresponding to muscle and brain isoforms, respectively. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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<strong>Gene Structure</strong>
|
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</span>
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</h4>
|
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</div>
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<span class="mim-text-font">
|
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<p>Schleithoff et al. (1999) determined that the CACNA2D1 gene spans over 150 kb and contains 40 exons. </p>
|
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</span>
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<div>
|
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<br />
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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<strong>Mapping</strong>
|
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
|
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<p>By PCR assay of Chinese hamster/human somatic cell hybrid DNAs, Powers et al. (1994) assigned the CACNL2A gene to chromosome 7. They refined the localization to 7q21-q22 by analysis of a panel of human/rodent somatic cell hybrids containing defined regions of human chromosome 7. </p><p>Iles et al. (1994) found that the CACNL2A gene and a neighboring polymorphic dinucleotide repeat marker, D7S849, were linked to the hepatocyte growth factor gene (HGF; 142409). Using a human chromosome 7-specific YAC library, they found that HGF was within approximately 110 to 380 kb of CACNL2A. They also mapped CACNL2A to 7q11.23-q21.1 by fluorescence in situ hybridization, the same location where D7S849 had been placed by analysis of human/hamster somatic cell hybrids. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Function</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>By studies in Xenopus oocytes, Williams et al. (1992) found that the alpha-2 subunit enhanced activity of a dihydropyrimidine (DHP)-sensitive, high voltage-activated, long-lasting calcium channel when coexpressed with an alpha-1D (CACNA1D; 114206) and beta-2 (CACNB2; 600003) subunits. The results suggested that the alpha-2 subunit plays an accessory role. </p><p>Self-biting and other self-injurious behaviors occur in a number of By expression studies in Xenopus oocytes, Yamaguchi et al. (2000) showed that the beta-2a (CACNB2) and alpha-2/delta subunits cooperatively increased membrane expression of the alpha-1c subunit, whereas their effects on voltage-dependence of the channel complex were additive. Furthermore, the beta-2a subunit, but not the alpha-2/delta subunit, enhanced channel opening. </p><p>Marais et al. (2001) found that the alpha-2/delta subunit binds the antiepileptic drug gabapentin. </p><p>Hoppa et al. (2012) showed that a trafficking step probably sets synaptic voltage-gated calcium channel (VGCC) levels in rats, because overexpression of the pore-forming alpha-1A VGCC subunit (CACNA1A; 601011) fails to change synaptic VGCC abundance or function. Alpha-2-deltas are a family of glycosylphosphatidylinositol (GPI)-anchored VGCC-associated subunits that, in addition to being the target of the potent neuropathic analgesics gabapentin and pregabalin (alpha-2-delta-1 (CACNA2D1) and alpha-2-delta-2 (CACNA2D2)), were also identified in a forward genetic screen for pain genes (alpha-2-delta-3 (CACNA2D3)). Hoppa et al. (2012) showed that these proteins confer powerful modulation of presynaptic function through 2 distinct molecular mechanisms. First, alpha-2-delta subunits set synaptic VGCC abundance, as predicted from their chaperone-like function when expressed in nonneuronal cells. Second, alpha-2-deltas configure synaptic VGCCs to drive exocytosis through an extracellular metal ion-dependent adhesion site (MIDAS), a conserved set of amino acids within the predicted von Willebrand A domain of alpha-2-delta. Expression of alpha-2-delta with an intact MIDAS motif leads to an 80% increase in release probability, while simultaneously protecting exocytosis from blockade by an intracellular calcium chelator. Alpha-2-deltas harboring MIDAS site mutations still drive synaptic accumulation of VGCCs; however, they no longer change release probability or sensitivity to intracellular calcium chelators. Hoppa et al. (2012) concluded that their data revealed dual functionality of these clinically important VGCC subunits, allowing synapses to make more efficient use of calcium entry to drive neurotransmitter release. </p>
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<h4>
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<span class="mim-font">
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<strong>Cytogenetics</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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<p>Vergult et al. (2015) reported 3 unrelated girls with intellectual disability and epilepsy associated with a heterozygous genomic alteration that disrupted the CACNA2D1 gene. One female patient had a de novo apparently balanced reciprocal translocation 46,X,t(X;7)(p10;q21.2). There was 100% skewing of X-chromosome inactivation in favor of the abnormal chromosome. The second patient had a de novo 7.5-Mb deletion on 7q21.11-q21.12 including 14 genes, as well as a maternally inherited 150-kb deletion on chromosome 16q24.1. This patient also had obesity with hyperinsulinism, which may have been caused by deletion of the CD36 gene (173510). The third patient had a 2.72-Mb deletion on 7q21.11 containing 5 genes; the deletion was inherited from her mother who had mild intellectual disability and was illiterate. The smallest region of overlap in the 2 patients with deletions encompassed 5 genes, including CACNA2D1. </p>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p><strong><em>Developmental and Epileptic Encephalopathy 110</em></strong></p><p>
