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Entry
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- *114205 - CALCIUM CHANNEL, VOLTAGE-DEPENDENT, L TYPE, ALPHA-1C SUBUNIT; CACNA1C
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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">*114205</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneStructure">Gene Structure</a>
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<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="#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/114205">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>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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</ul>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000151067;t=ENST00000399655" 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=775" 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=114205" 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=ENSG00000151067;t=ENST00000399655" 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_000719,NM_001129827,NM_001129829,NM_001129830,NM_001129831,NM_001129832,NM_001129833,NM_001129834,NM_001129835,NM_001129836,NM_001129837,NM_001129838,NM_001129839,NM_001129840,NM_001129841,NM_001129842,NM_001129843,NM_001129844,NM_001129846,NM_001167623,NM_001167624,NM_001167625,NM_199460,XM_006719017,XM_011521020,XM_011521023,XM_017019926,XM_017019927,XM_017019928,XM_017019929,XM_017019930,XM_017019931,XM_017019932,XM_017019933,XM_017019934,XM_017019935,XM_017019939,XM_017019943,XM_017019944,XM_017019945,XM_017019946,XM_017019947,XM_017019948,XM_017019949,XM_017019950,XM_017019953,XM_017019954,XM_017019955,XM_047429513,XM_047429514,XM_047429515,XM_047429516,XM_047429517,XM_047429518,XM_047429519,XM_047429520" 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_000719" 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=114205" 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=00246&isoform_id=00246_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/CACNA1C" 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/179754,179756,291895,463073,463079,463082,466355,508183,508185,508187,508189,508191,508193,508195,508197,508199,508201,509048,509068,509168,509178,509341,509344,951207,1729771,2960067,3387964,12750734,21636579,29466187,29466189,37547433,46812307,49618614,49618616,60933051,60933073,60933096,62087612,70673343,75914744,75914746,75914747,75914748,119609301,119609302,119609303,119609304,119609305,119609306,119609307,119609308,119609309,119609310,119609311,119609312,119609313,119609314,119609315,119609316,120433602,187955897,193788526,193788528,193788530,193788532,193788534,193788536,193788538,193788540,193788542,193788544,193788548,193788724,193788728,193788732,193794828,193794830,193794832,221044208,264681416,264681420,308153651,578822692,600971652,600971712,600971714,767971478,767971484,1034581482,1034581484,1034581486,1034581488,1034581490,1034581492,1034581494,1034581496,1034581498,1034581500,1034581508,1034581516,1034581518,1034581520,1034581522,1034581524,1034581526,1034581528,1034581530,1034581537,1034581540,1034581542,2217290948,2217290953,2217290955,2217290958,2217290961,2217290963,2217290968,2217290979,2462497893,2462497895,2462497897,2462497899,2462497901,2462497903,2462497905,2462497907,2462497909,2462497911,2462497913,2462497915,2462497917,2462497919,2462497921,2462497923,2462497925,2462497927,2462497929,2462497931,2462497933,2462497935,2462497937,2462497939,2462497941,2462497943,2462497945,2462497947,2462497949,2462497951,2462497953,2462497955,2462497957,2462534234,2462534236,2462534238,2462534240,2462534242,2462534244,2462534246,2462534248,2462534250,2462534252,2462534254,2462534256,2462534258,2462534260,2462534262,2462534264,2462534266,2462534268,2462534270,2462534272,2462534274,2462534276,2462534278,2462534280,2462534282,2462534284,2462534286,2462534288,2462534290,2462534292,2462534294,2462534296,2462534298" 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/Q13936" 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=775" 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=ENSG00000151067;t=ENST00000399655" 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=CACNA1C" 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=CACNA1C" 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+775" 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/CACNA1C" 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:775" 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/775" 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=chr12&hgg_gene=ENST00000399655.6&hgg_start=1970780&hgg_end=2697950&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:1390" class="mim-tip-hint" title="A ClinGen curated resource of genes and regions of the genome that are dosage sensitive and should be targeted on a cytogenomic array." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Dosage', 'domain': 'dosage.clinicalgenome.org'})">ClinGen Dosage</a></div>
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:1390" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=114205[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=114205[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/CACNA1C/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/ENSG00000151067" 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=CACNA1C" 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=CACNA1C" 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=CACNA1C" 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://databases.lovd.nl/genomed/home.php?select_db=CACNA1C" title="Zhejiang University-Adinovo Center CACNA1C Database" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">Zhejiang University-Adinov…</a></div><div style="margin-left: 0.5em;"><a href="http://www.fsm.it/cardmoc/" title="Gene Connection for the Heart" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">Gene Connection for the He…</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=CACNA1C&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/PA83" 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:1390" 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/FBgn0001991.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:103013" 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/CACNA1C#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:103013" 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/775/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/OMIA002886/" 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=775" 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=WBGene00001187;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-020129-1" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:775" 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=CACNA1C&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> 1230096008<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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114205
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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, L TYPE, ALPHA-1C SUBUNIT; CACNA1C
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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 1, CARDIAC MUSCLE; CACNL1A1<br />
|
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CCHL1A1<br />
|
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CaV1.2<br />
|
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CALCIUM CHANNEL, CARDIAC DIHYDROPYRIDINE-SENSITIVE, ALPHA-1 SUBUNIT<br />
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DHPR, ALPHA-1 SUBUNIT<br />
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CACH2
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=CACNA1C" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">CACNA1C</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/12/18?start=-3&limit=10&highlight=18">12p13.33</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr12:1970780-2697950&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'})">12:1,970,780-2,697,950</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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<span class="h4 mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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<a href="/clinicalSynopsis/table?mimNumber=611875,618447,620029,601005" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
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View Clinical Synopses
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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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<a href="/geneMap/12/18?start=-3&limit=10&highlight=18">
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12p13.33
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Brugada syndrome 3
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<a href="/entry/611875"> 611875 </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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Long QT syndrome 8
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<span class="mim-font">
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<a href="/entry/618447"> 618447 </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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Neurodevelopmental disorder with hypotonia, language delay, and skeletal defects with or without seizures
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<a href="/entry/620029"> 620029 </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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Timothy syndrome
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<a href="/entry/601005"> 601005 </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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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/114205" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
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<li><a href="/graph/radial/114205" 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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<h4>
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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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<h4 href="#mimDescriptionFold" id="mimDescriptionToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<span id="mimDescriptionToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<strong>Description</strong>
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<p>The CACNA1C gene encodes multiple isoforms of the pore-forming alpha-1C subunit of the long-lasting (L-type) voltage-gated calcium channel CaV1.2. It is an evolutionarily conserved protein expressed in the heart, lungs, brain, and smooth muscle, and is critical for calcium signaling, cellular and neuronal excitability, muscle contraction, and regulation of gene expression (summary by <a href="#9" class="mim-tip-reference" title="Bozarth, X., Dines, J. N., Cong, Q., Mirzaa, G. M., Foss, K., Lawrence Merritt, J., Thies, J., Mefford, H. C., Novotny, E. <strong>Expanding clinical phenotype in CACNA1C related disorders: From neonatal onset severe epileptic encephalopathy to late-onset epilepsy.</strong> Am. J. Med. Genet. 176A: 2733-2739, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30513141/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30513141</a>] [<a href="https://doi.org/10.1002/ajmg.a.40657" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30513141">Bozarth et al., 2018</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30513141" 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>Cloning and Expression</strong>
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<p>Activation of voltage-sensitive calcium channels by membrane depolarization triggers key cellular responses such as contraction, secretion, excitation, and electrical signaling (<a href="#45" class="mim-tip-reference" title="Tsien, R. W., Ellinor, P. T., Horne, W. A. <strong>Molecular diversity of voltage-dependent Ca(2+) channels.</strong> Trends Pharm. Sci. 12: 349-354, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1659003/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1659003</a>] [<a href="https://doi.org/10.1016/0165-6147(91)90595-j" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1659003">Tsien et al., 1991</a>). The L-type currents produced by voltage-sensitive calcium channels are blocked by 1,4-dihydropyridine (DHP) derivatives; thus, the channels responsible for these currents are referred to as DHP-sensitive. The skeletal muscle DHP-sensitive calcium channel is a complex of 5 subunits: alpha-1, alpha-2, beta, gamma, and delta. The DHP-sensitive calcium channels from cardiac muscle and the brain have pharmacologic and electrophysiologic properties that differ from those of the skeletal muscle channel. <a href="#31" class="mim-tip-reference" title="Powers, P. A., Gregg, R. G., Lalley, P. A., Liao, M., Hogan, K. <strong>Assignment of the human gene for the alpha-1 subunit of the cardiac DHP-sensitive Ca(2+) channel (CCHL1A1) to chromosome 12p12-pter.</strong> Genomics 10: 835-839, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1653763/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1653763</a>] [<a href="https://doi.org/10.1016/0888-7543(91)90471-p" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1653763">Powers et al. (1991)</a> isolated a clone for the human CCHL1A1 gene and partially sequenced it. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1653763+1659003" 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>Voltage-dependent calcium channels are made up of 4 repeated domains (I through IV) that each contain at least 6 membrane-spanning regions (S1 through S6), and the 4 domains are connected by linkers of variable length. By PCR of human heart, followed by sequence analysis, <a href="#29" class="mim-tip-reference" title="Perez-Reyes, E., Wei, X., Castellano, A., Birnbaumer, L. <strong>Molecular diversity of L-type calcium channels: evidence for alternative splicing of the transcripts of three non-allelic genes.</strong> J. Biol. Chem. 265: 20430-20436, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2173707/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2173707</a>]" pmid="2173707">Perez-Reyes et al. (1990)</a> identified 3 variants of CACNA1C, which they called CACH2. The variants differed in both the sequence of IVS3 and in the size of the linker between IVS3 and IVS4. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2173707" 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="#39" class="mim-tip-reference" title="Soldatov, N. M. <strong>Molecular diversity of L-type Ca(2+) channel transcripts in human fibroblasts.</strong> Proc. Nat. Acad. Sci. 89: 4628-4632, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1316612/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1316612</a>] [<a href="https://doi.org/10.1073/pnas.89.10.4628" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1316612">Soldatov (1992)</a> identified 4 sites of molecular diversity in human fibroblast CACNA1C, which they called HFCC. Three of these involved regions encoding transmembrane segments IIS6, IIIS2, and IVS3, which are important for channel gating, and the fourth was located at the C terminus. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1316612" 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="Schultz, D., Mikala, G., Yatani, A., Engle, D. B., Iles, D. E., Segers, B., Sinke, R. J., Weghuis, D. O., Klockner, U., Wakamori, M., Wang, J.-J., Melvin, D., Varadi, G., Schwartz, A. <strong>Cloning, chromosomal localization, and functional expression of the alpha-1 subunit of the L-type voltage-dependent calcium channel from normal human heart.</strong> Proc. Nat. Acad. Sci. 90: 6228-6232, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8392192/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8392192</a>] [<a href="https://doi.org/10.1073/pnas.90.13.6228" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8392192">Schultz et al. (1993)</a> obtained a full-length cDNA encoding CACNA1C by screening human heart cDNA libraries. The deduced 2,180-amino acid protein has a calculated molecular mass of 243.6 kD. CACNA1C contains 5 protein kinase A (see <a href="/entry/176911">176911</a>) phosphorylation sites and 4 putative N-glycosylation sites. Human and rabbit CACNA1C share almost 100% homology in the transmembrane regions. The dominant isoform in human heart contains a 71-amino acid insert with a potential CAMK2 (see <a href="/entry/607707">607707</a>) consensus sequence. Northern blot analysis detected a 9.4-kb transcript in heart. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8392192" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#5" class="mim-tip-reference" title="Blumenstein, Y., Kanevsky, N., Sahar, G., Barzilai, R., Ivanina, T., Dascal, N. <strong>A novel long N-terminal isoform of human L-type Ca(2+) channel is up-regulated by protein kinase C.</strong> J. Biol. Chem. 277: 3419-3423, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11741969/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11741969</a>] [<a href="https://doi.org/10.1074/jbc.C100642200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11741969">Blumenstein et al. (2002)</a> identified 2 CACNA1C transcripts in human heart that utilize alternative first exons, 1a or 1b. Exon 1a encodes a 46-amino acid N-terminal segment, and exon 1b encodes a 16-amino acid N-terminal segment. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11741969" 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 ribonuclease protection assay, <a href="#34" class="mim-tip-reference" title="Saada, N., Dai, B., Echetebu, C., Sarna, S. K., Palade, P. <strong>Smooth muscle uses another promoter to express primarily a form of human Ca(v)1.2 L-type calcium channel different from the principal heart form.</strong> Biochem. Biophys. Res. Commun. 302: 23-28, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12593842/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12593842</a>] [<a href="https://doi.org/10.1016/s0006-291x(03)00097-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12593842">Saada et al. (2003)</a> found that all smooth muscle-containing tissues examined (bladder, fetal aorta, lung, and intestine) expressed CANCA1C transcripts utilizing exon 1b. Only bladder and fetal aorta also expressed transcripts utilizing exon 1a. Primary cultures of colonic myocytes and coronary artery smooth muscle cells also predominantly expressed transcripts with exon 1b. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12593842" 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="#40" class="mim-tip-reference" title="Soldatov, N. M. <strong>Genomic structure of human L-type Ca(2+) channel.</strong> Genomics 22: 77-87, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7959794/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7959794</a>] [<a href="https://doi.org/10.1006/geno.1994.1347" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7959794">Soldatov (1994)</a> investigated the genomic organization of the CACNL1A1 gene by DNA sequencing of genomic and cDNA clones and PCR products. The gene spans an estimated 150 kb of the human genome and is composed of 44 invariant and 6 alternative exons. Data on cDNA cloning from both human fibroblasts and hippocampus indicated several regions of heterogeneity due to alternative splicing sites of the CACNL1A1 primary transcript. In addition, Southern blotting followed by partial sequencing indicated at least 3 different isoforms of L-type Ca(2+) channels. <a href="#40" class="mim-tip-reference" title="Soldatov, N. M. <strong>Genomic structure of human L-type Ca(2+) channel.</strong> Genomics 22: 77-87, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7959794/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7959794</a>] [<a href="https://doi.org/10.1006/geno.1994.1347" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7959794">Soldatov (1994)</a> suggested that the human L-type Ca(2+) channels are genetically regulated through generation of multiple splice variants of the mRNA, some of them in a tissue-specific manner, as well as via expression of different gene isoforms. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7959794" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#5" class="mim-tip-reference" title="Blumenstein, Y., Kanevsky, N., Sahar, G., Barzilai, R., Ivanina, T., Dascal, N. <strong>A novel long N-terminal isoform of human L-type Ca(2+) channel is up-regulated by protein kinase C.</strong> J. Biol. Chem. 277: 3419-3423, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11741969/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11741969</a>] [<a href="https://doi.org/10.1074/jbc.C100642200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11741969">Blumenstein et al. (2002)</a> identified an alternate 5-prime exon, 1a, that lies about 80 kb upstream of the alternate exon 1b in the CACNA1C gene. <a href="#34" class="mim-tip-reference" title="Saada, N., Dai, B., Echetebu, C., Sarna, S. K., Palade, P. <strong>Smooth muscle uses another promoter to express primarily a form of human Ca(v)1.2 L-type calcium channel different from the principal heart form.</strong> Biochem. Biophys. Res. Commun. 302: 23-28, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12593842/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12593842</a>] [<a href="https://doi.org/10.1016/s0006-291x(03)00097-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12593842">Saada et al. (2003)</a> demonstrated that exons 1a and 1b have separate functional upstream promoters. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11741969+12593842" 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 constructing oligonucleotides based on the human CCHL1A1 sequence and using them in PCR to amplify specifically this human gene in human-rodent somatic cell hybrids, <a href="#31" class="mim-tip-reference" title="Powers, P. A., Gregg, R. G., Lalley, P. A., Liao, M., Hogan, K. <strong>Assignment of the human gene for the alpha-1 subunit of the cardiac DHP-sensitive Ca(2+) channel (CCHL1A1) to chromosome 12p12-pter.