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Entry
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- *601011 - CALCIUM CHANNEL, VOLTAGE-DEPENDENT, P/Q TYPE, ALPHA-1A SUBUNIT; CACNA1A
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- OMIM
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*601011</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>
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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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<li role="presentation" style="margin-left: 1em">
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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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<li role="presentation" style="margin-left: 1em">
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<a href="#biochemicalFeatures">Biochemical Features</a>
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<li role="presentation" style="margin-left: 1em">
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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="#genotypePhenotypeCorrelations">Genotype/Phenotype Correlations</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>
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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/601011">Table View</a>
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</li>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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</li>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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</ul>
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</nav>
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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=ENSG00000141837;t=ENST00000360228" 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=773" 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=601011" 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=ENSG00000141837;t=ENST00000360228" 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_000068,NM_001127221,NM_001127222,NM_001174080,NM_023035" 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_001127222" 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=601011" 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=03004&isoform_id=03004_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/CACNA1A" 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/913716,1657333,1763628,1763630,1763632,1763636,1763638,2213911,2213913,2281752,3329353,3873285,5051979,6117976,7630181,9711929,119604767,119604768,119604769,119604770,119604771,119604772,148536844,148536846,157805256,187828880,187828892,199582627,291463273,1476413368" 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/O00555" 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=773" 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=ENSG00000141837;t=ENST00000360228" 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=CACNA1A" 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=CACNA1A" 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+773" 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/CACNA1A" 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:773" 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/773" 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=chr19&hgg_gene=ENST00000360228.11&hgg_start=13206442&hgg_end=13506479&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/gene-dosage/HGNC:1388" class="mim-tip-hint" title="A ClinGen curated resource of genes and regions of the genome that are dosage sensitive and should be targeted on a cytogenomic array." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Dosage', 'domain': 'dosage.clinicalgenome.org'})">ClinGen Dosage</a></div>
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<div><a href="https://medlineplus.gov/genetics/gene/cacna1a" class="mim-tip-hint" title="Consumer-friendly information about the effects of genetic variation on human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MedlinePlus Genetics', 'domain': 'medlineplus.gov'})">MedlinePlus Genetics</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=601011[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=601011[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
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<div><a href="https://www.deciphergenomics.org/gene/CACNA1A/overview/clinical-info" class="mim-tip-hint" title="DECIPHER" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'DECIPHER', 'domain': 'DECIPHER'})">DECIPHER</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000141837" 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=CACNA1A" 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=CACNA1A" 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=CACNA1A" 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="#mimLocusSpecificDBsFold" id="mimLocusSpecificDBsToggle" data-toggle="collapse" class="mim-tip-hint mimTriangleToggle" title="A gene-specific database of variation."><span id="mimLocusSpecificDBsToggleTriangle" class="small" style="margin-left: -0.8em;">►</span>Locus Specific DBs</div>
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<div id="mimLocusSpecificDBsFold" class="collapse">
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<div style="margin-left: 0.5em;"><a href="http://grenada.lumc.nl/LOVD2/FHM/home.php?select_db=CACNA1A" title="Familial Hemiplegic Migraine (FHM) Variation Database" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">Familial Hemiplegic Migrai…</a></div><div style="margin-left: 0.5em;"><a href="http://www.LOVD.nl/CACNA1A" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">CAC1A1A database at LOVD</a></div>
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</div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=CACNA1A&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/PA26007" 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:1388" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
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<div><a href="https://flybase.org/reports/FBgn0263111.html" class="mim-tip-hint" title="A Database of Drosophila Genes and Genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'FlyBase', 'domain': 'flybase.org'})">FlyBase</a></div>
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<div><a href="https://www.mousephenotype.org/data/genes/MGI:109482" 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/CACNA1A#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:109482" 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/773/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://omia.org/OMIA001270/" class="mim-tip-hint" title="Online Mendelian Inheritance in Animals (OMIA) is a database of genes, inherited disorders and traits in 191 animal species (other than human and mouse.)" target="_blank">OMIA</a></div>
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<div><a href="https://www.orthodb.org/?ncbi=773" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="https://wormbase.org/db/gene/gene?name=WBGene00006742;class=Gene" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name'{'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">Wormbase Gene</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-040724-26" 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="mimCellLines">
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellLinesLinksFold" id="mimCellLinesLinksToggle" 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="mimCellLinesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cell Lines</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="mimCellLinesLinksFold" 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://catalog.coriell.org/Search?q=OmimNum:601011" class="definition" title="Coriell Cell Repositories; cell cultures and DNA derived from cell cultures." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'CCR', 'domain': 'ccr.coriell.org'})">Coriell</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:773" 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=CACNA1A&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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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>SNOMEDCT:</strong> 1260329005, 230464001, 420932006, 715752006<br />
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">ICD+</a>
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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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601011
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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, P/Q TYPE, ALPHA-1A SUBUNIT; CACNA1A
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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-1 POLYPEPTIDE, ISOFORM 4; CACNL1A4<br />
|
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CaV2.1
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="includedTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
|
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Other entities represented in this entry:
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</span>
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</p>
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</div>
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<div>
|
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<span class="h3 mim-font">
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CACNA1A C-TERMINAL POLYPEPTIDE, INCLUDED
|
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</span>
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</div>
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<div>
|
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<span class="h4 mim-font">
|
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ALPHA-1A C-TERMINAL POLYPEPTIDE, INCLUDED<br />
|
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ALPHA-1ACT, INCLUDED
|
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</span>
|
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<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=CACNA1A" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">CACNA1A</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/19/355?start=-3&limit=10&highlight=355">19p13.13</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr19:13206442-13506479&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'})">19:13,206,442-13,506,479</a> </span>
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<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </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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Phenotype
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<a href="/clinicalSynopsis/table?mimNumber=617106,108500,141500,141500,183086" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
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Phenotype <br /> MIM number
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Inheritance
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Phenotype <br /> mapping key
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19p13.13
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Developmental and epileptic encephalopathy 42
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<a href="/entry/617106"> 617106 </a>
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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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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Episodic ataxia, type 2
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<span class="mim-font">
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<a href="/entry/108500"> 108500 </a>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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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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Migraine, familial hemiplegic, 1
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<a href="/entry/141500"> 141500 </a>
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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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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Migraine, familial hemiplegic, 1, with progressive cerebellar ataxia
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<a href="/entry/141500"> 141500 </a>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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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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Spinocerebellar ataxia 6
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<a href="/entry/183086"> 183086 </a>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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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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PheneGene Graphics <span class="caret"></span>
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</button>
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<ul class="dropdown-menu" style="width: 17em;">
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<li><a href="/graph/linear/601011" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
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<li><a href="/graph/radial/601011" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
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<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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<span class="mim-font">
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
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<strong>TEXT</strong>
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<span id="mimDescriptionToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<strong>Description</strong>
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<p>The CACNA1A gene encodes the transmembrane pore-forming subunit of the P/Q-type or CaV2.1 voltage-gated calcium channel (VGCC) (<a href="#36" class="mim-tip-reference" title="Kordasiewicz, H. B., Thompson, R. M., Clark, H. B., Gomez, C. M. <strong>C-termini of P/Q-type Ca(2+) channel alpha1A subunits translocate to nuclei and promote polyglutamine-mediated toxicity.</strong> Hum. Molec. Genet. 15: 1587-1599, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16595610/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16595610</a>] [<a href="https://doi.org/10.1093/hmg/ddl080" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16595610">Kordasiewicz et al., 2006</a>). Voltage-dependent Ca(2+) channels not only mediate the entry of Ca(2+) ions into excitable cells but are also involved in a variety of Ca(2+)-dependent processes, including muscle contraction, hormone or neurotransmitter release, and gene expression. <a href="#12" class="mim-tip-reference" title="Diriong, S., Lory, P., Williams, M. E., Ellis, S. B., Harpold, M. M., Taviaux, S. <strong>Chromosomal localization of the human genes for alpha-1A, alpha-1B, and alpha-1E voltage-dependent Ca(2+) channel subunits.</strong> Genomics 30: 605-609, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8825650/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8825650</a>] [<a href="https://doi.org/10.1006/geno.1995.1284" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8825650">Diriong et al. (1995)</a> noted that calcium channels are multisubunit complexes and that the channel activity is directed by a pore-forming alpha-1 subunit, which is often sufficient to generate voltage-sensitive Ca(2+) channel activity. There are at least 6 classes of alpha-1 subunits: alpha-1A, B, C, D, E, and S, which are derived from 6 genes representing members of a gene family. The auxiliary subunits beta (e.g., <a href="/entry/114207">114207</a>), alpha-2/delta, and gamma (e.g., <a href="/entry/114209">114209</a>) regulate channel activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8825650+16595610" 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 addition to full-length CACNA1A, use of an internal ribosomal entry site in the CACNA1A transcript generates the CACNA1A C-terminal polypeptide, or alpha-1ACT, which functions as a transcription factor that mediates cerebellar development (<a href="#13" class="mim-tip-reference" title="Du, X., Wang, J., Zhu, H., Rinaldo, L., Lamar, K.-M., Palmenberg, A. C., Hansel, C., Gomez, C. M. <strong>Second cistron in CACNA1A gene encodes a transcription factor mediating cerebellar development and SCA6.</strong> Cell 154: 118-133, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23827678/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23827678</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23827678[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/10.1016/j.cell.2013.05.059" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23827678">Du et al., 2013</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23827678" 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="#48" class="mim-tip-reference" title="Ophoff, R. A., Terwindt, G. M., Vergouwe, M. N., van Eijk, R., Oefner, P. J., Hoffman, S. M. G., Lamerdin, J. E., Mohrenweiser, H. W., Bulman, D. E., Ferrari, M., Haan, J., Lindhout, D., van Ommen, G.-J. B., Hofker, M. H., Ferrari, M. D., Frants, R. R. <strong>Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca(2+) channel gene CACNL1A4.</strong> Cell 87: 543-552, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8898206/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8898206</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)81373-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8898206">Ophoff et al. (1996)</a> characterized the CACNL1A4 gene and reported the amino acid sequence for residues 1 to 2262 of the protein. Northern analysis detected a 9.8-kb transcript in cerebellum, cerebral cortex, thalamus, and hypothalamus. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8898206" 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>CACNA1A C-Terminal Polypeptide</em></strong></p><p>
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<a href="#36" class="mim-tip-reference" title="Kordasiewicz, H. B., Thompson, R. M., Clark, H. B., Gomez, C. M. <strong>C-termini of P/Q-type Ca(2+) channel alpha1A subunits translocate to nuclei and promote polyglutamine-mediated toxicity.</strong> Hum. Molec. Genet. 15: 1587-1599, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16595610/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16595610</a>] [<a href="https://doi.org/10.1093/hmg/ddl080" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16595610">Kordasiewicz et al. (2006)</a> showed that a 75-kD human polypeptide consisting of the C terminus of CACNA1A is cleaved from the full-length protein and is present in the nucleus of HEK293 cells, as well as in mouse and human cerebellar Purkinje cells. Nuclear translocation depended partly on the presence of 3 nuclear localization signals within the C terminus. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16595610" 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="#44" class="mim-tip-reference" title="Li, L., Saegusa, H., Tanabe, T. <strong>Deficit of heat shock transcription factor 1-heat shock 70 kDa protein 1A axis determines the cell death vulnerability in a model of spinocerebellar ataxia type 6.</strong> Genes Cells 14: 1253-1269, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19817876/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19817876</a>] [<a href="https://doi.org/10.1111/j.1365-2443.2009.01348.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19817876">Li et al. (2009)</a> confirmed that C-terminal fragments of CACNA1A localized predominantly to the nucleus of HEK293 cells where they existed as speckle-like structures resembling promyelocytic leukemia nuclear bodies (PMLNBs). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19817876" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using mass spectrometric analysis, <a href="#13" class="mim-tip-reference" title="Du, X., Wang, J., Zhu, H., Rinaldo, L., Lamar, K.-M., Palmenberg, A. C., Hansel, C., Gomez, C. M. <strong>Second cistron in CACNA1A gene encodes a transcription factor mediating cerebellar development and SCA6.</strong> Cell 154: 118-133, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23827678/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23827678</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23827678[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/10.1016/j.cell.2013.05.059" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23827678">Du et al. (2013)</a> determined that the 75-kD CACNA1A C-terminal polypeptide, which they called alpha-1ACT, began with the N-terminal sequence MIMEY at amino acid 1960 within the IQ-like domain of full-length CACNA1A. This N-terminal sequence did not overlap with any protease cleavage site, and expression of alpha-1ACT appeared to be due to use of a cryptic internal ribosomal entry site in the CACNA1A transcript. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23827678" 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="#48" class="mim-tip-reference" title="Ophoff, R. A., Terwindt, G. M., Vergouwe, M. N., van Eijk, R., Oefner, P. J., Hoffman, S. M. G., Lamerdin, J. E., Mohrenweiser, H. W., Bulman, D. E., Ferrari, M., Haan, J., Lindhout, D., van Ommen, G.-J. B., Hofker, M. H., Ferrari, M. D., Frants, R. R. <strong>Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca(2+) channel gene CACNL1A4.</strong> Cell 87: 543-552, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8898206/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8898206</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)81373-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8898206">Ophoff et al. (1996)</a> found that the CACNA1A gene covers 300 kb and contains 47 exons. Sequencing of all exons and their surroundings revealed polymorphic variations, including a (CA)n-repeat (D19S1150) and a (CAG)n-repeat in the 3-prime-UTR. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8898206" 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="#63" class="mim-tip-reference" title="Trettel, F., Mantuano, E., Calabresi, V., Veneziano, L., Olsen, A. S., Georgescu, A., Gordon, L., Sabbadini, G., Frontali, M., Jodice, C. <strong>A fine physical map of the CACNA1A gene region on 19p13.1-p13.2 chromosome.</strong> Gene 241: 45-50, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10607897/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10607897</a>] [<a href="https://doi.org/10.1016/s0378-1119(99)00470-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10607897">Trettel et al. (2000)</a> determined that the CACNL1A4 gene is alternatively spliced. A second isoform contains an alternative exon 37 that differs from the first by 97 nucleotides. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10607897" 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 FISH, <a href="#12" class="mim-tip-reference" title="Diriong, S., Lory, P., Williams, M. E., Ellis, S. B., Harpold, M. M., Taviaux, S. <strong>Chromosomal localization of the human genes for alpha-1A, alpha-1B, and alpha-1E voltage-dependent Ca(2+) channel subunits.</strong> Genomics 30: 605-609, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8825650/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8825650</a>] [<a href="https://doi.org/10.1006/geno.1995.1284" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8825650">Diriong et al. (1995)</a> assigned the CACNA1A gene to chromosome 19p13. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8825650" 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>Ca(2+) currents have been described on the basis of their biophysical and pharmacologic properties and include L-, N-, T-, P-, Q-, and R- types. The distinctive properties of these Ca(2+) channel types are related primarily to the expression of a variety of alpha-1 isoforms (<a href="#17" class="mim-tip-reference" title="Dunlap, K., Luebke, J. I., Turner, T. J. <strong>Exocytotic Ca(2+) channels in mammalian central neurons.</strong> Trends Neurosci. 18: 89-98, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7537420/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7537420</a>]" pmid="7537420">Dunlap et al., 1995</a>). The alpha-1A isoform is abundantly expressed in neuronal tissue and corresponds to the P/Q Ca(2+) channel type. The B and E isoforms are also expressed in neuronal tissue and correspond to the N-type and R-type of Ca(2+) channels, respectively (<a href="#43" class="mim-tip-reference" title="Lehmann-Horn, F., Jurkat-Rott, K. <strong>Voltage-gated ion channels and hereditary disease.</strong> Physiol. Rev. 79: 1317-1372, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10508236/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10508236</a>] [<a href="https://doi.org/10.1152/physrev.1999.79.4.1317" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10508236">Lehmann-Horn and Jurkat-Rott, 1999</a>). The genes encoding the alpha-1A, B, and E isoforms are symbolized CACNL1A4 or CACNA1A, CACNL1A5 (<a href="/entry/601012">601012</a>), and CACNL1A6 (<a href="/entry/601013">601013</a>) and are located on 19p13, 9q34 and 1q25-q31, respectively (<a href="#12" class="mim-tip-reference" title="Diriong, S., Lory, P., Williams, M. E., Ellis, S. B., Harpold, M. M., Taviaux, S. <strong>Chromosomal localization of the human genes for alpha-1A, alpha-1B, and alpha-1E voltage-dependent Ca(2+) channel subunits.</strong> Genomics 30: 605-609, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8825650/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8825650</a>] [<a href="https://doi.org/10.1006/geno.1995.1284" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8825650">Diriong et al., 1995</a>). Alpha-1C, D, and S are involved with L-type Ca(2+) channels and are referred to as cardiac, neuroendocrine/brain, and skeletal muscle isoforms, respectively. They are encoded, respectively, by the CACNL1A1 gene (<a href="/entry/114205">114205</a>) on 12p13.3, the CACNL1A2 gene (<a href="/entry/114206">114206</a>) on 3p14.3, and the CACNL1A3 gene (<a href="/entry/114208">114208</a>) on 1q31-q32. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10508236+7537420+8825650" 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="#56" class="mim-tip-reference" title="Takamori, M., Iwasa, K., Komai, K. <strong>Antibodies to synthetic peptides of the alpha1A subunit of the voltage-gated calcium channel in Lambert-Eaton myasthenic syndrome.</strong> Neurology 48: 1261-1265, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9153453/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9153453</a>] [<a href="https://doi.org/10.1212/wnl.48.5.1261" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9153453">Takamori et al. (1997)</a> and <a href="#57" class="mim-tip-reference" title="Takamori, M. <strong>Lambert-Eaton myasthenic syndrome as an autoimmune calcium channelopathy.</strong> Biochem. Biophys. Res. Commun. 322: 1347-1351, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15336982/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15336982</a>] [<a href="https://doi.org/10.1016/j.bbrc.2004.08.040" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15336982">Takamori (2004)</a> presented evidence suggesting that the alpha-1A subunit of the P/Q-type voltage-gated calcium channel contains antigenic sites implicated in Lambert-Eaton myasthenic syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9153453+15336982" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#1" class="mim-tip-reference" title="Ackerman, M. J., Clapham, D. E. <strong>Ion channels--basic science and clinical disease.</strong> New Eng. J. Med. 336: 1575-1586, 1997. Note: Erratum: New Eng. J. Med. 337: 579 only, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9164815/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9164815</a>] [<a href="https://doi.org/10.1056/NEJM199705293362207" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9164815">Ackerman and Clapham (1997)</a> provided a comprehensive review of the role of ion channel defects in disease. They provided useful illustrations of the physiology and structure of ion channels and of patch-clamp measurement of ion channel activity. They also discussed the design and use of drugs that target ion channels. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9164815" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using chromatin immunoprecipitation-sequencing and RNA-sequencing analyses, <a href="#14" class="mim-tip-reference" title="Du, X., Wei, C., Hejazi Pastor, D. P., Rao, E. R., Li, Y., Grasselli, G., Godfrey, J., Palmenberg, A. C., Andrade, J., Hansel, C., Gomez, C. M. <strong>Alpha-1ACT is essential for survival and early cerebellar programming in a critical neonatal window.</strong> Neuron 102: 770-785, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30922876/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30922876</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30922876[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/10.1016/j.neuron.2019.02.036" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30922876">Du et al. (2019)</a> identified dynamic changes in alpha-1Act-mediated gene regulation in rat PC12 pheochromocytoma cells. Many of the alpha-1Act-regulated genes were involved in neurogenesis, synaptic function, and cell adhesion. Quantitative RT-PCR analysis revealed that CACNA1A mRNA expression was maximal in human cerebellum from birth to 20 years of age and decreased gradually until reaching a plateau at age 50 years. A similar expression pattern was observed in cerebellum over the mouse life span. <a href="#14" class="mim-tip-reference" title="Du, X., Wei, C., Hejazi Pastor, D. P., Rao, E. R., Li, Y., Grasselli, G., Godfrey, J., Palmenberg, A. C., Andrade, J., Hansel, C., Gomez, C. M. <strong>Alpha-1ACT is essential for survival and early cerebellar programming in a critical neonatal window.</strong> Neuron 102: 770-785, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30922876/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30922876</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30922876[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/10.1016/j.neuron.2019.02.036" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30922876">Du et al. (2019)</a> presented evidence suggesting that bicistronic expression is common to multiple members of the VGCC family. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30922876" 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>CACNA1A C-Terminal Polypeptide</em></strong></p><p>
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<a href="#13" class="mim-tip-reference" title="Du, X., Wang, J., Zhu, H., Rinaldo, L., Lamar, K.-M., Palmenberg, A. C., Hansel, C., Gomez, C. M. <strong>Second cistron in CACNA1A gene encodes a transcription factor mediating cerebellar development and SCA6.</strong> Cell 154: 118-133, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23827678/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23827678</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23827678[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/10.1016/j.cell.2013.05.059" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23827678">Du et al. (2013)</a> found that human alpha-1ACT bound an AT-rich enhancer element (TTATAA) in the 3-prime UTR of target genes, including BTG1 (<a href="/entry/109580">109580</a>), and increased expression of their reporter genes. Expression of alpha-1ACT in rat PC12 pheochromocytoma cells increased neurite outgrowth and expression of the predicted target gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23827678" 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="#47" class="mim-tip-reference" title="Nishimune, H., Sanes, J. R., Carlson, S. S. <strong>A synaptic laminin-calcium channel interaction organizes active zones in motor nerve terminals.</strong> Nature 432: 580-587, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15577901/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15577901</a>] [<a href="https://doi.org/10.1038/nature03112" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15577901">Nishimune et al. (2004)</a> showed that laminin beta-2 (LAMB2; <a href="/entry/150325">150325</a>), a component of the synaptic cleft at the neuromuscular junction, binds directly to calcium channels that are required for neurotransmitter release from motor nerve terminals. This interaction leads to clustering of channels which in turn recruit other presynaptic components. Perturbation of this interaction in vivo results in disassembly of neurotransmitter release sites, resembling defects previously observed in an autoimmune neuromuscular disorder, Lambert-Eaton myasthenic syndrome (<a href="/entry/600003">600003</a>). <a href="#47" class="mim-tip-reference" title="Nishimune, H., Sanes, J. R., Carlson, S. S. <strong>A synaptic laminin-calcium channel interaction organizes active zones in motor nerve terminals.</strong> Nature 432: 580-587, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15577901/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15577901</a>] [<a href="https://doi.org/10.1038/nature03112" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15577901">Nishimune et al. (2004)</a> concluded that their results identify an extracellular ligand of the voltage-gated calcium channel as well as a new laminin receptor, suggest a model for the development of nerve terminals, and provide clues to the pathogenesis of a synaptic disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15577901" 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 patients with episodic ataxia type 2 (EA2; <a href="/entry/108500">108500</a>), <a href="#48" class="mim-tip-reference" title="Ophoff, R. A., Terwindt, G. M., Vergouwe, M. N., van Eijk, R., Oefner, P. J., Hoffman, S. M. G., Lamerdin, J. E., Mohrenweiser, H. W., Bulman, D. E., Ferrari, M., Haan, J., Lindhout, D., van Ommen, G.-J. B., Hofker, M. H., Ferrari, M. D., Frants, R. R. <strong>Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca(2+) channel gene CACNL1A4.</strong> Cell 87: 543-552, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8898206/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8898206</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)81373-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8898206">Ophoff et al. (1996)</a> identified 2 mutations in the CACNA1A gene resulting in a disrupted reading frame. The first of these was deletion of a single C, nucleotide 4073 in codon 1266 (<a href="#0005">601011.0005</a>), leading to a frameshift in the putative translation product with a stop codon in the next exon (codon 1294). See also <a href="#0006">601011.0006</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8898206" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#22" class="mim-tip-reference" title="Eunson, L. H., Graves, T. D., Hanna, M. G. <strong>New calcium channel mutations predict aberrant RNA splicing in episodic ataxia.</strong> Neurology 65: 308-310, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16043807/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16043807</a>] [<a href="https://doi.org/10.1212/01.wnl.0000169020.82223.dd" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16043807">Eunson et al. (2005)</a> identified 2 splice site mutations in the CACNA1A gene in 2 unrelated families with EA2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16043807" 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="#49" class="mim-tip-reference" title="Riant, F., Lescoat, C., Vahedi, K., Kaphan, E., Toutain, A., Soisson, T., Wiener-Vacher, S. R., Tournier-Lasserve, E. <strong>Identification of CACNA1A large deletions in four patients with episodic ataxia.</strong> Neurogenetics 11: 101-106, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19633872/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19633872</a>] [<a href="https://doi.org/10.1007/s10048-009-0208-y" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19633872">Riant et al. (2010)</a> identified 4 different exonic deletions in the CACNA1A gene in 4 (14%) of 27 patients with episodic ataxia, in whom sequencing analysis was negative for CACNA1A point mutations. The EA2 phenotype in the patients with deletion was similar to that of patients with point mutations. The findings indicated that screening for deletions in the CACNA1A gene should also be done for a complete genetic workup. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19633872" 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="#42" class="mim-tip-reference" title="Labrum, R. W., Rajakulendran, S., Graves, T. D., Eunson, L. H., Bevan, R., Sweeney, M. G., Hammans, S. R., Tubridy, N., Britton, T., Carr, L. J., Ostergaard, J. R., Kennedy, C. R., Al-Memar, A., Kullmann, D. M., Schorge, S., Temple, K., Davis, M. B., Hanna, M. G. <strong>Large scale calcium channel gene rearrangements in episodic ataxia and hemiplegic migraine: implications for diagnostic testing.</strong> J. Med. Genet. 46: 786-791, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19586927/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19586927</a>] [<a href="https://doi.org/10.1136/jmg.2009.067967" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19586927">Labrum et al. (2009)</a> used multiplex ligation-dependent probe amplification (MLPA) to screen for large-scale genetic rearrangements in CACNA1A in 53 patients with a clinical diagnosis of episodic ataxia type 2 (EA2; <a href="/entry/108500">108500</a>) or familial hemiplegic migraine type 1 (FHM1; <a href="/entry/141500">141500</a>) in whom sequencing analysis was negative for CACNA1A point mutations. <a href="#42" class="mim-tip-reference" title="Labrum, R. W., Rajakulendran, S., Graves, T. D., Eunson, L. H., Bevan, R., Sweeney, M. G., Hammans, S. R., Tubridy, N., Britton, T., Carr, L. J., Ostergaard, J. R., Kennedy, C. R., Al-Memar, A., Kullmann, D. M., Schorge, S., Temple, K., Davis, M. B., Hanna, M. G. <strong>Large scale calcium channel gene rearrangements in episodic ataxia and hemiplegic migraine: implications for diagnostic testing.</strong> J. Med. Genet. 46: 786-791, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19586927/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19586927</a>] [<a href="https://doi.org/10.1136/jmg.2009.067967" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19586927">Labrum et al. (2009)</a> identified 5 previously unreported large-scale deletions in the CACNA1A gene in 6 families with EA2 and the first pathogenic duplication in CACNA1A in an index patient with isolated episodic diplopia without ataxia (<a href="#0030">601011.0030</a>) whose father reportedly had typical EA2 (<a href="#0030">601011.0030</a>). <a href="#42" class="mim-tip-reference" title="Labrum, R. W., Rajakulendran, S., Graves, T. D., Eunson, L. H., Bevan, R., Sweeney, M. G., Hammans, S. R., Tubridy, N., Britton, T., Carr, L. J., Ostergaard, J. R., Kennedy, C. R., Al-Memar, A., Kullmann, D. M., Schorge, S., Temple, K., Davis, M. B., Hanna, M. G. <strong>Large scale calcium channel gene rearrangements in episodic ataxia and hemiplegic migraine: implications for diagnostic testing.</strong> J. Med. Genet. 46: 786-791, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19586927/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19586927</a>] [<a href="https://doi.org/10.1136/jmg.2009.067967" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19586927">Labrum et al. (2009)</a> suggested that large-scale deletions and duplications can cause CACNA1A-associated channelopathies and that screening for large-scale rearrangements by rapid techniques such as MLPA should be considered as a first-line approach for genetic diagnostic testing of CACNA1A-associated channelopathies. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19586927" 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>Familial Hemiplegic Migraine 1</em></strong></p><p>