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In 2 unrelated boys with developmental and epileptic encephalopathy-110 (DEE110; 620149), Dahimene et al. (2022) identified homozygous or compound heterozygous mutations in the CACNA2D1 gene (114204.0001-114204.0003). The mutations, which were found by trio-based exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in both families. Patient 1 was homozygous for a frameshift allele, and patient 2 was compound heterozygous for a frameshift and a missense allele. Studies of patient fibroblasts and in vitro functional studies of cells transfected with the missense variant (G209D; 114204.0003) indicated that the variants resulted in a loss-of-function effect on calcium channel function. </p><p><strong><em>Associations Pending Confirmation</em></strong></p><p>
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A close association is formed at the skeletal muscle triadic junctions between the ryanodine receptor (RYR1; 180901) and the L-type voltage-dependent calcium channel, also referred to as the dihydropyridine receptor (DHPR), and the 2 channel complexes appear to function together in excitation-contraction coupling (Iles et al., 1994). Because of the association with the ryanodine receptor, other subunits of the L-type voltage-dependent calcium channel have been considered as possible sites of a mutation causing malignant hyperthermia susceptibility (MHS). In 6 families with susceptibility to malignant hyperthermia (MHS3; 154276) that were not linked to the RYR1 locus on chromosome 19, Iles et al. (1994) found linkage to D7S849. No recombination was observed between MHS and D7S849 and 2 other markers through 11 meioses in 1 well-characterized 3-generation pedigree. In affected members of a family linked to the MHS3 locus by Iles et al. (1994), Schleithoff et al. (1999) did not identify any pathogenic mutations in the coding region of the CACNA2D1 gene. </p><p>Templin et al. (2011) reported a single patient, a 17-year-old Caucasian girl, with short QT syndrome, which they designated SQTS6, manifesting as ventricular fibrillation and QTc of 329 ms, with a missense variant (c.2264G-C, ser755 to thr, S755T) in CACNA2D1. Her father and paternal grandmother also carried the variant, but her father had borderline short QTc interval (362 ms) and the grandmother's QTc interval was normal. Neither had any symptoms. Expression studies comparing wildtype and variant CACNA2D1 with other L-type calcium channel subunits in HEK293 cells showed that the mutant protein was expressed at levels comparable to wildtype protein, but that barium ion currents were reduced by 70% when the mutant channel was introduced, compared with wildtype CACNA2D1. Hamosh (2023) reported that the S755T variant was present in 1% of Ashkenazi Jews in gnomad (109/10,324, MAF of 0.01056), present in homozygosity in 2 individuals, and reported as benign by 4 independent clinical laboratories in ClinVar; it was present in a total of 241 of 281,304 individuals in gnomAD for an overall MAF of 8.57 x 10(-4) (February 8, 2023). </p>
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</span>
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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 porcine brain, Wang et al. (1999) identified putative gabapentin-bindings sites within the alpha-2/delta subunit and showed that an arg217-to-ala (R217A) substitution within the Cacna2d1 gene disrupted gabapentin binding. </p><p>In a mutant mouse line with the Cacna2d1 R217A substitution, Field et al. (2006) found significantly decreased binding of the analgesic pregabalin in multiple brain areas, including cortex, hippocampus, caudate putamen, lumbar dorsal horn, and cerebellum compared to wildtype controls. Pregabalin had no effect against chemically induced tonic pain or nerve injury-induced chronic pain in the mutant mice, whereas wildtype mice showed dose-dependent analgesia. </p>
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</span>
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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>3 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 DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 110</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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CACNA2D1, 4-BP DUP, 818GAAC
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<br />
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ClinVar: RCV002464992
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</span>
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<div>
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<span class="mim-text-font">
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<p>In a 4-year-old boy (patient 1), born of consanguineous Afghan parents, with developmental and epileptic encephalopathy-110 (DEE110; 620149), Dahimene et al. (2022) identified a homozygous 4-bp duplication (c.818_821dupGAAC, NM_000722.3) in the CACNA2D1 gene, resulting in a frameshift and premature termination (Ser275AsnfsTer13). The mutation, which was found by trio-based exome sequencing and confirmed by Sanger sequencing, was present in each unaffected parent in the heterozygous state. It was not present in the gnomAD database. Patient fibroblasts showed reduced levels of CACNA2D1 mRNA (6 to 9% compared to controls) and decreased levels of the full-length protein (10 to 12% compared to controls). These findings were consistent with nonsense-mediated mRNA decay and a loss-of-function effect of the mutation. </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 DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 110</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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CACNA2D1, 11-BP DUP, NT13
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<br />
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ClinVar: RCV002464993