</strong> Genomics 10: 835-839, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1653763/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1653763</a>] [<a href="https://doi.org/10.1016/0888-7543(91)90471-p" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1653763">Powers et al. (1991)</a> assigned the CCHL1A1 gene to 12pter-p12. Using a dinucleotide repeat for linkage analysis in the CEPH panel of families, <a href="#30" class="mim-tip-reference" title="Powers, P. A., Gregg, R. G., Hogan, K. <strong>Linkage mapping of the human gene for the alpha-1 subunit of the cardiac DHP-sensitive Ca(2+) channel (CACNL1A1) to chromosome 12p13.2-pter using a dinucleotide repeat.</strong> Genomics 14: 206-207, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1330882/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1330882</a>] [<a href="https://doi.org/10.1016/s0888-7543(05)80312-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1330882">Powers et al. (1992)</a> narrowed the assignment to 12pter-p13.2. The data placed CACNL1A1 distal to PRB1 (<a href="/entry/180989">180989</a>). By study of somatic cell hybrids, <a href="#43" class="mim-tip-reference" title="Sun, W., McPherson, J. D., Hoang, D. Q., Wasmuth, J. J., Evans, G. A., Montal, M. <strong>Mapping of a human brain voltage-gated calcium channel to human chromosome 12p13-pter.</strong> Genomics 14: 1092-1094, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1335957/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1335957</a>] [<a href="https://doi.org/10.1016/s0888-7543(05)80135-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1335957">Sun et al. (1992)</a> likewise assigned the CACNL1A1 gene to 12pter-p13. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1653763+1330882+1335957" 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="Schultz, D., Mikala, G., Yatani, A., Engle, D. B., Iles, D. E., Segers, B., Sinke, R. J., Weghuis, D. O., Klockner, U., Wakamori, M., Wang, J.-J., Melvin, D., Varadi, G., Schwartz, A. <strong>Cloning, chromosomal localization, and functional expression of the alpha-1 subunit of the L-type voltage-dependent calcium channel from normal human heart.</strong> Proc. Nat. Acad. Sci. 90: 6228-6232, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8392192/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8392192</a>] [<a href="https://doi.org/10.1073/pnas.90.13.6228" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8392192">Schultz et al. (1993)</a> localized the CCHL1A1 gene to 12p13.3 by study of a 12p somatic cell hybrid mapping panel and by fluorescence in situ hybridization. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8392192" 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>Studying 2 somatic cell hybrids containing either the der(12) or the der(X) from a mesothelioma with a translocation t(X;12)(q22;p13) as the only chromosomal change and applying PCR analysis based on genomic sequences, <a href="#1" class="mim-tip-reference" title="Aerssens, J., Chaffanet, M., Baens, M., Matthijs, G., Van Den Berghe, H., Cassiman, J.-J., Marynen, P. <strong>Regional assignment of seven loci to 12p13.2-pter by PCR analysis of somatic cell hybrids containing the der(12) or the der(X) chromosome from a mesothelioma showing t(X;12)(q22;p13).</strong> Genomics 20: 119-121, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8020938/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8020938</a>] [<a href="https://doi.org/10.1006/geno.1994.1136" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8020938">Aerssens et al. (1994)</a> mapped the CACNL1A1 gene distal to the 12p13 breakpoint and to VWF (<a href="/entry/613160">613160</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8020938" 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="#36" class="mim-tip-reference" title="Schultz, D., Mikala, G., Yatani, A., Engle, D. B., Iles, D. E., Segers, B., Sinke, R. J., Weghuis, D. O., Klockner, U., Wakamori, M., Wang, J.-J., Melvin, D., Varadi, G., Schwartz, A. <strong>Cloning, chromosomal localization, and functional expression of the alpha-1 subunit of the L-type voltage-dependent calcium channel from normal human heart.</strong> Proc. Nat. Acad. Sci. 90: 6228-6232, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8392192/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8392192</a>] [<a href="https://doi.org/10.1073/pnas.90.13.6228" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8392192">Schultz et al. (1993)</a> found that CACNA1C expressed in Xenopus oocytes produced a large inward Ba(2+) current upon depolarization. The channel opening probability was voltage dependent, and single channel analysis revealed native-like pharmacology and channel properties. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8392192" 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="#38" class="mim-tip-reference" title="Soldatov, N. M., Zuhlke, R. D., Bouron, A., Reuter, H. <strong>Molecular structures involved in L-type calcium channel inactivation: role of the carboxyl-terminal region encoded by exons 40-42 in alpha-1C subunit in the kinetics and Ca(2+) dependence of inactivation.</strong> J. Biol. Chem. 272: 3560-3566, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9013606/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9013606</a>] [<a href="https://doi.org/10.1074/jbc.272.6.3560" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9013606">Soldatov et al. (1997)</a> expressed 3 human hippocampus CACNA1C variants in Xenopus oocytes. The 3 variants were highly sensitive toward DHP, but showed large differences in gating properties. A segment spanning amino acids 1572 to 1651 in the cytoplasmic tail defined the channel inactivation rate, the Ca(2+)-dependent component of inactivation, and the voltage-dependent component of inactivation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9013606" 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="#18" class="mim-tip-reference" title="Klockner, U., Mikala, G., Eisfeld, J., Iles, D. E., Strobeck, M., Mershon, J. L., Schwartz, A., Varadi, G. <strong>Properties of three COOH-terminal splice variants of a human cardiac L-type Ca(2+)-channel alpha-1-subunit.</strong> Am. J. Physiol. 272: H1372-H1381, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9087614/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9087614</a>] [<a href="https://doi.org/10.1152/ajpheart.1997.272.3.H1372" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9087614">Klockner et al. (1997)</a> expressed 3 cardiac CACNA1C splice variants encoding proteins with different C termini in Xenopus oocytes and in human embryonic kidney cells. The channels showed insignificant differences in the kinetics and voltage dependence of the induced calcium channel currents. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9087614" 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 expression in Xenopus oocytes, <a href="#5" class="mim-tip-reference" title="Blumenstein, Y., Kanevsky, N., Sahar, G., Barzilai, R., Ivanina, T., Dascal, N. <strong>A novel long N-terminal isoform of human L-type Ca(2+) channel is up-regulated by protein kinase C.</strong> J. Biol. Chem. 277: 3419-3423, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11741969/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11741969</a>] [<a href="https://doi.org/10.1074/jbc.C100642200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11741969">Blumenstein et al. (2002)</a> found that a protein kinase C (see <a href="/entry/176960">176960</a>) activator enhanced the channel activity of the cardiac CACNA1C isoform containing the 46-amino acid N-terminal segment. CACNA1C with the alternate 16-amino acid N-terminal segment was inhibited. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11741969" 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 mode of calcium entry into a neuron plays a key role in determining which signaling pathways are activated and thus specifies a cellular response to calcium. Calcium influx through L-type voltage-activated channels (LTCs) is particularly effective at activating transcription factors such as CREB (<a href="/entry/123810">123810</a>) and MEF2 (see <a href="/entry/600660">600660</a>). <a href="#12" class="mim-tip-reference" title="Dolmetsch, R. E., Pajvani, U., Fife, K., Spotts, J. M., Greenberg, M. E. <strong>Signaling to the nucleus by an L-type calcium channel-calmodulin complex through the MAP kinase pathway.</strong> Science 294: 333-339, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11598293/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11598293</a>] [<a href="https://doi.org/10.1126/science.1063395" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11598293">Dolmetsch et al. (2001)</a> developed a functional knockin technique to investigate the features of LTCs that specifically couple them to the signaling pathways that regulate gene expression. They found that an isoleucine-glutamine (IQ) motif in the C terminus of the LTC that binds calcium-calmodulin (<a href="/entry/114180">114180</a>) is critical for conveying the calcium signaling to the nucleus. Calcium-calmodulin binding to the LTC was necessary for activation of the Ras/mitogen-activated protein kinase (MAPK) pathway, which conveys local calcium signals from the mouth of the LTC to the nucleus. Calmodulin functions as a local calcium sensor at the mouth of the LTC that activates the MAPK pathway and leads to the stimulation of genes that are essential for neuronal survival and plasticity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11598293" 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 understand the relationship between the number of calmodulin molecules regulating each L-type calcium channel and the number of calmodulin molecules privy to the local calcium signal from each channel, <a href="#23" class="mim-tip-reference" title="Mori, M. X., Erickson, M. G., Yue, D. T. <strong>Functional stoichiometry and local enrichment of calmodulin interacting with Ca(2+) channels.</strong> Science 304: 432-435, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15087548/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15087548</a>] [<a href="https://doi.org/10.1126/science.1093490" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15087548">Mori et al. (2004)</a> fused L-type calcium channels to single calmodulin molecules. These chimeric molecules revealed that a single calmodulin molecule directs L-type channel regulation. Similar fusion molecules were used to estimate the local calmodulin concentration near calcium channels. This estimate indicates marked enrichment of local calmodulin, as if a school of nearby calmodulins were poised to enhance the transduction of local calcium entry into diverse signaling pathways. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15087548" 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="Gomez-Ospina, N., Tsuruta, F., Barreto-Chang, O., Hu, L., Dolmetsch, R. <strong>The C terminus of the L-type voltage-gated calcium channel Ca(V)1.2 encodes a transcription factor.</strong> Cell 127: 591-606, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17081980/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17081980</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17081980[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.2006.10.017" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17081980">Gomez-Ospina et al. (2006)</a> found that a C-terminal fragment of CaV1.2 that they designated 'calcium channel-associated transcription regulator,' or CCAT, translocated to the nucleus in mouse and rat neurons, rat cardiac myocytes, and human embryonic kidney cells. Nuclear localization of CCAT was regulated both developmentally and by changes in intracellular calcium. CCAT bound to a nuclear protein, Nono (<a href="/entry/300084">300084</a>), associated with an endogenous promoter, and regulated expression of a wide variety of endogenous genes important for neuronal signaling and excitability in mammalian neurons. <a href="#16" class="mim-tip-reference" title="Gomez-Ospina, N., Tsuruta, F., Barreto-Chang, O., Hu, L., Dolmetsch, R. <strong>The C terminus of the L-type voltage-gated calcium channel Ca(V)1.2 encodes a transcription factor.</strong> Cell 127: 591-606, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17081980/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17081980</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17081980[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.2006.10.017" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17081980">Gomez-Ospina et al. (2006)</a> concluded that voltage-gated calcium channels can directly activate transcription. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17081980" 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="Tiwari, S., Zhang, Y., Heller, J., Abernethy, D. R., Soldatov, N. M. <strong>Atherosclerosis-related molecular alteration of the human Ca(V)1.2 calcium channel alpha-1C subunit.</strong> Proc. Nat. Acad. Sci. 103: 17024-17029, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17071743/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17071743</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17071743[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.0606539103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17071743">Tiwari et al. (2006)</a> studied vascular smooth muscle cells (VSMC) from atherosclerotic and nonatherosclerotic sections of arteries from 6 vascular surgery patients. In VSMC from nonatherosclerotic regions, RT-PCR analysis revealed an extended repertoire of CACNA1C transcripts characterized by the presence of exons 21 and 41A, whereas in VSMC affected by atherosclerosis, expression of CACNA1C was reduced and CACNA1C splice variants were replaced with a unique exon 22 isoform lacking exon 41A. Electrophysiologic studies of the channel splice variants revealed that molecular remodeling of CACNA1C subunits associated with atherosclerosis caused alterations in the kinetics and voltage-dependence of inactivation, recovery from inactivation, and rundown of the Ca(2+) current. <a href="#44" class="mim-tip-reference" title="Tiwari, S., Zhang, Y., Heller, J., Abernethy, D. R., Soldatov, N. M. <strong>Atherosclerosis-related molecular alteration of the human Ca(V)1.2 calcium channel alpha-1C subunit.</strong> Proc. Nat. Acad. Sci. 103: 17024-17029, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17071743/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17071743</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17071743[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.0606539103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17071743">Tiwari et al. (2006)</a> suggested that localized changes in cytokine expression generated by inflammation in atherosclerosis affect alternative splicing of the CACNA1C gene in human arteries, resulting in molecular and electrophysiologic remodeling of CACNA1C channels. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17071743" 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="#11" class="mim-tip-reference" title="Dick, I. E., Tadross, M. R., Liang, H., Tay, L. H., Yang, W., Yue, D. T. <strong>A modular switch for spatial Ca(2+) selectivity in the calmodulin regulation of Ca(v) channels.</strong> Nature 451: 830-834, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18235447/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18235447</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18235447[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/nature06529" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18235447">Dick et al. (2008)</a> showed that the spatial calcium ion selectivity of N-lobe calmodulin (<a href="/entry/114180">114180</a>) regulation is not invariably global but can be switched by a novel calcium ion/calmodulin binding site within the amino terminus of channels (NSCaTE, for N-terminal spatial calcium ion transforming element). Native Ca(v)2.2 channels lack this element and show N-lobe regulation with a global selectivity. On the introduction of NSCaTE into these channels, spatial calcium ion selectivity transforms from a global to local profile. Given this effect, <a href="#11" class="mim-tip-reference" title="Dick, I. E., Tadross, M. R., Liang, H., Tay, L. H., Yang, W., Yue, D. T. <strong>A modular switch for spatial Ca(2+) selectivity in the calmodulin regulation of Ca(v) channels.</strong> Nature 451: 830-834, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18235447/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18235447</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18235447[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/nature06529" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18235447">Dick et al. (2008)</a> examined Ca(v)1.2/Ca(v)1.3 channels, which naturally contain NSCaTE, and found that their N-lobe selectivity is indeed local. Disruption of this element produces a global selectivity, confirming the native function of NSCaTE. Thus, <a href="#11" class="mim-tip-reference" title="Dick, I. E., Tadross, M. R., Liang, H., Tay, L. H., Yang, W., Yue, D. T. <strong>A modular switch for spatial Ca(2+) selectivity in the calmodulin regulation of Ca(v) channels.</strong> Nature 451: 830-834, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18235447/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18235447</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18235447[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/nature06529" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18235447">Dick et al. (2008)</a> concluded that differences in spatial selectivity between advanced Ca(v)1 and Ca(v)2 channel isoforms are explained by the presence or absence of NSCaTE. Beyond functional effects, the position of NSCaTE on the channel's amino terminus indicates that calmodulin can bridge the amino terminus and carboxy terminus of channels. Finally, the modularity of NSCaTE offers practical means for understanding the basis of global calcium ion selectivity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18235447" 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="Park, C. Y., Shcheglovitov, A., Dolmetsch, R. <strong>The CRAC channel activator STIM1 binds and inhibits L-type voltage-gated calcium channels.</strong> Science 330: 101-105, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20929812/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20929812</a>] [<a href="https://doi.org/10.1126/science.1191027" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20929812">Park et al. (2010)</a> found that stromal interaction molecule-1 (STIM1; <a href="/entry/605921">605921</a>), the main activator of store-operated calcium channels, directly suppresses depolarization-induced opening of the voltage-gated calcium channel Ca(v)1.2. STIM1 binds to the C terminus of Ca(v)1.2 through its calcium release-activated calcium activation domain, acutely inhibits gating, and causes long-term internalization of the channel from the membrane. <a href="#28" class="mim-tip-reference" title="Park, C. Y., Shcheglovitov, A., Dolmetsch, R. <strong>The CRAC channel activator STIM1 binds and inhibits L-type voltage-gated calcium channels.</strong> Science 330: 101-105, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20929812/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20929812</a>] [<a href="https://doi.org/10.1126/science.1191027" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20929812">Park et al. (2010)</a> concluded that their results established a theretofore unknown function for STIM1 and provided a molecular mechanism to explain the reciprocal regulation of these 2 channels in cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20929812" 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="#48" class="mim-tip-reference" title="Wang, Y., Deng, X., Mancarella, S., Hendron, E., Eguchi, S., Soboloff, J., Tang, X. D., Gill, D. L. <strong>The calcium store sensor, STIM1, reciprocally controls Orai and Ca(v)1.2 channels.</strong> Science 330: 105-109, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20929813/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20929813</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20929813[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1191086" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20929813">Wang et al. (2010)</a> revealed a regulatory link between Orai channels (see <a href="/entry/610277">610277</a>) and Ca(v)1.2 channels mediated by the ubiquitous calcium-sensing STIM proteins. STIM1 activation by store depletion or mutational modification strongly suppresses voltage-operated calcium (Ca(v)1.2) channels while activating store-operated (Orai) channels. Both actions are mediated by the short STIM-Orai activating region (SOAR) of STIM1. STIM1 interacts with Ca(v)1.2 channels and localizes within discrete endoplasmic reticulum/plasma membrane junctions containing both Ca(v)1.2 and ORAI1 channels. Hence, STIM1 interacts with and reciprocally controls 2 major calcium channels hitherto thought to operate independently. <a href="#48" class="mim-tip-reference" title="Wang, Y., Deng, X., Mancarella, S., Hendron, E., Eguchi, S., Soboloff, J., Tang, X. D., Gill, D. L. <strong>The calcium store sensor, STIM1, reciprocally controls Orai and Ca(v)1.2 channels.</strong> Science 330: 105-109, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20929813/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20929813</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20929813[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1191086" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20929813">Wang et al. (2010)</a> concluded that such coordinated control of the widely expressed Ca(v)1.2 and Orai channels has major implications for calcium signal generation in excitable and nonexcitable cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20929813" 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 primary cultures of rat ventricular myocytes, <a href="#22" class="mim-tip-reference" title="Liu, W., Deng, J., Wang, G., Zhang, C., Luo, X., Yan, D., Su, Q., Liu, J. <strong>KCNE2 modulates cardiac L-type Ca(2+) channel.