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In 5 unrelated families with familial hemiplegic migraine (FHM1; <a href="/entry/141500">141500</a>), <a href="#48" class="mim-tip-reference" title="Ophoff, R. A., Terwindt, G. M., Vergouwe, M. N., van Eijk, R., Oefner, P. J., Hoffman, S. M. G., Lamerdin, J. E., Mohrenweiser, H. W., Bulman, D. E., Ferrari, M., Haan, J., Lindhout, D., van Ommen, G.-J. B., Hofker, M. H., Ferrari, M. D., Frants, R. R. <strong>Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca(2+) channel gene CACNL1A4.</strong> Cell 87: 543-552, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8898206/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8898206</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)81373-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8898206">Ophoff et al. (1996)</a> identified 4 different missense mutations in the CACNA1A gene (<a href="#0001">601011.0001</a>-<a href="#0004">601011.0004</a>). The authors raised the possibility that a similar defect may be involved in common types of migraine. Based on their mutational findings, <a href="#48" class="mim-tip-reference" title="Ophoff, R. A., Terwindt, G. M., Vergouwe, M. N., van Eijk, R., Oefner, P. J., Hoffman, S. M. G., Lamerdin, J. E., Mohrenweiser, H. W., Bulman, D. E., Ferrari, M., Haan, J., Lindhout, D., van Ommen, G.-J. B., Hofker, M. H., Ferrari, M. D., Frants, R. R. <strong>Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca(2+) channel gene CACNL1A4.</strong> Cell 87: 543-552, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8898206/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8898206</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)81373-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8898206">Ophoff et al. (1996)</a> suggested that FHM and EA2 are allelic channelopathies. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8898206" 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>To determine the pathophysiologic consequences of missense mutations in the pore-forming human alpha-1A subunit of neuronal P/Q-type calcium channels associated with FHM, <a href="#40" class="mim-tip-reference" title="Kraus, R. L., Sinnegger, M. J., Glossmann, H., Hering, S., Striessnig, J. <strong>Familial hemiplegic migraine mutations change alpha(1A)Ca(2+) channel kinetics.</strong> J. Biol. Chem. 273: 5586-5590, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9488686/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9488686</a>] [<a href="https://doi.org/10.1074/jbc.273.10.5586" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9488686">Kraus et al. (1998)</a> introduced 4 single mutations (R192Q, <a href="#0001">601011.0001</a>; T666M, <a href="#0002">601011.0002</a>; V714A, <a href="#0003">601011.0003</a>; and I1811L, <a href="#0004">601011.0004</a>) into alpha-1A and investigated possible changes in channel function after functional expression of mutant subunits in Xenopus laevis oocytes. Changes in channel gating were observed for mutants T666M, V714A, and I1811L, but not for R192Q. Barium current inactivation was slightly faster in mutants T666M and V714A than in wildtype. The time course of recovery from channel inactivation was slower than in wildtype in T666M and accelerated in V714A and I1811L. <a href="#40" class="mim-tip-reference" title="Kraus, R. L., Sinnegger, M. J., Glossmann, H., Hering, S., Striessnig, J. <strong>Familial hemiplegic migraine mutations change alpha(1A)Ca(2+) channel kinetics.</strong> J. Biol. Chem. 273: 5586-5590, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9488686/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9488686</a>] [<a href="https://doi.org/10.1074/jbc.273.10.5586" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9488686">Kraus et al. (1998)</a> concluded that 3 of the 4 FHM mutations, located at the putative channel pore, alter inactivation gating and provide a pathophysiologic basis for the postulated neuronal instability in patients with FHM. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9488686" 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="#41" class="mim-tip-reference" title="Kraus, R. L., Sinnegger, M. J., Koschak, A., Glossmann, H., Stenirri, S., Carrera, P., Striessnig, J. <strong>Three new familial hemiplegic migraine mutants affect P/Q-type Ca(2+) channel kinetics.</strong> J. Biol. Chem. 275: 9239-9243, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10734061/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10734061</a>] [<a href="https://doi.org/10.1074/jbc.275.13.9239" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10734061">Kraus et al. (2000)</a> continued their channel function studies with 3 additional mutations associated with FHM, including D715E (<a href="#0010">601011.0010</a>) and V1457L (<a href="#0019">601011.0019</a>). All 3 mutations significantly shifted the voltage dependence of activation to more negative potentials, resulting in altered calcium signaling by increasing channel activity at weak depolarizations. The authors suggested that these gating abnormalities underlie channel dysfunction in FHM. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10734061" 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="#62" class="mim-tip-reference" title="Tottene, A., Fellin, T., Pagnutti, S., Luvisetto, S., Striessnig, J., Fletcher, C., Pietrobon, D. <strong>Familial hemiplegic migraine mutations increase Ca(2+) influx through single human Ca(v)2.1 channels and decrease maximal Ca(v)2.1 current density in neurons.</strong> Proc. Nat. Acad. Sci. 99: 13284-13289, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12235360/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12235360</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12235360[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.192242399" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12235360">Tottene et al. (2002)</a> extended single-channel analysis to human voltage-gated P/Q type calcium channels (Ca(v)2.1) containing the V1457L mutation. This mutation increased the channel open probability by shifting its activation to more negative voltages and reduced both the unitary conductance and the density of functional channels in the membrane. To investigate the possibility of changes in Ca(v)2.1 function common to all FHM mutations, <a href="#62" class="mim-tip-reference" title="Tottene, A., Fellin, T., Pagnutti, S., Luvisetto, S., Striessnig, J., Fletcher, C., Pietrobon, D. <strong>Familial hemiplegic migraine mutations increase Ca(2+) influx through single human Ca(v)2.1 channels and decrease maximal Ca(v)2.1 current density in neurons.</strong> Proc. Nat. Acad. Sci. 99: 13284-13289, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12235360/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12235360</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12235360[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.192242399" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12235360">Tottene et al. (2002)</a> calculated the product of single-channel current and open probability as a measure of calcium ion influx through single Ca(v)2.1 channels. All 5 FHM mutants analyzed showed a single-channel calcium ion influx larger than wildtype. They also expressed the FHM mutants in cerebellar granular cells from mice null for the mutation. The FHM mutations invariably led to a decrease of the maximal Ca(v)2.1 current density in neurons. The data showed that mutational changes of functional channel densities can be different in different cell types, and uncovered 2 functional effects common to all FHM mutations analyzed: increase of single-channel calcium ion influx and decrease of maximal Ca(v)2.1 current density in neurons. <a href="#62" class="mim-tip-reference" title="Tottene, A., Fellin, T., Pagnutti, S., Luvisetto, S., Striessnig, J., Fletcher, C., Pietrobon, D. <strong>Familial hemiplegic migraine mutations increase Ca(2+) influx through single human Ca(v)2.1 channels and decrease maximal Ca(v)2.1 current density in neurons.</strong> Proc. Nat. Acad. Sci. 99: 13284-13289, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12235360/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12235360</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12235360[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.192242399" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12235360">Tottene et al. (2002)</a> hypothesized that these 2 apparently contradictory effects may underlie parallel processes of migraine and aura. This notion came from the clinical evidence that the migraine aura and the headache are not necessarily sequential, and that the aura may not be the trigger for the pain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12235360" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By studying mouse hippocampal neurons transfected with 4 human FHM1-related CACNA1A mutations (R192Q, T666M, V714A, and I1811L), <a href="#5" class="mim-tip-reference" title="Cao, Y.-Q., Tsien, R. W. <strong>Effects of familial hemiplegic migraine type 1 mutations on neuronal P/Q-type Ca(2+) channel activity and inhibitory synaptic transmission.</strong> Proc. Nat. Acad. Sci. 102: 2590-2595, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15699344/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15699344</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15699344[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.0409896102" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15699344">Cao and Tsien (2005)</a> observed that all 4 mutations resulted in decreased channel current without a change in voltage dependence. The mutant P/Q calcium channels were associated with a defect in GABA inhibitory transmission, although overall basal inhibitory transmission remained well preserved owing to a shift to N-type calcium channels. This shift increased the susceptibility to G protein-coupled modulation of presynaptic neurotransmission, which may be weakened in a heightened state of neuromodulation, like that provoked by triggers of migraine such as stress. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15699344" 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 approximately 20% of cases of FHM, the disease is associated with a mild permanent cerebellar ataxia which may be progressive (PCA). The CACNA1A gene is involved in about 50% of unselected hemiplegic migraine families and in all families with FHM/PCA. <a href="#16" class="mim-tip-reference" title="Ducros, A., Denier, C., Joutel, A., Vahedi, K., Michel, A., Darcel, F., Madigand, M., Guerouaou, D., Tison, F., Julien, J., Hirsch, E., Chedru, F., Bisgard, C., Lucotte, G., Despres, P., Billard, C., Barthez, M. A., Ponsot, G., Bousser, M. G., Tournier-Lasserve, E. <strong>Recurrence of the T666M calcium channel CACNA1A gene mutation in familial hemiplegic migraine with progressive cerebellar ataxia.</strong> Am. J. Hum. Genet. 64: 89-98, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9915947/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9915947</a>] [<a href="https://doi.org/10.1086/302192" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9915947">Ducros et al. (1999)</a> screened 16 families and 3 nonfamilial cases with HPM/PCA for specific CACNA1A mutations and found 9 families and 1 nonfamilial case with the same T666M mutation (<a href="#0002">601011.0002</a>), 1 novel mutation (D715E; <a href="#0010">601011.0010</a>) in 1 family, and no CAG repeat expansion. Both T666M and D715E substitutions were absent in 12 probands belonging to pure HPM families whose disease appeared to be linked to CACNA1A. Finally, haplotyping with neighboring markers suggested that T666M arose through recurrent mutational events. These data suggested that the PCA observed in 20% of HPM families results from specific pathophysiologic mechanisms. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9915947" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#15" class="mim-tip-reference" title="Ducros, A., Denier, C., Joutel, A., Cecillon, M., Lescoat, C., Vahedi, K., Darcel, F., Vicaut, E., Bousser, M.-G., Tournier-Lasserve, E. <strong>The clinical spectrum of familial hemiplegic migraine associated with mutations in a neuronal calcium channel.</strong> New Eng. J. Med. 345: 17-24, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11439943/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11439943</a>] [<a href="https://doi.org/10.1056/NEJM200107053450103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11439943">Ducros et al. (2001)</a> found 9 mutations in the CACNA1A gene in 15 of 16 probands of families affected by hemiplegic migraine and cerebellar signs, in 2 of 3 subjects with sporadic hemiplegic migraine and cerebellar signs, and in 4 of 12 probands of families affected by pure hemiplegic migraine. Genotyping of probands and relatives identified a total of 117 subjects with mutations whose clinical manifestations were assessed in detail. Of the subjects with mutations, 89% had attacks of hemiplegic migraine. One-third had severe attacks with coma, prolonged hemiplegia, or both, with full recovery. All 9 mutations, including 5 newly identified ones, were missense mutations. Six mutations were associated with hemiplegic migraine and cerebellar signs, and 83% of the subjects with these 6 mutations had nystagmus, ataxia, or both. Three mutations were associated with pure hemiplegic migraine. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11439943" 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="#35" class="mim-tip-reference" title="Kim, J.-S., Yue, Q., Jen, J. C., Nelson, S. F., Baloh, R. W. <strong>Familial migraine with vertigo: no mutations found in CACNA1A.</strong> Am. J. Med. Genet. 79: 148-151, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9741473/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9741473</a>] [<a href="https://doi.org/10.1002/(sici)1096-8628(19980901)79:2<148::aid-ajmg11>3.0.co;2-j" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9741473">Kim et al. (1998)</a> sought mutations in the CACNA1A gene in 9 propositi of families with migraine headaches and episodic vertigo inherited in an autosomal dominant pattern. All 47 exons and flanking introns were subjected to SSCP analysis of PCR-amplified genomic DNA. Several polymorphisms were found, but no mutations were identified in any of the 47 exons of the 9 patients. They also determined the CAG repeat length at the 3-prime end of CACNA1A. No index case had a CAG repeat length greater than 13 (normal less than 17). Thus, mutations in CACNA1A must be uncommon in families with migraine headaches and episodic vertigo. Other ion channel genes expressed in the brain and inner ear remained candidate genes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9741473" 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="#42" class="mim-tip-reference" title="Labrum, R. W., Rajakulendran, S., Graves, T. D., Eunson, L. H., Bevan, R., Sweeney, M. G., Hammans, S. R., Tubridy, N., Britton, T., Carr, L. J., Ostergaard, J. R., Kennedy, C. R., Al-Memar, A., Kullmann, D. M., Schorge, S., Temple, K., Davis, M. B., Hanna, M. G. <strong>Large scale calcium channel gene rearrangements in episodic ataxia and hemiplegic migraine: implications for diagnostic testing.</strong> J. Med. Genet. 46: 786-791, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19586927/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19586927</a>] [<a href="https://doi.org/10.1136/jmg.2009.067967" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19586927">Labrum et al. (2009)</a> used multiplex ligation-dependent probe amplification to screen for large-scale genetic rearrangements in CACNA1A in 53 patients with a clinical diagnosis of episodic ataxia type 2 or familial hemiplegic migraine type 1 in whom sequencing analysis was negative for CACNA1A point mutations. They identified a large-scale deletion in 1 patient with FHM1 (<a href="#0034">601011.0034</a>) and in several patients with EA2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19586927" 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>Spinocerebellar Ataxia 6</em></strong></p><p>
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<a href="#72" class="mim-tip-reference" title="Zhuchenko, O., Bailey, J., Bonnen, P., Ashizawa, T., Stockton, D. W., Amos, C., Dobyns, W. B., Subramony, S. H., Zoghbi, H. Y., Lee, C. C. <strong>Autosomal dominant cerebellar ataxia (SCA6) associated with small polyglutamine expansions in the alpha(1A)-voltage-dependent calcium channel.</strong> Nature Genet. 15: 62-69, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8988170/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8988170</a>] [<a href="https://doi.org/10.1038/ng0197-62" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8988170">Zhuchenko et al. (1997)</a> identified expansion of a CAG repeat (<a href="#0007">601011.0007</a>) predicted to code for polyglutamine in the C-terminal coding region of the CACNL1A4 gene in families with slowly progressive spinocerebellar ataxia designated SCA6 (<a href="/entry/183086">183086</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8988170" 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>Analysis of CAG repeat expansion in the CACNL1A4 gene by <a href="#29" class="mim-tip-reference" title="Ishikawa, K., Tanaka, H., Saito, M., Ohkoshi, N., Fujita, T., Yoshizawa, K., Ikeuchi, T., Watanabe, M., Hayashi, A., Takiyama, Y., Nishizawa, M., Nakano, I., Matsubayashi, K., Miwa, M., Shoji, S., Kanazawa, I., Tsuji, S., Mizusawa, H. <strong>Japanese families with autosomal dominant pure cerebellar ataxia map to chromosome 19p13.1-p13.2 and are strongly associated with mild CAG expansions in the spinocerebellar ataxia type 6 gene in chromosome 19p13.1.</strong> Am J. Hum. Genet. 61: 336-346, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9311738/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9311738</a>] [<a href="https://doi.org/10.1086/514867" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9311738">Ishikawa et al. (1997)</a> revealed expansion in 8 of 15 Japanese families with autosomal dominant cerebellar ataxia; all affected individuals had larger alleles (range of CAG repeats 21 to 25), compared with alleles observed in neurologically normal Japanese (range 5 to 20 repeats). Inverse correlation between the CAG-repeat number and the age of onset was found in affected individuals with expansion. The number of CAG repeats in expanded chromosomes was completely stable within each family, which was consistent with the fact that anticipation was not statistically proved in these SCA6 families. <a href="#29" class="mim-tip-reference" title="Ishikawa, K., Tanaka, H., Saito, M., Ohkoshi, N., Fujita, T., Yoshizawa, K., Ikeuchi, T., Watanabe, M., Hayashi, A., Takiyama, Y., Nishizawa, M., Nakano, I., Matsubayashi, K., Miwa, M., Shoji, S., Kanazawa, I., Tsuji, S., Mizusawa, H. <strong>Japanese families with autosomal dominant pure cerebellar ataxia map to chromosome 19p13.1-p13.2 and are strongly associated with mild CAG expansions in the spinocerebellar ataxia type 6 gene in chromosome 19p13.1.</strong> Am J. Hum. Genet. 61: 336-346, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9311738/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9311738</a>] [<a href="https://doi.org/10.1086/514867" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9311738">Ishikawa et al. (1997)</a> concluded that more than half of Japanese cases of ADPCA map to 19p and are strongly associated with the mild CAG expansion in the SCA6/CACNL1A4 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9311738" 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>Idiopathic Generalized Epilepsy</em></strong></p><p>
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<a href="#8" class="mim-tip-reference" title="Chioza, B., Wilkie, H., Nashef, L., Blower, J., McCormick, D., Sham, P., Asherson, P., Makoff, A. J. <strong>Association between the alpha-1A calcium channel gene CACNA1A and idiopathic generalized epilepsy.</strong> Neurology 56: 1245-1246, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11342703/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11342703</a>] [<a href="https://doi.org/10.1212/wnl.56.9.1245" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11342703">Chioza et al. (2001)</a> provided direct evidence that the CACNA1A gene is involved in the etiology of idiopathic generalized epilepsy (IGE; <a href="/entry/600669">600669</a>). They analyzed 4 single nucleotide polymorphisms (SNPs) from patients with IGE and found that 1 of them, SNP8, showed significant association with the disease. Because SNP8 is a silent polymorphism, the authors suggested that the association must be with a closely linked variant. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11342703" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Developmental and Epileptic Encephalopathy 42</em></strong></p><p>
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In 5 patients, including 2 sibs, with developmental and epileptic encephalopathy-42 (DEE42; <a href="/entry/617106">617106</a>), the <a href="#21" class="mim-tip-reference" title="Epi4K Consortium. <strong>De novo mutations in SLC1A2 and CACNA1A are important causes of epileptic encephalopathies.</strong> Am. J. Hum. Genet. 99: 287-298, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27476654/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27476654</a>] [<a href="https://doi.org/10.1016/j.ajhg.2016.06.003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27476654">Epi4K Consortium (2016)</a> identified 4 different heterozygous mutations in the CACNA1A gene (<a href="#0017">601011.0017</a>, <a href="#0035">601011.0035</a>-<a href="#0037">601011.0037</a>). The mutations were found by targeted sequencing of 27 candidate genes in 531 patients with a similar disorder. Functional studies of the variants and studies of patient cells were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27476654" 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="#27" class="mim-tip-reference" title="Hoffman, E. P., Gardner, K. <strong>Ion channels--molecular divining rods hit their clinical mark. (Editorial)</strong> New Eng. J. Med. 336: 1599-1600, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9164819/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9164819</a>] [<a href="https://doi.org/10.1056/NEJM199705293362211" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9164819">Hoffman and Gardner (1997)</a> pointed out that a drug designed to correct for the calcium-channel defect in patients with mutations of the CACNL1A4 gene may need to be completely 'phenotype-specific' as well as 'channel-specific' and may need to modulate the activity of the calcium channel differently between several disorders, despite the shared site of the biochemical defect. Conceivably, inhibitors of channel function may be effective in disorders caused by change-of-function mutations (e.g., in patients with hemiplegic migraine), whereas agents that stimulate the same channel might be beneficial in patients with loss-of-function mutations (such as those in episodic ataxia). Drugs that modulate the level of function of the channels may have little efficacy in patients with the SCA6 phenotype, since this disorder results from progressive cerebellar cell loss which is probably due to neurotoxicity of the polyglutamine peptide that is mutated in the disorder. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9164819" 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 a positional cloning approach, <a href="#23" class="mim-tip-reference" title="Fletcher, C. F., Lutz, C. M., O'Sullivan, T. N., Shaughnessy, J. D, Jr., Hawkes, R., Frankel, W. N., Copeland, N. G., Jenkins, N. A. <strong>Absence epilepsy in tottering mutant mice is associated with calcium channel defects.</strong> Cell 87: 607-617, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8929530/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8929530</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)81381-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8929530">Fletcher et al. (1996)</a> identified an alpha-1 voltage-sensitive Ca(2+) channel gene that is mutated in the 'tottering' mutations in tg and tg(la) mice. The tg mutation is a well-studied mutation that gives rise to behavioral arrest seizures, which may be compared to human absence (or petit mal) epilepsy (<a href="/entry/600131">600131</a>) and cerebellar ataxia. The tottering phenotype also includes motor seizures. <a href="#23" class="mim-tip-reference" title="Fletcher, C. F., Lutz, C. M., O'Sullivan, T. N., Shaughnessy, J. D, Jr., Hawkes, R., Frankel, W. N., Copeland, N. G., Jenkins, N. A. <strong>Absence epilepsy in tottering mutant mice is associated with calcium channel defects.</strong> Cell 87: 607-617, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8929530/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8929530</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)81381-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8929530">Fletcher et al. (1996)</a> noted that the tg leaner mice, tg(la), suffer from absence seizures but do not have motor seizures. These mice are severely ataxic. <a href="#23" class="mim-tip-reference" title="Fletcher, C. F., Lutz, C. M., O'Sullivan, T. N., Shaughnessy, J. D, Jr., Hawkes, R., Frankel, W. N., Copeland, N. G., Jenkins, N. A. <strong>Absence epilepsy in tottering mutant mice is associated with calcium channel defects.</strong> Cell 87: 607-617, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8929530/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8929530</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)81381-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8929530">Fletcher et al. (1996)</a> mapped the tg phenotype to mouse chromosome 8 in the vicinity of the Junb gene (<a href="/entry/165161">165161</a>). <a href="#23" class="mim-tip-reference" title="Fletcher, C. F., Lutz, C. M., O'Sullivan, T. N., Shaughnessy, J. D, Jr., Hawkes, R., Frankel, W. N., Copeland, N. G., Jenkins, N. A. <strong>Absence epilepsy in tottering mutant mice is associated with calcium channel defects.</strong> Cell 87: 607-617, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8929530/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8929530</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)81381-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8929530">Fletcher et al. (1996)</a> evaluated the Ca(2+) channel gene as a candidate for the tg locus using RT-PCR and sequencing. In the tg(la) mice they demonstrated a single G-to-A change in a splice donor site in the portion of the mouse gene encoding the putative regulatory C-terminal domain of the channel. This mutation resulted in several aberrant mRNA species, including insertion of 98 nucleotides at position 5901/2 and deletion of nucleotides 5763-5901, either of which altered the reading frame 3-prime to the mutations. The tg transcript contained a C-to-A transversion at position 1802 relative to the control sequence. <a href="#23" class="mim-tip-reference" title="Fletcher, C. F., Lutz, C. M., O'Sullivan, T. N., Shaughnessy, J. D, Jr., Hawkes, R., Frankel, W. N., Copeland, N. G., Jenkins, N. A. <strong>Absence epilepsy in tottering mutant mice is associated with calcium channel defects.</strong> Cell 87: 607-617, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8929530/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8929530</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)81381-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8929530">Fletcher et al. (1996)</a> reported that this alteration leads to a nonconservative proline-to-leucine amino acid substitution that may affect the pore function of the Ca(2+) channel. <a href="#23" class="mim-tip-reference" title="Fletcher, C. F., Lutz, C. M., O'Sullivan, T. N., Shaughnessy, J. D, Jr., Hawkes, R., Frankel, W. N., Copeland, N. G., Jenkins, N. A. <strong>Absence epilepsy in tottering mutant mice is associated with calcium channel defects.</strong> Cell 87: 607-617, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8929530/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8929530</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)81381-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8929530">Fletcher et al. (1996)</a> noted that this is the first gene identified as being involved in absence epilepsy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8929530" 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>The alpha-1 voltage-sensitive Ca(2+) channel sequence reported by <a href="#23" class="mim-tip-reference" title="Fletcher, C. F., Lutz, C. M., O'Sullivan, T. N., Shaughnessy, J. D, Jr., Hawkes, R., Frankel, W. N., Copeland, N. G., Jenkins, N. A. <strong>Absence epilepsy in tottering mutant mice is associated with calcium channel defects.</strong> Cell 87: 607-617, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8929530/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8929530</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)81381-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8929530">Fletcher et al. (1996)</a> is the mouse homolog of the human Ca(2+) channel alpha subunit, also designated CACNL1A4. It is noteworthy that the CACNL1A4 gene maps to chromosome 19p13 in a region that is homologous to the region of mouse chromosome 8 where tg maps. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8929530" 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 provocatively entitled minireview, 'Migraines in Mice?,' <a href="#26" class="mim-tip-reference" title="Hess, E. J. <strong>Migraines in mice?</strong> Cell 87: 1149-1151, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8980220/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8980220</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)81809-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8980220">Hess (1996)</a> compared the tottering/leaner mouse mutations with the human mutations in CACNL1A4. She referred to inherited ion channel mutations as channelopathies. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8980220" 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="#60" class="mim-tip-reference" title="Thibault, O., Landfield, P. W. <strong>Increase in single L-type calcium channels in hippocampal neurons during aging.</strong> Science 272: 1017-1019, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8638124/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8638124</a>] [<a href="https://doi.org/10.1126/science.272.5264.1017" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8638124">Thibault and Landfield (1996)</a> used partially dissociated hippocampal slice preparations to analyze single Ca(2+) channel activity in neurons of adult and aged rats. They reported that total L-type Ca(2+) channel activity increased primarily because of increased density of functional channels. They noted that learning in aged animals was inversely correlated with channel density. <a href="#60" class="mim-tip-reference" title="Thibault, O., Landfield, P. W. <strong>Increase in single L-type calcium channels in hippocampal neurons during aging.</strong> Science 272: 1017-1019, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8638124/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8638124</a>] [<a href="https://doi.org/10.1126/science.272.5264.1017" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8638124">Thibault and Landfield (1996)</a> postulated that the observed increase in functional Ca(2+) channels with aging could underlie the vulnerability of neurons to age-associated neurodegenerative conditions. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8638124" 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="#65" class="mim-tip-reference" title="van den Maagdenberg, A. M. J. M., Pietrobon, D., Pizzorusso, T., Kaja, S., Broos, L. A. M., Cesetti, T., van de Ven, R. C. G., Tottene, A., van der Kaa, J., Plomp, J. J., Frants, R. R., Ferrari, M. D. <strong>A Cacna1a knockin migraine mouse model with increased susceptibility to cortical spreading depression.</strong> Neuron 41: 701-710, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15003170/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15003170</a>] [<a href="https://doi.org/10.1016/s0896-6273(04)00085-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15003170">Van den Maagdenberg et al. (2004)</a> generated a transgenic mouse model carrying the human CACNA1A mutation R192Q (<a href="#0001">601011.0001</a>). Cultured cerebellar granule cells from R192Q mice showed increased Ca(v)2.1 channel current densities, which were activated at more negative voltages than wildtype channels. Neuromuscular synapses with the mutant CACNA1A channels had increased induced neurotransmission and increased spontaneous miniature endplate potential frequency at low Ca(2+) levels compared to controls, consistent with a gain of function. In addition, the intact transgenic animal showed increased susceptibility to cortical spreading depression, the likely mechanism for migraine aura. <a href="#65" class="mim-tip-reference" title="van den Maagdenberg, A. M. J. M., Pietrobon, D., Pizzorusso, T., Kaja, S., Broos, L. A. M., Cesetti, T., van de Ven, R. C. G., Tottene, A., van der Kaa, J., Plomp, J. J., Frants, R. R., Ferrari, M. D. <strong>A Cacna1a knockin migraine mouse model with increased susceptibility to cortical spreading depression.</strong> Neuron 41: 701-710, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15003170/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15003170</a>] [<a href="https://doi.org/10.1016/s0896-6273(04)00085-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15003170">Van den Maagdenberg et al. (2004)</a> concluded that the underlying mechanism in FHM is cortical hyperexcitability due to excessive release of excitatory amino acids in response to increased Ca(2+) influx through a defective Ca(v)2.1 channel. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15003170" 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>Near postnatal day 10, mice lacking P/Q-type calcium channels have difficulty walking, have absence seizures, and are ataxic and dystonic. Neurologic symptoms in these mice become more acute with age, until they are unable to walk and die at about 3 weeks of age (<a href="#34" class="mim-tip-reference" title="Jun, K., Piedras-Renteria, E. S., Smith, S. M., Wheeler, D. B., Lee, S. B., Lee, T. G., Chin, H., Adams, M. E., Scheller, R. H., Tsien, R. W., Shin, H.-S. <strong>Ablation of P/Q-type Ca(2+) channel currents, altered synaptic transmission, and progressive ataxia in mice lacking the alpha(1A)-subunit.</strong> Proc. Nat. Acad. Sci. 96: 15245-15250, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10611370/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10611370</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10611370[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.96.26.15245" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10611370">Jun et al., 1999</a>). Mutant animals also show increased density of T-type channels (CACNA1G; <a href="/entry/604065">604065</a>) that support low-threshold action potentials in the absence of P/Q-type channels (<a href="#54" class="mim-tip-reference" title="Song, I., Kim, D., Choi, S., Sun, M., Kim, Y., Shin, H.-S. <strong>Role of the alpha-1G T-type calcium channel in spontaneous absence seizures in mutant mice.</strong> J. Neurosci. 24: 5249-5257, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15175395/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15175395</a>] [<a href="https://doi.org/10.1523/JNEUROSCI.5546-03.2004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15175395">Song et al., 2004</a>). <a href="#45" class="mim-tip-reference" title="Llinas, R. R., Choi, S., Urbano, F. J., Shin, H.-S. <strong>Gamma-band deficiency and abnormal thalamocortical activity in P/Q-type channel mutant mice.</strong> Proc. Nat. Acad. Sci. 104: 17819-17824, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17968008/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17968008</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17968008[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.0707945104" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17968008">Llinas et al. (2007)</a> found that in vitro patch recordings of thalamic neurons from mice lacking P/Q-type channels showed no gamma band subthreshold oscillation, and voltage-sensitive dye imaging demonstrated absence of cortical gamma band-dependent columnar activation involving cortical inhibitory interneuron activity. In vivo EEGs showed persistent absence status and dramatically reduced gamma band activity. Pharmacologic blockade of T-type channels left knockout mice in a coma-like state, indicating that increased T-type channel expression in thalamocortical neurons was causally related to generation of absence seizures. <a href="#45" class="mim-tip-reference" title="Llinas, R. R., Choi, S., Urbano, F. J., Shin, H.-S. <strong>Gamma-band deficiency and abnormal thalamocortical activity in P/Q-type channel mutant mice.</strong> Proc. Nat. Acad. Sci. 104: 17819-17824, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17968008/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17968008</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17968008[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.0707945104" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17968008">Llinas et al. (2007)</a> concluded that P/Q-type calcium channels are essential for generation of gamma band activity and resultant cognitive function. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15175395+17968008+10611370" 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="#69" class="mim-tip-reference" title="Watase, K., Barrett, C. F., Miyazaki, T., Ishiguro, T., Ishikawa, K., Hu, Y., Unno, T., Sun, Y., Kasai, S., Watanabe, M., Gomez, C. M., Mizusawa, H., Tsien, R. W., Zoghbi, H. Y. <strong>Spinocerebellar ataxia type 6 knockin mice develop a progressive neuronal dysfunction with age-dependent accumulation of mutant Ca(v)2.1 channels.</strong> Proc. Nat. Acad. Sci. 105: 11987-11992, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18687887/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18687887</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18687887[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.0804350105" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18687887">Watase et al. (2008)</a> found that knockin mice expressing a hyperexpanded polyglutamine (84Q) Cacna1a repeat developed progressive motor impairment consistent with SCA6. Knockin mice with normal 14 CAG or expanded 30 CAG repeats did not show such defects. Electrophysiologic analysis of cerebellar Purkinje cells revealed similar calcium channel current density among the 3 mouse models, although all were decreased compared to wildtype due to decreased channel abundance. Neither voltage sensitivity of activation nor inactivation was altered in the Sca6(84Q) neurons, suggesting that the expanded CAG repeat does not per se affect the intrinsic electrophysiologic properties of the channels. Mice with the hyperexpanded polyglutamine repeat showed cytoplasmic neuronal inclusions, consistent with aggregation of mutant calcium channels. <a href="#69" class="mim-tip-reference" title="Watase, K., Barrett, C. F., Miyazaki, T., Ishiguro, T., Ishikawa, K., Hu, Y., Unno, T., Sun, Y., Kasai, S., Watanabe, M., Gomez, C. M., Mizusawa, H., Tsien, R. W., Zoghbi, H. Y. <strong>Spinocerebellar ataxia type 6 knockin mice develop a progressive neuronal dysfunction with age-dependent accumulation of mutant Ca(v)2.1 channels.</strong> Proc. Nat. Acad. Sci. 105: 11987-11992, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18687887/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18687887</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18687887[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.0804350105" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18687887">Watase et al. (2008)</a> concluded that the pathogenesis of SCA6 is related to an age-dependent process accompanied by accumulation of mutant CACNA1A channels resulting in a toxic gain-of-function effect. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18687887" 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="#67" class="mim-tip-reference" title="van Oosterhout, F., Michel, S., Deboer, T., Houben, T., van de Ven, R. C. G., Albus, H., Westerhout, J., Vansteensel, M. J., Ferrari, M. D., van den Maagdenberg, A. M. J. M., Meijer, J. H. <strong>Enhanced circadian phase resetting in R192Q Cav2.1 calcium channel migraine mice.</strong> Ann. Neurol. 64: 315-324, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18825664/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18825664</a>] [<a href="https://doi.org/10.1002/ana.21418" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18825664">Van Oosterhout et al. (2008)</a> found that R192Q-mutant mice showed atypical phase resetting of their circadian rhythms when subjected to 6-hour advance shifts of the light/dark cycle. Compared to controls, mutant mice showed a more than 2-fold enhanced adjustment of behavioral wheel-running activity and EEG patterns, as well as enhanced shifts of electrical activity of suprachiasmatic neurons (SCN) in vivo. No differences were observed for a 6-hour delay. The physiologic inhibitory process appeared to be mediated by CACNA1A channel-dependent afferent signaling from extra-SCN brain areas to the SCN. <a href="#67" class="mim-tip-reference" title="van Oosterhout, F., Michel, S., Deboer, T., Houben, T., van de Ven, R. C. G., Albus, H., Westerhout, J., Vansteensel, M. J., Ferrari, M. D., van den Maagdenberg, A. M. J. M., Meijer, J. H. <strong>Enhanced circadian phase resetting in R192Q Cav2.1 calcium channel migraine mice.</strong> Ann. Neurol. 64: 315-324, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18825664/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18825664</a>] [<a href="https://doi.org/10.1002/ana.21418" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18825664">Van Oosterhout et al. (2008)</a> interpreted the findings as suggesting that abrupt circadian rhythm changes may trigger migraine attacks, possibly because patients have an inadequate adaptation mechanism. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18825664" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#19" class="mim-tip-reference" title="Eikermann-Haerter, K., Dilekoz, E., Kudo, C., Savitz, S. I., Waeber, C., Baum, M. J., Ferrari, M. D., van den Maagdenberg, A. M. J. M., Moskowitz, M. A., Ayata, C. <strong>Genetic and hormonal factors modulate spreading depression and transient hemiparesis in mouse models of familial hemiplegic migraine type 1.</strong> J. Clin. Invest. 119: 99-109, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19104150/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19104150</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19104150[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI36059" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19104150">Eikermann-Haerter et al. (2009)</a> found that transgenic mice expressing the R192Q or S218L (<a href="#0017">601011.0017</a>) CACNA1A mutations had increased frequency and speed of spreading depression and enhanced corticostriatal propagation compared to wildtype mice after induction. Mutant mice also developed severe and prolonged neurologic deficits. The susceptibility to spreading depression and neurologic deficits was affected by allele dosage and was higher in S218L than R192Q mutants, similar to observations in humans. Female mutant mice were more susceptible to spreading depression and neurologic deficits than males, and this sex difference was abrogated by ovariectomy or senescence and partially restored by estrogen replacement. The findings implicating ovarian hormones in the observed sex differences in humans with FHM1. In a follow-up study, <a href="#18" class="mim-tip-reference" title="Eikermann-Haerter, K., Baum, M. J., Ferrari, M. D., van den Maagdenberg, A. M. J. M., Moskowitz, M. A., Ayata, C. <strong>Androgenic suppression of spreading depression in familial hemiplegic migraine type 1 mutant mice.</strong> Ann. Neurol. 66: 564-568, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19847904/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19847904</a>] [<a href="https://doi.org/10.1002/ana.21779" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19847904">Eikermann-Haerter et al. (2009)</a> demonstrated that orchidectomy in R192Q-mutant male mice increased susceptibility to cortical spreading depression, and that chronic testosterone replacement restored the lower susceptibility in mutant males. These findings implicated androgens as a modulating factor in genetically-enhanced susceptibility to cortical spreading depression. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=19104150+19847904" 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="#66" class="mim-tip-reference" title="van den Maagdenberg, A. M. J. M., Pizzorusso, T., Kaja, S., Terpolilli, N., Shapovalova, M., Hoebeek, F. E., Barrett, C. F., Gherardini, L., van de Ven, R. C. G., Todorov, B., Broos, L. A. M., Tottene, A., Gao, Z., Fodor, M., De Zeeuw, C. I., Frants, R. R., Plesnila, N., Plomp, J. J., Pietrobon, D., Ferrari, M. D. <strong>High cortical spreading depression susceptibility and migraine-associated symptoms in Ca(v)2.1 S218L mice.</strong> Ann. Neurol. 67: 85-98, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20186955/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20186955</a>] [<a href="https://doi.org/10.1002/ana.21815" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20186955">Van den Maagdenberg et al. (2010)</a> found that transgenic S218L homozygous mice had mild cerebellar ataxia and reduced arborization of proximal primary dendrites of cerebellar Purkinje neurons. They exhibited 2 types of spontaneous attacks: those consistent with hemiparesis observed in patients with FHM1 and attacks of generalized seizures that were fatal in some cases. In addition, homozygous mutant mice developed significant brain edema 24 hours after mild head impact, indicating that these mice mimicked the broad complex neurologic spectrum of spontaneous episodic, mild impact-triggered, and permanent clinical features seen in human patients heterozygous for the S218L mutation. In vitro studies on mouse cerebellar granule neurons showed that the S218L mutation increased whole-cell calcium current density at negative voltages, resulted in a leftward shift in voltage-dependent activation, and increased spontaneous neurotransmitter release, consistent with a gain of function. The calcium current in homozygous mutant cells was 6.6 times greater than that in wildtype neurons. Further studies showed that mutant mice had an increased susceptibility to successive cortical spreading depression events compared to wildtype and mutant R192Q mice. In general, all of the changes associated with the S218L mutation were quantitatively more pronounced than those observed with the R192Q mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20186955" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#13" class="mim-tip-reference" title="Du, X., Wang, J., Zhu, H., Rinaldo, L., Lamar, K.-M., Palmenberg, A. C., Hansel, C., Gomez, C. M. <strong>Second cistron in CACNA1A gene encodes a transcription factor mediating cerebellar development and SCA6.</strong> Cell 154: 118-133, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23827678/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23827678</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23827678[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/10.1016/j.cell.2013.05.059" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23827678">Du et al. (2013)</a> found that expression of alpha-1act partially improved the phenotype of Cacna1a-null mice and provided a modest improvement in survival. Expression of alpha-1act also partially improved synaptic activity and connections in Cacna1a-null cerebellar slice preparation. Alpha-1act with a pathologic polyQ expansion reduced viability of PC12 cells in culture and mediated ataxia and cerebellar cortical atrophy in transgenic mice. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23827678" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By characterizing a dose-dependent Cacna1a gene deficiency mouse model, <a href="#14" class="mim-tip-reference" title="Du, X., Wei, C., Hejazi Pastor, D. P., Rao, E. R., Li, Y., Grasselli, G., Godfrey, J., Palmenberg, A. C., Andrade, J., Hansel, C., Gomez, C. M. <strong>Alpha-1ACT is essential for survival and early cerebellar programming in a critical neonatal window.</strong> Neuron 102: 770-785, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30922876/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30922876</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30922876[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/10.1016/j.neuron.2019.02.036" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30922876">Du et al. (2019)</a> found that alpha-1Act drove dynamic gene regulation networks within cerebellar Purkinje cells and was indispensable for neonatal survival. Perinatal loss of alpha-1Act disrupted neurogenesis and synaptic regulatory networks, leading to motor dysfunction. In contrast, elimination of alpha-1Act in adulthood had minimal effects on cerebellum. The authors demonstrated a similar age-dependent pattern of alpha-1ACT gene regulation in human cerebellum, validating their observations in mouse cerebellum. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30922876" 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>ALLELIC VARIANTS (<a href="/help/faq#1_4"></strong>
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<strong>37 Selected Examples</a>):</strong>
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<a href="/allelicVariants/601011" class="btn btn-default" role="button"> Table View </a>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=601011[MIM]" class="btn btn-default mim-tip-hint" role="button" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a>
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<strong>.0001 MIGRAINE, FAMILIAL HEMIPLEGIC, 1</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121908211 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908211;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121908211" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121908211" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000009008 OR RCV001533156 OR RCV002512926 OR RCV003231095" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009008, RCV001533156, RCV002512926, RCV003231095" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009008...</a>
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<p>In 5 unrelated families with familial hemiplegic migraine (FHM1; <a href="/entry/141500">141500</a>), <a href="#48" class="mim-tip-reference" title="Ophoff, R. A., Terwindt, G. M., Vergouwe, M. N., van Eijk, R., Oefner, P. J., Hoffman, S. M. G., Lamerdin, J. E., Mohrenweiser, H. W., Bulman, D. E., Ferrari, M., Haan, J., Lindhout, D., van Ommen, G.-J. B., Hofker, M. H., Ferrari, M. D., Frants, R. R. <strong>Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca(2+) channel gene CACNL1A4.</strong> Cell 87: 543-552, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8898206/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8898206</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)81373-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8898206">Ophoff et al. (1996)</a> identified 4 different missense mutations in the CACNL1A4 gene. One of these mutations was a G-to-A transition at nucleotide 850 in exon 4 resulting in an arg192-to-gln (R192Q) amino acid substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8898206" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0002" class="mim-anchor"></a>
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<strong>.0002 MIGRAINE, FAMILIAL HEMIPLEGIC, 1</strong>
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MIGRAINE, FAMILIAL HEMIPLEGIC 1, WITH PROGRESSIVE CEREBELLAR ATAXIA, INCLUDED<br />
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MIGRAINE, SPORADIC HEMIPLEGIC, WITH PROGRESSIVE CEREBELLAR ATAXIA, INCLUDED
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CACNA1A, THR666MET
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121908212 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908212;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121908212" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121908212" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000009009 OR RCV000009010 OR RCV000504541 OR RCV000516650 OR RCV000802118 OR RCV001533159 OR RCV002051776 OR RCV002415406 OR RCV003233067 OR RCV005025039" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009009, RCV000009010, RCV000504541, RCV000516650, RCV000802118, RCV001533159, RCV002051776, RCV002415406, RCV003233067, RCV005025039" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009009...</a>
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<p>In families with hemiplegic migraine (FHM1; <a href="/entry/141500">141500</a>), <a href="#48" class="mim-tip-reference" title="Ophoff, R. A., Terwindt, G. M., Vergouwe, M. N., van Eijk, R., Oefner, P. J., Hoffman, S. M. G., Lamerdin, J. E., Mohrenweiser, H. W., Bulman, D. E., Ferrari, M., Haan, J., Lindhout, D., van Ommen, G.-J. B., Hofker, M. H., Ferrari, M. D., Frants, R. R. <strong>Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca(2+) channel gene CACNL1A4.</strong> Cell 87: 543-552, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8898206/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8898206</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)81373-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8898206">Ophoff et al. (1996)</a> discovered a C-to-T transition in nucleotide 2272 of CACNL1A4, resulting in a thr666-to-met (T666M) amino acid substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8898206" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#24" class="mim-tip-reference" title="Friend, K. L., Crimmins, D., Phan, T. G., Sue, C. M., Colley, A., Fung, V. S. C., Morris, J. G. L., Sutherland, G. R., Richards, R. I. <strong>Detection of a novel missense mutation and second recurrent mutation in the CACNA1A gene in individuals with EA-2 and FHM.</strong> Hum. Genet. 105: 261-265, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10987655/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10987655</a>] [<a href="https://doi.org/10.1007/s004390051099" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10987655">Friend et al. (1999)</a> found this recurrent mutation in exon 16 in an Australian patient with familial hemiplegic migraine. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10987655" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#16" class="mim-tip-reference" title="Ducros, A., Denier, C., Joutel, A., Vahedi, K., Michel, A., Darcel, F., Madigand, M., Guerouaou, D., Tison, F., Julien, J., Hirsch, E., Chedru, F., Bisgard, C., Lucotte, G., Despres, P., Billard, C., Barthez, M. A., Ponsot, G., Bousser, M. G., Tournier-Lasserve, E. <strong>Recurrence of the T666M calcium channel CACNA1A gene mutation in familial hemiplegic migraine with progressive cerebellar ataxia.</strong> Am. J. Hum. Genet. 64: 89-98, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9915947/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9915947</a>] [<a href="https://doi.org/10.1086/302192" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9915947">Ducros et al. (1999)</a> screened 16 families and 3 nonfamilial cases with hemiplegic migraine associated with progressive cerebellar ataxia (see <a href="/entry/141500">141500</a>). They found the T666M mutation in 9 families and 1 nonfamilial case. The T666M mutation was absent in 12 probands belonging to pure HPM families whose disease appeared to be linked to CACNA1A. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9915947" 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="#58" class="mim-tip-reference" title="Terwindt, G., Kors, E., Haan, J., Vermeulen, F., van den Maagdenberg, A., Frants, R., Ferrari, M. <strong>Mutation analysis of the CACNA1A calcium channel subunit gene in 27 patients with sporadic hemiplegic migraine.</strong> Arch. Neurol. 59: 1016-1018, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12056940/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12056940</a>] [<a href="https://doi.org/10.1001/archneur.59.6.1016" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12056940">Terwindt et al. (2002)</a> studied 27 patients with sporadic hemiplegic migraine and found the T666M mutation in a 78-year-old woman who had characteristic attacks starting at age 14 as well as interictal nystagmus, dysarthria, limb and gait ataxia, and cerebellar atrophy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12056940" 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="#37" class="mim-tip-reference" title="Kors, E. E., Haan, J., Giffin, N. J., Pazdera, L., Schnittger, C., Lennox, G. G., Terwindt, G. M., Vermeulen, F. L. M. J., Van den Maagdenberg, A. M. J. M., Frants, R. R., Ferrari, M. D. <strong>Expanding the phenotypic spectrum of the CACNA1A gene T666M mutation: a description of 5 families with familial hemiplegic migraine.</strong> Arch. Neurol. 60: 684-688, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12756131/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12756131</a>] [<a href="https://doi.org/10.1001/archneur.60.5.684" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12756131">Kors et al. (2003)</a> reported the clinical symptoms of 5 families with hemiplegic migraine and the T666M mutation. Three of the families displayed cerebellar ataxia, 3 had loss of consciousness or coma associated with episodes, 1 had attacks with confusion but without hemiparesis, and 1 had progressive cognitive dysfunction. The authors emphasized the inter- and intrafamilial clinical heterogeneity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12756131" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#3" class="mim-tip-reference" title="Barrett, C. F., Cao, Y.-Q., Tsien, R. W. <strong>Gating deficiency in a familial hemiplegic migraine type 1 mutant P/Q-type calcium channel.</strong> J. Biol. Chem. 280: 24064-24071, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15795222/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15795222</a>] [<a href="https://doi.org/10.1074/jbc.M502223200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15795222">Barrett et al. (2005)</a> found that CACNA1A channels with the T666M mutation were expressed and trafficked normally to the cell surface in transfected HEK293 cells. However, T666M mutant channels exhibited defective voltage-dependent gating to support calcium influx. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15795222" 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>.0003 MIGRAINE, FAMILIAL HEMIPLEGIC, 1</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121908213 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908213;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121908213" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121908213" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000009011 OR RCV001533160" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009011, RCV001533160" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009011...</a>
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<p>In families with hemiplegic migraine (FHM1; <a href="/entry/141500">141500</a>), <a href="#48" class="mim-tip-reference" title="Ophoff, R. A., Terwindt, G. M., Vergouwe, M. N., van Eijk, R., Oefner, P. J., Hoffman, S. M. G., Lamerdin, J. E., Mohrenweiser, H. W., Bulman, D. E., Ferrari, M., Haan, J., Lindhout, D., van Ommen, G.-J. B., Hofker, M. H., Ferrari, M. D., Frants, R. R. <strong>Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca(2+) channel gene CACNL1A4.</strong> Cell 87: 543-552, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8898206/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8898206</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)81373-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8898206">Ophoff et al. (1996)</a> identified a T-to-C transition in nucleotide 2416 of the CACNL1A4 gene, resulting in a val714-to-ala (V714A) amino acid substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8898206" 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>.0004 MIGRAINE, FAMILIAL HEMIPLEGIC, 1</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121908214 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908214;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121908214" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121908214" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000009012 OR RCV001390440 OR RCV001533163 OR RCV004791199" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009012, RCV001390440, RCV001533163, RCV004791199" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009012...</a>
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<p>In 2 unrelated families, <a href="#48" class="mim-tip-reference" title="Ophoff, R. A., Terwindt, G. M., Vergouwe, M. N., van Eijk, R., Oefner, P. J., Hoffman, S. M. G., Lamerdin, J. E., Mohrenweiser, H. W., Bulman, D. E., Ferrari, M., Haan, J., Lindhout, D., van Ommen, G.-J. B., Hofker, M. H., Ferrari, M. D., Frants, R. R. <strong>Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca(2+) channel gene CACNL1A4.</strong> Cell 87: 543-552, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8898206/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8898206</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)81373-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8898206">Ophoff et al. (1996)</a> found that members with hemiplegic migraine (FHM1; <a href="/entry/141500">141500</a>) had an A-to-C transversion at nucleotide 5706 of the CACNL1A4 gene, resulting in an ile1811-to-leu (I1811L) amino acid substitution in the gene product. The mutation occurred on different 19p13 haplotypes in the 2 families, indicating that this was a recurrent mutation rather than a founder effect. Cerebellar atrophy is said to occur in approximately 40% of chromosome 19-linked HPM families but not in unlinked HPM families (<a href="#59" class="mim-tip-reference" title="Terwindt, G. M., Ophoff, R. A., Haan, J., Frants, R. R., Ferrari, M. D. <strong>Familial hemiplegic migraine: a clinical comparison of families linked and unlinked to chromosome 19.</strong> Cephalalgia 16: 153-155, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8734765/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8734765</a>] [<a href="https://doi.org/10.1046/j.1468-2982.1996.1603153.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8734765">Terwindt et al., 1996</a>). Of the 2 families with the I1811L mutation, <a href="#48" class="mim-tip-reference" title="Ophoff, R. A., Terwindt, G. M., Vergouwe, M. N., van Eijk, R., Oefner, P. J., Hoffman, S. M. G., Lamerdin, J. E., Mohrenweiser, H. W., Bulman, D. E., Ferrari, M., Haan, J., Lindhout, D., van Ommen, G.-J. B., Hofker, M. H., Ferrari, M. D., Frants, R. R. <strong>Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca(2+) channel gene CACNL1A4.</strong> Cell 87: 543-552, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8898206/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8898206</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)81373-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8898206">Ophoff et al. (1996)</a> noted that only 1 displayed cerebellar atrophy and in that family only some members were affected. Apparently other factors in this amino acid substitution further contribute to the phenotypic variability. These factors may include genetic polymorphisms elsewhere in the gene or at other channel-related loci and the net effect of other ion channels on the polarity of the cell membrane. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8734765+8898206" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs587776692 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587776692;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs587776692" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs587776692" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In 2 unrelated patients with episodic ataxia type 2 (EA2; <a href="/entry/108500">108500</a>), <a href="#48" class="mim-tip-reference" title="Ophoff, R. A., Terwindt, G. M., Vergouwe, M. N., van Eijk, R., Oefner, P. J., Hoffman, S. M. G., Lamerdin, J. E., Mohrenweiser, H. W., Bulman, D. E., Ferrari, M., Haan, J., Lindhout, D., van Ommen, G.-J. B., Hofker, M. H., Ferrari, M. D., Frants, R. R. <strong>Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca(2+) channel gene CACNL1A4.</strong> Cell 87: 543-552, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8898206/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8898206</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)81373-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8898206">Ophoff et al. (1996)</a> identified mutations resulting in a disrupted reading frame. The first of these was deletion of a single C, nucleotide 4073 in codon 1266, leading to a frameshift in the putative translation product with a stop codon in the next exon (codon 1294). See also <a href="#0006">601011.0006</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8898206" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs587776693 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587776693;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs587776693" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs587776693" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000009014 OR RCV001781208" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009014, RCV001781208" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009014...</a>
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<p>In a patient with episodic ataxia type 2 (EA2; <a href="/entry/108500">108500</a>), <a href="#48" class="mim-tip-reference" title="Ophoff, R. A., Terwindt, G. M., Vergouwe, M. N., van Eijk, R., Oefner, P. J., Hoffman, S. M. G., Lamerdin, J. E., Mohrenweiser, H. W., Bulman, D. E., Ferrari, M., Haan, J., Lindhout, D., van Ommen, G.-J. B., Hofker, M. H., Ferrari, M. D., Frants, R. R. <strong>Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca(2+) channel gene CACNL1A4.</strong> Cell 87: 543-552, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8898206/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8898206</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)81373-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8898206">Ophoff et al. (1996)</a> identified a G-to-A transition in the first nucleotide of intron 24, changing the highly conserved GT dinucleotide of the intronic 5-prime splice junction. The mutation resulted in the loss of a BsaAI restriction site. The brain-specific expression of CACNL1A4 precluded testing the hypothesis that this mutation produced aberrantly spliced RNAs by retaining the intron or utilizing other cryptic 5-prime splice sites. Such was, however, presumably the case. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8898206" 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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CACNA1A, (CAG)n REPEAT EXPANSION, 21-30 REPEATS, EX47
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000009015 OR RCV000030866" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009015, RCV000030866" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009015...</a>
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<p><a href="#72" class="mim-tip-reference" title="Zhuchenko, O., Bailey, J., Bonnen, P., Ashizawa, T., Stockton, D. W., Amos, C., Dobyns, W. B., Subramony, S. H., Zoghbi, H. Y., Lee, C. C. <strong>Autosomal dominant cerebellar ataxia (SCA6) associated with small polyglutamine expansions in the alpha(1A)-voltage-dependent calcium channel.</strong> Nature Genet. 15: 62-69, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8988170/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8988170</a>] [<a href="https://doi.org/10.1038/ng0197-62" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8988170">Zhuchenko et al. (1997)</a> identified expansion of a CAG repeat predicted to encode for polyglutamine in exon 47 of the coding region of the CACNL1A4 gene in families with slowly progressive spinocerebellar ataxia designated SCA6 (<a href="/entry/183086">183086</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8988170" 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="#46" class="mim-tip-reference" title="Matsuyama, Z., Kawakami, H., Maruyama, H., Izumi, Y., Komure, O., Udaka, F., Kameyama, M., Nishio, T., Kuroda, Y., Nishimura, M., Nakamura, S. <strong>Molecular features of the CAG repeats of spinocerebellar ataxia 6 (SCA6).</strong> Hum. Molec. Genet. 6: 1283-1287, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9259274/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9259274</a>] [<a href="https://doi.org/10.1093/hmg/6.8.1283" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9259274">Matsuyama et al. (1997)</a> analyzed 60 SCA6 individuals from 39 independent Japanese SCA6 families and found that the CAG repeat length in the CACNL1A4 gene was inversely correlated with age of onset. SCA6 chromosomes contained 21 to 30 repeat units, whereas normal chromosomes displayed 6 to 17 repeats. There was no overlap between the normal and affected CAG repeat number. Anticipation was observed clinically in all 8 parent-child pairs examined; the mean age of onset was significantly lower (P = 0.0042) in children than in parents. However, a parent-child analysis showed an increase in the expansion of CAG repeats only in 1 pair and no diminution in any affected cases. The results suggested that factors other than CAG repeats may produce the clinical anticipation. A homozygotic case could not demonstrate unequivocal gene dosage effect on the age of onset. See also <a href="#29" class="mim-tip-reference" title="Ishikawa, K., Tanaka, H., Saito, M., Ohkoshi, N., Fujita, T., Yoshizawa, K., Ikeuchi, T., Watanabe, M., Hayashi, A., Takiyama, Y., Nishizawa, M., Nakano, I., Matsubayashi, K., Miwa, M., Shoji, S., Kanazawa, I., Tsuji, S., Mizusawa, H. <strong>Japanese families with autosomal dominant pure cerebellar ataxia map to chromosome 19p13.1-p13.2 and are strongly associated with mild CAG expansions in the spinocerebellar ataxia type 6 gene in chromosome 19p13.1.</strong> Am J. Hum. Genet. 61: 336-346, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9311738/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9311738</a>] [<a href="https://doi.org/10.1086/514867" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9311738">Ishikawa et al. (1997)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9311738+9259274" 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="#51" class="mim-tip-reference" title="Riess, O., Schols, L., Bottger, H., Nolte, D., Viera-Saecker, A. M. M., Schimming, C., Kreuz, F., Macek, M., Jr., Krebsova, A., Macek, M., Sr., Klockgether, T., Zuhlke, C., Laccone, F. A. <strong>SCA6 is caused by moderate CAG expansion in the alpha(1A)-voltage-dependent calcium channel gene.</strong> Hum. Molec. Genet. 6: 1289-1293, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9259275/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9259275</a>] [<a href="https://doi.org/10.1093/hmg/6.8.1289" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9259275">Riess et al. (1997)</a> found that the SCA6 mutation accounts for approximately 10% of autosomal dominant SCA in Germany. They observed the trinucleotide expansion in 4 ataxia patients without obvious family history of the disease, indicating the necessity to search for the SCA6 (CAG)n expansion even in sporadic patients. In their series of 32 patients, onset was usually late and the (CAG)n stretch varied between 22 and 28 trinucleotide units, the shortest trinucleotide repeat expansion causing spinocerebellar ataxia. Analyzing 248 apparently healthy octogenarians, <a href="#51" class="mim-tip-reference" title="Riess, O., Schols, L., Bottger, H., Nolte, D., Viera-Saecker, A. M. M., Schimming, C., Kreuz, F., Macek, M., Jr., Krebsova, A., Macek, M., Sr., Klockgether, T., Zuhlke, C., Laccone, F. A. <strong>SCA6 is caused by moderate CAG expansion in the alpha(1A)-voltage-dependent calcium channel gene.</strong> Hum. Molec. Genet. 6: 1289-1293, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9259275/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9259275</a>] [<a href="https://doi.org/10.1093/hmg/6.8.1289" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9259275">Riess et al. (1997)</a> found 1 allele of 18 repeats, the longest normal CAG repeat in the CACNL1A4 gene reported to that time. They could demonstrate no repeat instability of the expanded allele on transmission and no repeat instability was found for the normal allele in 431 meioses in the CEPH families. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9259275" 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="#52" class="mim-tip-reference" title="Sasaki, H., Kojima, H., Yabe, I., Tashiro, K., Hamada, T., Sawa, H., Hiraga, H., Nagashima, K. <strong>Neuropathological and molecular studies of spinocerebellar ataxia type 6 (SCA6).</strong> Acta Neuropath. 95: 199-204, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9498057/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9498057</a>] [<a href="https://doi.org/10.1007/s004010050787" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9498057">Sasaki et al. (1998)</a> described neuropathologic and molecular findings in a Japanese woman who died of lymphoma at the age of 61 years after a 7-year history of progressive pure cerebellar ataxia. Neuropathologic examination showed neuronal degeneration confined to the cerebellar Purkinje cells and, to a lesser degree, the granular cells, without involvement of other CNS structures. The pathologic selectivity correlated with the localized expression of the CACNA1A gene and coincided with the neurologic manifestations. The father and a sister were also affected. Each of the affected sisters was heterozygous for an expanded allele with a repeat size that fell into the range of the SCA6 mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9498057" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using a whole-cell voltage clamp technique, <a href="#61" class="mim-tip-reference" title="Toru, S., Murakoshi, T., Ishikawa, K., Saegusa, H., Fujigasaki, H., Uchihara, T., Nagayama, S., Osanai, M., Mizusawa, H., Tanabe, T. <strong>Spinocerebellar ataxia type 6 mutation alters P-type calcium channel function.</strong> J. Biol. Chem. 275: 10893-10898, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10753886/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10753886</a>] [<a href="https://doi.org/10.1074/jbc.275.15.10893" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10753886">Toru et al. (2000)</a> demonstrated functional alterations of human alpha-1A channels carrying various polyglutamine lengths in a model of SCA6. Alpha-1A channels lacking an asparagine-proline (NP) stretch in domain IV corresponded to P-type channels expressed in Purkinje cells, the main cell that is degenerated in SCA6. Polyglutamine elongation caused a proportional negative shift of voltage-dependent inactivation, and the authors hypothesized that the resulting reduction of calcium influx may contribute to Purkinje cell death. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10753886" 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="#36" class="mim-tip-reference" title="Kordasiewicz, H. B., Thompson, R. M., Clark, H. B., Gomez, C. M. <strong>C-termini of P/Q-type Ca(2+) channel alpha1A subunits translocate to nuclei and promote polyglutamine-mediated toxicity.</strong> Hum. Molec. Genet. 15: 1587-1599, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16595610/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16595610</a>] [<a href="https://doi.org/10.1093/hmg/ddl080" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16595610">Kordasiewicz et al. (2006)</a> found that the 75-kD C-terminal fragment of CACNA1A, which is the location of the polyglutamine tract expanded in SCA6, was translocated to the nucleus, where it was toxic to cells when in the expanded state. The polyglutamine-mediated cell toxicity was dependent on nuclear localization, suggesting that specific processing and localization of the mutant protein are involved in the pathogenesis of SCA6. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16595610" 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="#44" class="mim-tip-reference" title="Li, L., Saegusa, H., Tanabe, T. <strong>Deficit of heat shock transcription factor 1-heat shock 70 kDa protein 1A axis determines the cell death vulnerability in a model of spinocerebellar ataxia type 6.</strong> Genes Cells 14: 1253-1269, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19817876/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19817876</a>] [<a href="https://doi.org/10.1111/j.1365-2443.2009.01348.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19817876">Li et al. (2009)</a> found that HEK293 cells expressing an expanded (24 CAG repeats) C-terminal CACNA1A fragment showed decreased viability when exposed to toxic cadmium compared to cells with nonexpanded (13 CAG) repeats. However, there were no differences in viability under normal culture conditions. Cadmium treatment also disrupted PMLNBs and enhanced aggregation of C-terminal CACNA1A fragments, particularly in CAG-expanded cells. Immunocytochemical studies showed that cadmium-induced death was caspase-3 (CASP3; <a href="/entry/600636">600636</a>)-dependent, indicating apoptosis. Gene expression studies showed downregulation of the HSF1 (<a href="/entry/140580">140580</a>)-HSPA1A (<a href="/entry/140550">140550</a>) axis as an event in 24-CAG repeat cells that appeared to be critical for cellular toxicity. The findings were consistent with SCA6 pathogenesis being related to polyglutamine diseases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19817876" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#13" class="mim-tip-reference" title="Du, X., Wang, J., Zhu, H., Rinaldo, L., Lamar, K.-M., Palmenberg, A. C., Hansel, C., Gomez, C. M. <strong>Second cistron in CACNA1A gene encodes a transcription factor mediating cerebellar development and SCA6.</strong> Cell 154: 118-133, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23827678/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23827678</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23827678[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/10.1016/j.cell.2013.05.059" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23827678">Du et al. (2013)</a> found that expression of alpha-1ACT containing a pathologic polyQ expansion did not induce neurite outgrowth in PC12 cells and was unable to induce expression of genes targeted by wildtype alpha-1ACT. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23827678" 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="Craig, K., Takiyama, Y., Soong, B.-W., Jardim, L. B., Saraiva-Pereira, M. L., Lythgow, K., Morino, H., Maruyama, H., Kawakami, H., Chinnery, P. F. <strong>Pathogenic expansions of the SCA6 locus are associated with a common CACNA1A haplotype across the globe: founder effect or predisposing chromosome?</strong> Europ. J. Hum. Genet. 16: 841-847, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18285829/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18285829</a>] [<a href="https://doi.org/10.1038/ejhg.2008.20" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18285829">Craig et al. (2008)</a> identified a common core haplotype carrying the CACNA1A CAG repeat in 45 SCA6 families from different geographic regions, including Europe, Brazil, and Japan. The haplotype was also present in the unaffected father of a proven de novo Japanese patient, suggesting that the shared chromosome predisposes to the CAG repeat expansion at the SCA6 locus. The SCA6 expansion lies immediately downstream of a CpG island, which could act as a cis-acting element predisposing to repeat expansion, as observed for other CAG/CTG repeat diseases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18285829" 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 family with a clinical diagnosis of episodic ataxia-2 (EA2; <a href="/entry/108500">108500</a>), <a href="#32" class="mim-tip-reference" title="Jodice, C., Mantuano, E., Veneziano, L., Trettel, F., Sabbadini, G., Calandriello, L., Francia, A., Spadaro, M., Pierelli, F., Salvi, F., Ophoff, R. A., Frants, R. R., Frontali, M. <strong>Episodic ataxia type 2 (EA2) and spinocerebellar ataxia type 6 (SCA6) due to CAG repeat expansion in the CACNA1A gene on chromosome 19p.</strong> Hum. Molec. Genet. 6: 1973-1978, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9302278/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9302278</a>] [<a href="https://doi.org/10.1093/hmg/6.11.1973" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9302278">Jodice et al. (1997)</a> found a (CAG)23 repeat allele segregating in patients showing different interictal symptoms, ranging from nystagmus only to severe progressive cerebellar ataxia. No additional mutations in coding and intron-exon junction sequences in disequilibrium with the CAG expansion were found. In a second family, initially classified as autosomal dominant cerebellar ataxia of unknown type, an intergenerational allele size change showed that a (CAG)20 allele was associated with an EA2 phenotype and a (CAG)25 allele with progressive cerebellar ataxia. These results suggested that EA2 and SCA6 (<a href="/entry/183086">183086</a>) are the same disorder with a high phenotypic variability, at least partly related to the number of repeats, and suggested that the small expansions may not be as stable as previously reported. See also <a href="#0007">601011.0007</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9302278" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121908215 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908215;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121908215" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121908215" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000009018 OR RCV000009019 OR RCV001388786 OR RCV004700207" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009018, RCV000009019, RCV001388786, RCV004700207" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009018...</a>