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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 4-year-old boy (patient 2), born of unrelated parents, with developmental and epileptic encephalopathy-110 (DEE110; 620149), Dahimene et al. (2022) identified compound heterozygous mutations in the CACNA2D1 gene: an 11-bp duplication (c.13_23dupTGCCTGCTGGC, NM_000722.3), predicted to result in a frameshift and premature termination (Leu9AlafsTer5), and a c.626G-A transition in exon 7, resulting in a gly209-to-asp (G209D; 114204.0003) substitution at a highly conserved residue that is important for protein structure. The mutations, which were found by trio-based exome sequencing and confirmed by Sanger sequencing, showed parental segregation. The 11-bp duplication was present at a low frequency in the gnomAD database (0.003%), whereas G209D was absent from gnomAD. Patient fibroblasts showed normal levels of CACNA2D1 mRNA, but mildly decreased amounts of the full-length protein (31 to 38% compared to controls), suggesting that the frameshift allele resulted in a loss of function. In vitro cellular studies showed that the G209D mutation disrupted plasma expression of the protein, as it was reduced by about 80% at the cell membrane compared to controls. The G209D variant abolished the ability of CACNA2D1 to promote calcium currents in cells transfected with the mutation. The mutation also disrupted trafficking of calcium channels into hippocampal neurites and reduced complex formation with Ca(V)2.2 (see CACNA1B, 601012). The G209D mutant protein remained largely in the uncleaved immature form, suggesting it is likely retained in the endoplasmic reticulum. These data indicated that G209D is a loss-of-function allele. </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 DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 110</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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CACNA2D1, GLY209ASP
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<br />
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ClinVar: RCV002464994
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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>For discussion of the c.626G-A transition (c.626G-A, NM_000722.3) in exon 7 in the CACNA2D1 gene, resulting in gly209-to-asp (G209D) substitution, that was found in compound heterozygous state in a patient with developmental and epileptic encephalopathy-110 (DEE110; 620149) by Dahimene et al. (2022), see 114204.0002. </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>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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<p class="mim-text-font">
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Dahimene, S., von Elsner, L., Holling, T., Mattas, L. S., Pickard, J., Lessel, D., Pilch, K. S., Kadurin, I., Pratt, W. S., Zhulin, I. B., Dai, H., Hempel, M., Ruzhnikov, M. R. Z., Kutsche, K., Dolphin, A. C.
|
|
<strong>Biallelic CACNA2D1 loss-of-function variants cause early-onset developmental epileptic encephalopathy.</strong>
|
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Brain 145: 2721-2729, 2022.
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[PubMed: 35293990]
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[Full Text: https://doi.org/10.1093/brain/awac081]
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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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Field, M. J., Cox, P. J., Stott, E., Melrose, H., Offord, J., Su, T.-Z., Bramwell, S., Corradini, L., England, S., Winks, J., Kinloch, R. A., Hendrich, J., Dolphin, A. C., Webb, T., Williams, D.
|
|
<strong>Identification of the alpha-2-delta-1 subunit of voltage-dependent calcium channels as a molecular target for pain mediating the analgesic actions of pregabalin.</strong>
|
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Proc. Nat. Acad. Sci. 103: 17537-17542, 2006.
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[PubMed: 17088553]
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[Full Text: https://doi.org/10.1073/pnas.0409066103]
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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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Hamosh, A.
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<strong>Personal Communication.</strong>
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Baltimore, Md. 02/08/2023.
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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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Hoppa, M. B., Lana, B., Margas, W., Dolphin, A. C., Ryan, T. A.
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<strong>Alpha-2-delta expression sets presynaptic calcium channel abundance and release probability.</strong>
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Nature 486: 122-125, 2012.
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[PubMed: 22678293]
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[Full Text: https://doi.org/10.1038/nature11033]
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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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Iles, D. E., Lehmann-Horn, F., Scherer, S. W., Tsui, L.-C., Olde Weghuis, D., Suijkerbuijk, R. F., Heytens, L., Mikala, G., Schwartz, A., Ellis, F. R., Stewart, A. D., Deufel, T., Wieringa, B.
|
|
<strong>Localization of the gene encoding the alpha-2/delta-subunits of the L-type voltage-dependent calcium channel to chromosome 7q and analysis of the segregation of flanking markers in malignant hyperthermia susceptible families.</strong>
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Hum. Molec. Genet. 3: 969-975, 1994.
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[PubMed: 7951247]
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[Full Text: https://doi.org/10.1093/hmg/3.6.969]
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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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Marais, E., Klugbauer, N., Hofmann, F.
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<strong>Calcium channel alpha(2)delta subunits: structure and gabapentin binding.</strong>
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Molec. Pharm. 59: 1243-1248, 2001.