</strong> J. Molec. Cell. Cardiol. 72: 208-218, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24681347/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24681347</a>] [<a href="https://doi.org/10.1016/j.yjmcc.2014.03.013" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24681347">Liu et al. (2014)</a> found that human KCNE2 (<a href="/entry/603796">603796</a>) coimmunoprecipitated with and colocalized with Cav1.2, predominantly at transverse tubules. KCNE2 overexpression decreased Cav1.2 current magnitude and slightly altered its gating and kinetic properties, but it had no effect on Cav1.2 trafficking or membrane localization. Knockdown of endogenous Kcne2 increased Cav1.2-dependent calcium currents. KCNE2 copurified with the N-terminal inhibitory module of Cav1.2 and appeared to increase its inhibitory function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24681347" 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 mouse brain and human iPSCs from individuals with Timothy syndrome (TS; <a href="/entry/601005">601005</a>), <a href="#27" class="mim-tip-reference" title="Panagiotakos, G., Haveles, C., Arjun, A., Petrova, R., Rana, A., Portmann, T., Pasca, S. P., Palmer, T. D., Dolmetsch, R. E. <strong>Aberrant calcium channel splicing drives defects in cortical differentiation in Timothy syndrome.</strong> eLife 8: e51037, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31868578/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31868578</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31868578[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/10.7554/eLife.51037" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31868578">Panagiotakos et al. (2019)</a> provided evidence that the CACNA1C G406R mutation (<a href="#0001">114205.0001</a>) promotes use of alternatively spliced exon 8A and prevents a normal developmental switch in Ca(v)1.2 exon utilization, resulting in persistent expression of gain-of-function mutant channels during neuronal differentiation. In iPSC models, the TS variant reduces the abundance of SATB2-expressing cortical projection neurons, leading to excess CTIP2-positive neurons. <a href="#27" class="mim-tip-reference" title="Panagiotakos, G., Haveles, C., Arjun, A., Petrova, R., Rana, A., Portmann, T., Pasca, S. P., Palmer, T. D., Dolmetsch, R. E. <strong>Aberrant calcium channel splicing drives defects in cortical differentiation in Timothy syndrome.</strong> eLife 8: e51037, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31868578/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31868578</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31868578[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/10.7554/eLife.51037" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31868578">Panagiotakos et al. (2019)</a> showed that the expression of the TS-Ca(v)1.2 channels in the embryonic mouse cortex recapitulates these differentiation defects in a calcium-dependent manner and that in utero Ca(v)1.2 gain-and-loss of function reciprocally regulates the abundance of these neuronal populations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31868578" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#21" class="mim-tip-reference" title="Liu, G., Papa, A., Katchman, A. N., Zakharov, S. I., Roybal, D., Hennessey, J. A., Kushner, J., Yang, L., Chen, B.-X., Kushnir, A., Dangas, K., Gygi, S. P., Pitt, G. S., Colecraft, H. M., Ben-Johny, M., Kalocsay, M., Marx, S. O. <strong>Mechanism of adrenergic Ca(V)1.2 stimulation revealed by proximity proteomics.</strong> Nature 577: 695-700, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31969708/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31969708</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31969708[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/s41586-020-1947-z" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31969708">Liu et al. (2020)</a> identified the mechanism by which beta-adrenergic agonists stimulate voltage-gated calcium channels. <a href="#21" class="mim-tip-reference" title="Liu, G., Papa, A., Katchman, A. N., Zakharov, S. I., Roybal, D., Hennessey, J. A., Kushner, J., Yang, L., Chen, B.-X., Kushnir, A., Dangas, K., Gygi, S. P., Pitt, G. S., Colecraft, H. M., Ben-Johny, M., Kalocsay, M., Marx, S. O. <strong>Mechanism of adrenergic Ca(V)1.2 stimulation revealed by proximity proteomics.</strong> Nature 577: 695-700, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31969708/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31969708</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31969708[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/s41586-020-1947-z" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31969708">Liu et al. (2020)</a> expressed alpha-1C or beta-2B subunits conjugated to ascorbate peroxidase in mouse hearts, and used multiplexed quantitative proteomics to track hundreds of proteins in the proximity of CaV1.2. They observed that the calcium-channel inhibitor Rad (<a href="/entry/179503">179503</a>) is enriched in the CaV1.2 microenvironment but is depleted during beta-adrenergic stimulation. Phosphorylation by protein kinase A (see <a href="/entry/176911">176911</a>) of specific serine residues on Rad decreases its affinity for beta subunits and relieves constitutive inhibition of CaV1.2, observed as an increase in channel open probability. Expression of Rad or its homolog Rem (<a href="/entry/610388">610388</a>) in HEK293T cells also imparted stimulation of CaV1.3 (CACNA1D; <a href="/entry/114206">114206</a>) and CaV2.2 (CACNA1B; <a href="/entry/601012">601012</a>) by protein kinase A, revealing an evolutionarily conserved mechanism that confers adrenergic modulation upon voltage-gated calcium channels. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31969708" 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>Calcium-induced calcium release is a general mechanism that most cells use to amplify calcium signals. In heart cells, this mechanism is operated between voltage-gated L-type calcium channels (LCCs) in the plasma membrane and calcium release channels, commonly known as ryanodine receptors (see <a href="/entry/180901">180901</a>), in the sarcoplasmic reticulum. The calcium influx through LCCs traverses a cleft of roughly 12 nm formed by the cell surface and the sarcoplasmic reticulum membrane, and activates adjacent ryanodine receptors to release calcium in the form of calcium sparks (<a href="#10" class="mim-tip-reference" title="Cheng, H., Lederer, W. J., Cannell, M. B. <strong>Calcium sparks: elementary events underlying excitation-contraction coupling in heart muscle.</strong> Science 262: 740-744, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8235594/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8235594</a>] [<a href="https://doi.org/10.1126/science.8235594" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8235594">Cheng et al., 1993</a>). <a href="#47" class="mim-tip-reference" title="Wang, S.-Q., Song, L.-S., Lakatta, E. G., Cheng, H. <strong>Ca(2+) signalling between single L-type Ca(2+) channels and ryanodine receptors in heart cells.</strong> Nature 410: 592-596, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11279498/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11279498</a>] [<a href="https://doi.org/10.1038/35069083" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11279498">Wang et al. (2001)</a> determined the kinetics, fidelity, and stoichiometry of coupling between LCCs and ryanodine receptors. They showed that the local calcium signal produced by a single opening of an LCC, named a 'calcium sparklet,' can trigger about 4 to 6 ryanodine receptors to generate a calcium spark. The coupling between LCCs and ryanodine receptors is stochastic, as judged by the exponential distribution of the coupling latency. The fraction of sparklets that successfully triggers a spark is less than unity and declines in a use-dependent manner. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11279498+8235594" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><strong><em>Timothy Syndrome</em></strong></p><p>
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Timothy syndrome (TS; <a href="/entry/601005">601005</a>) is characterized by multiorgan dysfunction, including lethal arrhythmias, webbing of fingers and toes, congenital heart disease, immune deficiency, intermittent hypoglycemia, cognitive abnormalities, and autism. <a href="#42" class="mim-tip-reference" title="Splawski, I., Timothy, K. W., Sharpe, L. M., Decher, N., Kumar, P., Bloise, R., Napolitano, C., Schwartz, P. J., Joseph, R. M., Condouris, K., Tager-Flusberg, H., Priori, S. G., Sanguinetti, M. C., Keating, M. T. <strong>Ca(V)1.2 calcium channel dysfunction causes a multisystem disorder including arrhythmia and autism.</strong> Cell 119: 19-31, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15454078/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15454078</a>] [<a href="https://doi.org/10.1016/j.cell.2004.09.011" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15454078">Splawski et al. (2004)</a> showed that, in all available patients, TS resulted from an identical, de novo missense mutation (G406R; <a href="#0001">114205.0001</a>) in the alternatively spliced exon 8A of the CACNA1C gene. They found that CACNA1C was expressed in all tissues affected in TS. <a href="#42" class="mim-tip-reference" title="Splawski, I., Timothy, K. W., Sharpe, L. M., Decher, N., Kumar, P., Bloise, R., Napolitano, C., Schwartz, P. J., Joseph, R. M., Condouris, K., Tager-Flusberg, H., Priori, S. G., Sanguinetti, M. C., Keating, M. T. <strong>Ca(V)1.2 calcium channel dysfunction causes a multisystem disorder including arrhythmia and autism.</strong> Cell 119: 19-31, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15454078/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15454078</a>] [<a href="https://doi.org/10.1016/j.cell.2004.09.011" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15454078">Splawski et al. (2004)</a> stated that this likely induces intracellular Ca(2+) overload in multiple cell types. They noted that, in the heart, prolonged Ca(2+) current delays cardiomyocyte repolarization and increases risk of arrhythmia, the ultimate cause of death in TS. These findings established the importance of CACNA1C in human physiology and development and implicated Ca(2+) signaling in autism. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15454078" 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="Splawski, I., Timothy, K. W., Decher, N., Kumar, P., Sachse, F. B., Beggs, A. H., Sanguinetti, M. C., Keating, M. T. <strong>Severe arrhythmia disorder caused by cardiac L-type calcium channel mutations.</strong> Proc. Nat. Acad. Sci. 102: 8089-8096, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15863612/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15863612</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15863612[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.0502506102" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15863612">Splawski et al. (2005)</a> described 2 individuals with a severe variant of TS without syndactyly in whom they identified de novo missense mutations in exon 8 of the CACNA1C gene, G406R and G490R (<a href="#0002">114205.0002</a>). CACNA1C has alternatively spliced transcripts that are encoded by 2 mutually exclusive exons, 8 and 8A. The authors found that the exon 8-specific transcript was highly expressed in heart and brain, accounting for about 80% of CACNA1C mRNA. In functional studies, both mutations in exon 8 caused reduced channel inactivation, resulting in maintained depolarizing L-type calcium currents. Computer modeling showed prolongation of cardiomyocyte action potentials and delayed afterdepolarizations, factors that increase the risk of arrhythmia. <a href="#41" class="mim-tip-reference" title="Splawski, I., Timothy, K. W., Decher, N., Kumar, P., Sachse, F. B., Beggs, A. H., Sanguinetti, M. C., Keating, M. T. <strong>Severe arrhythmia disorder caused by cardiac L-type calcium channel mutations.</strong> Proc. Nat. Acad. Sci. 102: 8089-8096, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15863612/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15863612</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15863612[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.0502506102" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15863612">Splawski et al. (2005)</a> concluded that gain-of-function mutations in CACNA1C exons 8 and 8A cause distinct forms of TS. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15863612" 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 boy who died at age 3.75 years with QT prolongation and a Timothy syndrome phenotype, in whom analysis of an LQT gene panel was negative, including exons 8, 8A, and 9 of the CACNA1C gene, <a href="#7" class="mim-tip-reference" title="Boczek, N. J., Miller, E. M., Ye, D., Nesterenko, V. V., Tester, D. J., Antzelevitch, C., Czosek, R. J., Ackerman, M. J., Ware, S. M. <strong>Novel Timothy syndrome mutation leading to increase in CACNA1C window current.</strong> Heart Rhythm 12: 211-219, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25260352/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25260352</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25260352[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.hrthm.2014.09.051" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25260352">Boczek et al. (2015)</a> performed whole-exome sequencing and identified heterozygosity for a de novo missense mutation in exon 27 of the CACNA1C gene (I1166T; <a href="#0015">114205.0015</a>). Sanger sequencing confirmed the mutation and its absence in his parents; the variant was also not present in public variant databases. Functional analysis revealed a novel electrophysiologic phenotype distinct from that of classic TS mutations, which result in almost complete loss of inactivation of CaV1.2 channels. Instead, the I1166T mutation causes an overall loss of current density with a gain-of-function shift in activation, resulting in an increased window current. The authors noted that although extracardiac differences had been observed across various TS-associated CACNA1C mutations, the cardiac phenotype appeared to be consistent, with QT prolongation, arrhythmias, cardiac hypertrophy, and PDA being commonly reported. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25260352" 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 3 families with QT prolongation, hypertrophic cardiomyopathy, congenital heart defects, and/or sudden cardiac death, <a href="#8" class="mim-tip-reference" title="Boczek, N. J., Ye, D., Jin, F., Tester, D. J., Huseby, A., Bos, J. M., Johnson, A. J., Kanter, R., Ackerman, M. J. <strong>Identification and functional characterization of a novel CACNA1C-mediated cardiac disorder characterized by prolonged QT intervals with hypertrophic cardiomyopathy, congenital heart defects, and sudden cardiac death.</strong> Circ. Arrhythm. Electrophysiol. 8: 1122-1132, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26253506/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26253506</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26253506[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/10.1161/CIRCEP.115.002745" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26253506">Boczek et al. (2015)</a> identified heterozygosity for missense mutations at residue 518 in exon 12 of the CACNA1C gene: affected individuals from 2 families were heterozygous for an R518C substitution (<a href="#0016">114205.0016</a>), whereas an R518H substitution (<a href="#0017">114205.0017</a>) was found in the third family. None of the affected individuals exhibited extracardiac manifestations of Timothy syndrome. Functional analysis showed that the R518C/H variants result in a complex electrophysiologic phenotype including an overall loss of current density, increased window and late currents, and decelerating voltage-dependent inactivation resulting in constitutively active L-type calcium channels. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26253506" 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 14-year-old Japanese boy with a prolonged QT interval, dysmorphic facial features, intellectual disability, seizures, and autism spectrum disorder, <a href="#26" class="mim-tip-reference" title="Ozawa, J., Ohno, S., Saito, H., Saitoh, A., Matsuura, H., Horie, M. <strong>A novel CACNA1C mutation identified in a patient with Timothy syndrome without syndactyly exerts both marked loss- and gain-of-function effects.</strong> HeartRhythm Case Rep. 4: 273-277, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30023270/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30023270</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30023270[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.hrcr.2018.03.003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30023270">Ozawa et al. (2018)</a> screened a gene panel and identified heterozygosity for a de novo missense mutation in the CACNA1C gene (S643F; <a href="#0018">114205.0018</a>). Sanger sequencing confirmed the mutation and familial segregation, and it was not found in public variant databases. Functional analysis demonstrated an increase in late CaV1.2 currents as well as a marked reduction in peak currents with the S643F mutant compared to wildtype CACNA1C. In addition, the S643F channels never reached a fully inactivated state, with an inactivation level of 42% at maximum. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30023270" 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 14-year-old boy with QT prolongation, bradycardia, seizures, and autism spectrum disorder, <a href="#51" class="mim-tip-reference" title="Ye, D., Tester, D. J., Zhou, W., Papagiannis, J., Ackerman, M. J. <strong>A pore-localizing CACNA1C-E1115K missense mutation, identified in a patient with idiopathic QT prolongation, bradycardia, and autism spectrum disorder, converts the L-type calcium channel into a hybrid nonselective monovalent cation channel.</strong> Heart Rhythm 16: 270-278, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30172029/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30172029</a>] [<a href="https://doi.org/10.1016/j.hrthm.2018.08.030" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30172029">Ye et al. (2019)</a> analyzed a 13-gene LQTS panel and identified heterozygosity for a missense mutation in the CACNA1C gene (E1115K; <a href="#0019">114205.0019</a>). The mutation was not found in his unaffected mother or half sibs, or in the gnomAD database; DNA was unavailable from his father. Functional analysis showed that the mutation eliminates intrinsic calcium channel activity and converts the L-type calcium channel into a nonselective monovalent cation channel, with marked increases in both peak and persistent inward sodium currents and outward potassium/cesium currents. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30172029" 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>Brugada Syndrome</em></strong></p><p>
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<a href="#2" class="mim-tip-reference" title="Antzelevitch, C., Pollevick, G. D., Cordeiro, J. M., Casis, O., Sanguinetti, M. C., Aizawa, Y., Guerchicoff, A., Pfeiffer, R., Oliva, A., Wollnik, B., Gelber, P., Bonaros, E. P., Jr., and 11 others. <strong>Loss-of-function mutations in the cardiac calcium channel underlie a new clinical entity characterized by ST-segment elevation, short QT intervals, and sudden cardiac death.</strong> Circulation 115: 442-449, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17224476/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17224476</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17224476[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/10.1161/CIRCULATIONAHA.106.668392" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17224476">Antzelevitch et al. (2007)</a> screened 82 consecutive probands with a clinical diagnosis of Brugada syndrome for mutations in 16 ion channel genes. In 2 Brugada probands who exhibited shortened QTc intervals of less than or equal to 360 ms (see BRGDA3, <a href="/entry/611875">611875</a>), they identified heterozygosity for mutation in the CACNA1C gene (<a href="#0003">114205.0003</a> and <a href="#0004">114205.0004</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17224476" 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>Long QT Syndrome 8</em></strong></p><p>