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<p><a href="#70" class="mim-tip-reference" title="Yue, Q., Jen, J. C., Nelson, S. F., Baloh, R. W. <strong>Progressive ataxia due to a missense mutation in a calcium-channel gene.</strong> Am. J. Hum. Genet. 61: 1078-1087, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9345107/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9345107</a>] [<a href="https://doi.org/10.1086/301613" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9345107">Yue et al. (1997)</a> studied a family in which multiple members had severe progressive cerebellar ataxia involving the trunk, extremities, and speech (SCA6; <a href="/entry/183086">183086</a>). The proband started at age 15 years with gradual onset of imbalance and incoordination. Slurred speech was first noted in her twenties. She became confined to a wheelchair at the age of 44 years. By that time prominent atrophy of the cerebellum was demonstrated by magnetic resonance imaging. Two sons had episodes of vertigo and ataxia that were not responsive to acetazolamide, consistent with episodic ataxia type 2 (EA2; <a href="/entry/108500">108500</a>). Quantitative eye movement testing showed a consistent pattern of abnormalities localized to the cerebellum. Genotyping suggested linkage to 19p, and SSCP showed an aberrant migrating fragment in exon 6 of the CACNA1A gene which cosegregated with the disease. Sequencing of exon 6 identified a G-to-A transition in 1 allele, at nucleotide 1152, resulting in a predicted gly293-to-arg amino acid substitution. The CAG-repeat expansion associated with SCA6 (<a href="#0007">601011.0007</a>) was not present in any family member. <a href="#70" class="mim-tip-reference" title="Yue, Q., Jen, J. C., Nelson, S. F., Baloh, R. W. <strong>Progressive ataxia due to a missense mutation in a calcium-channel gene.</strong> Am. J. Hum. Genet. 61: 1078-1087, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9345107/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9345107</a>] [<a href="https://doi.org/10.1086/301613" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9345107">Yue et al. (1997)</a> indicated that replacement of a neutral amino acid (glycine) with a positively charged amino acid (arginine) near the center of the pore in domain I would likely lead to a distortion of the pore region. Two patients in the family had prominent ataxic episodes, whereas the other 2 patients had no episodes, suggesting that other factors such as modifying genes or metabolic factors such as hormone levels may be important in determining susceptibility to episodic dysfunction. On the other hand, all 4 patients exhibited gradually progressive ataxia, indicating that this pore mutation resulted in chronic increased intracellular calcium, ultimately leading to neuronal death. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9345107" 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="#68" class="mim-tip-reference" title="Wan, J., Khanna, R., Sandusky, M., Papazian, D. M., Jen, J. C., Baloh, R. W. <strong>CACNA1A mutations causing episodic and progressive ataxia alter channel trafficking and kinetics.</strong> Neurology 64: 2090-2097, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15985579/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15985579</a>] [<a href="https://doi.org/10.1212/01.WNL.0000167409.59089.C0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15985579">Wan et al. (2005)</a> performed functional expression studies of the G293R mutation in the family reported by <a href="#70" class="mim-tip-reference" title="Yue, Q., Jen, J. C., Nelson, S. F., Baloh, R. W. <strong>Progressive ataxia due to a missense mutation in a calcium-channel gene.</strong> Am. J. Hum. Genet. 61: 1078-1087, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9345107/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9345107</a>] [<a href="https://doi.org/10.1086/301613" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9345107">Yue et al. (1997)</a> and the adjacent C287Y mutation (<a href="#0025">601011.0025</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9345107+15985579" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0010 MIGRAINE, FAMILIAL HEMIPLEGIC 1, WITH PROGRESSIVE CEREBELLAR ATAXIA</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121908218 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908218;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121908218" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121908218" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000009020" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009020" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009020</a>
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<p>In affected members of a family (F10) with hemiplegic migraine associated with progressive cerebellar ataxia (see <a href="/entry/145000">145000</a>), <a href="#16" class="mim-tip-reference" title="Ducros, A., Denier, C., Joutel, A., Vahedi, K., Michel, A., Darcel, F., Madigand, M., Guerouaou, D., Tison, F., Julien, J., Hirsch, E., Chedru, F., Bisgard, C., Lucotte, G., Despres, P., Billard, C., Barthez, M. A., Ponsot, G., Bousser, M. G., Tournier-Lasserve, E. <strong>Recurrence of the T666M calcium channel CACNA1A gene mutation in familial hemiplegic migraine with progressive cerebellar ataxia.</strong> Am. J. Hum. Genet. 64: 89-98, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9915947/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9915947</a>] [<a href="https://doi.org/10.1086/302192" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9915947">Ducros et al. (1999)</a> identified C-to-G transversion in the CACNA1A gene, resulting in an asp715-to-glu (D715E) mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9915947" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121908216 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908216;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121908216" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121908216" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000009017 OR RCV000517293 OR RCV001381850 OR RCV001542800" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009017, RCV000517293, RCV001381850, RCV001542800" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009017...</a>
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<p><a href="#24" class="mim-tip-reference" title="Friend, K. L., Crimmins, D., Phan, T. G., Sue, C. M., Colley, A., Fung, V. S. C., Morris, J. G. L., Sutherland, G. R., Richards, R. I. <strong>Detection of a novel missense mutation and second recurrent mutation in the CACNA1A gene in individuals with EA-2 and FHM.</strong> Hum. Genet. 105: 261-265, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10987655/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10987655</a>] [<a href="https://doi.org/10.1007/s004390051099" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10987655">Friend et al. (1999)</a> found a 5260G-A transition in exon 32 of the CACNA1A gene, resulting in an arg1666-to-his amino acid substitution, in a patient with episodic ataxia (EA2; <a href="/entry/108500">108500</a>). The amino acid substitution occurred in a highly conserved position within the gene. This represented the first point mutation that did not result in a proposed truncated protein. One member of the family, who had inherited both the mutation and the affected haplotype, had no clinical evidence of cerebellar dysfunction. On examination, he had no signs of nystagmus on lateral gaze, and his balance and cerebellar examination were within normal limits. He did, however, experience migraines. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10987655" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0012 EPISODIC ATAXIA, TYPE 2</strong>
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CACNA1A, PHE1491SER
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121908233 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908233;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121908233" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121908233" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000009021" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009021" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009021</a>
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<p><a href="#25" class="mim-tip-reference" title="Guida, S., Trettel, F., Pagnutti, S., Mantuano, E., Tottene, A., Veneziano, L., Fellin, T., Spadaro, M., Stauderman, K. A., Williams, M. E., Volsen, S., Ophoff, R. A., Frants, R. R., Jodice, C., Frontali, M., Pietrobon, D. <strong>Complete loss of P/Q calcium channel activity caused by a CACNA1A missense mutation carried by patients with episodic ataxia type 2.</strong> Am. J. Hum. Genet. 68: 759-764, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11179022/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11179022</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11179022[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/318804" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11179022">Guida et al. (2001)</a> reported the first functional analysis of a novel missense mutation associated with an EA2 phenotype: a T-to-C transition at nucleotide 4747 in exon 28 of the CACNA1A gene, predicted to change a highly conserved phenylalanine residue to a serine at codon 1491, located in the putative transmembrane segment S6 of domain III. Patch-clamp recording in HEK 293 cells, coexpressing the mutagenized human alpha-1A subunit, together with the human beta and alpha-delta subunits, showed that channel activity was completely abolished, although the mutated protein was expressed in the cell. These results indicated that a complete loss of P/Q channel function is the mechanism underlying EA2, whether due to truncating or to missense mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11179022" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0013 MIGRAINE, FAMILIAL HEMIPLEGIC, 1</strong>
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CACNA1A, TYR1385CYS
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121908219 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908219;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121908219" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121908219" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000009022" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009022" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009022</a>
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<p>In a patient with hemiplegic migraine associated with coma, hyperthermia, meningeal signs, and partial seizures, <a href="#64" class="mim-tip-reference" title="Vahedi, K., Denier, C., Ducros, A., Bousson, V., Levy, C., Chabriat, H., Haguenau, M., Tournier-Lasserve, E., Bousser, M. G. <strong>CACNA1A gene de novo mutation causing hemiplegic migraine, coma, and cerebellar atrophy.</strong> Neurology 55: 1040-1042, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11061267/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11061267</a>] [<a href="https://doi.org/10.1212/wnl.55.7.1040" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11061267">Vahedi et al. (2000)</a> identified a de novo A-to-G transition (TAC to TGC) at codon 1385 of the CACNA1A gene, resulting in a tyrosine-to-cysteine amino acid substitution in the alpha-1A subunit of the P/Q-type calcium channel. The mutation was not detected in 200 control chromosomes or in either of the healthy parents, suggesting that the mutation is not a polymorphism. The mutation is in the highly conserved segment 5 of the third domain of the calcium channel, an area previously shown to be important in familial hemiplegic migraine (<a href="#48" class="mim-tip-reference" title="Ophoff, R. A., Terwindt, G. M., Vergouwe, M. N., van Eijk, R., Oefner, P. J., Hoffman, S. M. G., Lamerdin, J. E., Mohrenweiser, H. W., Bulman, D. E., Ferrari, M., Haan, J., Lindhout, D., van Ommen, G.-J. B., Hofker, M. H., Ferrari, M. D., Frants, R. R. <strong>Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca(2+) channel gene CACNL1A4.</strong> Cell 87: 543-552, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8898206/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8898206</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)81373-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8898206">Ophoff et al., 1996</a>; <a href="#16" class="mim-tip-reference" title="Ducros, A., Denier, C., Joutel, A., Vahedi, K., Michel, A., Darcel, F., Madigand, M., Guerouaou, D., Tison, F., Julien, J., Hirsch, E., Chedru, F., Bisgard, C., Lucotte, G., Despres, P., Billard, C., Barthez, M. A., Ponsot, G., Bousser, M. G., Tournier-Lasserve, E. <strong>Recurrence of the T666M calcium channel CACNA1A gene mutation in familial hemiplegic migraine with progressive cerebellar ataxia.</strong> Am. J. Hum. Genet. 64: 89-98, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9915947/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9915947</a>] [<a href="https://doi.org/10.1086/302192" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9915947">Ducros et al., 1999</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9915947+8898206+11061267" 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>.0014 EPISODIC ATAXIA, TYPE 2</strong>
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CACNA1A, GLU1757LYS
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121908226 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908226;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121908226" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121908226" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000009023" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009023" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009023</a>
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<p>In 4 members of a family with onset of episodic ataxia type 2 (EA2; <a href="/entry/108500">108500</a>) after age 30, <a href="#11" class="mim-tip-reference" title="Denier, C., Ducros, A., Durr, A., Eymard, B., Chassande, B., Tournier-Lasserve, E. <strong>Missense CACNA1A mutation causing episodic ataxia type 2.</strong> Arch. Neurol. 58: 292-295, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11176968/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11176968</a>] [<a href="https://doi.org/10.1001/archneur.58.2.292" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11176968">Denier et al. (2001)</a> identified a G-to-A change in exon 35 of the CACNA1A gene, resulting in a glu1757-to-lys substitution. The authors did not detect the mutation in 200 control chromosomes. The mutation affects a highly conserved amino acid located in the pore loop, which plays a major role in the function of the channel. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11176968" 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>.0015 EPISODIC ATAXIA, TYPE 2</strong>
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CACNA1A, 1-BP INS, 3091G
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs587776694 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587776694;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs587776694" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs587776694" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000009024" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009024" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009024</a>
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<p><a href="#53" class="mim-tip-reference" title="Scoggan, K. A., Chandra, T., Nelson, R., Hahn, A. F., Bulman, D. E. <strong>Identification of two novel mutations in the CACNA1A gene responsible for episodic ataxia type 2. (Letter)</strong> J. Med. Genet. 38: 249-253, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11370629/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11370629</a>] [<a href="https://doi.org/10.1136/jmg.38.4.249" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11370629">Scoggan et al. (2001)</a> identified a 1-bp insertion at nucleotide 3091 of the CACNA1A gene (3091insG) in an individual with episodic ataxia type 2 (EA2; <a href="/entry/108500">108500</a>). <a href="#53" class="mim-tip-reference" title="Scoggan, K. A., Chandra, T., Nelson, R., Hahn, A. F., Bulman, D. E. <strong>Identification of two novel mutations in the CACNA1A gene responsible for episodic ataxia type 2. (Letter)</strong> J. Med. Genet. 38: 249-253, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11370629/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11370629</a>] [<a href="https://doi.org/10.1136/jmg.38.4.249" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11370629">Scoggan et al. (2001)</a> believed this to be the first mutation identified to occur in an intracellular loop of the CACNA1A protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11370629" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs587776695 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587776695;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs587776695" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs587776695" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p><a href="#53" class="mim-tip-reference" title="Scoggan, K. A., Chandra, T., Nelson, R., Hahn, A. F., Bulman, D. E. <strong>Identification of two novel mutations in the CACNA1A gene responsible for episodic ataxia type 2. (Letter)</strong> J. Med. Genet. 38: 249-253, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11370629/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11370629</a>] [<a href="https://doi.org/10.1136/jmg.38.4.249" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11370629">Scoggan et al. (2001)</a> identified a 1-bp deletion at nucleotide 5123 of the CACNA1A gene (5123delG) in an individual with episodic ataxia type 2 (EA2; <a href="/entry/108500">108500</a>). <a href="#53" class="mim-tip-reference" title="Scoggan, K. A., Chandra, T., Nelson, R., Hahn, A. F., Bulman, D. E. <strong>Identification of two novel mutations in the CACNA1A gene responsible for episodic ataxia type 2. (Letter)</strong> J. Med. Genet. 38: 249-253, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11370629/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11370629</a>] [<a href="https://doi.org/10.1136/jmg.38.4.249" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11370629">Scoggan et al. (2001)</a> believed this to be the most 3-prime CACNA1A mutation reported to that time. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11370629" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121908225 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908225;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121908225" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121908225" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000009027 OR RCV000502832 OR RCV001390632 OR RCV001533157 OR RCV002272012 OR RCV003150928" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009027, RCV000502832, RCV001390632, RCV001533157, RCV002272012, RCV003150928" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009027...</a>
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<p>Noting that familial hemiplegic migraine (FHM1; <a href="/entry/141500">141500</a>) can be triggered by minor head trauma, <a href="#39" class="mim-tip-reference" title="Kors, E. E., Terwindt, G. M., Vermeulen, F. L. M. G., Fitzsimons, R. B., Jardine, P. E., Heywood, P., Love, S., van den Maagdenberg, A. M. J. M., Haan, J., Frants, R. R., Ferrari, M. D. <strong>Delayed cerebral edema and fatal coma after minor head trauma: role of the CACNA1A calcium channel subunit gene and relationship with familial hemiplegic migraine.</strong> Ann. Neurol. 49: 753-760, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11409427/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11409427</a>] [<a href="https://doi.org/10.1002/ana.1031" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11409427">Kors et al. (2001)</a> investigated a role for CACNA1A in 'delayed cerebral edema,' a severe, sometimes even fatal, cerebral edema and coma occurring after a lucid interval as a result of trivial head trauma. In 2 patients with the phenomenon from a family with extreme familial hemiplegic migraine and in 1 patient whose parent had familial hemiplegic migraine and whose family suffered from various neurologic abnormalities, <a href="#39" class="mim-tip-reference" title="Kors, E. E., Terwindt, G. M., Vermeulen, F. L. M. G., Fitzsimons, R. B., Jardine, P. E., Heywood, P., Love, S., van den Maagdenberg, A. M. J. M., Haan, J., Frants, R. R., Ferrari, M. D. <strong>Delayed cerebral edema and fatal coma after minor head trauma: role of the CACNA1A calcium channel subunit gene and relationship with familial hemiplegic migraine.</strong> Ann. Neurol. 49: 753-760, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11409427/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11409427</a>] [<a href="https://doi.org/10.1002/ana.1031" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11409427">Kors et al. (2001)</a> identified heterozygosity for a mutation in the CACNA1A gene, resulting in the replacement of a hydrophilic serine for a hydrophobic leucine at residue 218 (S218L) in the highly conserved intracellular loop of the alpha-1A subunit. The authors suggested a pathogenic mechanism involving ionic perturbation resulting from inappropriately depolarized ion channels. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11409427" 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="#7" class="mim-tip-reference" title="Chan, Y.-C., Burgunder, J.-M., Wilder-Smith, E., Chew, S.-E., Lam-Mok-Sing, K. M. J., Sharma, V., Ong, B. K. C. <strong>Electroencephalographic changes and seizures in familial hemiplegic migraine patients with the CACNA1A gene S218L mutation.</strong> J. Clin. Neurosci. 15: 891-894, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18313928/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18313928</a>] [<a href="https://doi.org/10.1016/j.jocn.2007.01.013" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18313928">Chan et al. (2008)</a> reported 3 Malaysian sibs with FHM1 due to heterozygosity for a 935C-T transition in exon 5 of the CACNA1A gene, resulting in the S218L mutation. The phenotype of the hemiplegic migraine episodes was severe in the older brother and sister, each of whom became comatose on at least 1 occasion. A history of generalized seizures was associated with mild head trauma in the older boy and with febrile illness in the younger boy. The older brother and sister also had cerebellar atrophy on brain MRI. EEG studies of them during hemiplegic attacks showed evidence of depressed cortical activity contralateral to the hemiparesis, perhaps representing cortical spreading depression due to a defect in calcium channel activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18313928" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Developmental and Epileptic Encephalopathy 42</em></strong></p><p>
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In a girl (patient T21924) with developmental and epileptic encephalopathy-42 (DEE42; <a href="/entry/617106">617106</a>), the <a href="#21" class="mim-tip-reference" title="Epi4K Consortium. <strong>De novo mutations in SLC1A2 and CACNA1A are important causes of epileptic encephalopathies.</strong> Am. J. Hum. Genet. 99: 287-298, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27476654/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27476654</a>] [<a href="https://doi.org/10.1016/j.ajhg.2016.06.003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27476654">Epi4K Consortium (2016)</a> identified a heterozygous c.653C-T transition (c.653C-T, NM_023035.2) in the CACNA1A gene, resulting in a ser218-to-leu (S218L) substitution. Functional studies of the variant and studies of patient cells were not performed. The mutation was not found in the unaffected mother; DNA from the unaffected father was not available. The authors considered this change to be a variant of unknown significance, noting that it had previously been found in a patient with familial hemiplegic migraine with progressive cerebellar ataxia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27476654" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121908217 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908217;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs121908217?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121908217" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121908217" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000009028 OR RCV000009029 OR RCV000009030 OR RCV000517519 OR RCV001380080 OR RCV001533158 OR RCV002227018 OR RCV004766989" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009028, RCV000009029, RCV000009030, RCV000517519, RCV001380080, RCV001533158, RCV002227018, RCV004766989" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009028...</a>
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<p>In 2 Italian sisters with familial hemiplegic migraine (FHM1; <a href="/entry/141500">141500</a>) and late-onset cerebellar ataxia and cerebellar atrophy, <a href="#4" class="mim-tip-reference" title="Battistini, S., Stenirri, S., Piatti, M., Gelfi, C., Righetti, P. G., Rocchi, R., Giannini, F., Battistini, N., Guazzi, G. C., Ferrari, M., Carrera, P. <strong>A new CACNA1A gene mutation in acetazolamide-responsive familial hemiplegic migraine and ataxia.</strong> Neurology 53: 38-43, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10408534/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10408534</a>] [<a href="https://doi.org/10.1212/wnl.53.1.38" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10408534">Battistini et al. (1999)</a> identified an arg583-to-gln (R583Q) mutation in a putative voltage sensor domain of the CACNA1A gene. The frequency and severity of the attacks increased near the sixth decade for both patients, when the cerebellar signs developed. Acetazolamide was effective prophylactic therapy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10408534" 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="#58" class="mim-tip-reference" title="Terwindt, G., Kors, E., Haan, J., Vermeulen, F., van den Maagdenberg, A., Frants, R., Ferrari, M. <strong>Mutation analysis of the CACNA1A calcium channel subunit gene in 27 patients with sporadic hemiplegic migraine.</strong> Arch. Neurol. 59: 1016-1018, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12056940/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12056940</a>] [<a href="https://doi.org/10.1001/archneur.59.6.1016" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12056940">Terwindt et al. (2002)</a> studied 27 patients with sporadic hemiplegic migraine and found the R583Q mutation in a 16-year-old boy with no cerebellar signs. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12056940" 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 large Portuguese family in which 17 patients over 4 generations were affected with hemiplegic migraine and/or progressive cerebellar ataxia-6 (SCA6; <a href="/entry/183086">183086</a>), <a href="#2" class="mim-tip-reference" title="Alonso, I., Barros, J., Tuna, A., Coelho, J., Sequeiros, J., Silveira, I., Coutinho, P. <strong>Phenotypes of spinocerebellar ataxia type 6 and familial hemiplegic migraine caused by a unique CACNA1A missense mutation in patients from a large family.</strong> Arch. Neurol. 60: 610-614, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12707077/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12707077</a>] [<a href="https://doi.org/10.1001/archneur.60.4.610" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12707077">Alonso et al. (2003)</a> found that all patients shared a common haplotype and carried the R583Q mutation. Mean age at onset for hemiplegic migraine symptoms was in the second decade and onset of cerebellar signs was approximately 20 years later. Four patients, all under the age of 18 years, had only hemiplegic migraine, 8 patients had isolated progressive cerebellar ataxia, and 5 patients had both hemiplegic migraine and cerebellar ataxia. Several patients reported symptoms triggered by minor head trauma. <a href="#2" class="mim-tip-reference" title="Alonso, I., Barros, J., Tuna, A., Coelho, J., Sequeiros, J., Silveira, I., Coutinho, P. <strong>Phenotypes of spinocerebellar ataxia type 6 and familial hemiplegic migraine caused by a unique CACNA1A missense mutation in patients from a large family.</strong> Arch. Neurol. 60: 610-614, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12707077/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12707077</a>] [<a href="https://doi.org/10.1001/archneur.60.4.610" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12707077">Alonso et al. (2003)</a> postulated that the mutation, which occurs in a transmembrane segment of the voltage sensor of the channel, may cause a shift in the voltage dependence of the channel, leading to an increase in intracellular calcium. They suggested that episodic ataxia-2 (EA2; <a href="/entry/108500">108500</a>), SCA6, and familial hemiplegic migraine are not only allelic disorders, but may be the same disorder with great phenotypic variability. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12707077" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#10" class="mim-tip-reference" title="De Vries, B., Freilinger, T., Vanmolkot, K. R. J., Koenderink, J. B., Stam, A. H., Terwindt, G. M., Babini, E., van den Boogerd, E.H., van den Heuvel, J. J. M. W., Frants, R. R., Haan, J., Pusch, M., van den Maagdenberg, A. M. J. M., Ferrari, M. D., Dichgans, M. <strong>Systematic analysis of three FHM genes in 39 sporadic patients with hemiplegic migraine.</strong> Neurology 69: 2170-2176, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18056581/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18056581</a>] [<a href="https://doi.org/10.1212/01.wnl.0000295670.01629.5a" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18056581">De Vries et al. (2007)</a> identified a 2021G-A transition in the CACNA1A gene, resulting in an R583Q substitution, in a patient who developed FHM at age 13 years. The mutation was also identified in his mother, who had migraine with aura. The findings suggested either reduced penetrance or a common pathogenetic mechanism for both hemiplegic and nonhemiplegic migraine. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18056581" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121908237 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908237;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121908237" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121908237" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a 5-generation Caucasian family originating from northeastern Italy, in which the average age of onset of familial hemiplegic migraine (FHM1; <a href="/entry/141500">141500</a>) was 33.8 years, <a href="#6" class="mim-tip-reference" title="Carrera, P., Piatti, M., Stenirri, S., Grimaldi, L. M. E., Marchioni, E., Curcio, M., Righetti, P. G., Ferrari, M., Gelfi, C. <strong>Genetic heterogeneity in Italian families with familial hemiplegic migraine.</strong> Neurology 53: 26-32, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10408532/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10408532</a>] [<a href="https://doi.org/10.1212/wnl.53.1.26" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10408532">Carrera et al. (1999)</a> found a G-to-T transversion at nucleotide position 4644 in exon 27 of the CACNA1A gene, which resulted in a val1457-to-leu (V1457L) amino acid substitution. All patients had clinical symptoms preceded by aura, followed by hemiparesis and various degrees of aphasia congruent with the hemispheric dominance of each individual. Patients did not report cerebellar ataxia or coma. <a href="#6" class="mim-tip-reference" title="Carrera, P., Piatti, M., Stenirri, S., Grimaldi, L. M. E., Marchioni, E., Curcio, M., Righetti, P. G., Ferrari, M., Gelfi, C. <strong>Genetic heterogeneity in Italian families with familial hemiplegic migraine.</strong> Neurology 53: 26-32, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10408532/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10408532</a>] [<a href="https://doi.org/10.1212/wnl.53.1.26" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10408532">Carrera et al. (1999)</a> noted that the location of the mutation, in the putative pore-forming (P) region between the S5-S6 transmembrane domains in motif III of CACNA1A, suggests a potential for interference in transmembrane conductance. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10408532" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000009031 OR RCV001851752 OR RCV004700208 OR RCV004786248" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009031, RCV001851752, RCV004700208, RCV004786248" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009031...</a>
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<p><a href="#71" class="mim-tip-reference" title="Yue, Q., Jen, J. C., Thwe, M. M., Nelson, S. F., Baloh, R. W. <strong>De novo mutation in CACNA1A caused acetazolamide-responsive episodic ataxia.</strong> Am. J. Med. Genet. 77: 298-301, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9600739/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9600739</a>] [<a href="https://doi.org/10.1002/(sici)1096-8628(19980526)77:4<298::aid-ajmg9>3.0.co;2-j" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9600739">Yue et al. (1998)</a> reported a patient with episodic ataxia type 2 (EA2; <a href="/entry/108500">108500</a>) who carried a 4410C-T substitution in exon 23 of the CACNA1A gene, resulting in an arg1281-to-ter (R1281X) mutation that predicts a truncated product containing only the first 2 domains of the protein. The patient experienced attacks of vertigo, truncal and limb ataxia, nystagmus, and diffuse weakness during ataxic spells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9600739" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By use of whole-cell patch-clamp recordings, <a href="#30" class="mim-tip-reference" title="Jen, J., Wan, J., Graves, M., Yu, H., Mock, A. F., Coulin, C. J., Kim, G., Yue, Q., Papazian, D. M., Baloh, R. W. <strong>Loss-of-function EA2 mutations are associated with impaired neuromuscular transmission.</strong> Neurology 57: 1843-1848, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11723274/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11723274</a>] [<a href="https://doi.org/10.1212/wnl.57.10.1843" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11723274">Jen et al. (2001)</a> demonstrated that the R1281X, R1549X (<a href="#0021">601011.0021</a>), and F1406C (<a href="#0022">601011.0022</a>) mutations, when expressed in COS-7 cells, resulted in markedly diminished barium current density and amplitude compared with the wildtype gene. They used single-fiber EMG (SFEMG) recordings to examine synaptic transmission at the neuromuscular junction in the 3 patients who carried these mutations, all of whom complained of episodic weakness. The SFEMG demonstrated abnormal neuromuscular transmission in vivo, suggesting that these mutations contributed to the symptoms of weakness described by the patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11723274" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121909324 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121909324;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121909324" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121909324" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000009032 OR RCV000622947 OR RCV000763032 OR RCV002466397 OR RCV002512927" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009032, RCV000622947, RCV000763032, RCV002466397, RCV002512927" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009032...</a>
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<p><a href="#31" class="mim-tip-reference" title="Jen, J., Yue, Q., Nelson, S. F., Yu, H., Litt, M., Nutt, J., Baloh, R. W. <strong>A novel nonsense mutation in CACNA1A causes episodic ataxia and hemiplegia.</strong> Neurology 53: 34-37, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10408533/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10408533</a>] [<a href="https://doi.org/10.1212/wnl.53.1.34" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10408533">Jen et al. (1999)</a> reported affected members of a family with episodic ataxia type 2 (EA2; <a href="/entry/108500">108500</a>) who carried a 4914C-T substitution in exon 29 of the CACNA1A gene. The substitution resulted in an arg1549-to-ter (R1549X) mutation (reported in the article as ARG1547TER) that predicts a truncated product containing the first 3 domains of the protein. The patients experienced attacks of vertigo, truncal and limb ataxia, nystagmus, and diffuse weakness during ataxic spells. See also <a href="#0020">601011.0020</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10408533" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121908227 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908227;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121908227" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121908227" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000009033" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009033" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009033</a>