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[PubMed: 11306709]
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[Full Text: https://doi.org/10.1124/mol.59.5.1243]
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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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Powers, P. A., Scherer, S. W., Tsui, L.-C., Gregg, R. G., Hogan, K.
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<strong>Localization of the gene encoding the alpha-2/delta subunit (CACNL2A) of the human skeletal muscle voltage-dependent Ca(2+) channel to chromosome 7q21-q22 by somatic cell hybrid analysis.</strong>
|
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Genomics 19: 192-193, 1994.
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[PubMed: 8188232]
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[Full Text: https://doi.org/10.1006/geno.1994.1044]
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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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Schleithoff, L., Mehrke, G., Reutlinger, B., Lehmann-Horn, F.
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<strong>Genomic structure and functional expression of a human alpha-2/delta calcium channel subunit gene (CACNA2).</strong>
|
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Genomics 61: 201-209, 1999.
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[PubMed: 10534405]
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[Full Text: https://doi.org/10.1006/geno.1999.5941]
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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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Templin, C., Ghadri, J. R., Rougier, J. S., Baumer, A., Kaplan, V., Albesa, M., Sticht, H., Rauch, A., Puleo, C., Hu, D., Barajas-Martinez, H., Antzelevitch, C., Luscher, T. F., Abriel, H., Duru, F.
|
|
<strong>Identification of a novel loss-of-function calcium channel gene mutation in short QT syndrome (SQTS6).</strong>
|
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Europ. Heart J. 32: 1077-1088, 2011.
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[PubMed: 21383000]
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[Full Text: https://doi.org/10.1093/eurheartj/ehr076]
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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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Vergult, S., Dheedene, A., Meurs, A., Faes, F., Isidor, B., Janssens, S., Gautier, A., Le Caignec, C., Menten, B.
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<strong>Genomic aberrations of the CACNA2D1 gene in three patients with epilepsy and intellectual disability.</strong>
|
|
Europ. J. Hum. Genet. 23: 628-632, 2015.
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[PubMed: 25074461]
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[Full Text: https://doi.org/10.1038/ejhg.2014.141]
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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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Wang, M., Offord, J., Oxender, D. L., Su, T.-Z.
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<strong>Structural requirement of the calcium-channel subunit alpha-2-delta for gabapentin binding.</strong>
|
|
Biochem. J. 342: 313-320, 1999.
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[PubMed: 10455017]
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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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Williams, M. E., Feldman, D. H., McCue, A. F., Brenner, R., Velicelebi, G., Ellis, S. B., Harpold, M. M.
|
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<strong>Structure and functional expression of alpha-1, alpha-2, and beta subunits of a novel human neuronal calcium channel subtype.</strong>
|
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Neuron 8: 71-84, 1992.
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[PubMed: 1309651]
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[Full Text: https://doi.org/10.1016/0896-6273(92)90109-q]
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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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Yamaguchi, H., Okuda, M., Mikala, G., Fukasawa, K., Varadi, G.
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<strong>Cloning of the beta-2a subunit of the voltage-dependent calcium channel from human heart: cooperative effect of alpha-2/delta and beta-2a on the membrane expression of the alpha-1c subunit.</strong>
|
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Biochem. Biophys. Res. Commun. 267: 156-163, 2000.
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[PubMed: 10623591]
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[Full Text: https://doi.org/10.1006/bbrc.1999.1926]
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</p>
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</li>
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Ada Hamosh - updated : 02/08/2023<br>Cassandra L. Kniffin - updated : 12/3/2015<br>Ada Hamosh - updated : 7/17/2012<br>Cassandra L. Kniffin - updated : 2/7/2008<br>Cassandra L. Kniffin - updated : 12/12/2006<br>Patricia A. Hartz - updated : 11/11/2004<br>Victor A. McKusick - edited : 6/23/1997<br>Victor A. McKusick - updated : 6/17/1997
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Victor A. McKusick : 2/9/1994
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alopez : 02/08/2023<br>carol : 12/08/2022<br>alopez : 12/07/2022<br>ckniffin : 12/06/2022<br>carol : 06/22/2017<br>carol : 12/08/2015<br>ckniffin : 12/3/2015<br>alopez : 7/17/2012<br>terry : 7/17/2012<br>wwang : 2/21/2008<br>ckniffin : 2/7/2008<br>terry : 9/19/2007<br>terry : 9/18/2007<br>wwang : 12/21/2006<br>ckniffin : 12/12/2006<br>mgross : 11/11/2004<br>mgross : 10/18/2001<br>alopez : 6/18/1999<br>terry : 6/23/1997<br>terry : 6/17/1997<br>jason : 7/27/1994<br>mimadm : 5/18/1994<br>carol : 2/9/1994
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