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By trio-based whole-exome sequencing in a large multigeneration family segregating long QT syndrome (LQT8; <a href="/entry/618447">618447</a>) without mutation in known causative genes, <a href="#6" class="mim-tip-reference" title="Boczek, N. J., Best, J. M., Tester, D. J., Giudicessi, J. R., Middha, S., Evans, J. M., Kamp, T. J., Ackerman, M. J. <strong>Exome sequencing and systems biology converge to identify novel mutations in the L-type calcium channel, CACNA1C, linked to autosomal dominant long QT syndrome.</strong> Circ. Cardiovasc. Genet. 6: 279-289, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23677916/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23677916</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23677916[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/10.1161/CIRCGENETICS.113.000138" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23677916">Boczek et al. (2013)</a> identified heterozygosity for a missense mutation in the CACNA1C gene (P857R; <a href="#0005">114205.0005</a>) that segregated with the disorder in the family. By sequencing the CACNA1C gene in 102 unrelated patients with LQT without a molecular basis, <a href="#6" class="mim-tip-reference" title="Boczek, N. J., Best, J. M., Tester, D. J., Giudicessi, J. R., Middha, S., Evans, J. M., Kamp, T. J., Ackerman, M. J. <strong>Exome sequencing and systems biology converge to identify novel mutations in the L-type calcium channel, CACNA1C, linked to autosomal dominant long QT syndrome.</strong> Circ. Cardiovasc. Genet. 6: 279-289, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23677916/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23677916</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23677916[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/10.1161/CIRCGENETICS.113.000138" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23677916">Boczek et al. (2013)</a> identified 3 patients with heterozygous missense mutations in the CACNA1C gene (see, e.g., <a href="#0006">114205.0006</a>-<a href="#0007">114205.0007</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23677916" 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 screening 278 Japanese probands with LQT who were negative for mutation in known causative genes, <a href="#14" class="mim-tip-reference" title="Fukuyama, M., Wang, Q., Kato, K., Ohno, S., Ding, W.-G., Toyoda, F., Itoh, H., Kimura, H., Makiyama, T., Ito, M., Matsuura, H., Horie, M. <strong>Long QT syndrome type 8: novel CACNA2C mutations causing QT prolongation and variant phenotypes.</strong> Europace 16: 1828-1837, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24728418/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24728418</a>] [<a href="https://doi.org/10.1093/europace/euu063" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24728418">Fukuyama et al. (2014)</a> identified 5 novel CACNA1C variants (see, e.g., R858H, <a href="#0008">114205.0008</a> and A582D, <a href="#0009">114205.0009</a>) in 7 probands. The variants were absent in the NHLBI Exome Variant Server database and in 500 reference alleles from 250 Japanese controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24728418" 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 Sanger sequencing of the LQT1 through LQT8 genes in 540 probands with LQT, <a href="#49" class="mim-tip-reference" title="Wemhoner, K., Friedrich, C., Stallmeyer, B., Coffey, A. J., Grace, A., Zumhagen, S., Seebohm, G., Ortiz-Bonnin, B., Rinne, S., Sachse, F. B., Shulze-Bahr, E., Decher, N. <strong>Gain-of-function mutations in the calcium channel CACNA1C (Cav1.2) cause non-syndromic long-QT but not Timothy syndrome.</strong> J. Molec. Cell. Cardiol. 80: 186-195, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25633834/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25633834</a>] [<a href="https://doi.org/10.1016/j.yjmcc.2015.01.002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25633834">Wemhoner et al. (2015)</a> identified 6 patients with heterozygous mutations in the CACNA1C gene (see, e.g., I1475M, <a href="#0010">114205.0010</a>). The mutations segregated with the phenotype in the families. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25633834" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In affected members of a 5-generation European family with LQT8, <a href="#15" class="mim-tip-reference" title="Gardner, R. J. M., Crozier, I. G., Binfield, A. L., Love, D. R., Lehnert, K., Gibson, K., Lintott, C. J., Snell, R. G., Jacobsen, J. C., Jones, P. P., Waddell-Smith, K. E., Kennedy, M. A., Skinner, J. R. <strong>Penetrance and expressivity of the R858H CACNA1C variant in a five-generation pedigree segregating an arrhythmogenic channelopathy.</strong> Molec. Genet. Genomic Med. 7: e00476, 2019. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30345660/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30345660</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30345660[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/mgg3.476" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30345660">Gardner et al. (2019)</a> identified heterozygosity for the R858H mutation in the CACNA1C gene that was previously identified by <a href="#14" class="mim-tip-reference" title="Fukuyama, M., Wang, Q., Kato, K., Ohno, S., Ding, W.-G., Toyoda, F., Itoh, H., Kimura, H., Makiyama, T., Ito, M., Matsuura, H., Horie, M. <strong>Long QT syndrome type 8: novel CACNA2C mutations causing QT prolongation and variant phenotypes.</strong> Europace 16: 1828-1837, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24728418/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24728418</a>] [<a href="https://doi.org/10.1093/europace/euu063" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24728418">Fukuyama et al. (2014)</a> in Japanese patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=30345660+24728418" 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>Neurodevelopmental Disorder with Hypotonia, Language Delay, and Skeletal Defects with or without Seizures</em></strong></p><p>
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In a 5-year-old Japanese girl with neurodevelopmental disorder with hypotonia, language delay, and skeletal defects with seizures (NEDHLSS; <a href="/entry/620029">620029</a>), <a href="#19" class="mim-tip-reference" title="Kosaki, R., Ono, H., Terashima, H., Kosaki, K. <strong>Timothy syndrome-like condition with syndactyly but without prolongation of the QT interval.</strong> Am. J. Med. Genet. 176A: 1657-1661, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29736926/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29736926</a>] [<a href="https://doi.org/10.1002/ajmg.a.38833" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29736926">Kosaki et al. (2018)</a> identified a de novo heterozygous missense variant (c.3070A-G, NM_199460.3; R1024G) in exon 24 of the CACNA1C gene. The variant was found by exome sequencing. Functional studies of the variant and studies of patient cells were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29736926" 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 an 18-month-old girl, born of unrelated parents, with NEDHLSS, <a href="#9" class="mim-tip-reference" title="Bozarth, X., Dines, J. N., Cong, Q., Mirzaa, G. M., Foss, K., Lawrence Merritt, J., Thies, J., Mefford, H. C., Novotny, E. <strong>Expanding clinical phenotype in CACNA1C related disorders: From neonatal onset severe epileptic encephalopathy to late-onset epilepsy.</strong> Am. J. Med. Genet. 176A: 2733-2739, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30513141/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30513141</a>] [<a href="https://doi.org/10.1002/ajmg.a.40657" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30513141">Bozarth et al. (2018)</a> identified a de novo heterozygous missense mutation in the CACNA1C gene (V1363M; <a href="#0011">114205.0011</a>). The mutation, which was found by trio-based exome sequencing, was not present in public databases, including gnomAD. Functional studies of the variant and studies of patient cells were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30513141" 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 14 unrelated patients (P1-P14) with NEDHLSS, <a href="#32" class="mim-tip-reference" title="Rodan, L. H., Spillmann, R. C., Kurata, H. T., Lamothe, S. M., Maghera, J., Jamra, R. A., Alkelai, A., Antonarakis, S. E., Atallah, I., Bar-Yosef, O., Bilan, F., Bjorgo, K., and 46 others. <strong>Phenotypic expansion of CACNA1C-associated disorders to include isolated neurological manifestations.</strong> Genet. Med. 23: 1922-1932, 2021. Note: Erratum: Genet. Med. 23: 2016 only, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34163037/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34163037</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=34163037[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/s41436-021-01232-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34163037">Rodan et al. (2021)</a> identified de novo heterozygous nontruncating mutations (13 missense and 1 in-frame deletion) in the CACNA1C gene (see, e.g., L614P, <a href="#0012">114205.0012</a>; L657F, <a href="#0013">114205.0013</a>; and L1408V, <a href="#0014">114205.0014</a>). The mutations, which were found by exome sequencing, were not present in the gnomAD database. The patients were ascertained through the GeneMatcher Program after exome sequencing was performed. Electrophysiologic patch-clamp voltage studies in HEK293 cells transfected with a subset of the mutations showed no or variable effects on the channel current, both increased and decreased. The authors noted that their studies used the canonical transcript, but that the CACNA1C gene undergoes extensive splicing and interacts with multiple accessory subunits. They postulated a dominant-negative effect rather than haploinsufficiency. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34163037" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Associations Pending Confirmation</em></strong></p><p>
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For discussion of a possible association between hyperinsulinemic hypoglycemia (see <a href="/entry/256450">256450</a>) and variation in the CACNA1C gene, see <a href="#0020">114205.0020</a>.</p><p><a href="#4" class="mim-tip-reference" title="Blancard, M., Debbiche, A., Kato, K., Cardin, C., Sabrina, G., Gandjbakhch, E., Probst, V., Haissaguerre, M., Extramiana, F., Hocini, M., Olivier, G., Leenhardt, A., Guicheney, P., Rougier, J.-S. <strong>An African loss-of-function CACNA1C variant p.T1787M associated with a risk of ventricular fibrillation.</strong> Sci. Rep. 8: 14619, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30279520/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30279520</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30279520[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/s41598-018-32867-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30279520">Blancard et al. (2018)</a> analyzed the CaV1.2-related genes CACNA1C, CACNB2 (<a href="/entry/600003">600003</a>), and CACNA2D1 (<a href="/entry/114204">114204</a>) in 65 probands with Brugada syndrome, short QT syndrome, early repolarization syndrome, or idiopathic ventricular fibrillation, and identified 6 missense variants in the CACNA1C gene in 5 probands. Functional analysis showed no major alterations in channel function with 5 of the variants. The sixth variant, a T1787M substitution (c.5360C-T, NM_000719), was present in 2 probands (cases 1 and 2), both of whom were resuscitated from cardiac arrest. Case 1 was a Franco-Cameroonian man with an early repolarization pattern on electrocardiogram (ECG), and case 2 was a woman from La Reunion, in whom torsades de pointes originating from Purkinje fibers was detected. Both underwent placement of a cardioverter/defibrillator device, with brief or nonsustained ventricular tachycardia detected in the following years. Family history of cardiac events and ECG screening of family members were negative. Case 2 had an asymptomatic daughter who also carried the T1787M variant. The T1787M variant was present in the ExAC database at a minor allele frequency of 0.12%, found mostly in the African population, in heterozygous state in 113 of 3,565 individuals as well as in homozygosity in 1 individual. Both probands also carried a second missense variant in CACNA1C, neither of which was considered to be pathogenic; each had an unaffected son carrying only that second variant, and case 2 had an unaffected sister carrying only the second variant. Patch-clamp studies revealed that the T1787M variant reduces calcium and barium currents by increasing C terminal-mediated autoinhibition, and also increases voltage-dependent inhibition. The authors concluded that T1787M, present in 0.8% of the African population, was a risk factor for ventricular arrhythmia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30279520" 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="#32" class="mim-tip-reference" title="Rodan, L. H., Spillmann, R. C., Kurata, H. T., Lamothe, S. M., Maghera, J., Jamra, R. A., Alkelai, A., Antonarakis, S. E., Atallah, I., Bar-Yosef, O., Bilan, F., Bjorgo, K., and 46 others. <strong>Phenotypic expansion of CACNA1C-associated disorders to include isolated neurological manifestations.</strong> Genet. Med. 23: 1922-1932, 2021. Note: Erratum: Genet. Med. 23: 2016 only, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34163037/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34163037</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=34163037[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/s41436-021-01232-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34163037">Rodan et al. (2021)</a> identified heterozygous putative truncating mutations in the CACNA1C gene in 11 individuals (P15-P22C) from 8 unrelated families with variable neurologic deficits. The phenotype was not as severe as in those with nontruncating mutations. In 3 families with truncating variants, the variant was paternally inherited with variable penetrance and expressivity. Variants occurred de novo in the other individuals. The variants occurred throughout the gene and included nonsense, frameshift, and splice site, all predicted to result in a truncated protein; all but one were predicted to trigger nonsense-mediated mRNA decay. None of the variants were present in the gnomAD database. Functional studies of the variants and studies of patient cells were not performed. The authors postulated haploinsufficiency as a possible pathogenetic mechanism, but noted that this gene undergoes complex alternative splicing, which presents a challenge in interpreting the effect of the variants. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34163037" 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>Exclusion Studies</em></strong></p><p>
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<a href="#24" class="mim-tip-reference" title="O'Brien, R. O., Taske, N. L., Hansbro, P. M., Matthaei, K. I., Hogan, S. P., Denborough, M. A., Foster, P. S. <strong>Exclusion of defects in the skeletal muscle specific regions of the DHPR alpha-1 subunit as frequent causes of malignant hyperthermia.</strong> J. Med. Genet. 32: 913-914, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8592342/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8592342</a>] [<a href="https://doi.org/10.1136/jmg.32.11.913" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8592342">O'Brien et al. (1995)</a> found no defects in several functional segments (II-III loop or IS3/IS3-IS4 segment) of this gene in a malignant hyperthermia kindred. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8592342" 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="#46" class="mim-tip-reference" title="Valenzuela, D., Han, X., Mende, U., Fankhauser, C., Mashimo, H., Huang, P., Pfeffer, J., Neer, E. J., Fishman, M. C. <strong>G-alpha-o is necessary for muscarinic regulation of Ca(2+) channels in mouse heart.</strong> Proc. Nat. Acad. Sci. 94: 1727-2732, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9050846/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9050846</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9050846[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.94.5.1727" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9050846">Valenzuela et al. (1997)</a> generated knockout mice lacking both forms of Go-alpha (<a href="/entry/139311">139311</a>) by homologous recombination and studied the muscarinic regulation of calcium channels in cardiac muscles in Go-alpha -/- mice and controls. There was no difference in the effect of isoproterenol on the L-type voltage-dependent calcium channel in ventricular myocytes of both groups, but the inhibitory effect of carbamylcholine was almost completely abolished in the Go-alpha -/- group. This demonstrated that, in the heart, Go-alpha is specifically required for transmission of signals from the muscarinic receptor to the L-type voltage-dependent calcium channel. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9050846" 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 positional cloning, <a href="#33" class="mim-tip-reference" title="Rottbauer, W., Baker, K., Wo, Z. G., Mohideen, M.-A. P. K., Cantiello, H. F., Fishman, M. C. <strong>Growth and function of the embryonic heart depend upon the cardiac-specific L-type calcium channel alpha-1 subunit.</strong> Dev. Cell 1: 265-275, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11702785/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11702785</a>] [<a href="https://doi.org/10.1016/s1534-5807(01)00023-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11702785">Rottbauer et al. (2001)</a> found that mutations in the zebrafish homolog of CACNA1C, which they called C-LTCC, are responsible for the embryonic lethal island beat (isl) phenotype. The mutations abolish L-type calcium currents in isl cardiomyocytes and the ventricle consequently fails to grow and is electrically silent. <a href="#33" class="mim-tip-reference" title="Rottbauer, W., Baker, K., Wo, Z. G., Mohideen, M.-A. P. K., Cantiello, H. F., Fishman, M. C. <strong>Growth and function of the embryonic heart depend upon the cardiac-specific L-type calcium channel alpha-1 subunit.</strong> Dev. Cell 1: 265-275, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11702785/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11702785</a>] [<a href="https://doi.org/10.1016/s1534-5807(01)00023-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11702785">Rottbauer et al. (2001)</a> concluded that calcium signaling via C-LTCC can regulate heart growth independently of contraction and plays distinctive roles in fashioning both form and function of the 2 developing chambers in zebrafish. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11702785" 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="#25" class="mim-tip-reference" title="Oudit, G. Y., Sun, H., Trivieri, M. G., Koch, S. E., Dawood, F., Ackerley, C., Yazdanpanah, M., Wilson, G. J., Schwartz, A., Liu, P. P., Backx, P. H. <strong>L-type Ca(2+) channels provide a major pathway for iron entry into cardiomyocytes in iron-overload cardiomyopathy.</strong> Nature Med. 9: 1187-1194, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12937413/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12937413</a>] [<a href="https://doi.org/10.1038/nm920" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12937413">Oudit et al. (2003)</a> hypothesized that in iron-overload disorders, iron accumulation in the heart depends on ferrous iron permeation through the L-type voltage-dependent calcium channel (LVDCC), a promiscuous divalent cation transporter. Iron overload in mice was associated with increased mortality, systolic and diastolic dysfunction, bradycardia, hypotension, increased myocardial fibrosis, and elevated oxidative stress. Treatment with LVDCC blockers (amlodipine and verapamil) at therapeutic levels inhibited the LVDCC current in cardiomyocytes, attenuated myocardial iron accumulation and oxidative stress, improved survival, prevented hypotension, and preserved heart structure and function. Consistent with the role of these channels in myocardial iron uptake, iron-overloaded transgenic mice with cardiac-specific overexpression of Cacna1c had 2-fold higher myocardial iron and oxidative stress levels, as well as greater impairment in cardiac function, compared with littermate controls. LVDCC blockade was again protective. <a href="#25" class="mim-tip-reference" title="Oudit, G. Y., Sun, H., Trivieri, M. G., Koch, S. E., Dawood, F., Ackerley, C., Yazdanpanah, M., Wilson, G. J., Schwartz, A., Liu, P. P., Backx, P. H. <strong>L-type Ca(2+) channels provide a major pathway for iron entry into cardiomyocytes in iron-overload cardiomyopathy.</strong> Nature Med. 9: 1187-1194, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12937413/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12937413</a>] [<a href="https://doi.org/10.1038/nm920" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12937413">Oudit et al. (2003)</a> concluded that cardiac L-type voltage-dependent calcium channels are key transporters of iron into cardiomyocytes under iron-overload conditions. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12937413" 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="Schulla, V., Renstrom, E., Feil, R., Feil, S., Franklin, I., Gjinovci, A., Jing, X. J., Laux, D., Lundquist, I., Magnuson, M. A., Obermuller, S., Olofsson, C. S., Salehi, A., Wendt, A., Klugbauer, N., Wollheim, C. B., Rorsman, P., Hofmann, F. <strong>Impaired insulin secretion and glucose tolerance in beta cell-selective Ca(v)1.2 Ca(2+) channel null mice.</strong> EMBO J. 22: 3844-3854, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12881419/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12881419</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12881419[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/emboj/cdg389" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12881419">Schulla et al. (2003)</a> noted that Cacna1c-knockout mice die in utero. They found that pancreatic beta cell-specific knockout of Cacna1c in mice decreased whole-cell Ca(2+) current by approximately 45% and caused almost complete loss of first-phase insulin secretion, resulting in systemic glucose intolerance. Loss of insulin secretion was also associated with the disappearance of a rapid component of exocytosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12881419" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using RT-PCR, <a href="#37" class="mim-tip-reference" title="Smedler, E., Louhivuori, L., Romanov, R. A., Masini, D., Dehnisch Ellstrom, I., Wang, C., Caramia, M., West, Z., Zhang, S., Rebellato, P., Malmersjo, S., Brusini, I., Kanatani, S., Fisone, G., Harkany, T., Uhlen, P. <strong>Disrupted Cacna1c gene expression perturbs spontaneous Ca(2+) activity causing abnormal brain development and increased anxiety.</strong> Proc. Nat. Acad. Sci. 119: e2108768119, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35135875/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35135875</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=35135875[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.2108768119" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="35135875">Smedler et al. (2022)</a> found that Cacna1c was upregulated on day 8 of mouse embryonic stem cell differentiation. Deletion of Cacna1c specifically in neurons of developing forebrain in mice disrupted spontaneous calcium activity. Portions of brains of mutant mice were statistically smaller than controls, and these mice displayed anxiety in behavioral tests, mimicking certain human psychiatric phenotypes. <a href="#37" class="mim-tip-reference" title="Smedler, E., Louhivuori, L., Romanov, R. A., Masini, D., Dehnisch Ellstrom, I., Wang, C., Caramia, M., West, Z., Zhang, S., Rebellato, P., Malmersjo, S., Brusini, I., Kanatani, S., Fisone, G., Harkany, T., Uhlen, P. <strong>Disrupted Cacna1c gene expression perturbs spontaneous Ca(2+) activity causing abnormal brain development and increased anxiety.</strong> Proc. Nat. Acad. Sci. 119: e2108768119, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35135875/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35135875</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=35135875[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.2108768119" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="35135875">Smedler et al. (2022)</a> proposed that Cacna1c acts as a molecular switch and that its disruption during embryogenesis perturbs Ca(2+) handling and neural development. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=35135875" 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>20 Selected Examples</a>):</strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=114205[MIM]" class="btn btn-default mim-tip-hint" role="button" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs79891110 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs79891110;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=rs79891110" 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=rs79891110" 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=RCV000019199 OR RCV000058285 OR RCV000170771 OR RCV000199739 OR RCV002354166 OR RCV003224103 OR RCV003332999 OR RCV003985262" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000019199, RCV000058285, RCV000170771, RCV000199739, RCV002354166, RCV003224103, RCV003332999, RCV003985262" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000019199...</a>