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<p><a href="#30" class="mim-tip-reference" title="Jen, J., Wan, J., Graves, M., Yu, H., Mock, A. F., Coulin, C. J., Kim, G., Yue, Q., Papazian, D. M., Baloh, R. W. <strong>Loss-of-function EA2 mutations are associated with impaired neuromuscular transmission.</strong> Neurology 57: 1843-1848, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11723274/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11723274</a>] [<a href="https://doi.org/10.1212/wnl.57.10.1843" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11723274">Jen et al. (2001)</a> reported a patient with episodic ataxia type 2 (EA2; <a href="/entry/108500">108500</a>) who also developed progressive episodic weakness beginning in his teens. Mutation analysis revealed a 4486T-G change in exon 26 of the CACNA1A gene, resulting in a phe1406-to-cys (F1406) change in the putative P loop of the protein between domains 3 and 4, which may disrupt pore formation. See also <a href="#0020">601011.0020</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11723274" 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>.0023 EPISODIC ATAXIA, TYPE 2, AND EPILEPSY</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs267606696 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267606696;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs267606696?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs267606696" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs267606696" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000009034 OR RCV001836705" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009034, RCV001836705" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009034...</a>
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<p>In an isolated case of a boy with seizures, episodic ataxia type 2 (EA2; <a href="/entry/108500">108500</a>), and interictal progressive cerebellar signs, <a href="#33" class="mim-tip-reference" title="Jouvenceau, A., Eunson, L. H., Spauschus, A., Ramesh, V., Zuberi, S. M., Kullmann, D. M., Hanna, M. G. <strong>Human epilepsy associated with dysfunction of the brain P/Q-type calcium channel.</strong> Lancet 358: 801-807, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11564488/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11564488</a>] [<a href="https://doi.org/10.1016/S0140-6736(01)05971-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11564488">Jouvenceau et al. (2001)</a> identified a heterozygous 5733C-T transition in the CACNA1A gene, resulting in a premature stop codon (arg1820 to ter; R1820X) between the last transmembrane segment (IVS6) and the intracellular C terminus of the mature protein. Functional expression studies indicated a dominant-negative effect on channel conductance. <a href="#33" class="mim-tip-reference" title="Jouvenceau, A., Eunson, L. H., Spauschus, A., Ramesh, V., Zuberi, S. M., Kullmann, D. M., Hanna, M. G. <strong>Human epilepsy associated with dysfunction of the brain P/Q-type calcium channel.</strong> Lancet 358: 801-807, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11564488/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11564488</a>] [<a href="https://doi.org/10.1016/S0140-6736(01)05971-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11564488">Jouvenceau et al. (2001)</a> noted that mouse models of absence epilepsy and cerebellar degeneration harbor mutations in the CACNA1A gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11564488" 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="#28" class="mim-tip-reference" title="Holtmann, M., Opp, J., Tokarzewski, M., Korn-Merker, E. <strong>Human epilepsy, episodic ataxia type 2, and migraine. (Letter)</strong> Lancet 359: 170-171, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11809294/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11809294</a>] [<a href="https://doi.org/10.1016/S0140-6736(02)07355-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11809294">Holtmann et al. (2002)</a> reported a family in which a father and daughter had idiopathic focal epilepsy, episodic ataxia type 2, and migraine. Four other family members had migraine, and 2 had reported seizures. <a href="#28" class="mim-tip-reference" title="Holtmann, M., Opp, J., Tokarzewski, M., Korn-Merker, E. <strong>Human epilepsy, episodic ataxia type 2, and migraine. (Letter)</strong> Lancet 359: 170-171, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11809294/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11809294</a>] [<a href="https://doi.org/10.1016/S0140-6736(02)07355-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11809294">Holtmann et al. (2002)</a> suggested that the cooccurrence of periodic neurologic disorders in their family was similar to that in the case presented by <a href="#33" class="mim-tip-reference" title="Jouvenceau, A., Eunson, L. H., Spauschus, A., Ramesh, V., Zuberi, S. M., Kullmann, D. M., Hanna, M. G. <strong>Human epilepsy associated with dysfunction of the brain P/Q-type calcium channel.</strong> Lancet 358: 801-807, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11564488/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11564488</a>] [<a href="https://doi.org/10.1016/S0140-6736(01)05971-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11564488">Jouvenceau et al. (2001)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11809294+11564488" 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>.0024 MIGRAINE, FAMILIAL HEMIPLEGIC, 1</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121909326 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121909326;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121909326" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121909326" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000009035 OR RCV000009036 OR RCV000157056 OR RCV001049766 OR RCV001804718 OR RCV002273923 OR RCV002345236" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009035, RCV000009036, RCV000157056, RCV001049766, RCV001804718, RCV002273923, RCV002345236" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009035...</a>
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<p>In a mother and her 2 adult children who had familial hemiplegic migraine (FHM1; <a href="/entry/141500">141500</a>) and childhood-onset of cerebellar ataxia (SCA6; <a href="/entry/183086">183086</a>), <a href="#38" class="mim-tip-reference" title="Kors, E. E., Melberg, A., Vanmolkot, K. R. J., Kumlien, E., Haan, J., Raininko, R., Flink, R., Ginjaar, H. B., Frants, R. R., Ferrari, M. D., van den Maagdenberg, A. M. J. M. <strong>Childhood epilepsy, familial hemiplegic migraine, cerebellar ataxia, and a new CACNA1A mutation.</strong> Neurology 63: 1136-1137, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15452324/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15452324</a>] [<a href="https://doi.org/10.1212/01.wnl.0000138571.48593.fc" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15452324">Kors et al. (2004)</a> identified a heterozygous 5405T-C transition in exon 33 of the CACNA1A gene, resulting in an ile1710-to-thr (I1710T) substitution within transmembrane segment 5 of the fourth domain of the protein. <a href="#38" class="mim-tip-reference" title="Kors, E. E., Melberg, A., Vanmolkot, K. R. J., Kumlien, E., Haan, J., Raininko, R., Flink, R., Ginjaar, H. B., Frants, R. R., Ferrari, M. D., van den Maagdenberg, A. M. J. M. <strong>Childhood epilepsy, familial hemiplegic migraine, cerebellar ataxia, and a new CACNA1A mutation.</strong> Neurology 63: 1136-1137, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15452324/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15452324</a>] [<a href="https://doi.org/10.1212/01.wnl.0000138571.48593.fc" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15452324">Kors et al. (2004)</a> stated that the affected residue is strongly conserved. In addition to FHM1 and SCA6, both children had complex partial and generalized tonic-clonic seizures that occurred independently of the FHM attacks and were restricted to childhood. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15452324" 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>.0025 EPISODIC ATAXIA, TYPE 2</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121908236 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908236;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121908236" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121908236" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In affected members of a family with episodic ataxia type 2 (EA2; <a href="/entry/108500">108500</a>) and mild baseline ataxia, <a href="#68" class="mim-tip-reference" title="Wan, J., Khanna, R., Sandusky, M., Papazian, D. M., Jen, J. C., Baloh, R. W. <strong>CACNA1A mutations causing episodic and progressive ataxia alter channel trafficking and kinetics.</strong> Neurology 64: 2090-2097, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15985579/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15985579</a>] [<a href="https://doi.org/10.1212/01.WNL.0000167409.59089.C0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15985579">Wan et al. (2005)</a> identified a 1096G-A transition in exon 6 of the CACNA1A gene, resulting in a cys287-to-tyr (C287Y) substitution in the putative P loop between transmembrane segments S5 and S6 within domain I of the protein. The mutation is adjacent to another mutation, G293R (<a href="#0009">601011.0009</a>), in the same region of the protein. Functional expression studies of both mutations indicated that the mutant channels exhibited decreased current densities (31 to 35% of wildtype), which were partially restored by cooling. Immunofluorescence studies showed that the mutant proteins accumulated in the endoplasmic reticulum. The findings suggested that the mutations caused misfolding and altered trafficking of the protein, resulting in a defect in plasma membrane targeting. Once expressed at the cell surface, the mutant channels were able to conduct current but with altered biophysical properties. <a href="#68" class="mim-tip-reference" title="Wan, J., Khanna, R., Sandusky, M., Papazian, D. M., Jen, J. C., Baloh, R. W. <strong>CACNA1A mutations causing episodic and progressive ataxia alter channel trafficking and kinetics.</strong> Neurology 64: 2090-2097, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15985579/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15985579</a>] [<a href="https://doi.org/10.1212/01.WNL.0000167409.59089.C0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15985579">Wan et al. (2005)</a> hypothesized that the episodic features of EA2 result from altered channel function, while the interictal features result from protein mishandling, eventually leading to cerebellar neuronal death. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15985579" 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>.0026 EPISODIC ATAXIA, TYPE 2</strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000009038" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009038" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009038</a>
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<p>In 3 affected members of a family with episodic ataxia type 2 (EA2; <a href="/entry/108500">108500</a>), <a href="#50" class="mim-tip-reference" title="Riant, F., Mourtada, R., Saugier-Veber, P., Tournier-Lasserve, E. <strong>Large CACNA1A deletion in a family with episodic ataxia type 2.</strong> Arch. Neurol. 65: 817-820, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18541804/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18541804</a>] [<a href="https://doi.org/10.1001/archneur.65.6.817" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18541804">Riant et al. (2008)</a> identified a heterozygous 39.5-kb deletion in the CACNA1A gene, resulting in the removal of the last 16 coding exons of the gene. Sequence analysis of the deletion boundaries suggested that the deletion arose through homologous recombination of Alu sequences. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18541804" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0027" class="mim-anchor"></a>
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<strong>.0027 MIGRAINE, FAMILIAL HEMIPLEGIC, 1</strong>
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CACNA1A, ARG1347GLN
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121908230 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908230;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121908230" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121908230" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000009039 OR RCV000516653 OR RCV004766990 OR RCV004795386" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009039, RCV000516653, RCV004766990, RCV004795386" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009039...</a>
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<p>In affected members of 4 unrelated families with familial hemiplegic migraine-1 (FHM1; <a href="/entry/141500">141500</a>), <a href="#55" class="mim-tip-reference" title="Stam, A. H., Vanmolkot, K. R. J., Kremer, H. P. H., Gartner, J., Brown, J., Leshinsky-Silver, E., Gilad, R., Kors, E. E., Frankhuizen, W. S., Ginjaar, H. B., Haan, J., Frants, R. R., Ferrari, M. D., van den Maagdenberg, A. M. J. M., Terwindt, G. M. <strong>CACNA1A R1347Q: a frequent recurrent mutation in hemiplegic migraine.</strong> Clin. Genet. 74: 481-485, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18400034/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18400034</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2008.00996.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18400034">Stam et al. (2008)</a> identified a heterozygous 4040G-A transition in exon 25 of the CACNA1A gene, resulting in an arg1347-to-gln (R1347Q) substitution in the S4 segment of protein domain III. Haplotype analysis excluded a founder effect. In 3 of the 4 families, age at onset was before age 3 years. Two patients in 1 family also had focal seizures. <a href="#55" class="mim-tip-reference" title="Stam, A. H., Vanmolkot, K. R. J., Kremer, H. P. H., Gartner, J., Brown, J., Leshinsky-Silver, E., Gilad, R., Kors, E. E., Frankhuizen, W. S., Ginjaar, H. B., Haan, J., Frants, R. R., Ferrari, M. D., van den Maagdenberg, A. M. J. M., Terwindt, G. M. <strong>CACNA1A R1347Q: a frequent recurrent mutation in hemiplegic migraine.</strong> Clin. Genet. 74: 481-485, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18400034/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18400034</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2008.00996.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18400034">Stam et al. (2008)</a> stated that the R1347Q mutation was the third most common CACNA1A mutation associated with FHM1, after T666M (<a href="#0002">601011.0002</a>) and R583Q (<a href="#0018">601011.0018</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18400034" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0028" class="mim-anchor"></a>
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<span class="mim-font">
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<strong>.0028 EPISODIC ATAXIA, TYPE 2</strong>
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<span class="mim-text-font">
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<div style="float: left;">
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CACNA1A, 146.1-KB DEL
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</div>
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</span>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000009040" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009040" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009040</a>
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</span>
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<span class="mim-text-font">
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<p>In 2 affected members of a family with episodic ataxia type 2 (EA2; <a href="/entry/108500">108500</a>), <a href="#42" class="mim-tip-reference" title="Labrum, R. W., Rajakulendran, S., Graves, T. D., Eunson, L. H., Bevan, R., Sweeney, M. G., Hammans, S. R., Tubridy, N., Britton, T., Carr, L. J., Ostergaard, J. R., Kennedy, C. R., Al-Memar, A., Kullmann, D. M., Schorge, S., Temple, K., Davis, M. B., Hanna, M. G. <strong>Large scale calcium channel gene rearrangements in episodic ataxia and hemiplegic migraine: implications for diagnostic testing.</strong> J. Med. Genet. 46: 786-791, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19586927/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19586927</a>] [<a href="https://doi.org/10.1136/jmg.2009.067967" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19586927">Labrum et al. (2009)</a> identified a heterozygous 146.1-kb deletion in the CACNA1A gene, resulting in deletion of exon 4 Exon 4 encodes the S4 voltage sensor segment of domain I and the removal of this exon is likely to have deleterious effects on kinetic parameters, such as the voltage dependence of activation. The deletion was not detected in a panel of 180 normal control chromosomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19586927" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0029" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0029 EPISODIC ATAXIA, TYPE 2</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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<div style="float: left;">
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CACNA1A, 35.7-KB DEL
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</div>
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</span>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000009041" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009041" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009041</a>
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</span>
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<span class="mim-text-font">
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<p>In 8 affected members of a 4-generation family with episodic ataxia type 2 (EA2; <a href="/entry/108500">108500</a>), <a href="#42" class="mim-tip-reference" title="Labrum, R. W., Rajakulendran, S., Graves, T. D., Eunson, L. H., Bevan, R., Sweeney, M. G., Hammans, S. R., Tubridy, N., Britton, T., Carr, L. J., Ostergaard, J. R., Kennedy, C. R., Al-Memar, A., Kullmann, D. M., Schorge, S., Temple, K., Davis, M. B., Hanna, M. G. <strong>Large scale calcium channel gene rearrangements in episodic ataxia and hemiplegic migraine: implications for diagnostic testing.</strong> J. Med. Genet. 46: 786-791, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19586927/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19586927</a>] [<a href="https://doi.org/10.1136/jmg.2009.067967" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19586927">Labrum et al. (2009)</a> identified a heterozygous 35.7-kb deletion in the CACNA1A gene, resulting in deletion of exon 6. The deletion was not identified in an unaffected member of this family or in a panel of 180 normal control chromosomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19586927" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0030" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0030 EPISODIC ATAXIA, TYPE 2</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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<div style="float: left;">
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CACNA1A, 35.7-KB DUP
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</div>
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</span>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000009042" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009042" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009042</a>
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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 an index patient with isolated episodic diplopia without ataxia, <a href="#42" class="mim-tip-reference" title="Labrum, R. W., Rajakulendran, S., Graves, T. D., Eunson, L. H., Bevan, R., Sweeney, M. G., Hammans, S. R., Tubridy, N., Britton, T., Carr, L. J., Ostergaard, J. R., Kennedy, C. R., Al-Memar, A., Kullmann, D. M., Schorge, S., Temple, K., Davis, M. B., Hanna, M. G. <strong>Large scale calcium channel gene rearrangements in episodic ataxia and hemiplegic migraine: implications for diagnostic testing.</strong> J. Med. Genet. 46: 786-791, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19586927/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19586927</a>] [<a href="https://doi.org/10.1136/jmg.2009.067967" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19586927">Labrum et al. (2009)</a> identified a heterozygous 35.7-kb duplication in the CACNA1A gene, resulting in duplication of exon 6. The patient's father reportedly had typical episodic ataxia type 2 (EA2; <a href="/entry/108500">108500</a>). The duplication was not detected in a panel of 180 normal control chromosomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19586927" 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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</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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<a id="0031" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0031 EPISODIC ATAXIA, TYPE 2</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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<div style="float: left;">
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CACNA1A, 7.4-KB DEL
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</div>
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</span>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000009043" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009043" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009043</a>
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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 proband with episodic ataxia type 2 (EA2; <a href="/entry/108500">108500</a>), <a href="#42" class="mim-tip-reference" title="Labrum, R. W., Rajakulendran, S., Graves, T. D., Eunson, L. H., Bevan, R., Sweeney, M. G., Hammans, S. R., Tubridy, N., Britton, T., Carr, L. J., Ostergaard, J. R., Kennedy, C. R., Al-Memar, A., Kullmann, D. M., Schorge, S., Temple, K., Davis, M. B., Hanna, M. G. <strong>Large scale calcium channel gene rearrangements in episodic ataxia and hemiplegic migraine: implications for diagnostic testing.</strong> J. Med. Genet. 46: 786-791, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19586927/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19586927</a>] [<a href="https://doi.org/10.1136/jmg.2009.067967" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19586927">Labrum et al. (2009)</a> identified a heterozygous 7.4-kb deletion in the CACNA1A gene, resulting in deletion of exon 27. The deletion was not detected in a panel of 180 normal control chromosomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19586927" 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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</span>
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<div>
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<br />
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<div>
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<a id="0032" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0032 EPISODIC ATAXIA, TYPE 2</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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<div style="float: left;">
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CACNA1A, 86.1-KB DEL
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</div>
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</span>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000009044" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009044" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009044</a>
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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 proband with episodic ataxia type 2 (EA2; <a href="/entry/108500">108500</a>), <a href="#42" class="mim-tip-reference" title="Labrum, R. W., Rajakulendran, S., Graves, T. D., Eunson, L. H., Bevan, R., Sweeney, M. G., Hammans, S. R., Tubridy, N., Britton, T., Carr, L. J., Ostergaard, J. R., Kennedy, C. R., Al-Memar, A., Kullmann, D. M., Schorge, S., Temple, K., Davis, M. B., Hanna, M. G. <strong>Large scale calcium channel gene rearrangements in episodic ataxia and hemiplegic migraine: implications for diagnostic testing.</strong> J. Med. Genet. 46: 786-791, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19586927/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19586927</a>] [<a href="https://doi.org/10.1136/jmg.2009.067967" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19586927">Labrum et al. (2009)</a> identified a heterozygous 86.1-kb deletion in the CACNA1A gene, resulting in deletion of exons 20 to 38. The deletion was not detected in a panel of 180 normal control chromosomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19586927" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div>
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<div>
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<a id="0033" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0033 EPISODIC ATAXIA, TYPE 2</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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<div style="float: left;">
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CACNA1A, 18.2-KB DEL
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</div>
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</span>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000009045" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009045" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009045</a>
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</span>
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</div>
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<p>In 2 unrelated patients with episodic ataxia type 2 (EA2; <a href="/entry/108500">108500</a>), <a href="#42" class="mim-tip-reference" title="Labrum, R. W., Rajakulendran, S., Graves, T. D., Eunson, L. H., Bevan, R., Sweeney, M. G., Hammans, S. R., Tubridy, N., Britton, T., Carr, L. J., Ostergaard, J. R., Kennedy, C. R., Al-Memar, A., Kullmann, D. M., Schorge, S., Temple, K., Davis, M. B., Hanna, M. G. <strong>Large scale calcium channel gene rearrangements in episodic ataxia and hemiplegic migraine: implications for diagnostic testing.</strong> J. Med. Genet. 46: 786-791, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19586927/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19586927</a>] [<a href="https://doi.org/10.1136/jmg.2009.067967" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19586927">Labrum et al. (2009)</a> identified a heterozygous 18.2-kb deletion in the CACNA1A gene, resulting in deletion of exons 39 to 47. The deletion was not detected in a panel of 180 normal control chromosomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19586927" 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>.0034 MIGRAINE, FAMILIAL HEMIPLEGIC, 1</strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000009046" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009046" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009046</a>
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<p>In a patient with sporadic hemiplegic migraine (FHM1; <a href="/entry/141500">141500</a>), <a href="#42" class="mim-tip-reference" title="Labrum, R. W., Rajakulendran, S., Graves, T. D., Eunson, L. H., Bevan, R., Sweeney, M. G., Hammans, S. R., Tubridy, N., Britton, T., Carr, L. J., Ostergaard, J. R., Kennedy, C. R., Al-Memar, A., Kullmann, D. M., Schorge, S., Temple, K., Davis, M. B., Hanna, M. G. <strong>Large scale calcium channel gene rearrangements in episodic ataxia and hemiplegic migraine: implications for diagnostic testing.</strong> J. Med. Genet. 46: 786-791, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19586927/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19586927</a>] [<a href="https://doi.org/10.1136/jmg.2009.067967" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19586927">Labrum et al. (2009)</a> identified a heterozygous 18.2-kb deletion in the CACNA1A gene, resulting in deletion of exons 39 to 47. The deletion was not detected in a panel of 180 normal control chromosomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19586927" 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>.0035 DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 42</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs886037944 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs886037944;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs886037944" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs886037944" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000240952" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000240952" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000240952</a>
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<p>In a 4-year-old boy (patient EG1371) with developmental and epileptic encephalopathy-42 (DEE42; <a href="/entry/617106">617106</a>), the <a href="#21" class="mim-tip-reference" title="Epi4K Consortium. <strong>De novo mutations in SLC1A2 and CACNA1A are important causes of epileptic encephalopathies.</strong> Am. J. Hum. Genet. 99: 287-298, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27476654/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27476654</a>] [<a href="https://doi.org/10.1016/j.ajhg.2016.06.003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27476654">Epi4K Consortium (2016)</a> identified a de novo heterozygous c.301G-C transversion (c.301G-C, NM_023035.2) in the CACNA1A gene, resulting in a glu101-to-gln (E101Q) substitution. Functional studies of the variant and studies of patient cells were not performed. He had onset of tonic seizures at 4 weeks of age. EEG showed epilepsy of infancy with migrating focal seizures (EIMFS). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27476654" 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>.0036 DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 42</strong>
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CACNA1A, ALA713THR
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000240888 OR RCV000255263 OR RCV000623106 OR RCV000763034 OR RCV001380078 OR RCV001814128 OR RCV002227102 OR RCV002274954" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000240888, RCV000255263, RCV000623106, RCV000763034, RCV001380078, RCV001814128, RCV002227102, RCV002274954" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000240888...</a>
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<p>In 2 unrelated patients (patients T23039 and T24139) with developmental and epileptic encephalopathy-42 (DEE42; <a href="/entry/617106">617106</a>), the <a href="#21" class="mim-tip-reference" title="Epi4K Consortium. <strong>De novo mutations in SLC1A2 and CACNA1A are important causes of epileptic encephalopathies.</strong> Am. J. Hum. Genet. 99: 287-298, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27476654/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27476654</a>] [<a href="https://doi.org/10.1016/j.ajhg.2016.06.003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27476654">Epi4K Consortium (2016)</a> identified a heterozygous c.2137G-A transition (c.2137G-A, NM_023035.2) in the CACNA1A gene, resulting in an ala713-to-thr (A713T) substitution. The mutation in 1 patient occurred de novo, where the mutation in the other patient and his similarly affected sib (patient T24629) was inherited from the unaffected mother who was somatic mosaic for the mutation (6.3% mutational load in the mother's lymphocytes). The same mutation had also been identified in a patient with DEE42 by the <a href="#20" class="mim-tip-reference" title="Epi4K Consortium and Epilepsy Phenome/Genome Project. <strong>De novo mutations in epileptic encephalopathies.</strong> Nature 501: 217-221, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23934111/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23934111</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23934111[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/nature12439" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23934111">EPI4K Consortium and Epilepsy Phenome/Genome Project (2013)</a>. Functional studies of the variant and studies of patient cells were not performed. The patients had onset of seizures in the neonatal period. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=23934111+27476654" 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>.0037 DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 42</strong>
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CACNA1A, ALA1511SER
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs886037946 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs886037946;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs886037946" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs886037946" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000240915" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000240915" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000240915</a>
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<p>In a girl (patient EG1519) with developmental and epileptic encephalopathy-42 (DEE42; <a href="/entry/617106">617106</a>), the <a href="#21" class="mim-tip-reference" title="Epi4K Consortium. <strong>De novo mutations in SLC1A2 and CACNA1A are important causes of epileptic encephalopathies.</strong> Am. J. Hum. Genet. 99: 287-298, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27476654/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27476654</a>] [<a href="https://doi.org/10.1016/j.ajhg.2016.06.003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27476654">Epi4K Consortium (2016)</a> identified a de novo heterozygous c.4531G-T transversion (c.4531G-T, NM_023035.2) in the SLC1A2 gene, resulting in an ala1511-to-ser (A1511S) substitution. The mutation was not found in the Exome Sequencing Project, 1000 Genomes Project, or ExAC databases. Functional studies of the variant and studies of patient cells were not performed. The patient had onset of status epilepticus on the first day of life. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27476654" 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="Ackerman1997" class="mim-anchor"></a>
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Ackerman, M. J., Clapham, D. E.
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<strong>Ion channels--basic science and clinical disease.</strong>
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New Eng. J. Med. 336: 1575-1586, 1997. Note: Erratum: New Eng. J. Med. 337: 579 only, 1997.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9164815/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9164815</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9164815" 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/10.1056/NEJM199705293362207" target="_blank">Full Text</a>]
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Alonso, I., Barros, J., Tuna, A., Coelho, J., Sequeiros, J., Silveira, I., Coutinho, P.
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<strong>Phenotypes of spinocerebellar ataxia type 6 and familial hemiplegic migraine caused by a unique CACNA1A missense mutation in patients from a large family.</strong>
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Arch. Neurol. 60: 610-614, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12707077/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12707077</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12707077" 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/10.1001/archneur.60.4.610" target="_blank">Full Text</a>]
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Barrett, C. F., Cao, Y.-Q., Tsien, R. W.
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<strong>Gating deficiency in a familial hemiplegic migraine type 1 mutant P/Q-type calcium channel.</strong>
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J. Biol. Chem. 280: 24064-24071, 2005.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15795222/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15795222</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15795222" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1074/jbc.M502223200" target="_blank">Full Text</a>]
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Battistini, S., Stenirri, S., Piatti, M., Gelfi, C., Righetti, P. G., Rocchi, R., Giannini, F., Battistini, N., Guazzi, G. C., Ferrari, M., Carrera, P.
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[<a href="https://doi.org/10.1212/wnl.53.1.38" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1212/01.wnl.0000295670.01629.5a" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/s004010050787" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1212/01.WNL.0000167409.59089.C0" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="69" class="mim-anchor"></a>
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<a id="Watase2008" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Watase, K., Barrett, C. F., Miyazaki, T., Ishiguro, T., Ishikawa, K., Hu, Y., Unno, T., Sun, Y., Kasai, S., Watanabe, M., Gomez, C. M., Mizusawa, H., Tsien, R. W., Zoghbi, H. Y.
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|
<strong>Spinocerebellar ataxia type 6 knockin mice develop a progressive neuronal dysfunction with age-dependent accumulation of mutant Ca(v)2.1 channels.</strong>
|
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Proc. Nat. Acad. Sci. 105: 11987-11992, 2008.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18687887/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18687887</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18687887[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=18687887" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1073/pnas.0804350105" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="70" class="mim-anchor"></a>
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<a id="Yue1997" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Yue, Q., Jen, J. C., Nelson, S. F., Baloh, R. W.
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<strong>Progressive ataxia due to a missense mutation in a calcium-channel gene.</strong>
|
|
Am. J. Hum. Genet. 61: 1078-1087, 1997.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9345107/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9345107</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9345107" 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/10.1086/301613" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="71" class="mim-anchor"></a>
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<a id="Yue1998" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Yue, Q., Jen, J. C., Thwe, M. M., Nelson, S. F., Baloh, R. W.
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|
<strong>De novo mutation in CACNA1A caused acetazolamide-responsive episodic ataxia.</strong>
|
|
Am. J. Med. Genet. 77: 298-301, 1998.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9600739/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9600739</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9600739" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/(sici)1096-8628(19980526)77:4<298::aid-ajmg9>3.0.co;2-j" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="72" class="mim-anchor"></a>
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<a id="Zhuchenko1997" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Zhuchenko, O., Bailey, J., Bonnen, P., Ashizawa, T., Stockton, D. W., Amos, C., Dobyns, W. B., Subramony, S. H., Zoghbi, H. Y., Lee, C. C.