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<p>In 13 patients with Timothy syndrome (TS; <a href="/entry/601005">601005</a>), <a href="#42" class="mim-tip-reference" title="Splawski, I., Timothy, K. W., Sharpe, L. M., Decher, N., Kumar, P., Bloise, R., Napolitano, C., Schwartz, P. J., Joseph, R. M., Condouris, K., Tager-Flusberg, H., Priori, S. G., Sanguinetti, M. C., Keating, M. T. <strong>Ca(V)1.2 calcium channel dysfunction causes a multisystem disorder including arrhythmia and autism.</strong> Cell 119: 19-31, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15454078/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15454078</a>] [<a href="https://doi.org/10.1016/j.cell.2004.09.011" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15454078">Splawski et al. (2004)</a> analyzed the alternatively spliced exon 8A of the CACNA1C gene and identified heterozygosity for a de novo c.1216G-A transition, resulting in a gly406-to-arg (G406R) substitution at a highly conserved residue at the C-terminal end of the sixth transmembrane segment of domain I. Functional analysis revealed that the G406R mutation produced maintained inward Ca(2+) currents by causing nearly complete loss of voltage-dependent channel inactivation. The G406R mutation was not identified in 180 ethnically matched control samples. In 1 family with 2 affected children, the clinically unaffected mother was mosaic for the G406R mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15454078" 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 girl who died at age 6 years with severe Timothy syndrome (see <a href="/entry/601005">601005</a>) without syndactyly, <a href="#41" class="mim-tip-reference" title="Splawski, I., Timothy, K. W., Decher, N., Kumar, P., Sachse, F. B., Beggs, A. H., Sanguinetti, M. C., Keating, M. T. <strong>Severe arrhythmia disorder caused by cardiac L-type calcium channel mutations.</strong> Proc. Nat. Acad. Sci. 102: 8089-8096, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15863612/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15863612</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15863612[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.0502506102" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15863612">Splawski et al. (2005)</a> identified a G406R mutation in exon 8 of the CACNA1C gene, which is analogous to that previously found in exon 8A (<a href="#42" class="mim-tip-reference" title="Splawski, I., Timothy, K. W., Sharpe, L. M., Decher, N., Kumar, P., Bloise, R., Napolitano, C., Schwartz, P. J., Joseph, R. M., Condouris, K., Tager-Flusberg, H., Priori, S. G., Sanguinetti, M. C., Keating, M. T. <strong>Ca(V)1.2 calcium channel dysfunction causes a multisystem disorder including arrhythmia and autism.</strong> Cell 119: 19-31, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15454078/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15454078</a>] [<a href="https://doi.org/10.1016/j.cell.2004.09.011" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15454078">Splawski et al., 2004</a>). The exon 8 splice variant was found to be highly expressed in heart and brain (80% of CACNA1C mRNA), and this patient had a longer average QT interval and more severe arrhythmias than patients with the analogous mutation in exon 8A. She was born by cesarean section at 38 weeks' gestation due to severe bradycardia, and at birth had 2:1 atrioventricular block with a QTc of 730 ms. Despite receiving an implantable pacemaker in the neonatal period, she had multiple episodes of severe arrhythmias requiring cardioversion or resuscitation in infancy. Cervical sympathetic ganglionectomy and ventricular pacemaker placement at 4 months of age were unsuccessful in reducing arrhythmias. She also experienced seizures, static encephalopathy, and severe developmental delay. She died at age 6 years due to ventricular fibrillation. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15454078+15863612" 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 severely affected infant with Timothy syndrome, <a href="#13" class="mim-tip-reference" title="Etheridge, S. P., Bowles, N. E., Arrington, C. B., Pilcher, T., Rope, A., Wilde, A. A. M., Alders, M., Saarel, E. V., Tavernier, R., Timothy, K. W., Tristani-Firouzi, M. <strong>Somatic mosaicism contributes to phenotypic variation in Timothy syndrome.</strong> Am. J. Med. Genet. 155A: 2578-2583, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21910241/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21910241</a>] [<a href="https://doi.org/10.1002/ajmg.a.34223" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21910241">Etheridge et al. (2011)</a> identified heterozygosity for the G406R mutation in exon 8 of the CACNA1C gene. The proband's mildly affected father, who had cutaneous syndactyly of the feet and a prolonged QTc of 480 ms, but who had never experienced syncope or seizure, was also heterozygous for G406R; however, he was found to be mosaic for the mutation, showing only a minor peak for the mutant allele. An unrelated, moderately affected 14-year-old girl, who was not symptomatic until adolescence, was also mosaic for G406R, with a minor peak for the mutant allele. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21910241" 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>Variant Function</em></strong></p><p>
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By measuring whole-cell currents in transfected HEK293 cells, <a href="#3" class="mim-tip-reference" title="Barrett, C. F., Tsien, R. W. <strong>The Timothy syndrome mutation differentially affects voltage- and calcium-dependent inactivation of Ca(V)1.2 L-type calcium channels.</strong> Proc. Nat. Acad. Sci. 105: 2157-2162, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18250309/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18250309</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18250309[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.0710501105" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18250309">Barrett and Tsien (2008)</a> demonstrated that the G406R mutation powerfully and selectively slows voltage-dependent inactivation (VDI), while sparing or possibly speeding the kinetics of Ca(2+)-dependent inactivation (CDI). Dissociation of VDI and CDI was further substantiated by measurements of Ca(2+) channel gating currents. In addition, CDI did not proceed to completeness but leveled off at approximately 50%, consistent with a change in gating modes and not an absorbing inactivation process. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18250309" 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 explore the effect of the Timothy syndrome mutation G406R in the CaV1.2 channel on the electrical activity and contraction of human cardiomyocytes, <a href="#50" class="mim-tip-reference" title="Yazawa, M., Hsueh, B., Jia, X., Pasca, A. M., Bernstein, J. A., Hallmayer, J., Dolmetsch, R. E. <strong>Using induced pluripotent stem cells to investigate cardiac phenotypes in Timothy syndrome.</strong> Nature 471: 230-234, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21307850/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21307850</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21307850[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/nature09855" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21307850">Yazawa et al. (2011)</a> reprogrammed human skin cells from Timothy syndrome patients to generate induced pluripotent stem cells, and differentiated those cells into cardiomyocytes. Electrophysiologic recording and calcium imaging studies of these cells revealed irregular contraction, excess calcium influx, prolonged action potentials, irregular electrical activity, and abnormal calcium transients in ventricular-like cells. <a href="#50" class="mim-tip-reference" title="Yazawa, M., Hsueh, B., Jia, X., Pasca, A. M., Bernstein, J. A., Hallmayer, J., Dolmetsch, R. E. <strong>Using induced pluripotent stem cells to investigate cardiac phenotypes in Timothy syndrome.</strong> Nature 471: 230-234, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21307850/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21307850</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21307850[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/nature09855" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21307850">Yazawa et al. (2011)</a> found that roscovitine, a compound that increases the voltage-dependent inactivation of CaV1.2, restored the electrical and calcium signaling properties of cardiomyocytes from Timothy syndrome patients. <a href="#50" class="mim-tip-reference" title="Yazawa, M., Hsueh, B., Jia, X., Pasca, A. M., Bernstein, J. A., Hallmayer, J., Dolmetsch, R. E. <strong>Using induced pluripotent stem cells to investigate cardiac phenotypes in Timothy syndrome.</strong> Nature 471: 230-234, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21307850/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21307850</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21307850[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/nature09855" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21307850">Yazawa et al. (2011)</a> concluded that their study provided new opportunities for studying the molecular and cellular mechanisms of cardiac arrhythmias in humans and provided a robust assay for developing drugs to treat these diseases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21307850" 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">rs80315385 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs80315385;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=rs80315385" 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=rs80315385" 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 21-year-old man with severe Timothy syndrome (<a href="/entry/601005">601005</a>) without syndactyly, <a href="#41" class="mim-tip-reference" title="Splawski, I., Timothy, K. W., Decher, N., Kumar, P., Sachse, F. B., Beggs, A. H., Sanguinetti, M. C., Keating, M. T. <strong>Severe arrhythmia disorder caused by cardiac L-type calcium channel mutations.</strong> Proc. Nat. Acad. Sci. 102: 8089-8096, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15863612/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15863612</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15863612[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.0502506102" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15863612">Splawski et al. (2005)</a> identified a 1204G-A transition in exon 8 of the CACNA1C gene, resulting in a gly402-to-ser (G402S) substitution. The exon 8 splice variant was found to be highly expressed in heart and brain (80% of CACNA1C mRNA), and this patient had a longer average QT interval and more severe arrhythmias than patients with a mutation in exon 8A (see <a href="#0001">114205.0001</a>). The patient was apparently well until age 4 years, when he experienced cardiac arrest while at play and was diagnosed with long QT syndrome. He continued to have episodes of cardiac arrest, ultimately receiving an automatic defibrillator. At age 21, he was still experiencing weekly nocturnal cardiac arrhythmias that were associated with night terrors. Comparison of mutant peaks in DNA from oral mucosa and blood revealed that the patient was a mosaic; the authors noted that this might account for his relatively milder phenotype compared to the other patient with a mutation in exon 8 (see <a href="#0001">114205.0001</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15863612" 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 13-year-old Finnish girl with Timothy syndrome, <a href="#17" class="mim-tip-reference" title="Hiippala, A., Tallila, J., Myllykangas, S., Koskenvuo, J. W., Alastalo, T.-P. <strong>Expanding the phenotype of Timothy syndrome type 2: an adolescent with ventricular fibrillation but normal development.</strong> Am. J. Med. Genet. 167A: 629-634, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25691416/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25691416</a>] [<a href="https://doi.org/10.1002/ajmg.a.36924" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25691416">Hiippala et al. (2015)</a> identified heterozygosity for the G402S mutation in the CACNA1C gene. Her unaffected parents did not carry the mutation. Calculating the ratio of mutated and normal alleles from the next-generation sequencing (NGS) reads revealed that the proband was mosaic for the mutation, with only 37% of the reads representing the mutated allele and 61% showing the normal allele. Sanger sequencing of blood- and saliva-derived DNA confirmed the mutation; in both samples, the mutation peak was slightly weaker than the normal genotype, consistent with the allele distribution detected by NGS. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25691416" 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> rs121912775 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121912775;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/rs121912775?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=rs121912775" 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=rs121912775" 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=RCV000019201 OR RCV000058286 OR RCV000170775 OR RCV000334098 OR RCV000586094 OR RCV000618330 OR RCV001085545 OR RCV001256682 OR RCV003944830" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000019201, RCV000058286, RCV000170775, RCV000334098, RCV000586094, RCV000618330, RCV001085545, RCV001256682, RCV003944830" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000019201...</a>
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<p>In a 41-year-old male of Turkish descent with Brugada syndrome and a shortened QTc interval (BRGDA3; <a href="/entry/611875">611875</a>), <a href="#2" class="mim-tip-reference" title="Antzelevitch, C., Pollevick, G. D., Cordeiro, J. M., Casis, O., Sanguinetti, M. C., Aizawa, Y., Guerchicoff, A., Pfeiffer, R., Oliva, A., Wollnik, B., Gelber, P., Bonaros, E. P., Jr., and 11 others. <strong>Loss-of-function mutations in the cardiac calcium channel underlie a new clinical entity characterized by ST-segment elevation, short QT intervals, and sudden cardiac death.</strong> Circulation 115: 442-449, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17224476/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17224476</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17224476[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/10.1161/CIRCULATIONAHA.106.668392" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17224476">Antzelevitch et al. (2007)</a> identified a heterozygous 1468G-A transition in exon 10 of the CACNA1C gene, predicted to result in a gly490-to-arg (G490R) substitution in the cytoplasmic linker between domains I and II within a highly conserved region of the protein. The proband also carried 2 polymorphisms in CACNA1C, P1820L and V1821M, which were found in 31 and 27 of 114 healthy controls, respectively. The G490R mutation was also found in his 2 daughters, who had QTc intervals of 360 and 370 ms, respectively; the daughter with the longer QTc interval also carried a known K897T polymorphism in the KCNH2 gene. Patch-clamp experiments in Chinese hamster ovary (CHO) cells demonstrated a marked reduction in current amplitude of mutant channels compared to wildtype, although voltage at peak current was unchanged; confocal microscopy revealed normal trafficking of channels containing G490R CaV1.2 subunits. The G490R mutation was not found in 640 ethnically matched control alleles. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17224476" 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">rs121912776 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121912776;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=rs121912776" 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=rs121912776" 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=RCV000019202 OR RCV000058283" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000019202, RCV000058283" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000019202...</a>
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<p>In a 44-year-old white male of European descent with Brugada syndrome and a shortened QTc interval (BRGDA3; <a href="/entry/611875">611875</a>), <a href="#2" class="mim-tip-reference" title="Antzelevitch, C., Pollevick, G. D., Cordeiro, J. M., Casis, O., Sanguinetti, M. C., Aizawa, Y., Guerchicoff, A., Pfeiffer, R., Oliva, A., Wollnik, B., Gelber, P., Bonaros, E. P., Jr., and 11 others. <strong>Loss-of-function mutations in the cardiac calcium channel underlie a new clinical entity characterized by ST-segment elevation, short QT intervals, and sudden cardiac death.</strong> Circulation 115: 442-449, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17224476/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17224476</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17224476[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/10.1161/CIRCULATIONAHA.106.668392" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17224476">Antzelevitch et al. (2007)</a> identified a heterozygous 116C-T transition in exon 2 of the CACNA1C gene, predicted to result in an ala39-to-val (A39V) substitution near the N terminus within a highly conserved region of the protein. The mutation was not found in 404 ethnically matched control alleles. Patch-clamp experiments in CHO cells demonstrated a marked reduction in current amplitude of mutant channels compared to wildtype, although voltage at peak current was unchanged; confocal microscopy revealed a defect in trafficking of A39V CaV1.2 channels. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17224476" 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="0005" class="mim-anchor"></a>
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<strong>.0005 LONG QT SYNDROME 8</strong>
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CACNA1C, PRO857ARG
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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> rs750835733 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs750835733;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/rs750835733?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=rs750835733" 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=rs750835733" 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=RCV000782177 OR RCV001856203" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000782177, RCV001856203" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000782177...</a>
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<p>By trio-based whole-exome sequencing in a large multigeneration family segregating long QT syndrome (LQT8; <a href="/entry/618447">618447</a>) without mutation in known causative genes, <a href="#6" class="mim-tip-reference" title="Boczek, N. J., Best, J. M., Tester, D. J., Giudicessi, J. R., Middha, S., Evans, J. M., Kamp, T. J., Ackerman, M. J. <strong>Exome sequencing and systems biology converge to identify novel mutations in the L-type calcium channel, CACNA1C, linked to autosomal dominant long QT syndrome.</strong> Circ. Cardiovasc. Genet. 6: 279-289, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23677916/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23677916</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23677916[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/10.1161/CIRCGENETICS.113.000138" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23677916">Boczek et al. (2013)</a> identified heterozygosity for a c.2570C-G transition in the CACNA1C gene, resulting in a pro857-to-arg (P857R) substitution in the PEST domain. The mutation segregated with the disease in the family and was not found in the 1000 Genomes Project or NHLBI ESP databases or in 200 Danish Beijing Genomics Institute exomes or an additional 680 ethnically matched controls. Functional studies of the variant revealed a 113% increase in peak current amplitude and an increase in surface expression of the Cav1.2 channel compared to wildtype, consistent with a gain of function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23677916" 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>.0006 LONG QT SYNDROME 8</strong>
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CACNA1C, PRO857LEU
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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> rs750835733 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs750835733;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/rs750835733?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=rs750835733" 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=rs750835733" 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=RCV000208178 OR RCV000782178" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000208178, RCV000782178" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000208178...</a>
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<p>By sequencing the CACNA1C gene in an asymptomatic 15-year-old boy who was diagnosed with long QT syndrome (LQT8; <a href="/entry/618447">618447</a>) following the unexplained death of his 12-year-old sister during sleep, <a href="#6" class="mim-tip-reference" title="Boczek, N. J., Best, J. M., Tester, D. J., Giudicessi, J. R., Middha, S., Evans, J. M., Kamp, T. J., Ackerman, M. J. <strong>Exome sequencing and systems biology converge to identify novel mutations in the L-type calcium channel, CACNA1C, linked to autosomal dominant long QT syndrome.</strong> Circ. Cardiovasc. Genet. 6: 279-289, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23677916/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23677916</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23677916[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/10.1161/CIRCGENETICS.113.000138" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23677916">Boczek et al. (2013)</a> identified a c.2570C-T transition, resulting in a pro857-to-leu (P857L) substitution in the PEST domain. No mutations in previously identified causative genes had been found, and the mutation segregated with the phenotype in available family members tested, including the unaffected father and affected mother and maternal grandmother. The variant was not found in the 1000 Genomes Project or NHLBI Exome Sequencing project databases or in 680 controls. No functional studies were reported. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23677916" 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="0007" class="mim-anchor"></a>
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<strong>.0007 LONG QT SYNDROME 8</strong>
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CACNA1C, LYS834GLU
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1555836187 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1555836187;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=rs1555836187" 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=rs1555836187" 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=RCV000782179 OR RCV005092337" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000782179, RCV005092337" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000782179...</a>
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<p>By sequencing the CACNA1C gene in a 15-year-old girl with long QT syndrome-8 (LQT8; <a href="/entry/618447">618447</a>), who had a personal history of syncope, QTc of 475 ms, and a negative family history, <a href="#6" class="mim-tip-reference" title="Boczek, N. J., Best, J. M., Tester, D. J., Giudicessi, J. R., Middha, S., Evans, J. M., Kamp, T. J., Ackerman, M. J. <strong>Exome sequencing and systems biology converge to identify novel mutations in the L-type calcium channel, CACNA1C, linked to autosomal dominant long QT syndrome.</strong> Circ. Cardiovasc. Genet. 6: 279-289, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23677916/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23677916</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23677916[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/10.1161/CIRCGENETICS.113.000138" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23677916">Boczek et al. (2013)</a> identified a c.2500A-G transition, resulting in a lys834-to-glu (K834E) substitution in the PEST domain. The variant was not found in the 1000 Genomes Project or NHLBI Exome Sequencing project databases or in 680 controls. No functional studies were reported. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23677916" 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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CACNA1C, ARG858HIS (<a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs786205753;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs786205753</a>)
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs786205753 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs786205753;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=rs786205753" 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=rs786205753" 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=RCV000550877 OR RCV000782180 OR RCV001509415 OR RCV002453577" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000550877, RCV000782180, RCV001509415, RCV002453577" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000550877...</a>
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<p>In affected members of 3 Japanese families (families 4, 5 and 6) with long QT syndrome (LQT8; <a href="/entry/618447">618447</a>), <a href="#14" class="mim-tip-reference" title="Fukuyama, M., Wang, Q., Kato, K., Ohno, S., Ding, W.-G., Toyoda, F., Itoh, H., Kimura, H., Makiyama, T., Ito, M., Matsuura, H., Horie, M. <strong>Long QT syndrome type 8: novel CACNA2C mutations causing QT prolongation and variant phenotypes.</strong> Europace 16: 1828-1837, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24728418/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24728418</a>] [<a href="https://doi.org/10.1093/europace/euu063" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24728418">Fukuyama et al. (2014)</a> identified heterozygosity for a c.2573G-A transition in the CACNA1C gene, resulting in an arg858-to-his (R858H) substitution. Functional studies showed that the peak calcium currents in R858H mutant channels were significantly larger than those of wildtype. Activation of the R858H channel showed an approximately 2 mV negative shift compared with wildtype, whereas inactivation of the mutant channel showed an approximately 2 mV positive shift, consistent with a gain-of-function effect. The variant was not found in the NHLBI Exome Variant Server database or in 500 reference alleles from 250 Japanese controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24728418" 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="Gardner, R. J. M., Crozier, I. G., Binfield, A. L., Love, D. R., Lehnert, K., Gibson, K., Lintott, C. J., Snell, R. G., Jacobsen, J. C., Jones, P. P., Waddell-Smith, K. E., Kennedy, M. A., Skinner, J. R. <strong>Penetrance and expressivity of the R858H CACNA1C variant in a five-generation pedigree segregating an arrhythmogenic channelopathy.</strong> Molec. Genet. Genomic Med. 7: e00476, 2019. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30345660/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30345660</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30345660[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/mgg3.476" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30345660">Gardner et al. (2019)</a> identified heterozygosity for a c.2573G-A transition (c.2573G-A, NM_000719.6) in the CACNA1C gene, resulting in the R858H substitution, in affected members of a 5-generation European family segregating long QT. The R858H variant was not found in the ExAC database. No functional studies were performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30345660" 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">rs1568469857 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1568469857;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=rs1568469857" 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=rs1568469857" 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 12-year-old girl and her mother with long QT syndrome (LQT8; <a href="/entry/618447">618447</a>), <a href="#14" class="mim-tip-reference" title="Fukuyama, M., Wang, Q., Kato, K., Ohno, S., Ding, W.-G., Toyoda, F., Itoh, H., Kimura, H., Makiyama, T., Ito, M., Matsuura, H., Horie, M. <strong>Long QT syndrome type 8: novel CACNA2C mutations causing QT prolongation and variant phenotypes.</strong> Europace 16: 1828-1837, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24728418/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24728418</a>] [<a href="https://doi.org/10.1093/europace/euu063" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24728418">Fukuyama et al. (2014)</a> identified heterozygosity for a c.1745C-A transition in the CACNA1C gene, resulting in an ala582-to-asp (A582D) substitution. The A582D mutant channel displayed significantly slower inactivation compared with wildtype. Inactivation of the mutant A582D channel showed an approximately 2 mV positive shift compared to wildtype, indicating a gain-of-function effect. The variant was not found in the NHLBI Exome Variant Server database or in 500 reference alleles from 250 Japanese controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24728418" 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">rs1569139160 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1569139160;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=rs1569139160" 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=rs1569139160" 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=RCV000782182" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000782182" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000782182</a>
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<p>In a 14-year-old girl with long QT syndrome (LQT8; <a href="/entry/618447">618447</a>), <a href="#49" class="mim-tip-reference" title="Wemhoner, K., Friedrich, C., Stallmeyer, B., Coffey, A. J., Grace, A., Zumhagen, S., Seebohm, G., Ortiz-Bonnin, B., Rinne, S., Sachse, F. B., Shulze-Bahr, E., Decher, N. <strong>Gain-of-function mutations in the calcium channel CACNA1C (Cav1.2) cause non-syndromic long-QT but not Timothy syndrome.</strong> J. Molec. Cell. Cardiol. 80: 186-195, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25633834/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25633834</a>] [<a href="https://doi.org/10.1016/j.yjmcc.2015.01.002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25633834">Wemhoner et al. (2015)</a> identified heterozygosity for a c.4425C-G transition in the CACNA1C gene, resulting in an ile1475-to-met (I1475M) substitution. The I1475M mutation showed a leftward shift in the peak current amplitude compared to wildtype, indicating a gain-of-function effect. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25633834" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0011 NEURODEVELOPMENTAL DISORDER WITH HYPOTONIA, LANGUAGE DELAY, AND SKELETAL DEFECTS WITH SEIZURES</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">rs1555968941 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1555968941;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=rs1555968941" 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=rs1555968941" 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=RCV000523935 OR RCV002283488 OR RCV003985375" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000523935, RCV002283488, RCV003985375" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000523935...</a>
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<p>In an 18-month-old girl, born of unrelated parents, with neurodevelopmental disorder with hypotonia, language delay, and skeletal defects with seizures (NEDHLSS; <a href="/entry/620029">620029</a>), <a href="#9" class="mim-tip-reference" title="Bozarth, X., Dines, J. N., Cong, Q., Mirzaa, G. M., Foss, K., Lawrence Merritt, J., Thies, J., Mefford, H. C., Novotny, E. <strong>Expanding clinical phenotype in CACNA1C related disorders: From neonatal onset severe epileptic encephalopathy to late-onset epilepsy.</strong> Am. J. Med. Genet. 176A: 2733-2739, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30513141/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30513141</a>] [<a href="https://doi.org/10.1002/ajmg.a.40657" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30513141">Bozarth et al. (2018)</a> identified a de novo heterozygous c.4087G-A transition (c.4087G-A, NM_000719.6) in the CACNA1C gene, resulting in a val1363-to-met (V1363M) substitution at a highly conserved residue in the fifth transmembrane helix in domain IV. The mutation, which was found by trio-based exome sequencing, was not present in public databases, including gnomAD. Functional studies of the variant and studies of patient cells were not performed. The patient had poor overall growth, hypotonia, severe global developmental delay with inability to track visually, mild distal skeletal anomalies, and early-onset refractory seizures. She did not have cardiac involvement. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30513141" 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 NEURODEVELOPMENTAL DISORDER WITH HYPOTONIA, LANGUAGE DELAY, AND SKELETAL DEFECTS WITH SEIZURES</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">rs1057518994 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1057518994;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=rs1057518994" 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=rs1057518994" 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=RCV000415023 OR RCV002283478" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000415023, RCV002283478" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000415023...</a>
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<p>In a 24-year-old man (P8) with neurodevelopmental disorder with hypotonia, language delay, and skeletal defects with seizures (NEDHLSS; <a href="/entry/620029">620029</a>), <a href="#32" class="mim-tip-reference" title="Rodan, L. H., Spillmann, R. C., Kurata, H. T., Lamothe, S. M., Maghera, J., Jamra, R. A., Alkelai, A., Antonarakis, S. E., Atallah, I., Bar-Yosef, O., Bilan, F., Bjorgo, K., and 46 others. <strong>Phenotypic expansion of CACNA1C-associated disorders to include isolated neurological manifestations.</strong> Genet. Med. 23: 1922-1932, 2021. Note: Erratum: Genet. Med. 23: 2016 only, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34163037/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34163037</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=34163037[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/s41436-021-01232-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34163037">Rodan et al. (2021)</a> a de novo heterozygous c.1841T-C transition (c.1841T-C, NM_000719) in the CACNA1C gene, resulting in a leu614-to-pro (L614P) substitution. The mutation, which was found by exome sequencing, was not present in the gnomAD database. Electrophysiologic patch-clamp voltage studies in transfected HEK293 cells showed that the CACNA1C L614P tended to cause a current increase, suggesting a gain of function, but the differences were not statistically significant. The patient had no cardiac involvement. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34163037" 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 NEURODEVELOPMENTAL DISORDER WITH HYPOTONIA, LANGUAGE DELAY, AND SKELETAL DEFECTS WITH SEIZURES</strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV002284054" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV002284054" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV002284054</a>
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<p>In a 15-year-old girl (P9) with neurodevelopmental disorder with hypotonia, language delay, and skeletal defects with seizures (NEDHLSS; <a href="/entry/620029">620029</a>), <a href="#32" class="mim-tip-reference" title="Rodan, L. H., Spillmann, R. C., Kurata, H. T., Lamothe, S. M., Maghera, J., Jamra, R. A., Alkelai, A., Antonarakis, S. E., Atallah, I., Bar-Yosef, O., Bilan, F., Bjorgo, K., and 46 others. <strong>Phenotypic expansion of CACNA1C-associated disorders to include isolated neurological manifestations.</strong> Genet. Med. 23: 1922-1932, 2021. Note: Erratum: Genet. Med. 23: 2016 only, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34163037/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34163037</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=34163037[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/s41436-021-01232-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34163037">Rodan et al. (2021)</a> identified a de novo heterozygous c.1969C-T transition (c.1969C-T, NM_000719) in the CACNA1C gene, resulting in a leu657-to-phe (L657F) substitution. The mutation, which was found by exome sequencing, was not present in the gnomAD database. Compared to wildtype, the L657F variant was associated with increased CACNA1C protein levels. Electrophysiologic patch-clamp voltage studies in transfected HEK293 cells showed that the L657F mutation resulted in a dramatic increase in calcium current compared to controls, suggesting a gain-of-function effect. The patient had no cardiac involvement. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34163037" 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 NEURODEVELOPMENTAL DISORDER WITH HYPOTONIA, LANGUAGE DELAY, AND SKELETAL DEFECTS WITH SEIZURES</strong>
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CACNA1C, LEU1408VAL
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV002284055" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV002284055" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV002284055</a>
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<p>In a 6.8-year-old girl (P12) with neurodevelopmental disorder with hypotonia, language delay, and skeletal defects with seizures (NEDHLSS; <a href="/entry/620029">620029</a>), <a href="#32" class="mim-tip-reference" title="Rodan, L. H., Spillmann, R. C., Kurata, H. T., Lamothe, S. M., Maghera, J., Jamra, R. A., Alkelai, A., Antonarakis, S. E., Atallah, I., Bar-Yosef, O., Bilan, F., Bjorgo, K., and 46 others. <strong>Phenotypic expansion of CACNA1C-associated disorders to include isolated neurological manifestations.</strong> Genet. Med. 23: 1922-1932, 2021. Note: Erratum: Genet. Med. 23: 2016 only, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34163037/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34163037</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=34163037[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/s41436-021-01232-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34163037">Rodan et al. (2021)</a> identified a de novo heterozygous c.4222C-G transversion (c.4222C-G, NM_000719) in the CACNA1C gene, resulting in a leu1408-to-val (L1408V) substitution. The mutation, which was found by exome sequencing, was not present in the gnomAD database. Additional variants in other genes were also identified, including in CACNA1G (<a href="/entry/604065">604065</a>). Electrophysiologic patch-clamp voltage studies in transfected HEK293 cells showed that the CACNA1C L1408V mutation resulted in an overall reduction in current density compared to controls, with unaltered activation kinetics. The patient had possible cardiac ventricular conduction delay and trace cardiac valvular regurgitation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34163037" 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 TIMOTHY SYNDROME</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">rs797044881 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs797044881;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=rs797044881" 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=rs797044881" 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=RCV000190696 OR RCV001795308" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000190696, RCV001795308" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000190696...</a>
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<p>In a boy who died at age 3.75 years with QT prolongation and a Timothy syndrome phenotype (TS; <a href="/entry/601005">601005</a>), <a href="#7" class="mim-tip-reference" title="Boczek, N. J., Miller, E. M., Ye, D., Nesterenko, V. V., Tester, D. J., Antzelevitch, C., Czosek, R. J., Ackerman, M. J., Ware, S. M. <strong>Novel Timothy syndrome mutation leading to increase in CACNA1C window current.</strong> Heart Rhythm 12: 211-219, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25260352/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25260352</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25260352[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.hrthm.2014.09.051" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25260352">Boczek et al. (2015)</a> identified heterozygosity for a de novo c.3497T-C transition in exon 27 of the CACNA1C gene, resulting in an ile1166-to-thr (I1166T) substitution at a highly conserved residue within the third repeat. Sanger sequencing confirmed the mutation and its absence in his parents; the variant was also not present in the 1000 Genomes Project or NHLBI EVS databases. Whole-cell patch-clamp analysis of the heterologously expressed L-type calcium channel revealed that the I1166T mutation causes an overall loss of current density with a gain-of-function shift in activation, resulting in an increased window current. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25260352" 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>.0016 TIMOTHY SYNDROME</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">rs786205748 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs786205748;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=rs786205748" 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=rs786205748" 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=RCV000170780 OR RCV000232889 OR RCV002250585 OR RCV002287377 OR RCV002399602" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000170780, RCV000232889, RCV002250585, RCV002287377, RCV002399602" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000170780...</a>