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|
<strong>Autosomal dominant cerebellar ataxia (SCA6) associated with small polyglutamine expansions in the alpha(1A)-voltage-dependent calcium channel.</strong>
|
|
Nature Genet. 15: 62-69, 1997.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8988170/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8988170</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8988170" 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/ng0197-62" target="_blank">Full Text</a>]
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</p>
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</div>
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</ol>
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<div>
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<br />
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</div>
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</div>
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<div>
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<a id="contributors" class="mim-anchor"></a>
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<div class="row">
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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</span>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Bao Lige - updated : 10/04/2019
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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 : 09/19/2016<br>Patricia A. Hartz - updated : 8/18/2015<br>Cassandra L. Kniffin - updated : 1/25/2011<br>Cassandra L. Kniffin - updated : 9/30/2010<br>Cassandra L. Kniffin - updated : 8/16/2010<br>Cassandra L. Kniffin - updated : 5/11/2010<br>Nara Sobreira - updated : 3/11/2010<br>Cassandra L. Kniffin - updated : 3/1/2010<br>Cassandra L. Kniffin - updated : 8/4/2009<br>Cassandra L. Kniffin - updated : 6/24/2009<br>Cassandra L. Kniffin - updated : 6/5/2009<br>Cassandra L. Kniffin - updated : 2/16/2009<br>Cassandra L. Kniffin - updated : 1/22/2009<br>Cassandra L. Kniffin - updated : 1/6/2009<br>Cassandra L. Kniffin - updated : 4/3/2008<br>Patricia A. Hartz - updated : 2/7/2008<br>Cassandra L. Kniffin - updated : 11/1/2005<br>Cassandra L. Kniffin - updated : 6/9/2005<br>Cassandra L. Kniffin - updated : 3/1/2005<br>Ada Hamosh - updated : 1/19/2005<br>Cassandra L. Kniffin - updated : 11/17/2004<br>Cassandra L. Kniffin - updated : 6/2/2003<br>Cassandra L. Kniffin - updated : 5/28/2003<br>Cassandra L. Kniffin - updated : 1/28/2003<br>Cassandra L. Kniffin - updated : 12/6/2002<br>Cassandra L. Kniffin - reorganized : 9/23/2002<br>Cassandra L. Kniffin - updated : 9/23/2002<br>Michael J. Wright - updated : 7/1/2002<br>Cassandra L. Kniffin - updated : 6/14/2002<br>Cassandra L. Kniffin - updated : 6/3/2002<br>Cassandra L. Kniffin - updated : 5/24/2002<br>Victor A. McKusick - updated : 12/5/2001<br>Victor A. McKusick - updated : 9/5/2001<br>Kathryn R. Wagner - updated : 3/30/2001<br>Victor A. McKusick - updated : 3/19/2001<br>Carol A. Bocchini - updated : 2/19/2001<br>Ada Hamosh - updated : 9/25/2000<br>Victor A. McKusick - updated : 2/2/2000<br>George E. Tiller - updated : 1/18/2000<br>Victor A. McKusick - updated : 2/8/1999<br>Victor A. McKusick - updated : 10/14/1998<br>Victor A. McKusick - updated : 9/18/1998<br>Ada Hamosh - updated : 8/12/1998<br>Victor A. McKusick - updated : 7/1/1998<br>Victor A. McKusick - updated : 11/26/1997<br>Victor A. McKusick - updated : 11/12/1997<br>Victor A. McKusick - updated : 11/4/1997<br>Victor A. McKusick - updated : 9/24/1997<br>Victor A. McKusick - updated : 8/25/1997<br>Victor A. McKusick - updated : 6/20/1997<br>Victor A. McKusick - updated : 2/3/1997<br>Moyra Smith - updated : 12/29/1996<br>Moyra Smith - updated : 5/15/1996
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="creationDate" class="mim-anchor"></a>
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<div class="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 : 1/23/1996
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</span>
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</div>
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</div>
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</div>
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<a id="editHistory" class="mim-anchor"></a>
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<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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<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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carol : 09/25/2022
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</span>
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</div>
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</div>
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<div class="row collapse" id="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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alopez : 11/19/2020<br>carol : 11/11/2020<br>alopez : 11/10/2020<br>joanna : 10/18/2020<br>carol : 08/24/2020<br>carol : 08/21/2020<br>carol : 11/01/2019<br>alopez : 10/31/2019<br>mgross : 10/04/2019<br>alopez : 05/15/2019<br>alopez : 09/07/2017<br>carol : 05/25/2017<br>alopez : 09/21/2016<br>alopez : 09/20/2016<br>ckniffin : 09/19/2016<br>mgross : 08/27/2015<br>mcolton : 8/18/2015<br>terry : 2/7/2013<br>terry : 6/7/2012<br>wwang : 2/17/2011<br>ckniffin : 1/25/2011<br>terry : 11/3/2010<br>wwang : 9/30/2010<br>ckniffin : 9/30/2010<br>wwang : 8/24/2010<br>ckniffin : 8/16/2010<br>wwang : 5/14/2010<br>ckniffin : 5/11/2010<br>carol : 5/6/2010<br>terry : 3/11/2010<br>wwang : 3/3/2010<br>ckniffin : 3/1/2010<br>carol : 9/2/2009<br>wwang : 8/31/2009<br>ckniffin : 8/4/2009<br>wwang : 7/22/2009<br>ckniffin : 6/24/2009<br>wwang : 6/5/2009<br>ckniffin : 5/29/2009<br>wwang : 3/6/2009<br>ckniffin : 2/16/2009<br>wwang : 1/26/2009<br>ckniffin : 1/22/2009<br>wwang : 1/13/2009<br>ckniffin : 1/6/2009<br>terry : 6/6/2008<br>wwang : 4/15/2008<br>ckniffin : 4/3/2008<br>mgross : 2/19/2008<br>mgross : 2/19/2008<br>terry : 2/7/2008<br>wwang : 11/21/2005<br>wwang : 11/2/2005<br>ckniffin : 11/1/2005<br>wwang : 6/21/2005<br>wwang : 6/15/2005<br>ckniffin : 6/9/2005<br>wwang : 3/8/2005<br>ckniffin : 3/1/2005<br>wwang : 1/31/2005<br>wwang : 1/26/2005<br>terry : 1/19/2005<br>tkritzer : 11/23/2004<br>ckniffin : 11/17/2004<br>alopez : 7/27/2004<br>terry : 7/26/2004<br>tkritzer : 6/11/2003<br>tkritzer : 6/9/2003<br>ckniffin : 6/2/2003<br>ckniffin : 5/28/2003<br>ckniffin : 2/11/2003<br>carol : 2/10/2003<br>carol : 2/10/2003<br>tkritzer : 2/3/2003<br>ckniffin : 1/28/2003<br>carol : 12/16/2002<br>carol : 12/16/2002<br>tkritzer : 12/13/2002<br>ckniffin : 12/6/2002<br>alopez : 11/4/2002<br>carol : 11/1/2002<br>tkritzer : 10/25/2002<br>ckniffin : 10/2/2002<br>carol : 9/23/2002<br>ckniffin : 9/23/2002<br>carol : 9/23/2002<br>ckniffin : 9/23/2002<br>ckniffin : 9/5/2002<br>alopez : 7/3/2002<br>terry : 7/1/2002<br>ckniffin : 6/17/2002<br>carol : 6/17/2002<br>carol : 6/17/2002<br>ckniffin : 6/14/2002<br>ckniffin : 6/3/2002<br>carol : 5/24/2002<br>carol : 5/24/2002<br>ckniffin : 5/24/2002<br>alopez : 12/11/2001<br>terry : 12/5/2001<br>alopez : 9/10/2001<br>terry : 9/5/2001<br>cwells : 4/5/2001<br>carol : 3/30/2001<br>terry : 3/30/2001<br>cwells : 3/30/2001<br>terry : 3/19/2001<br>carol : 2/19/2001<br>alopez : 10/3/2000<br>terry : 9/25/2000<br>carol : 2/4/2000<br>terry : 2/2/2000<br>alopez : 1/18/2000<br>alopez : 11/15/1999<br>carol : 4/2/1999<br>carol : 2/18/1999<br>terry : 2/8/1999<br>carol : 10/20/1998<br>terry : 10/14/1998<br>dkim : 9/23/1998<br>terry : 9/18/1998<br>carol : 8/12/1998<br>terry : 7/29/1998<br>terry : 7/1/1998<br>dkim : 6/30/1998<br>carol : 6/26/1998<br>jenny : 12/2/1997<br>terry : 11/26/1997<br>jenny : 11/12/1997<br>terry : 11/4/1997<br>terry : 11/4/1997<br>dholmes : 10/6/1997<br>dholmes : 10/6/1997<br>terry : 9/30/1997<br>terry : 9/24/1997<br>mark : 8/25/1997<br>mark : 8/25/1997<br>jenny : 6/27/1997<br>jenny : 6/20/1997<br>mark : 6/11/1997<br>mark : 6/11/1997<br>mark : 6/9/1997<br>terry : 2/6/1997<br>terry : 2/3/1997<br>jenny : 1/14/1997<br>terry : 1/8/1997<br>mark : 12/29/1996<br>terry : 12/26/1996<br>terry : 11/18/1996<br>terry : 11/15/1996<br>carol : 5/22/1996<br>carol : 5/15/1996<br>terry : 2/6/1996<br>mark : 1/23/1996
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</span>
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</div>
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</div>
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</div>
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<div class="container visible-print-block">
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<div>
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<h3>
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<span class="mim-font">
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<strong>*</strong> 601011
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</span>
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</h3>
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</div>
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<div>
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<h3>
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<span class="mim-font">
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CALCIUM CHANNEL, VOLTAGE-DEPENDENT, P/Q TYPE, ALPHA-1A SUBUNIT; CACNA1A
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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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<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-1 POLYPEPTIDE, ISOFORM 4; CACNL1A4<br />
|
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CaV2.1
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
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<div>
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<p>
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<span class="mim-font">
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Other entities represented in this entry:
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</span>
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</p>
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</div>
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<div>
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<span class="h3 mim-font">
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CACNA1A C-TERMINAL POLYPEPTIDE, INCLUDED
|
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</span>
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</div>
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<div>
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<span class="h4 mim-font">
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ALPHA-1A C-TERMINAL POLYPEPTIDE, INCLUDED<br />
|
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ALPHA-1ACT, INCLUDED
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</span>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: CACNA1A</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>SNOMEDCT:</strong> 1260329005, 230464001, 420932006, 715752006;
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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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<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: 19p13.13
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Genomic coordinates <span class="small">(GRCh38)</span> : 19:13,206,442-13,506,479 </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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<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>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="5">
|
|
<span class="mim-font">
|
|
19p13.13
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|
</span>
|
|
</td>
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|
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<td>
|
|
<span class="mim-font">
|
|
Developmental and epileptic encephalopathy 42
|
|
</span>
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|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
617106
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|
</span>
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|
</td>
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<td>
|
|
<span class="mim-font">
|
|
Autosomal dominant
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|
</span>
|
|
</td>
|
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<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
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</td>
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|
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</tr>
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<tr>
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<td>
|
|
<span class="mim-font">
|
|
Episodic ataxia, type 2
|
|
</span>
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</td>
|
|
<td>
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<span class="mim-font">
|
|
108500
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal dominant
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|
</span>
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|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
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|
</td>
|
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</tr>
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|
|
|
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<tr>
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<td>
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|
<span class="mim-font">
|
|
Migraine, familial hemiplegic, 1
|
|
</span>
|
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</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
141500
|
|
</span>
|
|
</td>
|
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<td>
|
|
<span class="mim-font">
|
|
Autosomal dominant
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|
</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
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</td>
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</tr>
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|
|
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<tr>
|
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<td>
|
|
<span class="mim-font">
|
|
Migraine, familial hemiplegic, 1, with progressive cerebellar ataxia
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
141500
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal dominant
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
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</tr>
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|
|
|
|
|
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<tr>
|
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<td>
|
|
<span class="mim-font">
|
|
Spinocerebellar ataxia 6
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
183086
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal dominant
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
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</tr>
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|
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|
|
|
|
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|
|
</tbody>
|
|
</table>
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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>TEXT</strong>
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</span>
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</h4>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>Description</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
|
|
<p>The CACNA1A gene encodes the transmembrane pore-forming subunit of the P/Q-type or CaV2.1 voltage-gated calcium channel (VGCC) (Kordasiewicz et al., 2006). Voltage-dependent Ca(2+) channels not only mediate the entry of Ca(2+) ions into excitable cells but are also involved in a variety of Ca(2+)-dependent processes, including muscle contraction, hormone or neurotransmitter release, and gene expression. Diriong et al. (1995) noted that calcium channels are multisubunit complexes and that the channel activity is directed by a pore-forming alpha-1 subunit, which is often sufficient to generate voltage-sensitive Ca(2+) channel activity. There are at least 6 classes of alpha-1 subunits: alpha-1A, B, C, D, E, and S, which are derived from 6 genes representing members of a gene family. The auxiliary subunits beta (e.g., 114207), alpha-2/delta, and gamma (e.g., 114209) regulate channel activity. </p><p>In addition to full-length CACNA1A, use of an internal ribosomal entry site in the CACNA1A transcript generates the CACNA1A C-terminal polypeptide, or alpha-1ACT, which functions as a transcription factor that mediates cerebellar development (Du et al., 2013). </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>Ophoff et al. (1996) characterized the CACNL1A4 gene and reported the amino acid sequence for residues 1 to 2262 of the protein. Northern analysis detected a 9.8-kb transcript in cerebellum, cerebral cortex, thalamus, and hypothalamus. </p><p><strong><em>CACNA1A C-Terminal Polypeptide</em></strong></p><p>
|
|
Kordasiewicz et al. (2006) showed that a 75-kD human polypeptide consisting of the C terminus of CACNA1A is cleaved from the full-length protein and is present in the nucleus of HEK293 cells, as well as in mouse and human cerebellar Purkinje cells. Nuclear translocation depended partly on the presence of 3 nuclear localization signals within the C terminus. </p><p>Li et al. (2009) confirmed that C-terminal fragments of CACNA1A localized predominantly to the nucleus of HEK293 cells where they existed as speckle-like structures resembling promyelocytic leukemia nuclear bodies (PMLNBs). </p><p>Using mass spectrometric analysis, Du et al. (2013) determined that the 75-kD CACNA1A C-terminal polypeptide, which they called alpha-1ACT, began with the N-terminal sequence MIMEY at amino acid 1960 within the IQ-like domain of full-length CACNA1A. This N-terminal sequence did not overlap with any protease cleavage site, and expression of alpha-1ACT appeared to be due to use of a cryptic internal ribosomal entry site in the CACNA1A transcript. </p>
|
|
</span>
|
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<div>
|
|
<br />
|
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</div>
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<div>
|
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<h4>
|
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<span class="mim-font">
|
|
<strong>Gene Structure</strong>
|
|
</span>
|
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</h4>
|
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</div>
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<span class="mim-text-font">
|
|
<p>Ophoff et al. (1996) found that the CACNA1A gene covers 300 kb and contains 47 exons. Sequencing of all exons and their surroundings revealed polymorphic variations, including a (CA)n-repeat (D19S1150) and a (CAG)n-repeat in the 3-prime-UTR. </p><p>Trettel et al. (2000) determined that the CACNL1A4 gene is alternatively spliced. A second isoform contains an alternative exon 37 that differs from the first by 97 nucleotides. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Mapping</strong>
|
|
</span>
|
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</h4>
|
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</div>
|
|
|
|
|
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|
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<span class="mim-text-font">
|
|
<p>By FISH, Diriong et al. (1995) assigned the CACNA1A gene to chromosome 19p13. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Gene Function</strong>
|
|
</span>
|
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</h4>
|
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</div>
|
|
|
|
|
|
|
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<span class="mim-text-font">
|
|
<p>Ca(2+) currents have been described on the basis of their biophysical and pharmacologic properties and include L-, N-, T-, P-, Q-, and R- types. The distinctive properties of these Ca(2+) channel types are related primarily to the expression of a variety of alpha-1 isoforms (Dunlap et al., 1995). The alpha-1A isoform is abundantly expressed in neuronal tissue and corresponds to the P/Q Ca(2+) channel type. The B and E isoforms are also expressed in neuronal tissue and correspond to the N-type and R-type of Ca(2+) channels, respectively (Lehmann-Horn and Jurkat-Rott, 1999). The genes encoding the alpha-1A, B, and E isoforms are symbolized CACNL1A4 or CACNA1A, CACNL1A5 (601012), and CACNL1A6 (601013) and are located on 19p13, 9q34 and 1q25-q31, respectively (Diriong et al., 1995). Alpha-1C, D, and S are involved with L-type Ca(2+) channels and are referred to as cardiac, neuroendocrine/brain, and skeletal muscle isoforms, respectively. They are encoded, respectively, by the CACNL1A1 gene (114205) on 12p13.3, the CACNL1A2 gene (114206) on 3p14.3, and the CACNL1A3 gene (114208) on 1q31-q32. </p><p>Takamori et al. (1997) and Takamori (2004) presented evidence suggesting that the alpha-1A subunit of the P/Q-type voltage-gated calcium channel contains antigenic sites implicated in Lambert-Eaton myasthenic syndrome. </p><p>Ackerman and Clapham (1997) provided a comprehensive review of the role of ion channel defects in disease. They provided useful illustrations of the physiology and structure of ion channels and of patch-clamp measurement of ion channel activity. They also discussed the design and use of drugs that target ion channels. </p><p>Using chromatin immunoprecipitation-sequencing and RNA-sequencing analyses, Du et al. (2019) identified dynamic changes in alpha-1Act-mediated gene regulation in rat PC12 pheochromocytoma cells. Many of the alpha-1Act-regulated genes were involved in neurogenesis, synaptic function, and cell adhesion. Quantitative RT-PCR analysis revealed that CACNA1A mRNA expression was maximal in human cerebellum from birth to 20 years of age and decreased gradually until reaching a plateau at age 50 years. A similar expression pattern was observed in cerebellum over the mouse life span. Du et al. (2019) presented evidence suggesting that bicistronic expression is common to multiple members of the VGCC family. </p><p><strong><em>CACNA1A C-Terminal Polypeptide</em></strong></p><p>
|
|
Du et al. (2013) found that human alpha-1ACT bound an AT-rich enhancer element (TTATAA) in the 3-prime UTR of target genes, including BTG1 (109580), and increased expression of their reporter genes. Expression of alpha-1ACT in rat PC12 pheochromocytoma cells increased neurite outgrowth and expression of the predicted target gene. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Biochemical Features</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
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<span class="mim-text-font">
|
|
<p>Nishimune et al. (2004) showed that laminin beta-2 (LAMB2; 150325), a component of the synaptic cleft at the neuromuscular junction, binds directly to calcium channels that are required for neurotransmitter release from motor nerve terminals. This interaction leads to clustering of channels which in turn recruit other presynaptic components. Perturbation of this interaction in vivo results in disassembly of neurotransmitter release sites, resembling defects previously observed in an autoimmune neuromuscular disorder, Lambert-Eaton myasthenic syndrome (600003). Nishimune et al. (2004) concluded that their results identify an extracellular ligand of the voltage-gated calcium channel as well as a new laminin receptor, suggest a model for the development of nerve terminals, and provide clues to the pathogenesis of a synaptic disease. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Molecular Genetics</strong>
|
|
</span>
|
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</h4>
|
|
</div>
|
|
|
|
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|
|
|
<span class="mim-text-font">
|
|
<p><strong><em>Episodic Ataxia Type 2</em></strong></p><p>
|
|
In 2 unrelated patients with episodic ataxia type 2 (EA2; 108500), Ophoff et al. (1996) identified 2 mutations in the CACNA1A gene resulting in a disrupted reading frame. The first of these was deletion of a single C, nucleotide 4073 in codon 1266 (601011.0005), leading to a frameshift in the putative translation product with a stop codon in the next exon (codon 1294). See also 601011.0006. </p><p>Eunson et al. (2005) identified 2 splice site mutations in the CACNA1A gene in 2 unrelated families with EA2. </p><p>Riant et al. (2010) identified 4 different exonic deletions in the CACNA1A gene in 4 (14%) of 27 patients with episodic ataxia, in whom sequencing analysis was negative for CACNA1A point mutations. The EA2 phenotype in the patients with deletion was similar to that of patients with point mutations. The findings indicated that screening for deletions in the CACNA1A gene should also be done for a complete genetic workup. </p><p>Labrum et al. (2009) used multiplex ligation-dependent probe amplification (MLPA) to screen for large-scale genetic rearrangements in CACNA1A in 53 patients with a clinical diagnosis of episodic ataxia type 2 (EA2; 108500) or familial hemiplegic migraine type 1 (FHM1; 141500) in whom sequencing analysis was negative for CACNA1A point mutations. Labrum et al. (2009) identified 5 previously unreported large-scale deletions in the CACNA1A gene in 6 families with EA2 and the first pathogenic duplication in CACNA1A in an index patient with isolated episodic diplopia without ataxia (601011.0030) whose father reportedly had typical EA2 (601011.0030). Labrum et al. (2009) suggested that large-scale deletions and duplications can cause CACNA1A-associated channelopathies and that screening for large-scale rearrangements by rapid techniques such as MLPA should be considered as a first-line approach for genetic diagnostic testing of CACNA1A-associated channelopathies. </p><p><strong><em>Familial Hemiplegic Migraine 1</em></strong></p><p>
|
|
In 5 unrelated families with familial hemiplegic migraine (FHM1; 141500), Ophoff et al. (1996) identified 4 different missense mutations in the CACNA1A gene (601011.0001-601011.0004). The authors raised the possibility that a similar defect may be involved in common types of migraine. Based on their mutational findings, Ophoff et al. (1996) suggested that FHM and EA2 are allelic channelopathies. </p><p>To determine the pathophysiologic consequences of missense mutations in the pore-forming human alpha-1A subunit of neuronal P/Q-type calcium channels associated with FHM, Kraus et al. (1998) introduced 4 single mutations (R192Q, 601011.0001; T666M, 601011.0002; V714A, 601011.0003; and I1811L, 601011.0004) into alpha-1A and investigated possible changes in channel function after functional expression of mutant subunits in Xenopus laevis oocytes. Changes in channel gating were observed for mutants T666M, V714A, and I1811L, but not for R192Q. Barium current inactivation was slightly faster in mutants T666M and V714A than in wildtype. The time course of recovery from channel inactivation was slower than in wildtype in T666M and accelerated in V714A and I1811L. Kraus et al. (1998) concluded that 3 of the 4 FHM mutations, located at the putative channel pore, alter inactivation gating and provide a pathophysiologic basis for the postulated neuronal instability in patients with FHM. </p><p>Kraus et al. (2000) continued their channel function studies with 3 additional mutations associated with FHM, including D715E (601011.0010) and V1457L (601011.0019). All 3 mutations significantly shifted the voltage dependence of activation to more negative potentials, resulting in altered calcium signaling by increasing channel activity at weak depolarizations. The authors suggested that these gating abnormalities underlie channel dysfunction in FHM. </p><p>Tottene et al. (2002) extended single-channel analysis to human voltage-gated P/Q type calcium channels (Ca(v)2.1) containing the V1457L mutation. This mutation increased the channel open probability by shifting its activation to more negative voltages and reduced both the unitary conductance and the density of functional channels in the membrane. To investigate the possibility of changes in Ca(v)2.1 function common to all FHM mutations, Tottene et al. (2002) calculated the product of single-channel current and open probability as a measure of calcium ion influx through single Ca(v)2.1 channels. All 5 FHM mutants analyzed showed a single-channel calcium ion influx larger than wildtype. They also expressed the FHM mutants in cerebellar granular cells from mice null for the mutation. The FHM mutations invariably led to a decrease of the maximal Ca(v)2.1 current density in neurons. The data showed that mutational changes of functional channel densities can be different in different cell types, and uncovered 2 functional effects common to all FHM mutations analyzed: increase of single-channel calcium ion influx and decrease of maximal Ca(v)2.1 current density in neurons. Tottene et al. (2002) hypothesized that these 2 apparently contradictory effects may underlie parallel processes of migraine and aura. This notion came from the clinical evidence that the migraine aura and the headache are not necessarily sequential, and that the aura may not be the trigger for the pain. </p><p>By studying mouse hippocampal neurons transfected with 4 human FHM1-related CACNA1A mutations (R192Q, T666M, V714A, and I1811L), Cao and Tsien (2005) observed that all 4 mutations resulted in decreased channel current without a change in voltage dependence. The mutant P/Q calcium channels were associated with a defect in GABA inhibitory transmission, although overall basal inhibitory transmission remained well preserved owing to a shift to N-type calcium channels. This shift increased the susceptibility to G protein-coupled modulation of presynaptic neurotransmission, which may be weakened in a heightened state of neuromodulation, like that provoked by triggers of migraine such as stress. </p><p>In approximately 20% of cases of FHM, the disease is associated with a mild permanent cerebellar ataxia which may be progressive (PCA). The CACNA1A gene is involved in about 50% of unselected hemiplegic migraine families and in all families with FHM/PCA. Ducros et al. (1999) screened 16 families and 3 nonfamilial cases with HPM/PCA for specific CACNA1A mutations and found 9 families and 1 nonfamilial case with the same T666M mutation (601011.0002), 1 novel mutation (D715E; 601011.0010) in 1 family, and no CAG repeat expansion. Both T666M and D715E substitutions were absent in 12 probands belonging to pure HPM families whose disease appeared to be linked to CACNA1A. Finally, haplotyping with neighboring markers suggested that T666M arose through recurrent mutational events. These data suggested that the PCA observed in 20% of HPM families results from specific pathophysiologic mechanisms. </p><p>Ducros et al. (2001) found 9 mutations in the CACNA1A gene in 15 of 16 probands of families affected by hemiplegic migraine and cerebellar signs, in 2 of 3 subjects with sporadic hemiplegic migraine and cerebellar signs, and in 4 of 12 probands of families affected by pure hemiplegic migraine. Genotyping of probands and relatives identified a total of 117 subjects with mutations whose clinical manifestations were assessed in detail. Of the subjects with mutations, 89% had attacks of hemiplegic migraine. One-third had severe attacks with coma, prolonged hemiplegia, or both, with full recovery. All 9 mutations, including 5 newly identified ones, were missense mutations. Six mutations were associated with hemiplegic migraine and cerebellar signs, and 83% of the subjects with these 6 mutations had nystagmus, ataxia, or both. Three mutations were associated with pure hemiplegic migraine. </p><p>Kim et al. (1998) sought mutations in the CACNA1A gene in 9 propositi of families with migraine headaches and episodic vertigo inherited in an autosomal dominant pattern. All 47 exons and flanking introns were subjected to SSCP analysis of PCR-amplified genomic DNA. Several polymorphisms were found, but no mutations were identified in any of the 47 exons of the 9 patients. They also determined the CAG repeat length at the 3-prime end of CACNA1A. No index case had a CAG repeat length greater than 13 (normal less than 17). Thus, mutations in CACNA1A must be uncommon in families with migraine headaches and episodic vertigo. Other ion channel genes expressed in the brain and inner ear remained candidate genes. </p><p>Labrum et al. (2009) used multiplex ligation-dependent probe amplification to screen for large-scale genetic rearrangements in CACNA1A in 53 patients with a clinical diagnosis of episodic ataxia type 2 or familial hemiplegic migraine type 1 in whom sequencing analysis was negative for CACNA1A point mutations. They identified a large-scale deletion in 1 patient with FHM1 (601011.0034) and in several patients with EA2. </p><p><strong><em>Spinocerebellar Ataxia 6</em></strong></p><p>
|
|
Zhuchenko et al. (1997) identified expansion of a CAG repeat (601011.0007) predicted to code for polyglutamine in the C-terminal coding region of the CACNL1A4 gene in families with slowly progressive spinocerebellar ataxia designated SCA6 (183086). </p><p>Analysis of CAG repeat expansion in the CACNL1A4 gene by Ishikawa et al. (1997) revealed expansion in 8 of 15 Japanese families with autosomal dominant cerebellar ataxia; all affected individuals had larger alleles (range of CAG repeats 21 to 25), compared with alleles observed in neurologically normal Japanese (range 5 to 20 repeats). Inverse correlation between the CAG-repeat number and the age of onset was found in affected individuals with expansion. The number of CAG repeats in expanded chromosomes was completely stable within each family, which was consistent with the fact that anticipation was not statistically proved in these SCA6 families. Ishikawa et al. (1997) concluded that more than half of Japanese cases of ADPCA map to 19p and are strongly associated with the mild CAG expansion in the SCA6/CACNL1A4 gene. </p><p><strong><em>Idiopathic Generalized Epilepsy</em></strong></p><p>
|
|
Chioza et al. (2001) provided direct evidence that the CACNA1A gene is involved in the etiology of idiopathic generalized epilepsy (IGE; 600669). They analyzed 4 single nucleotide polymorphisms (SNPs) from patients with IGE and found that 1 of them, SNP8, showed significant association with the disease. Because SNP8 is a silent polymorphism, the authors suggested that the association must be with a closely linked variant. </p><p><strong><em>Developmental and Epileptic Encephalopathy 42</em></strong></p><p>
|
|
In 5 patients, including 2 sibs, with developmental and epileptic encephalopathy-42 (DEE42; 617106), the Epi4K Consortium (2016) identified 4 different heterozygous mutations in the CACNA1A gene (601011.0017, 601011.0035-601011.0037). The mutations were found by targeted sequencing of 27 candidate genes in 531 patients with a similar disorder. Functional studies of the variants and studies of patient cells were not performed. </p>
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</span>
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<div>
|
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<br />
|
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>Genotype/Phenotype Correlations</strong>
|
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
|
|
<p>Hoffman and Gardner (1997) pointed out that a drug designed to correct for the calcium-channel defect in patients with mutations of the CACNL1A4 gene may need to be completely 'phenotype-specific' as well as 'channel-specific' and may need to modulate the activity of the calcium channel differently between several disorders, despite the shared site of the biochemical defect. Conceivably, inhibitors of channel function may be effective in disorders caused by change-of-function mutations (e.g., in patients with hemiplegic migraine), whereas agents that stimulate the same channel might be beneficial in patients with loss-of-function mutations (such as those in episodic ataxia). Drugs that modulate the level of function of the channels may have little efficacy in patients with the SCA6 phenotype, since this disorder results from progressive cerebellar cell loss which is probably due to neurotoxicity of the polyglutamine peptide that is mutated in the disorder. </p>
|