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<p>In affected individuals from 2 families (pedigrees 1 and 2) with QT prolongation, hypertrophic cardiomyopathy, congenital heart defects, and/or sudden cardiac death (TS; <a href="/entry/601005">601005</a>), <a href="#8" class="mim-tip-reference" title="Boczek, N. J., Ye, D., Jin, F., Tester, D. J., Huseby, A., Bos, J. M., Johnson, A. J., Kanter, R., Ackerman, M. J. <strong>Identification and functional characterization of a novel CACNA1C-mediated cardiac disorder characterized by prolonged QT intervals with hypertrophic cardiomyopathy, congenital heart defects, and sudden cardiac death.</strong> Circ. Arrhythm. Electrophysiol. 8: 1122-1132, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26253506/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26253506</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26253506[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/10.1161/CIRCEP.115.002745" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26253506">Boczek et al. (2015)</a> identified heterozygosity for a c.1552C-T transition in exon 12 of the CACNA1C gene, resulting in an arg518-to-cys (R58C) substitution that segregated with disease. None of the affected individuals exhibited extracardiac manifestations of Timothy syndrome. Functional analysis demonstrated that the R518C variant results in a complex electrophysiologic phenotype including an overall approximately 60% loss of current density, increased window and late currents, and decelerating voltage-dependent inactivation resulting in constitutively active L-type calcium channels. In addition, confocal imaging showed a higher proportion of mutant channels in the center versus the periphery of the cell compared to wildtype channels, suggesting the possibility of a trafficking defect. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26253506" 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="0017" class="mim-anchor"></a>
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<strong>.0017 TIMOTHY SYNDROME</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> rs1057517711 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1057517711;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/rs1057517711?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=rs1057517711" 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=rs1057517711" 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=RCV000412828 OR RCV000584800 OR RCV000631664 OR RCV001808785 OR RCV002230228 OR RCV002288982 OR RCV002402099" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000412828, RCV000584800, RCV000631664, RCV001808785, RCV002230228, RCV002288982, RCV002402099" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000412828...</a>
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<p>In 2 sisters and a female cousin (pedigree 3) with QT prolongation, hypertrophic cardiomyopathy, congenital heart defects, and/or sudden cardiac death (TS; <a href="/entry/601005">601005</a>), <a href="#8" class="mim-tip-reference" title="Boczek, N. J., Ye, D., Jin, F., Tester, D. J., Huseby, A., Bos, J. M., Johnson, A. J., Kanter, R., Ackerman, M. J. <strong>Identification and functional characterization of a novel CACNA1C-mediated cardiac disorder characterized by prolonged QT intervals with hypertrophic cardiomyopathy, congenital heart defects, and sudden cardiac death.</strong> Circ. Arrhythm. Electrophysiol. 8: 1122-1132, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26253506/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26253506</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26253506[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/10.1161/CIRCEP.115.002745" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26253506">Boczek et al. (2015)</a> identified heterozygosity for a variant in exon 12 of the CACNA1C gene, resulting in an arg518-to-his (R518H) substitution. DNA was unavailable from their affected mothers and maternal grandfather. None of the affected individuals in this family exhibited extracardiac manifestations of Timothy syndrome. Functional analysis demonstrated that the R518H variant results in a complex electrophysiologic phenotype including an overall approximately 60% loss of current density as well as increased window and late currents. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26253506" 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>.0018 TIMOTHY SYNDROME</strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV002286523 OR RCV004697202" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV002286523, RCV004697202" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV002286523...</a>
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<p>In a 14-year-old Japanese boy with a prolonged QT interval, dysmorphic facial features, intellectual disability, seizures, and autism spectrum disorder (TS; <a href="/entry/601005">601005</a>), <a href="#26" class="mim-tip-reference" title="Ozawa, J., Ohno, S., Saito, H., Saitoh, A., Matsuura, H., Horie, M. <strong>A novel CACNA1C mutation identified in a patient with Timothy syndrome without syndactyly exerts both marked loss- and gain-of-function effects.</strong> HeartRhythm Case Rep. 4: 273-277, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30023270/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30023270</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30023270[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.hrcr.2018.03.003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30023270">Ozawa et al. (2018)</a> screened a gene panel and identified heterozygosity for a de novo ser643-to-phe (S643F) substitution in the CACNA1C gene, at a highly conserved residue within the S4-S5 linker of domain II. Sanger sequencing confirmed the mutation and its absence in his unaffected parents and sibs, and it was not present in the 1000 Genomes Project or NHLBI EVS databases. The patient experienced cardiac arrest at age 13 years, followed by recurrent episodes of torsades de pointes and ventricular fibrillation, and he underwent placement of a cardioverter-defibrillator device. Functional analysis in a heterologous expression system demonstrated an increase in late CaV1.2 currents as well as a marked reduction in peak currents with the S643F mutant compared to wildtype CACNA1C. Evaluation of inactivation gating showed an extraordinary decrease in voltage-dependent inactivation with the S643F channels, which exhibited inactivation levels of 38 to 42% at maximum and never reached a fully inactivated state. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30023270" 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>.0019 TIMOTHY SYNDROME</strong>
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CACNA1C, GLU1115LYS
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs199473391 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs199473391;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=rs199473391" 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=rs199473391" 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=RCV000058287 OR RCV000475353 OR RCV001795047 OR RCV002490650 OR RCV004786338" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000058287, RCV000475353, RCV001795047, RCV002490650, RCV004786338" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000058287...</a>
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<p>In a 14-year-old boy with QT prolongation, bradycardia, seizures, and autism spectrum disorder (TS; <a href="/entry/601005">601005</a>), <a href="#51" class="mim-tip-reference" title="Ye, D., Tester, D. J., Zhou, W., Papagiannis, J., Ackerman, M. J. <strong>A pore-localizing CACNA1C-E1115K missense mutation, identified in a patient with idiopathic QT prolongation, bradycardia, and autism spectrum disorder, converts the L-type calcium channel into a hybrid nonselective monovalent cation channel.</strong> Heart Rhythm 16: 270-278, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30172029/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30172029</a>] [<a href="https://doi.org/10.1016/j.hrthm.2018.08.030" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30172029">Ye et al. (2019)</a> analyzed a 13-gene long-QT syndrome panel and identified heterozygosity for a glu1115-to-lys (E1115K) substitution the CACNA1C gene, at a highly conserved residue within the DIII-S5/S6 pore region. The mutation was not found in his unaffected mother or half sibs, or in the gnomAD database; DNA was unavailable from his father. Functional analysis showed that the mutation eliminates intrinsic calcium channel activity and converts the L-type calcium channel into a nonselective monovalent cation channel, with marked increases in both peak and persistent inward sodium currents and outward potassium/cesium currents. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30172029" 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>.0020 VARIANT OF UNKNOWN SIGNIFICANCE</strong>
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CACNA1C, LEU566PRO
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV002287885" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV002287885" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV002287885</a>
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<p>This variant is classified as a variant of unknown significance because its contribution to hyperinsulinemic hypoglycemia (see <a href="/entry/256450">256450</a>) has not been confirmed.</p><p>In a 17-year-old girl with nonsyndromic congenital hyperinsulinemic hypoglycemia, <a href="#20" class="mim-tip-reference" title="Kummer, S., Rinne, S., Seemann, G., Bachmann, N., Timothy, K., Thornton, P. S., Pillekamp, F., Mayatepek, E., Bergmann, C., Meissner, T., Decher, N. <strong>Hyperinsulinemic hypoglycemia associated with a CaV1.2 variant with mixed gain- and loss-of-function effects.</strong> Int. J. Molec. Sci. 23: 8097, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35897673/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35897673</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=35897673[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/10.3390/ijms23158097" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="35897673">Kummer et al. (2022)</a> identified heterozygosity for a c.1679T-C transition (c.1679T-C, NM_000719.6) in exon 13 of the CACNA1C gene, resulting in a leu566-to-pro (L566P) substitution at a highly conserved residue within the S2-S3 linker of the second domain. The mutation was not found in the proband's unaffected mother or in the 1000 Genomes Project or gnomAD databases; DNA was unavailable from the deceased father. Sanger sequencing of DNA from blood and buccal swabs from the proband showed no indication of low-grade mosaicism restricted to particular tissues. The proband also carried 2 heterozygous variants of unknown significance in genes associated with disturbed glucose regulation, ALMS1 (<a href="/entry/606844">606844</a>) and ETFB (<a href="/entry/130410">130410</a>). The proband had a generalized seizure after overnight fasting at 8 months of age; during the subsequent hospitalization recurrent episodes of hypoglycemia were documented, and metabolic evaluation showed a typical profile for hyperinsulinemic hypoglycemia. Echocardiography was normal and remained so. Electrocardiography showed QTc intervals in the normal or upper normal range, with QTc prolongation on only 2 occasions, once during treatment with nifedipine; there were no signs of cardiac arrhythmias. Electrophysiologic characterization of CACNA1C L566P mutant channels by voltage-clamp recordings in Xenopus oocytes revealed loss of function due to reduced peak current amplitudes, as well as diverse gain-of-function effects due to impaired voltage-dependent inactivation, including a slowing of the rate, an altered voltage dependence, and a reduced steady-state of inactivation. Technical difficulties prevented the establishment of a beta-cell model for validating the consequences of the mutant channels. The authors reviewed the medical records of 5 patients who had Timothy syndrome (<a href="/entry/601005">601005</a>) and reported hypoglycemic episodes, but noted that those episodes appeared to be biochemically more diverse than congenital hyperinsulinism. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=35897673" 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="Aerssens1994" class="mim-anchor"></a>
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Aerssens, J., Chaffanet, M., Baens, M., Matthijs, G., Van Den Berghe, H., Cassiman, J.-J., Marynen, P.
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<strong>Regional assignment of seven loci to 12p13.2-pter by PCR analysis of somatic cell hybrids containing the der(12) or the der(X) chromosome from a mesothelioma showing t(X;12)(q22;p13).</strong>
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Genomics 20: 119-121, 1994.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8020938/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8020938</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8020938" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1006/geno.1994.1136" target="_blank">Full Text</a>]
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Antzelevitch, C., Pollevick, G. D., Cordeiro, J. M., Casis, O., Sanguinetti, M. C., Aizawa, Y., Guerchicoff, A., Pfeiffer, R., Oliva, A., Wollnik, B., Gelber, P., Bonaros, E. P., Jr., and 11 others.
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<strong>Loss-of-function mutations in the cardiac calcium channel underlie a new clinical entity characterized by ST-segment elevation, short QT intervals, and sudden cardiac death.</strong>
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Circulation 115: 442-449, 2007.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17224476/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17224476</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17224476[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=17224476" 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/10.1161/CIRCULATIONAHA.106.668392" target="_blank">Full Text</a>]
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Barrett, C. F., Tsien, R. W.
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<strong>The Timothy syndrome mutation differentially affects voltage- and calcium-dependent inactivation of Ca(V)1.2 L-type calcium channels.</strong>
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Proc. Nat. Acad. Sci. 105: 2157-2162, 2008.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18250309/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18250309</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18250309[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=18250309" 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.0710501105" target="_blank">Full Text</a>]
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Blancard, M., Debbiche, A., Kato, K., Cardin, C., Sabrina, G., Gandjbakhch, E., Probst, V., Haissaguerre, M., Extramiana, F., Hocini, M., Olivier, G., Leenhardt, A., Guicheney, P., Rougier, J.-S.
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<strong>An African loss-of-function CACNA1C variant p.T1787M associated with a risk of ventricular fibrillation.</strong>
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Sci. Rep. 8: 14619, 2018.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30279520/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30279520</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30279520[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=30279520" 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/s41598-018-32867-4" target="_blank">Full Text</a>]
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<a id="Blumenstein2002" class="mim-anchor"></a>
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|
<div class="">
|
|
<p class="mim-text-font">
|
|
Blumenstein, Y., Kanevsky, N., Sahar, G., Barzilai, R., Ivanina, T., Dascal, N.
|
|
<strong>A novel long N-terminal isoform of human L-type Ca(2+) channel is up-regulated by protein kinase C.</strong>
|
|
J. Biol. Chem. 277: 3419-3423, 2002.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11741969/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11741969</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11741969" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1074/jbc.C100642200" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="6" class="mim-anchor"></a>
|
|
<a id="Boczek2013" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Boczek, N. J., Best, J. M., Tester, D. J., Giudicessi, J. R., Middha, S., Evans, J. M., Kamp, T. J., Ackerman, M. J.
|
|
<strong>Exome sequencing and systems biology converge to identify novel mutations in the L-type calcium channel, CACNA1C, linked to autosomal dominant long QT syndrome.</strong>
|
|
Circ. Cardiovasc. Genet. 6: 279-289, 2013.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23677916/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23677916</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23677916[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=23677916" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1161/CIRCGENETICS.113.000138" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="7" class="mim-anchor"></a>
|
|
<a id="Boczek2015" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Boczek, N. J., Miller, E. M., Ye, D., Nesterenko, V. V., Tester, D. J., Antzelevitch, C., Czosek, R. J., Ackerman, M. J., Ware, S. M.
|
|
<strong>Novel Timothy syndrome mutation leading to increase in CACNA1C window current.</strong>
|
|
Heart Rhythm 12: 211-219, 2015.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25260352/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25260352</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25260352[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=25260352" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1016/j.hrthm.2014.09.051" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="8" class="mim-anchor"></a>
|
|
<a id="Boczek2015" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Boczek, N. J., Ye, D., Jin, F., Tester, D. J., Huseby, A., Bos, J. M., Johnson, A. J., Kanter, R., Ackerman, M. J.
|
|
<strong>Identification and functional characterization of a novel CACNA1C-mediated cardiac disorder characterized by prolonged QT intervals with hypertrophic cardiomyopathy, congenital heart defects, and sudden cardiac death.</strong>
|
|
Circ. Arrhythm. Electrophysiol. 8: 1122-1132, 2015.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26253506/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26253506</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26253506[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=26253506" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1161/CIRCEP.115.002745" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="9" class="mim-anchor"></a>
|
|
<a id="Bozarth2018" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Bozarth, X., Dines, J. N., Cong, Q., Mirzaa, G. M., Foss, K., Lawrence Merritt, J., Thies, J., Mefford, H. C., Novotny, E.
|
|
<strong>Expanding clinical phenotype in CACNA1C related disorders: From neonatal onset severe epileptic encephalopathy to late-onset epilepsy.</strong>
|
|
Am. J. Med. Genet. 176A: 2733-2739, 2018.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30513141/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30513141</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30513141" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1002/ajmg.a.40657" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="10" class="mim-anchor"></a>
|
|
<a id="Cheng1993" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Cheng, H., Lederer, W. J., Cannell, M. B.
|
|
<strong>Calcium sparks: elementary events underlying excitation-contraction coupling in heart muscle.</strong>
|
|
Science 262: 740-744, 1993.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8235594/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8235594</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8235594" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1126/science.8235594" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="11" class="mim-anchor"></a>
|
|
<a id="Dick2008" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Dick, I. E., Tadross, M. R., Liang, H., Tay, L. H., Yang, W., Yue, D. T.
|
|
<strong>A modular switch for spatial Ca(2+) selectivity in the calmodulin regulation of Ca(v) channels.</strong>
|
|
Nature 451: 830-834, 2008.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18235447/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18235447</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18235447[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=18235447" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1038/nature06529" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="12" class="mim-anchor"></a>
|
|
<a id="Dolmetsch2001" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Dolmetsch, R. E., Pajvani, U., Fife, K., Spotts, J. M., Greenberg, M. E.
|
|
<strong>Signaling to the nucleus by an L-type calcium channel-calmodulin complex through the MAP kinase pathway.</strong>
|
|
Science 294: 333-339, 2001.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11598293/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11598293</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11598293" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1126/science.1063395" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="13" class="mim-anchor"></a>
|
|
<a id="Etheridge2011" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Etheridge, S. P., Bowles, N. E., Arrington, C. B., Pilcher, T., Rope, A., Wilde, A. A. M., Alders, M., Saarel, E. V., Tavernier, R., Timothy, K. W., Tristani-Firouzi, M.