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>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>By a positional cloning approach, Fletcher et al. (1996) identified an alpha-1 voltage-sensitive Ca(2+) channel gene that is mutated in the 'tottering' mutations in tg and tg(la) mice. The tg mutation is a well-studied mutation that gives rise to behavioral arrest seizures, which may be compared to human absence (or petit mal) epilepsy (600131) and cerebellar ataxia. The tottering phenotype also includes motor seizures. Fletcher et al. (1996) noted that the tg leaner mice, tg(la), suffer from absence seizures but do not have motor seizures. These mice are severely ataxic. Fletcher et al. (1996) mapped the tg phenotype to mouse chromosome 8 in the vicinity of the Junb gene (165161). Fletcher et al. (1996) evaluated the Ca(2+) channel gene as a candidate for the tg locus using RT-PCR and sequencing. In the tg(la) mice they demonstrated a single G-to-A change in a splice donor site in the portion of the mouse gene encoding the putative regulatory C-terminal domain of the channel. This mutation resulted in several aberrant mRNA species, including insertion of 98 nucleotides at position 5901/2 and deletion of nucleotides 5763-5901, either of which altered the reading frame 3-prime to the mutations. The tg transcript contained a C-to-A transversion at position 1802 relative to the control sequence. Fletcher et al. (1996) reported that this alteration leads to a nonconservative proline-to-leucine amino acid substitution that may affect the pore function of the Ca(2+) channel. Fletcher et al. (1996) noted that this is the first gene identified as being involved in absence epilepsy. </p><p>The alpha-1 voltage-sensitive Ca(2+) channel sequence reported by Fletcher et al. (1996) is the mouse homolog of the human Ca(2+) channel alpha subunit, also designated CACNL1A4. It is noteworthy that the CACNL1A4 gene maps to chromosome 19p13 in a region that is homologous to the region of mouse chromosome 8 where tg maps. </p><p>In a provocatively entitled minireview, 'Migraines in Mice?,' Hess (1996) compared the tottering/leaner mouse mutations with the human mutations in CACNL1A4. She referred to inherited ion channel mutations as channelopathies. </p><p>Thibault and Landfield (1996) used partially dissociated hippocampal slice preparations to analyze single Ca(2+) channel activity in neurons of adult and aged rats. They reported that total L-type Ca(2+) channel activity increased primarily because of increased density of functional channels. They noted that learning in aged animals was inversely correlated with channel density. Thibault and Landfield (1996) postulated that the observed increase in functional Ca(2+) channels with aging could underlie the vulnerability of neurons to age-associated neurodegenerative conditions. </p><p>Van den Maagdenberg et al. (2004) generated a transgenic mouse model carrying the human CACNA1A mutation R192Q (601011.0001). Cultured cerebellar granule cells from R192Q mice showed increased Ca(v)2.1 channel current densities, which were activated at more negative voltages than wildtype channels. Neuromuscular synapses with the mutant CACNA1A channels had increased induced neurotransmission and increased spontaneous miniature endplate potential frequency at low Ca(2+) levels compared to controls, consistent with a gain of function. In addition, the intact transgenic animal showed increased susceptibility to cortical spreading depression, the likely mechanism for migraine aura. Van den Maagdenberg et al. (2004) concluded that the underlying mechanism in FHM is cortical hyperexcitability due to excessive release of excitatory amino acids in response to increased Ca(2+) influx through a defective Ca(v)2.1 channel. </p><p>Near postnatal day 10, mice lacking P/Q-type calcium channels have difficulty walking, have absence seizures, and are ataxic and dystonic. Neurologic symptoms in these mice become more acute with age, until they are unable to walk and die at about 3 weeks of age (Jun et al., 1999). Mutant animals also show increased density of T-type channels (CACNA1G; 604065) that support low-threshold action potentials in the absence of P/Q-type channels (Song et al., 2004). Llinas et al. (2007) found that in vitro patch recordings of thalamic neurons from mice lacking P/Q-type channels showed no gamma band subthreshold oscillation, and voltage-sensitive dye imaging demonstrated absence of cortical gamma band-dependent columnar activation involving cortical inhibitory interneuron activity. In vivo EEGs showed persistent absence status and dramatically reduced gamma band activity. Pharmacologic blockade of T-type channels left knockout mice in a coma-like state, indicating that increased T-type channel expression in thalamocortical neurons was causally related to generation of absence seizures. Llinas et al. (2007) concluded that P/Q-type calcium channels are essential for generation of gamma band activity and resultant cognitive function. </p><p>Watase et al. (2008) found that knockin mice expressing a hyperexpanded polyglutamine (84Q) Cacna1a repeat developed progressive motor impairment consistent with SCA6. Knockin mice with normal 14 CAG or expanded 30 CAG repeats did not show such defects. Electrophysiologic analysis of cerebellar Purkinje cells revealed similar calcium channel current density among the 3 mouse models, although all were decreased compared to wildtype due to decreased channel abundance. Neither voltage sensitivity of activation nor inactivation was altered in the Sca6(84Q) neurons, suggesting that the expanded CAG repeat does not per se affect the intrinsic electrophysiologic properties of the channels. Mice with the hyperexpanded polyglutamine repeat showed cytoplasmic neuronal inclusions, consistent with aggregation of mutant calcium channels. Watase et al. (2008) concluded that the pathogenesis of SCA6 is related to an age-dependent process accompanied by accumulation of mutant CACNA1A channels resulting in a toxic gain-of-function effect. </p><p>Van Oosterhout et al. (2008) found that R192Q-mutant mice showed atypical phase resetting of their circadian rhythms when subjected to 6-hour advance shifts of the light/dark cycle. Compared to controls, mutant mice showed a more than 2-fold enhanced adjustment of behavioral wheel-running activity and EEG patterns, as well as enhanced shifts of electrical activity of suprachiasmatic neurons (SCN) in vivo. No differences were observed for a 6-hour delay. The physiologic inhibitory process appeared to be mediated by CACNA1A channel-dependent afferent signaling from extra-SCN brain areas to the SCN. Van Oosterhout et al. (2008) interpreted the findings as suggesting that abrupt circadian rhythm changes may trigger migraine attacks, possibly because patients have an inadequate adaptation mechanism. </p><p>Eikermann-Haerter et al. (2009) found that transgenic mice expressing the R192Q or S218L (601011.0017) CACNA1A mutations had increased frequency and speed of spreading depression and enhanced corticostriatal propagation compared to wildtype mice after induction. Mutant mice also developed severe and prolonged neurologic deficits. The susceptibility to spreading depression and neurologic deficits was affected by allele dosage and was higher in S218L than R192Q mutants, similar to observations in humans. Female mutant mice were more susceptible to spreading depression and neurologic deficits than males, and this sex difference was abrogated by ovariectomy or senescence and partially restored by estrogen replacement. The findings implicating ovarian hormones in the observed sex differences in humans with FHM1. In a follow-up study, Eikermann-Haerter et al. (2009) demonstrated that orchidectomy in R192Q-mutant male mice increased susceptibility to cortical spreading depression, and that chronic testosterone replacement restored the lower susceptibility in mutant males. These findings implicated androgens as a modulating factor in genetically-enhanced susceptibility to cortical spreading depression. </p><p>Van den Maagdenberg et al. (2010) found that transgenic S218L homozygous mice had mild cerebellar ataxia and reduced arborization of proximal primary dendrites of cerebellar Purkinje neurons. They exhibited 2 types of spontaneous attacks: those consistent with hemiparesis observed in patients with FHM1 and attacks of generalized seizures that were fatal in some cases. In addition, homozygous mutant mice developed significant brain edema 24 hours after mild head impact, indicating that these mice mimicked the broad complex neurologic spectrum of spontaneous episodic, mild impact-triggered, and permanent clinical features seen in human patients heterozygous for the S218L mutation. In vitro studies on mouse cerebellar granule neurons showed that the S218L mutation increased whole-cell calcium current density at negative voltages, resulted in a leftward shift in voltage-dependent activation, and increased spontaneous neurotransmitter release, consistent with a gain of function. The calcium current in homozygous mutant cells was 6.6 times greater than that in wildtype neurons. Further studies showed that mutant mice had an increased susceptibility to successive cortical spreading depression events compared to wildtype and mutant R192Q mice. In general, all of the changes associated with the S218L mutation were quantitatively more pronounced than those observed with the R192Q mutation. </p><p>Du et al. (2013) found that expression of alpha-1act partially improved the phenotype of Cacna1a-null mice and provided a modest improvement in survival. Expression of alpha-1act also partially improved synaptic activity and connections in Cacna1a-null cerebellar slice preparation. Alpha-1act with a pathologic polyQ expansion reduced viability of PC12 cells in culture and mediated ataxia and cerebellar cortical atrophy in transgenic mice. </p><p>By characterizing a dose-dependent Cacna1a gene deficiency mouse model, Du et al. (2019) found that alpha-1Act drove dynamic gene regulation networks within cerebellar Purkinje cells and was indispensable for neonatal survival. Perinatal loss of alpha-1Act disrupted neurogenesis and synaptic regulatory networks, leading to motor dysfunction. In contrast, elimination of alpha-1Act in adulthood had minimal effects on cerebellum. The authors demonstrated a similar age-dependent pattern of alpha-1ACT gene regulation in human cerebellum, validating their observations in mouse cerebellum. </p>
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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>37 Selected Examples):</strong>
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<span class="mim-font">
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<strong>.0001 MIGRAINE, FAMILIAL HEMIPLEGIC, 1</strong>
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CACNA1A, ARG192GLN
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SNP: rs121908211,
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ClinVar: RCV000009008, RCV001533156, RCV002512926, RCV003231095
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<span class="mim-text-font">
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<p>In 5 unrelated families with familial hemiplegic migraine (FHM1; 141500), Ophoff et al. (1996) identified 4 different missense mutations in the CACNL1A4 gene. One of these mutations was a G-to-A transition at nucleotide 850 in exon 4 resulting in an arg192-to-gln (R192Q) amino acid substitution. </p>
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<span class="mim-font">
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<strong>.0002 MIGRAINE, FAMILIAL HEMIPLEGIC, 1</strong>
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<span class="mim-text-font">
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MIGRAINE, FAMILIAL HEMIPLEGIC 1, WITH PROGRESSIVE CEREBELLAR ATAXIA, INCLUDED<br />
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MIGRAINE, SPORADIC HEMIPLEGIC, WITH PROGRESSIVE CEREBELLAR ATAXIA, INCLUDED
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<span class="mim-text-font">
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CACNA1A, THR666MET
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SNP: rs121908212,
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ClinVar: RCV000009009, RCV000009010, RCV000504541, RCV000516650, RCV000802118, RCV001533159, RCV002051776, RCV002415406, RCV003233067, RCV005025039
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<p>In families with hemiplegic migraine (FHM1; 141500), Ophoff et al. (1996) discovered a C-to-T transition in nucleotide 2272 of CACNL1A4, resulting in a thr666-to-met (T666M) amino acid substitution. </p><p>Friend et al. (1999) found this recurrent mutation in exon 16 in an Australian patient with familial hemiplegic migraine. </p><p>Ducros et al. (1999) screened 16 families and 3 nonfamilial cases with hemiplegic migraine associated with progressive cerebellar ataxia (see 141500). They found the T666M mutation in 9 families and 1 nonfamilial case. The T666M mutation was absent in 12 probands belonging to pure HPM families whose disease appeared to be linked to CACNA1A. </p><p>Terwindt et al. (2002) studied 27 patients with sporadic hemiplegic migraine and found the T666M mutation in a 78-year-old woman who had characteristic attacks starting at age 14 as well as interictal nystagmus, dysarthria, limb and gait ataxia, and cerebellar atrophy. </p><p>Kors et al. (2003) reported the clinical symptoms of 5 families with hemiplegic migraine and the T666M mutation. Three of the families displayed cerebellar ataxia, 3 had loss of consciousness or coma associated with episodes, 1 had attacks with confusion but without hemiparesis, and 1 had progressive cognitive dysfunction. The authors emphasized the inter- and intrafamilial clinical heterogeneity. </p><p>Barrett et al. (2005) found that CACNA1A channels with the T666M mutation were expressed and trafficked normally to the cell surface in transfected HEK293 cells. However, T666M mutant channels exhibited defective voltage-dependent gating to support calcium influx. </p>
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<h4>
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<span class="mim-font">
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<strong>.0003 MIGRAINE, FAMILIAL HEMIPLEGIC, 1</strong>
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CACNA1A, VAL714ALA
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SNP: rs121908213,
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ClinVar: RCV000009011, RCV001533160
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<span class="mim-text-font">
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<p>In families with hemiplegic migraine (FHM1; 141500), Ophoff et al. (1996) identified a T-to-C transition in nucleotide 2416 of the CACNL1A4 gene, resulting in a val714-to-ala (V714A) amino acid substitution. </p>
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<h4>
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<span class="mim-font">
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<strong>.0004 MIGRAINE, FAMILIAL HEMIPLEGIC, 1</strong>
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</span>
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</h4>
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CACNA1A, ILE1811LEU
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SNP: rs121908214,
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ClinVar: RCV000009012, RCV001390440, RCV001533163, RCV004791199
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<span class="mim-text-font">
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<p>In 2 unrelated families, Ophoff et al. (1996) found that members with hemiplegic migraine (FHM1; 141500) had an A-to-C transversion at nucleotide 5706 of the CACNL1A4 gene, resulting in an ile1811-to-leu (I1811L) amino acid substitution in the gene product. The mutation occurred on different 19p13 haplotypes in the 2 families, indicating that this was a recurrent mutation rather than a founder effect. Cerebellar atrophy is said to occur in approximately 40% of chromosome 19-linked HPM families but not in unlinked HPM families (Terwindt et al., 1996). Of the 2 families with the I1811L mutation, Ophoff et al. (1996) noted that only 1 displayed cerebellar atrophy and in that family only some members were affected. Apparently other factors in this amino acid substitution further contribute to the phenotypic variability. These factors may include genetic polymorphisms elsewhere in the gene or at other channel-related loci and the net effect of other ion channels on the polarity of the cell membrane. </p>
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<h4>
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<span class="mim-font">
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<strong>.0005 EPISODIC ATAXIA, TYPE 2</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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CACNA1A, 1-BP DEL, 4073C
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SNP: rs587776692,
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ClinVar: RCV000009013
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<span class="mim-text-font">
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<p>In 2 unrelated patients with episodic ataxia type 2 (EA2; 108500), Ophoff et al. (1996) identified mutations resulting in a disrupted reading frame. The first of these was deletion of a single C, nucleotide 4073 in codon 1266, leading to a frameshift in the putative translation product with a stop codon in the next exon (codon 1294). See also 601011.0006. </p>
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<h4>
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<span class="mim-font">
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<strong>.0006 EPISODIC ATAXIA, TYPE 2</strong>
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</span>
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</h4>
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CACNA1A, IVS24DS, G-A, +1
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<br />
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SNP: rs587776693,
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ClinVar: RCV000009014, RCV001781208
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<span class="mim-text-font">
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<p>In a patient with episodic ataxia type 2 (EA2; 108500), Ophoff et al. (1996) identified a G-to-A transition in the first nucleotide of intron 24, changing the highly conserved GT dinucleotide of the intronic 5-prime splice junction. The mutation resulted in the loss of a BsaAI restriction site. The brain-specific expression of CACNL1A4 precluded testing the hypothesis that this mutation produced aberrantly spliced RNAs by retaining the intron or utilizing other cryptic 5-prime splice sites. Such was, however, presumably the case. </p>
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<h4>
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<span class="mim-font">
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<strong>.0007 SPINOCEREBELLAR ATAXIA 6</strong>
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</h4>
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CACNA1A, (CAG)n REPEAT EXPANSION, 21-30 REPEATS, EX47
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ClinVar: RCV000009015, RCV000030866
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<span class="mim-text-font">
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<p>Zhuchenko et al. (1997) identified expansion of a CAG repeat predicted to encode for polyglutamine in exon 47 of the coding region of the CACNL1A4 gene in families with slowly progressive spinocerebellar ataxia designated SCA6 (183086). </p><p>Matsuyama et al. (1997) analyzed 60 SCA6 individuals from 39 independent Japanese SCA6 families and found that the CAG repeat length in the CACNL1A4 gene was inversely correlated with age of onset. SCA6 chromosomes contained 21 to 30 repeat units, whereas normal chromosomes displayed 6 to 17 repeats. There was no overlap between the normal and affected CAG repeat number. Anticipation was observed clinically in all 8 parent-child pairs examined; the mean age of onset was significantly lower (P = 0.0042) in children than in parents. However, a parent-child analysis showed an increase in the expansion of CAG repeats only in 1 pair and no diminution in any affected cases. The results suggested that factors other than CAG repeats may produce the clinical anticipation. A homozygotic case could not demonstrate unequivocal gene dosage effect on the age of onset. See also Ishikawa et al. (1997). </p><p>Riess et al. (1997) found that the SCA6 mutation accounts for approximately 10% of autosomal dominant SCA in Germany. They observed the trinucleotide expansion in 4 ataxia patients without obvious family history of the disease, indicating the necessity to search for the SCA6 (CAG)n expansion even in sporadic patients. In their series of 32 patients, onset was usually late and the (CAG)n stretch varied between 22 and 28 trinucleotide units, the shortest trinucleotide repeat expansion causing spinocerebellar ataxia. Analyzing 248 apparently healthy octogenarians, Riess et al. (1997) found 1 allele of 18 repeats, the longest normal CAG repeat in the CACNL1A4 gene reported to that time. They could demonstrate no repeat instability of the expanded allele on transmission and no repeat instability was found for the normal allele in 431 meioses in the CEPH families. </p><p>Sasaki et al. (1998) described neuropathologic and molecular findings in a Japanese woman who died of lymphoma at the age of 61 years after a 7-year history of progressive pure cerebellar ataxia. Neuropathologic examination showed neuronal degeneration confined to the cerebellar Purkinje cells and, to a lesser degree, the granular cells, without involvement of other CNS structures. The pathologic selectivity correlated with the localized expression of the CACNA1A gene and coincided with the neurologic manifestations. The father and a sister were also affected. Each of the affected sisters was heterozygous for an expanded allele with a repeat size that fell into the range of the SCA6 mutation. </p><p>Using a whole-cell voltage clamp technique, Toru et al. (2000) demonstrated functional alterations of human alpha-1A channels carrying various polyglutamine lengths in a model of SCA6. Alpha-1A channels lacking an asparagine-proline (NP) stretch in domain IV corresponded to P-type channels expressed in Purkinje cells, the main cell that is degenerated in SCA6. Polyglutamine elongation caused a proportional negative shift of voltage-dependent inactivation, and the authors hypothesized that the resulting reduction of calcium influx may contribute to Purkinje cell death. </p><p>Kordasiewicz et al. (2006) found that the 75-kD C-terminal fragment of CACNA1A, which is the location of the polyglutamine tract expanded in SCA6, was translocated to the nucleus, where it was toxic to cells when in the expanded state. The polyglutamine-mediated cell toxicity was dependent on nuclear localization, suggesting that specific processing and localization of the mutant protein are involved in the pathogenesis of SCA6. </p><p>Li et al. (2009) found that HEK293 cells expressing an expanded (24 CAG repeats) C-terminal CACNA1A fragment showed decreased viability when exposed to toxic cadmium compared to cells with nonexpanded (13 CAG) repeats. However, there were no differences in viability under normal culture conditions. Cadmium treatment also disrupted PMLNBs and enhanced aggregation of C-terminal CACNA1A fragments, particularly in CAG-expanded cells. Immunocytochemical studies showed that cadmium-induced death was caspase-3 (CASP3; 600636)-dependent, indicating apoptosis. Gene expression studies showed downregulation of the HSF1 (140580)-HSPA1A (140550) axis as an event in 24-CAG repeat cells that appeared to be critical for cellular toxicity. The findings were consistent with SCA6 pathogenesis being related to polyglutamine diseases. </p><p>Du et al. (2013) found that expression of alpha-1ACT containing a pathologic polyQ expansion did not induce neurite outgrowth in PC12 cells and was unable to induce expression of genes targeted by wildtype alpha-1ACT. </p><p>Craig et al. (2008) identified a common core haplotype carrying the CACNA1A CAG repeat in 45 SCA6 families from different geographic regions, including Europe, Brazil, and Japan. The haplotype was also present in the unaffected father of a proven de novo Japanese patient, suggesting that the shared chromosome predisposes to the CAG repeat expansion at the SCA6 locus. The SCA6 expansion lies immediately downstream of a CpG island, which could act as a cis-acting element predisposing to repeat expansion, as observed for other CAG/CTG repeat diseases. </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>.0008 EPISODIC ATAXIA, TYPE 2</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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CACNA1A, (CAG)n REPEAT EXPANSION, 20-23 REPEATS, EX47
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<br />
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ClinVar: RCV000009015, RCV000030866
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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 family with a clinical diagnosis of episodic ataxia-2 (EA2; 108500), Jodice et al. (1997) found a (CAG)23 repeat allele segregating in patients showing different interictal symptoms, ranging from nystagmus only to severe progressive cerebellar ataxia. No additional mutations in coding and intron-exon junction sequences in disequilibrium with the CAG expansion were found. In a second family, initially classified as autosomal dominant cerebellar ataxia of unknown type, an intergenerational allele size change showed that a (CAG)20 allele was associated with an EA2 phenotype and a (CAG)25 allele with progressive cerebellar ataxia. These results suggested that EA2 and SCA6 (183086) are the same disorder with a high phenotypic variability, at least partly related to the number of repeats, and suggested that the small expansions may not be as stable as previously reported. See also 601011.0007. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0009 SPINOCEREBELLAR ATAXIA 6</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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EPISODIC ATAXIA, TYPE 2, INCLUDED
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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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CACNA1A, GLY293ARG
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<br />
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SNP: rs121908215,
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ClinVar: RCV000009018, RCV000009019, RCV001388786, RCV004700207
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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>Yue et al. (1997) studied a family in which multiple members had severe progressive cerebellar ataxia involving the trunk, extremities, and speech (SCA6; 183086). The proband started at age 15 years with gradual onset of imbalance and incoordination. Slurred speech was first noted in her twenties. She became confined to a wheelchair at the age of 44 years. By that time prominent atrophy of the cerebellum was demonstrated by magnetic resonance imaging. Two sons had episodes of vertigo and ataxia that were not responsive to acetazolamide, consistent with episodic ataxia type 2 (EA2; 108500). Quantitative eye movement testing showed a consistent pattern of abnormalities localized to the cerebellum. Genotyping suggested linkage to 19p, and SSCP showed an aberrant migrating fragment in exon 6 of the CACNA1A gene which cosegregated with the disease. Sequencing of exon 6 identified a G-to-A transition in 1 allele, at nucleotide 1152, resulting in a predicted gly293-to-arg amino acid substitution. The CAG-repeat expansion associated with SCA6 (601011.0007) was not present in any family member. Yue et al. (1997) indicated that replacement of a neutral amino acid (glycine) with a positively charged amino acid (arginine) near the center of the pore in domain I would likely lead to a distortion of the pore region. Two patients in the family had prominent ataxic episodes, whereas the other 2 patients had no episodes, suggesting that other factors such as modifying genes or metabolic factors such as hormone levels may be important in determining susceptibility to episodic dysfunction. On the other hand, all 4 patients exhibited gradually progressive ataxia, indicating that this pore mutation resulted in chronic increased intracellular calcium, ultimately leading to neuronal death. </p><p>Wan et al. (2005) performed functional expression studies of the G293R mutation in the family reported by Yue et al. (1997) and the adjacent C287Y mutation (601011.0025). </p>
|
|
</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 MIGRAINE, FAMILIAL HEMIPLEGIC 1, WITH PROGRESSIVE CEREBELLAR ATAXIA</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
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<span class="mim-text-font">
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CACNA1A, ASP715GLU
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<br />
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SNP: rs121908218,
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ClinVar: RCV000009020
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In affected members of a family (F10) with hemiplegic migraine associated with progressive cerebellar ataxia (see 145000), Ducros et al. (1999) identified C-to-G transversion in the CACNA1A gene, resulting in an asp715-to-glu (D715E) mutation. </p>
|
|
</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0011 EPISODIC ATAXIA, TYPE 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
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<span class="mim-text-font">
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CACNA1A, ARG1666HIS
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<br />
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SNP: rs121908216,
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|
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ClinVar: RCV000009017, RCV000517293, RCV001381850, RCV001542800
|
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|
|
</span>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>Friend et al. (1999) found a 5260G-A transition in exon 32 of the CACNA1A gene, resulting in an arg1666-to-his amino acid substitution, in a patient with episodic ataxia (EA2; 108500). The amino acid substitution occurred in a highly conserved position within the gene. This represented the first point mutation that did not result in a proposed truncated protein. One member of the family, who had inherited both the mutation and the affected haplotype, had no clinical evidence of cerebellar dysfunction. On examination, he had no signs of nystagmus on lateral gaze, and his balance and cerebellar examination were within normal limits. He did, however, experience migraines. </p>
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|
</span>
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</div>
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<div>
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|
<br />
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</div>
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</div>
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<div>
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|
<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0012 EPISODIC ATAXIA, TYPE 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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<div>
|
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<span class="mim-text-font">
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|
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CACNA1A, PHE1491SER
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<br />
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|
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SNP: rs121908233,
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|
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ClinVar: RCV000009021
|
|
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|
|
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</span>
|
|
</div>
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<div>
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<span class="mim-text-font">
|
|
<p>Guida et al. (2001) reported the first functional analysis of a novel missense mutation associated with an EA2 phenotype: a T-to-C transition at nucleotide 4747 in exon 28 of the CACNA1A gene, predicted to change a highly conserved phenylalanine residue to a serine at codon 1491, located in the putative transmembrane segment S6 of domain III. Patch-clamp recording in HEK 293 cells, coexpressing the mutagenized human alpha-1A subunit, together with the human beta and alpha-delta subunits, showed that channel activity was completely abolished, although the mutated protein was expressed in the cell. These results indicated that a complete loss of P/Q channel function is the mechanism underlying EA2, whether due to truncating or to missense mutations. </p>
|
|
</span>
|
|
</div>
|
|
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<div>
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|
<br />
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</div>
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</div>
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<div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0013 MIGRAINE, FAMILIAL HEMIPLEGIC, 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
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|
|
|
CACNA1A, TYR1385CYS
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|
|
<br />
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|
|
SNP: rs121908219,
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|
|
ClinVar: RCV000009022
|
|
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|
|
|
</span>
|
|
</div>
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|
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|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with hemiplegic migraine associated with coma, hyperthermia, meningeal signs, and partial seizures, Vahedi et al. (2000) identified a de novo A-to-G transition (TAC to TGC) at codon 1385 of the CACNA1A gene, resulting in a tyrosine-to-cysteine amino acid substitution in the alpha-1A subunit of the P/Q-type calcium channel. The mutation was not detected in 200 control chromosomes or in either of the healthy parents, suggesting that the mutation is not a polymorphism. The mutation is in the highly conserved segment 5 of the third domain of the calcium channel, an area previously shown to be important in familial hemiplegic migraine (Ophoff et al., 1996; Ducros et al., 1999). </p>
|
|
</span>
|
|
</div>
|
|
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<div>
|
|
<br />
|
|
</div>
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|
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</div>
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<div>
|
|
|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0014 EPISODIC ATAXIA, TYPE 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
CACNA1A, GLU1757LYS
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|
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<br />
|
|
|
|
SNP: rs121908226,
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|
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|
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ClinVar: RCV000009023
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 4 members of a family with onset of episodic ataxia type 2 (EA2; 108500) after age 30, Denier et al. (2001) identified a G-to-A change in exon 35 of the CACNA1A gene, resulting in a glu1757-to-lys substitution. The authors did not detect the mutation in 200 control chromosomes. The mutation affects a highly conserved amino acid located in the pore loop, which plays a major role in the function of the channel. </p>
|
|
</span>
|
|
</div>
|
|
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|
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|
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<div>
|
|
<br />
|
|
</div>
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|
|
|
</div>
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|
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|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0015 EPISODIC ATAXIA, TYPE 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
CACNA1A, 1-BP INS, 3091G
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs587776694,
|
|
|
|
|
|
|
|
ClinVar: RCV000009024
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Scoggan et al. (2001) identified a 1-bp insertion at nucleotide 3091 of the CACNA1A gene (3091insG) in an individual with episodic ataxia type 2 (EA2; 108500). Scoggan et al. (2001) believed this to be the first mutation identified to occur in an intracellular loop of the CACNA1A protein. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0016 EPISODIC ATAXIA, TYPE 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
CACNA1A, 1-BP DEL, 5123G
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs587776695,
|
|
|
|
|
|
|
|
ClinVar: RCV000009025
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Scoggan et al. (2001) identified a 1-bp deletion at nucleotide 5123 of the CACNA1A gene (5123delG) in an individual with episodic ataxia type 2 (EA2; 108500). Scoggan et al. (2001) believed this to be the most 3-prime CACNA1A mutation reported to that time. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
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|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0017 MIGRAINE, FAMILIAL HEMIPLEGIC 1, WITH PROGRESSIVE CEREBELLAR ATAXIA</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
CACNA1A, SER218LEU ({dbSNP rs121908225})
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121908225,
|
|
|
|
|
|
|
|
ClinVar: RCV000009027, RCV000502832, RCV001390632, RCV001533157, RCV002272012, RCV003150928
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Noting that familial hemiplegic migraine (FHM1; 141500) can be triggered by minor head trauma, Kors et al. (2001) investigated a role for CACNA1A in 'delayed cerebral edema,' a severe, sometimes even fatal, cerebral edema and coma occurring after a lucid interval as a result of trivial head trauma. In 2 patients with the phenomenon from a family with extreme familial hemiplegic migraine and in 1 patient whose parent had familial hemiplegic migraine and whose family suffered from various neurologic abnormalities, Kors et al. (2001) identified heterozygosity for a mutation in the CACNA1A gene, resulting in the replacement of a hydrophilic serine for a hydrophobic leucine at residue 218 (S218L) in the highly conserved intracellular loop of the alpha-1A subunit. The authors suggested a pathogenic mechanism involving ionic perturbation resulting from inappropriately depolarized ion channels. </p><p>Chan et al. (2008) reported 3 Malaysian sibs with FHM1 due to heterozygosity for a 935C-T transition in exon 5 of the CACNA1A gene, resulting in the S218L mutation. The phenotype of the hemiplegic migraine episodes was severe in the older brother and sister, each of whom became comatose on at least 1 occasion. A history of generalized seizures was associated with mild head trauma in the older boy and with febrile illness in the younger boy. The older brother and sister also had cerebellar atrophy on brain MRI. EEG studies of them during hemiplegic attacks showed evidence of depressed cortical activity contralateral to the hemiparesis, perhaps representing cortical spreading depression due to a defect in calcium channel activity. </p><p><strong><em>Developmental and Epileptic Encephalopathy 42</em></strong></p><p>
|
|
In a girl (patient T21924) with developmental and epileptic encephalopathy-42 (DEE42; 617106), the Epi4K Consortium (2016) identified a heterozygous c.653C-T transition (c.653C-T, NM_023035.2) in the CACNA1A gene, resulting in a ser218-to-leu (S218L) substitution. Functional studies of the variant and studies of patient cells were not performed. The mutation was not found in the unaffected mother; DNA from the unaffected father was not available. The authors considered this change to be a variant of unknown significance, noting that it had previously been found in a patient with familial hemiplegic migraine with progressive cerebellar ataxia. </p>
|
|
</span>
|
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
|
|
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|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0018 MIGRAINE, FAMILIAL HEMIPLEGIC, 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
MIGRAINE, FAMILIAL HEMIPLEGIC 1, WITH PROGRESSIVE CEREBELLAR ATAXIA, INCLUDED<br />
|
|
MIGRAINE, SPORADIC HEMIPLEGIC, INCLUDED<br />
|
|
SPINOCEREBELLAR ATAXIA 6, INCLUDED
|
|
</span>
|
|
</div>
|
|
|
|
|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
CACNA1A, ARG583GLN
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121908217,
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|
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|
|
|
gnomAD: rs121908217,
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|
|
ClinVar: RCV000009028, RCV000009029, RCV000009030, RCV000517519, RCV001380080, RCV001533158, RCV002227018, RCV004766989
|
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|
|
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</span>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 Italian sisters with familial hemiplegic migraine (FHM1; 141500) and late-onset cerebellar ataxia and cerebellar atrophy, Battistini et al. (1999) identified an arg583-to-gln (R583Q) mutation in a putative voltage sensor domain of the CACNA1A gene. The frequency and severity of the attacks increased near the sixth decade for both patients, when the cerebellar signs developed. Acetazolamide was effective prophylactic therapy. </p><p>Terwindt et al. (2002) studied 27 patients with sporadic hemiplegic migraine and found the R583Q mutation in a 16-year-old boy with no cerebellar signs. </p><p>In a large Portuguese family in which 17 patients over 4 generations were affected with hemiplegic migraine and/or progressive cerebellar ataxia-6 (SCA6; 183086), Alonso et al. (2003) found that all patients shared a common haplotype and carried the R583Q mutation. Mean age at onset for hemiplegic migraine symptoms was in the second decade and onset of cerebellar signs was approximately 20 years later. Four patients, all under the age of 18 years, had only hemiplegic migraine, 8 patients had isolated progressive cerebellar ataxia, and 5 patients had both hemiplegic migraine and cerebellar ataxia. Several patients reported symptoms triggered by minor head trauma. Alonso et al. (2003) postulated that the mutation, which occurs in a transmembrane segment of the voltage sensor of the channel, may cause a shift in the voltage dependence of the channel, leading to an increase in intracellular calcium. They suggested that episodic ataxia-2 (EA2; 108500), SCA6, and familial hemiplegic migraine are not only allelic disorders, but may be the same disorder with great phenotypic variability. </p><p>De Vries et al. (2007) identified a 2021G-A transition in the CACNA1A gene, resulting in an R583Q substitution, in a patient who developed FHM at age 13 years. The mutation was also identified in his mother, who had migraine with aura. The findings suggested either reduced penetrance or a common pathogenetic mechanism for both hemiplegic and nonhemiplegic migraine. </p>
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|
</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0019 MIGRAINE, FAMILIAL HEMIPLEGIC, 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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<div>
|
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<span class="mim-text-font">
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|
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CACNA1A, VAL1457LEU
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|
<br />
|
|
|
|
SNP: rs121908237,
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|
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|
|
ClinVar: RCV000009026, RCV001533162
|
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|
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|
|
</span>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 5-generation Caucasian family originating from northeastern Italy, in which the average age of onset of familial hemiplegic migraine (FHM1; 141500) was 33.8 years, Carrera et al. (1999) found a G-to-T transversion at nucleotide position 4644 in exon 27 of the CACNA1A gene, which resulted in a val1457-to-leu (V1457L) amino acid substitution. All patients had clinical symptoms preceded by aura, followed by hemiparesis and various degrees of aphasia congruent with the hemispheric dominance of each individual. Patients did not report cerebellar ataxia or coma. Carrera et al. (1999) noted that the location of the mutation, in the putative pore-forming (P) region between the S5-S6 transmembrane domains in motif III of CACNA1A, suggests a potential for interference in transmembrane conductance. </p>
|
|
</span>
|
|
</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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|
<span class="mim-font">
|
|
<strong>.0020 EPISODIC ATAXIA, TYPE 2</strong>
|
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</span>
|
|
</h4>
|
|
</div>
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<div>
|
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<span class="mim-text-font">
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CACNA1A, ARG1281TER
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|
<br />
|
|
|
|
SNP: rs121909323,
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|
|
|
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ClinVar: RCV000009031, RCV001851752, RCV004700208, RCV004786248
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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>Yue et al. (1998) reported a patient with episodic ataxia type 2 (EA2; 108500) who carried a 4410C-T substitution in exon 23 of the CACNA1A gene, resulting in an arg1281-to-ter (R1281X) mutation that predicts a truncated product containing only the first 2 domains of the protein. The patient experienced attacks of vertigo, truncal and limb ataxia, nystagmus, and diffuse weakness during ataxic spells. </p><p>By use of whole-cell patch-clamp recordings, Jen et al. (2001) demonstrated that the R1281X, R1549X (601011.0021), and F1406C (601011.0022) mutations, when expressed in COS-7 cells, resulted in markedly diminished barium current density and amplitude compared with the wildtype gene. They used single-fiber EMG (SFEMG) recordings to examine synaptic transmission at the neuromuscular junction in the 3 patients who carried these mutations, all of whom complained of episodic weakness. The SFEMG demonstrated abnormal neuromuscular transmission in vivo, suggesting that these mutations contributed to the symptoms of weakness described by the patients. </p>
|
|
</span>
|
|
</div>
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|
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<div>
|
|
<br />
|
|
</div>
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|
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</div>
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|
<div>
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|
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|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0021 EPISODIC ATAXIA, TYPE 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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|
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<div>
|
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<span class="mim-text-font">
|
|
|
|
CACNA1A, ARG1549TER
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|
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|
<br />
|
|
|
|
SNP: rs121909324,
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|
|
|
|
|
|
|
ClinVar: RCV000009032, RCV000622947, RCV000763032, RCV002466397, RCV002512927
|
|
|
|
|
|
</span>
|
|
</div>
|
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|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Jen et al. (1999) reported affected members of a family with episodic ataxia type 2 (EA2; 108500) who carried a 4914C-T substitution in exon 29 of the CACNA1A gene. The substitution resulted in an arg1549-to-ter (R1549X) mutation (reported in the article as ARG1547TER) that predicts a truncated product containing the first 3 domains of the protein. The patients experienced attacks of vertigo, truncal and limb ataxia, nystagmus, and diffuse weakness during ataxic spells. See also 601011.0020. </p>
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|
</span>
|
|
</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0022 EPISODIC ATAXIA, TYPE 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
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|
|
|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
CACNA1A, PHE1406CYS
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|
|
|
|
|
<br />
|
|
|
|
SNP: rs121908227,
|
|
|
|
|
|
|
|
ClinVar: RCV000009033
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Jen et al. (2001) reported a patient with episodic ataxia type 2 (EA2; 108500) who also developed progressive episodic weakness beginning in his teens. Mutation analysis revealed a 4486T-G change in exon 26 of the CACNA1A gene, resulting in a phe1406-to-cys (F1406) change in the putative P loop of the protein between domains 3 and 4, which may disrupt pore formation. See also 601011.0020. </p>
|
|
</span>
|
|
</div>
|
|
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|
|
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<div>
|
|
<br />
|
|
</div>
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|
|
|
</div>
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|
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<div>
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|
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|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0023 EPISODIC ATAXIA, TYPE 2, AND EPILEPSY</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
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|
|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
CACNA1A, ARG1820TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs267606696,
|
|
|
|
|
|
gnomAD: rs267606696,
|
|
|
|
|
|
ClinVar: RCV000009034, RCV001836705
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In an isolated case of a boy with seizures, episodic ataxia type 2 (EA2; 108500), and interictal progressive cerebellar signs, Jouvenceau et al. (2001) identified a heterozygous 5733C-T transition in the CACNA1A gene, resulting in a premature stop codon (arg1820 to ter; R1820X) between the last transmembrane segment (IVS6) and the intracellular C terminus of the mature protein. Functional expression studies indicated a dominant-negative effect on channel conductance. Jouvenceau et al. (2001) noted that mouse models of absence epilepsy and cerebellar degeneration harbor mutations in the CACNA1A gene. </p><p>Holtmann et al. (2002) reported a family in which a father and daughter had idiopathic focal epilepsy, episodic ataxia type 2, and migraine. Four other family members had migraine, and 2 had reported seizures. Holtmann et al. (2002) suggested that the cooccurrence of periodic neurologic disorders in their family was similar to that in the case presented by Jouvenceau et al. (2001). </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
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|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0024 MIGRAINE, FAMILIAL HEMIPLEGIC, 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
SPINOCEREBELLAR ATAXIA 6, INCLUDED
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
CACNA1A, ILE1710THR
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121909326,
|
|
|
|
|
|
|
|
ClinVar: RCV000009035, RCV000009036, RCV000157056, RCV001049766, RCV001804718, RCV002273923, RCV002345236
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a mother and her 2 adult children who had familial hemiplegic migraine (FHM1; 141500) and childhood-onset of cerebellar ataxia (SCA6; 183086), Kors et al. (2004) identified a heterozygous 5405T-C transition in exon 33 of the CACNA1A gene, resulting in an ile1710-to-thr (I1710T) substitution within transmembrane segment 5 of the fourth domain of the protein. Kors et al. (2004) stated that the affected residue is strongly conserved. In addition to FHM1 and SCA6, both children had complex partial and generalized tonic-clonic seizures that occurred independently of the FHM attacks and were restricted to childhood. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0025 EPISODIC ATAXIA, TYPE 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
CACNA1A, CYS287TYR
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121908236,
|
|
|
|
|
|
|
|
ClinVar: RCV000009037
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members of a family with episodic ataxia type 2 (EA2; 108500) and mild baseline ataxia, Wan et al. (2005) identified a 1096G-A transition in exon 6 of the CACNA1A gene, resulting in a cys287-to-tyr (C287Y) substitution in the putative P loop between transmembrane segments S5 and S6 within domain I of the protein. The mutation is adjacent to another mutation, G293R (601011.0009), in the same region of the protein. Functional expression studies of both mutations indicated that the mutant channels exhibited decreased current densities (31 to 35% of wildtype), which were partially restored by cooling. Immunofluorescence studies showed that the mutant proteins accumulated in the endoplasmic reticulum. The findings suggested that the mutations caused misfolding and altered trafficking of the protein, resulting in a defect in plasma membrane targeting. Once expressed at the cell surface, the mutant channels were able to conduct current but with altered biophysical properties. Wan et al. (2005) hypothesized that the episodic features of EA2 result from altered channel function, while the interictal features result from protein mishandling, eventually leading to cerebellar neuronal death. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0026 EPISODIC ATAXIA, TYPE 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
CACNA1A, 39.5-KB DEL
|
|
|
|
|
|
<br />
|
|
|
|
|
|
|
|
ClinVar: RCV000009038
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 3 affected members of a family with episodic ataxia type 2 (EA2; 108500), Riant et al. (2008) identified a heterozygous 39.5-kb deletion in the CACNA1A gene, resulting in the removal of the last 16 coding exons of the gene. Sequence analysis of the deletion boundaries suggested that the deletion arose through homologous recombination of Alu sequences. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0027 MIGRAINE, FAMILIAL HEMIPLEGIC, 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
CACNA1A, ARG1347GLN
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121908230,
|
|
|
|
|
|
|
|
ClinVar: RCV000009039, RCV000516653, RCV004766990, RCV004795386
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members of 4 unrelated families with familial hemiplegic migraine-1 (FHM1; 141500), Stam et al. (2008) identified a heterozygous 4040G-A transition in exon 25 of the CACNA1A gene, resulting in an arg1347-to-gln (R1347Q) substitution in the S4 segment of protein domain III. Haplotype analysis excluded a founder effect. In 3 of the 4 families, age at onset was before age 3 years. Two patients in 1 family also had focal seizures. Stam et al. (2008) stated that the R1347Q mutation was the third most common CACNA1A mutation associated with FHM1, after T666M (601011.0002) and R583Q (601011.0018). </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0028 EPISODIC ATAXIA, TYPE 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
CACNA1A, 146.1-KB DEL
|
|
|
|
|
|
<br />
|
|
|
|
|
|
|
|
ClinVar: RCV000009040
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 affected members of a family with episodic ataxia type 2 (EA2; 108500), Labrum et al. (2009) identified a heterozygous 146.1-kb deletion in the CACNA1A gene, resulting in deletion of exon 4 Exon 4 encodes the S4 voltage sensor segment of domain I and the removal of this exon is likely to have deleterious effects on kinetic parameters, such as the voltage dependence of activation. The deletion was not detected in a panel of 180 normal control chromosomes. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0029 EPISODIC ATAXIA, TYPE 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
CACNA1A, 35.7-KB DEL
|
|
|
|
|
|
<br />
|
|
|
|
|
|
|
|
ClinVar: RCV000009041
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 8 affected members of a 4-generation family with episodic ataxia type 2 (EA2; 108500), Labrum et al. (2009) identified a heterozygous 35.7-kb deletion in the CACNA1A gene, resulting in deletion of exon 6. The deletion was not identified in an unaffected member of this family or in a panel of 180 normal control chromosomes. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0030 EPISODIC ATAXIA, TYPE 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
CACNA1A, 35.7-KB DUP
|
|
|
|
|
|
<br />
|
|
|
|
|
|
|
|
ClinVar: RCV000009042
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In an index patient with isolated episodic diplopia without ataxia, Labrum et al. (2009) identified a heterozygous 35.7-kb duplication in the CACNA1A gene, resulting in duplication of exon 6. The patient's father reportedly had typical episodic ataxia type 2 (EA2; 108500). The duplication was not detected in a panel of 180 normal control chromosomes. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0031 EPISODIC ATAXIA, TYPE 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
CACNA1A, 7.4-KB DEL
|
|
|
|
|
|
<br />
|
|
|
|
|
|
|
|
ClinVar: RCV000009043
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a proband with episodic ataxia type 2 (EA2; 108500), Labrum et al. (2009) identified a heterozygous 7.4-kb deletion in the CACNA1A gene, resulting in deletion of exon 27. The deletion was not detected in a panel of 180 normal control chromosomes. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0032 EPISODIC ATAXIA, TYPE 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
CACNA1A, 86.1-KB DEL
|
|
|
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<br />
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ClinVar: RCV000009044
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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 proband with episodic ataxia type 2 (EA2; 108500), Labrum et al. (2009) identified a heterozygous 86.1-kb deletion in the CACNA1A gene, resulting in deletion of exons 20 to 38. The deletion was not detected in a panel of 180 normal control chromosomes. </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>.0033 EPISODIC ATAXIA, TYPE 2</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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CACNA1A, 18.2-KB DEL
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<br />
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ClinVar: RCV000009045
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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 2 unrelated patients with episodic ataxia type 2 (EA2; 108500), Labrum et al. (2009) identified a heterozygous 18.2-kb deletion in the CACNA1A gene, resulting in deletion of exons 39 to 47. The deletion was not detected in a panel of 180 normal control chromosomes. </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>.0034 MIGRAINE, FAMILIAL HEMIPLEGIC, 1</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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CACNA1A, 18.2-KB DEL
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<br />
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ClinVar: RCV000009046
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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 patient with sporadic hemiplegic migraine (FHM1; 141500), Labrum et al. (2009) identified a heterozygous 18.2-kb deletion in the CACNA1A gene, resulting in deletion of exons 39 to 47. The deletion was not detected in a panel of 180 normal control chromosomes. </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>.0035 DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 42</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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CACNA1A, GLU101GLN
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<br />
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SNP: rs886037944,
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ClinVar: RCV000240952
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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 EG1371) with developmental and epileptic encephalopathy-42 (DEE42; 617106), the Epi4K Consortium (2016) identified a de novo heterozygous c.301G-C transversion (c.301G-C, NM_023035.2) in the CACNA1A gene, resulting in a glu101-to-gln (E101Q) substitution. Functional studies of the variant and studies of patient cells were not performed. He had onset of tonic seizures at 4 weeks of age. EEG showed epilepsy of infancy with migrating focal seizures (EIMFS). </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>.0036 DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 42</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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CACNA1A, ALA713THR
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<br />
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ClinVar: RCV000240888, RCV000255263, RCV000623106, RCV000763034, RCV001380078, RCV001814128, RCV002227102, RCV002274954
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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 2 unrelated patients (patients T23039 and T24139) with developmental and epileptic encephalopathy-42 (DEE42; 617106), the Epi4K Consortium (2016) identified a heterozygous c.2137G-A transition (c.2137G-A, NM_023035.2) in the CACNA1A gene, resulting in an ala713-to-thr (A713T) substitution. The mutation in 1 patient occurred de novo, where the mutation in the other patient and his similarly affected sib (patient T24629) was inherited from the unaffected mother who was somatic mosaic for the mutation (6.3% mutational load in the mother's lymphocytes). The same mutation had also been identified in a patient with DEE42 by the EPI4K Consortium and Epilepsy Phenome/Genome Project (2013). Functional studies of the variant and studies of patient cells were not performed. The patients had onset of seizures in the neonatal period. </p>
|
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0037 DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 42</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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CACNA1A, ALA1511SER
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<br />
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SNP: rs886037946,
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ClinVar: RCV000240915
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</span>
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</div>
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<div>
|
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<span class="mim-text-font">
|
|
<p>In a girl (patient EG1519) with developmental and epileptic encephalopathy-42 (DEE42; 617106), the Epi4K Consortium (2016) identified a de novo heterozygous c.4531G-T transversion (c.4531G-T, NM_023035.2) in the SLC1A2 gene, resulting in an ala1511-to-ser (A1511S) substitution. The mutation was not found in the Exome Sequencing Project, 1000 Genomes Project, or ExAC databases. Functional studies of the variant and studies of patient cells were not performed. The patient had onset of status epilepticus on the first day of life. </p>
|
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>REFERENCES</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<ol>
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<li>
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|
Ackerman, M. J., Clapham, D. E.
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Alonso, I., Barros, J., Tuna, A., Coelho, J., Sequeiros, J., Silveira, I., Coutinho, P.
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<strong>Phenotypes of spinocerebellar ataxia type 6 and familial hemiplegic migraine caused by a unique CACNA1A missense mutation in patients from a large family.</strong>
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Barrett, C. F., Cao, Y.-Q., Tsien, R. W.
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<strong>A new CACNA1A gene mutation in acetazolamide-responsive familial hemiplegic migraine and ataxia.</strong>
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Neurology 53: 38-43, 1999.
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Cao, Y.-Q., Tsien, R. W.
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<strong>Effects of familial hemiplegic migraine type 1 mutations on neuronal P/Q-type Ca(2+) channel activity and inhibitory synaptic transmission.</strong>
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Carrera, P., Piatti, M., Stenirri, S., Grimaldi, L. M. E., Marchioni, E., Curcio, M., Righetti, P. G., Ferrari, M., Gelfi, C.
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<strong>Genetic heterogeneity in Italian families with familial hemiplegic migraine.</strong>
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Neurology 53: 26-32, 1999.
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Chan, Y.-C., Burgunder, J.-M., Wilder-Smith, E., Chew, S.-E., Lam-Mok-Sing, K. M. J., Sharma, V., Ong, B. K. C.
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<strong>Electroencephalographic changes and seizures in familial hemiplegic migraine patients with the CACNA1A gene S218L mutation.</strong>
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Chioza, B., Wilkie, H., Nashef, L., Blower, J., McCormick, D., Sham, P., Asherson, P., Makoff, A. J.
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<strong>Association between the alpha-1A calcium channel gene CACNA1A and idiopathic generalized epilepsy.</strong>
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Neurology 56: 1245-1246, 2001.
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<p class="mim-text-font">
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Craig, K., Takiyama, Y., Soong, B.-W., Jardim, L. B., Saraiva-Pereira, M. L., Lythgow, K., Morino, H., Maruyama, H., Kawakami, H., Chinnery, P. F.
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<strong>Pathogenic expansions of the SCA6 locus are associated with a common CACNA1A haplotype across the globe: founder effect or predisposing chromosome?</strong>
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<strong>Systematic analysis of three FHM genes in 39 sporadic patients with hemiplegic migraine.</strong>
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Neurology 69: 2170-2176, 2007.
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Denier, C., Ducros, A., Durr, A., Eymard, B., Chassande, B., Tournier-Lasserve, E.
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Diriong, S., Lory, P., Williams, M. E., Ellis, S. B., Harpold, M. M., Taviaux, S.
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<strong>Chromosomal localization of the human genes for alpha-1A, alpha-1B, and alpha-1E voltage-dependent Ca(2+) channel subunits.</strong>
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Genomics 30: 605-609, 1995.
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[PubMed: 8825650]
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[Full Text: https://doi.org/10.1006/geno.1995.1284]
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<p class="mim-text-font">
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Du, X., Wang, J., Zhu, H., Rinaldo, L., Lamar, K.-M., Palmenberg, A. C., Hansel, C., Gomez, C. M.
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<strong>Second cistron in CACNA1A gene encodes a transcription factor mediating cerebellar development and SCA6.</strong>
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Cell 154: 118-133, 2013.
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[PubMed: 23827678]
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<p class="mim-text-font">
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Du, X., Wei, C., Hejazi Pastor, D. P., Rao, E. R., Li, Y., Grasselli, G., Godfrey, J., Palmenberg, A. C., Andrade, J., Hansel, C., Gomez, C. M.
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<strong>Alpha-1ACT is essential for survival and early cerebellar programming in a critical neonatal window.</strong>
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Neuron 102: 770-785, 2019.
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[PubMed: 30922876]
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[Full Text: https://doi.org/10.1016/j.neuron.2019.02.036]
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<li>
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<p class="mim-text-font">
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Ducros, A., Denier, C., Joutel, A., Cecillon, M., Lescoat, C., Vahedi, K., Darcel, F., Vicaut, E., Bousser, M.-G., Tournier-Lasserve, E.
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<strong>The clinical spectrum of familial hemiplegic migraine associated with mutations in a neuronal calcium channel.</strong>
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New Eng. J. Med. 345: 17-24, 2001.
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[PubMed: 11439943]
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[Full Text: https://doi.org/10.1056/NEJM200107053450103]
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<p class="mim-text-font">
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Ducros, A., Denier, C., Joutel, A., Vahedi, K., Michel, A., Darcel, F., Madigand, M., Guerouaou, D., Tison, F., Julien, J., Hirsch, E., Chedru, F., Bisgard, C., Lucotte, G., Despres, P., Billard, C., Barthez, M. A., Ponsot, G., Bousser, M. G., Tournier-Lasserve, E.
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<strong>Recurrence of the T666M calcium channel CACNA1A gene mutation in familial hemiplegic migraine with progressive cerebellar ataxia.</strong>
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Am. J. Hum. Genet. 64: 89-98, 1999.
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[PubMed: 9915947]
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[Full Text: https://doi.org/10.1086/302192]
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</p>
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<p class="mim-text-font">
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Dunlap, K., Luebke, J. I., Turner, T. J.
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<strong>Exocytotic Ca(2+) channels in mammalian central neurons.</strong>
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Trends Neurosci. 18: 89-98, 1995.
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[PubMed: 7537420]
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</p>
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Eikermann-Haerter, K., Baum, M. J., Ferrari, M. D., van den Maagdenberg, A. M. J. M., Moskowitz, M. A., Ayata, C.
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<strong>Androgenic suppression of spreading depression in familial hemiplegic migraine type 1 mutant mice.</strong>
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Ann. Neurol. 66: 564-568, 2009.
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[PubMed: 19847904]
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[Full Text: https://doi.org/10.1002/ana.21779]
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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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Bao Lige - updated : 10/04/2019<br>Cassandra L. Kniffin - updated : 09/19/2016<br>Patricia A. Hartz - updated : 8/18/2015<br>Cassandra L. Kniffin - updated : 1/25/2011<br>Cassandra L. Kniffin - updated : 9/30/2010<br>Cassandra L. Kniffin - updated : 8/16/2010<br>Cassandra L. Kniffin - updated : 5/11/2010<br>Nara Sobreira - updated : 3/11/2010<br>Cassandra L. Kniffin - updated : 3/1/2010<br>Cassandra L. Kniffin - updated : 8/4/2009<br>Cassandra L. Kniffin - updated : 6/24/2009<br>Cassandra L. Kniffin - updated : 6/5/2009<br>Cassandra L. Kniffin - updated : 2/16/2009<br>Cassandra L. Kniffin - updated : 1/22/2009<br>Cassandra L. Kniffin - updated : 1/6/2009<br>Cassandra L. Kniffin - updated : 4/3/2008<br>Patricia A. Hartz - updated : 2/7/2008<br>Cassandra L. Kniffin - updated : 11/1/2005<br>Cassandra L. Kniffin - updated : 6/9/2005<br>Cassandra L. Kniffin - updated : 3/1/2005<br>Ada Hamosh - updated : 1/19/2005<br>Cassandra L. Kniffin - updated : 11/17/2004<br>Cassandra L. Kniffin - updated : 6/2/2003<br>Cassandra L. Kniffin - updated : 5/28/2003<br>Cassandra L. Kniffin - updated : 1/28/2003<br>Cassandra L. Kniffin - updated : 12/6/2002<br>Cassandra L. Kniffin - reorganized : 9/23/2002<br>Cassandra L. Kniffin - updated : 9/23/2002<br>Michael J. Wright - updated : 7/1/2002<br>Cassandra L. Kniffin - updated : 6/14/2002<br>Cassandra L. Kniffin - updated : 6/3/2002<br>Cassandra L. Kniffin - updated : 5/24/2002<br>Victor A. McKusick - updated : 12/5/2001<br>Victor A. McKusick - updated : 9/5/2001<br>Kathryn R. Wagner - updated : 3/30/2001<br>Victor A. McKusick - updated : 3/19/2001<br>Carol A. Bocchini - updated : 2/19/2001<br>Ada Hamosh - updated : 9/25/2000<br>Victor A. McKusick - updated : 2/2/2000<br>George E. Tiller - updated : 1/18/2000<br>Victor A. McKusick - updated : 2/8/1999<br>Victor A. McKusick - updated : 10/14/1998<br>Victor A. McKusick - updated : 9/18/1998<br>Ada Hamosh - updated : 8/12/1998<br>Victor A. McKusick - updated : 7/1/1998<br>Victor A. McKusick - updated : 11/26/1997<br>Victor A. McKusick - updated : 11/12/1997<br>Victor A. McKusick - updated : 11/4/1997<br>Victor A. McKusick - updated : 9/24/1997<br>Victor A. McKusick - updated : 8/25/1997<br>Victor A. McKusick - updated : 6/20/1997<br>Victor A. McKusick - updated : 2/3/1997<br>Moyra Smith - updated : 12/29/1996<br>Moyra Smith - updated : 5/15/1996
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Victor A. McKusick : 1/23/1996
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carol : 09/25/2022<br>alopez : 11/19/2020<br>carol : 11/11/2020<br>alopez : 11/10/2020<br>joanna : 10/18/2020<br>carol : 08/24/2020<br>carol : 08/21/2020<br>carol : 11/01/2019<br>alopez : 10/31/2019<br>mgross : 10/04/2019<br>alopez : 05/15/2019<br>alopez : 09/07/2017<br>carol : 05/25/2017<br>alopez : 09/21/2016<br>alopez : 09/20/2016<br>ckniffin : 09/19/2016<br>mgross : 08/27/2015<br>mcolton : 8/18/2015<br>terry : 2/7/2013<br>terry : 6/7/2012<br>wwang : 2/17/2011<br>ckniffin : 1/25/2011<br>terry : 11/3/2010<br>wwang : 9/30/2010<br>ckniffin : 9/30/2010<br>wwang : 8/24/2010<br>ckniffin : 8/16/2010<br>wwang : 5/14/2010<br>ckniffin : 5/11/2010<br>carol : 5/6/2010<br>terry : 3/11/2010<br>wwang : 3/3/2010<br>ckniffin : 3/1/2010<br>carol : 9/2/2009<br>wwang : 8/31/2009<br>ckniffin : 8/4/2009<br>wwang : 7/22/2009<br>ckniffin : 6/24/2009<br>wwang : 6/5/2009<br>ckniffin : 5/29/2009<br>wwang : 3/6/2009<br>ckniffin : 2/16/2009<br>wwang : 1/26/2009<br>ckniffin : 1/22/2009<br>wwang : 1/13/2009<br>ckniffin : 1/6/2009<br>terry : 6/6/2008<br>wwang : 4/15/2008<br>ckniffin : 4/3/2008<br>mgross : 2/19/2008<br>mgross : 2/19/2008<br>terry : 2/7/2008<br>wwang : 11/21/2005<br>wwang : 11/2/2005<br>ckniffin : 11/1/2005<br>wwang : 6/21/2005<br>wwang : 6/15/2005<br>ckniffin : 6/9/2005<br>wwang : 3/8/2005<br>ckniffin : 3/1/2005<br>wwang : 1/31/2005<br>wwang : 1/26/2005<br>terry : 1/19/2005<br>tkritzer : 11/23/2004<br>ckniffin : 11/17/2004<br>alopez : 7/27/2004<br>terry : 7/26/2004<br>tkritzer : 6/11/2003<br>tkritzer : 6/9/2003<br>ckniffin : 6/2/2003<br>ckniffin : 5/28/2003<br>ckniffin : 2/11/2003<br>carol : 2/10/2003<br>carol : 2/10/2003<br>tkritzer : 2/3/2003<br>ckniffin : 1/28/2003<br>carol : 12/16/2002<br>carol : 12/16/2002<br>tkritzer : 12/13/2002<br>ckniffin : 12/6/2002<br>alopez : 11/4/2002<br>carol : 11/1/2002<br>tkritzer : 10/25/2002<br>ckniffin : 10/2/2002<br>carol : 9/23/2002<br>ckniffin : 9/23/2002<br>carol : 9/23/2002<br>ckniffin : 9/23/2002<br>ckniffin : 9/5/2002<br>alopez : 7/3/2002<br>terry : 7/1/2002<br>ckniffin : 6/17/2002<br>carol : 6/17/2002<br>carol : 6/17/2002<br>ckniffin : 6/14/2002<br>ckniffin : 6/3/2002<br>carol : 5/24/2002<br>carol : 5/24/2002<br>ckniffin : 5/24/2002<br>alopez : 12/11/2001<br>terry : 12/5/2001<br>alopez : 9/10/2001<br>terry : 9/5/2001<br>cwells : 4/5/2001<br>carol : 3/30/2001<br>terry : 3/30/2001<br>cwells : 3/30/2001<br>terry : 3/19/2001<br>carol : 2/19/2001<br>alopez : 10/3/2000<br>terry : 9/25/2000<br>carol : 2/4/2000<br>terry : 2/2/2000<br>alopez : 1/18/2000<br>alopez : 11/15/1999<br>carol : 4/2/1999<br>carol : 2/18/1999<br>terry : 2/8/1999<br>carol : 10/20/1998<br>terry : 10/14/1998<br>dkim : 9/23/1998<br>terry : 9/18/1998<br>carol : 8/12/1998<br>terry : 7/29/1998<br>terry : 7/1/1998<br>dkim : 6/30/1998<br>carol : 6/26/1998<br>jenny : 12/2/1997<br>terry : 11/26/1997<br>jenny : 11/12/1997<br>terry : 11/4/1997<br>terry : 11/4/1997<br>dholmes : 10/6/1997<br>dholmes : 10/6/1997<br>terry : 9/30/1997<br>terry : 9/24/1997<br>mark : 8/25/1997<br>mark : 8/25/1997<br>jenny : 6/27/1997<br>jenny : 6/20/1997<br>mark : 6/11/1997<br>mark : 6/11/1997<br>mark : 6/9/1997<br>terry : 2/6/1997<br>terry : 2/3/1997<br>jenny : 1/14/1997<br>terry : 1/8/1997<br>mark : 12/29/1996<br>terry : 12/26/1996<br>terry : 11/18/1996<br>terry : 11/15/1996<br>carol : 5/22/1996<br>carol : 5/15/1996<br>terry : 2/6/1996<br>mark : 1/23/1996
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