|
|
<strong>Somatic mosaicism contributes to phenotypic variation in Timothy syndrome.</strong>
|
|
Am. J. Med. Genet. 155A: 2578-2583, 2011.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21910241/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21910241</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21910241" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1002/ajmg.a.34223" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="14" class="mim-anchor"></a>
|
|
<a id="Fukuyama2014" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Fukuyama, M., Wang, Q., Kato, K., Ohno, S., Ding, W.-G., Toyoda, F., Itoh, H., Kimura, H., Makiyama, T., Ito, M., Matsuura, H., Horie, M.
|
|
<strong>Long QT syndrome type 8: novel CACNA2C mutations causing QT prolongation and variant phenotypes.</strong>
|
|
Europace 16: 1828-1837, 2014.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24728418/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24728418</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24728418" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1093/europace/euu063" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="15" class="mim-anchor"></a>
|
|
<a id="Gardner2019" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Gardner, R. J. M., Crozier, I. G., Binfield, A. L., Love, D. R., Lehnert, K., Gibson, K., Lintott, C. J., Snell, R. G., Jacobsen, J. C., Jones, P. P., Waddell-Smith, K. E., Kennedy, M. A., Skinner, J. R.
|
|
<strong>Penetrance and expressivity of the R858H CACNA1C variant in a five-generation pedigree segregating an arrhythmogenic channelopathy.</strong>
|
|
Molec. Genet. Genomic Med. 7: e00476, 2019. Note: Electronic Article.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30345660/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30345660</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30345660[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=30345660" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1002/mgg3.476" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="16" class="mim-anchor"></a>
|
|
<a id="Gomez-Ospina2006" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Gomez-Ospina, N., Tsuruta, F., Barreto-Chang, O., Hu, L., Dolmetsch, R.
|
|
<strong>The C terminus of the L-type voltage-gated calcium channel Ca(V)1.2 encodes a transcription factor.</strong>
|
|
Cell 127: 591-606, 2006.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17081980/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17081980</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17081980[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=17081980" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1016/j.cell.2006.10.017" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="17" class="mim-anchor"></a>
|
|
<a id="Hiippala2015" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Hiippala, A., Tallila, J., Myllykangas, S., Koskenvuo, J. W., Alastalo, T.-P.
|
|
<strong>Expanding the phenotype of Timothy syndrome type 2: an adolescent with ventricular fibrillation but normal development.</strong>
|
|
Am. J. Med. Genet. 167A: 629-634, 2015.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25691416/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25691416</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25691416" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1002/ajmg.a.36924" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="18" class="mim-anchor"></a>
|
|
<a id="Klockner1997" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Klockner, U., Mikala, G., Eisfeld, J., Iles, D. E., Strobeck, M., Mershon, J. L., Schwartz, A., Varadi, G.
|
|
<strong>Properties of three COOH-terminal splice variants of a human cardiac L-type Ca(2+)-channel alpha-1-subunit.</strong>
|
|
Am. J. Physiol. 272: H1372-H1381, 1997.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9087614/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9087614</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9087614" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1152/ajpheart.1997.272.3.H1372" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="19" class="mim-anchor"></a>
|
|
<a id="Kosaki2018" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Kosaki, R., Ono, H., Terashima, H., Kosaki, K.
|
|
<strong>Timothy syndrome-like condition with syndactyly but without prolongation of the QT interval.</strong>
|
|
Am. J. Med. Genet. 176A: 1657-1661, 2018.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29736926/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29736926</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29736926" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1002/ajmg.a.38833" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="20" class="mim-anchor"></a>
|
|
<a id="Kummer2022" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Kummer, S., Rinne, S., Seemann, G., Bachmann, N., Timothy, K., Thornton, P. S., Pillekamp, F., Mayatepek, E., Bergmann, C., Meissner, T., Decher, N.
|
|
<strong>Hyperinsulinemic hypoglycemia associated with a CaV1.2 variant with mixed gain- and loss-of-function effects.</strong>
|
|
Int. J. Molec. Sci. 23: 8097, 2022.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35897673/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35897673</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=35897673[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=35897673" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.3390/ijms23158097" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="21" class="mim-anchor"></a>
|
|
<a id="Liu2020" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Liu, G., Papa, A., Katchman, A. N., Zakharov, S. I., Roybal, D., Hennessey, J. A., Kushner, J., Yang, L., Chen, B.-X., Kushnir, A., Dangas, K., Gygi, S. P., Pitt, G. S., Colecraft, H. M., Ben-Johny, M., Kalocsay, M., Marx, S. O.
|
|
<strong>Mechanism of adrenergic Ca(V)1.2 stimulation revealed by proximity proteomics.</strong>
|
|
Nature 577: 695-700, 2020.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31969708/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31969708</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31969708[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=31969708" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1038/s41586-020-1947-z" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="22" class="mim-anchor"></a>
|
|
<a id="Liu2014" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Liu, W., Deng, J., Wang, G., Zhang, C., Luo, X., Yan, D., Su, Q., Liu, J.
|
|
<strong>KCNE2 modulates cardiac L-type Ca(2+) channel.</strong>
|
|
J. Molec. Cell. Cardiol. 72: 208-218, 2014.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24681347/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24681347</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24681347" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1016/j.yjmcc.2014.03.013" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="23" class="mim-anchor"></a>
|
|
<a id="Mori2004" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Mori, M. X., Erickson, M. G., Yue, D. T.
|
|
<strong>Functional stoichiometry and local enrichment of calmodulin interacting with Ca(2+) channels.</strong>
|
|
Science 304: 432-435, 2004.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15087548/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15087548</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15087548" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1126/science.1093490" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="24" class="mim-anchor"></a>
|
|
<a id="O'Brien1995" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
O'Brien, R. O., Taske, N. L., Hansbro, P. M., Matthaei, K. I., Hogan, S. P., Denborough, M. A., Foster, P. S.
|
|
<strong>Exclusion of defects in the skeletal muscle specific regions of the DHPR alpha-1 subunit as frequent causes of malignant hyperthermia.</strong>
|
|
J. Med. Genet. 32: 913-914, 1995.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8592342/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8592342</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8592342" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1136/jmg.32.11.913" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="25" class="mim-anchor"></a>
|
|
<a id="Oudit2003" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Oudit, G. Y., Sun, H., Trivieri, M. G., Koch, S. E., Dawood, F., Ackerley, C., Yazdanpanah, M., Wilson, G. J., Schwartz, A., Liu, P. P., Backx, P. H.
|
|
<strong>L-type Ca(2+) channels provide a major pathway for iron entry into cardiomyocytes in iron-overload cardiomyopathy.</strong>
|
|
Nature Med. 9: 1187-1194, 2003.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12937413/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12937413</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12937413" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1038/nm920" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="26" class="mim-anchor"></a>
|
|
<a id="Ozawa2018" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Ozawa, J., Ohno, S., Saito, H., Saitoh, A., Matsuura, H., Horie, M.
|
|
<strong>A novel CACNA1C mutation identified in a patient with Timothy syndrome without syndactyly exerts both marked loss- and gain-of-function effects.</strong>
|
|
HeartRhythm Case Rep. 4: 273-277, 2018.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30023270/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30023270</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30023270[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=30023270" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1016/j.hrcr.2018.03.003" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="27" class="mim-anchor"></a>
|
|
<a id="Panagiotakos2019" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Panagiotakos, G., Haveles, C., Arjun, A., Petrova, R., Rana, A., Portmann, T., Pasca, S. P., Palmer, T. D., Dolmetsch, R. E.
|
|
<strong>Aberrant calcium channel splicing drives defects in cortical differentiation in Timothy syndrome.</strong>
|
|
eLife 8: e51037, 2019.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31868578/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31868578</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31868578[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=31868578" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.7554/eLife.51037" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="28" class="mim-anchor"></a>
|
|
<a id="Park2010" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Park, C. Y., Shcheglovitov, A., Dolmetsch, R.
|
|
<strong>The CRAC channel activator STIM1 binds and inhibits L-type voltage-gated calcium channels.</strong>
|
|
Science 330: 101-105, 2010.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20929812/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20929812</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20929812" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1126/science.1191027" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="29" class="mim-anchor"></a>
|
|
<a id="Perez-Reyes1990" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Perez-Reyes, E., Wei, X., Castellano, A., Birnbaumer, L.
|
|
<strong>Molecular diversity of L-type calcium channels: evidence for alternative splicing of the transcripts of three non-allelic genes.</strong>
|
|
J. Biol. Chem. 265: 20430-20436, 1990.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2173707/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2173707</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2173707" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="30" class="mim-anchor"></a>
|
|
<a id="Powers1992" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Powers, P. A., Gregg, R. G., Hogan, K.
|
|
<strong>Linkage mapping of the human gene for the alpha-1 subunit of the cardiac DHP-sensitive Ca(2+) channel (CACNL1A1) to chromosome 12p13.2-pter using a dinucleotide repeat.</strong>
|
|
Genomics 14: 206-207, 1992.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1330882/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1330882</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1330882" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1016/s0888-7543(05)80312-x" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="31" class="mim-anchor"></a>
|
|
<a id="Powers1991" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Powers, P. A., Gregg, R. G., Lalley, P. A., Liao, M., Hogan, K.
|
|
<strong>Assignment of the human gene for the alpha-1 subunit of the cardiac DHP-sensitive Ca(2+) channel (CCHL1A1) to chromosome 12p12-pter.</strong>
|
|
Genomics 10: 835-839, 1991.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1653763/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1653763</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1653763" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1016/0888-7543(91)90471-p" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="32" class="mim-anchor"></a>
|
|
<a id="Rodan2021" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Rodan, L. H., Spillmann, R. C., Kurata, H. T., Lamothe, S. M., Maghera, J., Jamra, R. A., Alkelai, A., Antonarakis, S. E., Atallah, I., Bar-Yosef, O., Bilan, F., Bjorgo, K., and 46 others.
|
|
<strong>Phenotypic expansion of CACNA1C-associated disorders to include isolated neurological manifestations.</strong>
|
|
Genet. Med. 23: 1922-1932, 2021. Note: Erratum: Genet. Med. 23: 2016 only, 2021.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34163037/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34163037</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=34163037[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=34163037" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1038/s41436-021-01232-8" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="33" class="mim-anchor"></a>
|
|
<a id="Rottbauer2001" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Rottbauer, W., Baker, K., Wo, Z. G., Mohideen, M.-A. P. K., Cantiello, H. F., Fishman, M. C.
|
|
<strong>Growth and function of the embryonic heart depend upon the cardiac-specific L-type calcium channel alpha-1 subunit.</strong>
|
|
Dev. Cell 1: 265-275, 2001.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11702785/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11702785</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11702785" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1016/s1534-5807(01)00023-5" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="34" class="mim-anchor"></a>
|
|
<a id="Saada2003" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Saada, N., Dai, B., Echetebu, C., Sarna, S. K., Palade, P.
|
|
<strong>Smooth muscle uses another promoter to express primarily a form of human Ca(v)1.2 L-type calcium channel different from the principal heart form.</strong>
|
|
Biochem. Biophys. Res. Commun. 302: 23-28, 2003.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12593842/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12593842</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12593842" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1016/s0006-291x(03)00097-4" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="35" class="mim-anchor"></a>
|
|
<a id="Schulla2003" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Schulla, V., Renstrom, E., Feil, R., Feil, S., Franklin, I., Gjinovci, A., Jing, X. J., Laux, D., Lundquist, I., Magnuson, M. A., Obermuller, S., Olofsson, C. S., Salehi, A., Wendt, A., Klugbauer, N., Wollheim, C. B., Rorsman, P., Hofmann, F.
|
|
<strong>Impaired insulin secretion and glucose tolerance in beta cell-selective Ca(v)1.2 Ca(2+) channel null mice.</strong>
|
|
EMBO J. 22: 3844-3854, 2003.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12881419/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12881419</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12881419[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=12881419" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1093/emboj/cdg389" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="36" class="mim-anchor"></a>
|
|
<a id="Schultz1993" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Schultz, D., Mikala, G., Yatani, A., Engle, D. B., Iles, D. E., Segers, B., Sinke, R. J., Weghuis, D. O., Klockner, U., Wakamori, M., Wang, J.-J., Melvin, D., Varadi, G., Schwartz, A.
|
|
<strong>Cloning, chromosomal localization, and functional expression of the alpha-1 subunit of the L-type voltage-dependent calcium channel from normal human heart.</strong>
|
|
Proc. Nat. Acad. Sci. 90: 6228-6232, 1993.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8392192/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8392192</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8392192" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1073/pnas.90.13.6228" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="37" class="mim-anchor"></a>
|
|
<a id="Smedler2022" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Smedler, E., Louhivuori, L., Romanov, R. A., Masini, D., Dehnisch Ellstrom, I., Wang, C., Caramia, M., West, Z., Zhang, S., Rebellato, P., Malmersjo, S., Brusini, I., Kanatani, S., Fisone, G., Harkany, T., Uhlen, P.
|
|
<strong>Disrupted Cacna1c gene expression perturbs spontaneous Ca(2+) activity causing abnormal brain development and increased anxiety.</strong>
|
|
Proc. Nat. Acad. Sci. 119: e2108768119, 2022.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35135875/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35135875</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=35135875[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=35135875" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1073/pnas.2108768119" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="38" class="mim-anchor"></a>
|
|
<a id="Soldatov1997" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Soldatov, N. M., Zuhlke, R. D., Bouron, A., Reuter, H.
|
|
<strong>Molecular structures involved in L-type calcium channel inactivation: role of the carboxyl-terminal region encoded by exons 40-42 in alpha-1C subunit in the kinetics and Ca(2+) dependence of inactivation.</strong>
|
|
J. Biol. Chem. 272: 3560-3566, 1997.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9013606/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9013606</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9013606" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1074/jbc.272.6.3560" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="39" class="mim-anchor"></a>
|
|
<a id="Soldatov1992" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Soldatov, N. M.
|
|
<strong>Molecular diversity of L-type Ca(2+) channel transcripts in human fibroblasts.</strong>
|
|
Proc. Nat. Acad. Sci. 89: 4628-4632, 1992.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1316612/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1316612</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1316612" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1073/pnas.89.10.4628" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="40" class="mim-anchor"></a>
|
|
<a id="Soldatov1994" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Soldatov, N. M.
|
|
<strong>Genomic structure of human L-type Ca(2+) channel.</strong>
|
|
Genomics 22: 77-87, 1994.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7959794/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7959794</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7959794" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1006/geno.1994.1347" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="41" class="mim-anchor"></a>
|
|
<a id="Splawski2005" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Splawski, I., Timothy, K. W., Decher, N., Kumar, P., Sachse, F. B., Beggs, A. H., Sanguinetti, M. C., Keating, M. T.
|
|
<strong>Severe arrhythmia disorder caused by cardiac L-type calcium channel mutations.</strong>
|
|
Proc. Nat. Acad. Sci. 102: 8089-8096, 2005.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15863612/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15863612</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15863612[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=15863612" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1073/pnas.0502506102" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="42" class="mim-anchor"></a>
|
|
<a id="Splawski2004" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Splawski, I., Timothy, K. W., Sharpe, L. M., Decher, N., Kumar, P., Bloise, R., Napolitano, C., Schwartz, P. J., Joseph, R. M., Condouris, K., Tager-Flusberg, H., Priori, S. G., Sanguinetti, M. C., Keating, M. T.
|
|
<strong>Ca(V)1.2 calcium channel dysfunction causes a multisystem disorder including arrhythmia and autism.</strong>
|
|
Cell 119: 19-31, 2004.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15454078/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15454078</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15454078" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1016/j.cell.2004.09.011" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="43" class="mim-anchor"></a>
|
|
<a id="Sun1992" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Sun, W., McPherson, J. D., Hoang, D. Q., Wasmuth, J. J., Evans, G. A., Montal, M.
|
|
<strong>Mapping of a human brain voltage-gated calcium channel to human chromosome 12p13-pter.</strong>
|
|
Genomics 14: 1092-1094, 1992.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1335957/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1335957</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1335957" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1016/s0888-7543(05)80135-1" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="44" class="mim-anchor"></a>
|
|
<a id="Tiwari2006" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Tiwari, S., Zhang, Y., Heller, J., Abernethy, D. R., Soldatov, N. M.
|
|
<strong>Atherosclerosis-related molecular alteration of the human Ca(V)1.2 calcium channel alpha-1C subunit.</strong>
|
|
Proc. Nat. Acad. Sci. 103: 17024-17029, 2006.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17071743/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17071743</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17071743[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=17071743" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1073/pnas.0606539103" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="45" class="mim-anchor"></a>
|
|
<a id="Tsien1991" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Tsien, R. W., Ellinor, P. T., Horne, W. A.
|
|
<strong>Molecular diversity of voltage-dependent Ca(2+) channels.</strong>
|
|
Trends Pharm. Sci. 12: 349-354, 1991.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1659003/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1659003</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1659003" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1016/0165-6147(91)90595-j" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="46" class="mim-anchor"></a>
|
|
<a id="Valenzuela1997" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Valenzuela, D., Han, X., Mende, U., Fankhauser, C., Mashimo, H., Huang, P., Pfeffer, J., Neer, E. J., Fishman, M. C.
|
|
<strong>G-alpha-o is necessary for muscarinic regulation of Ca(2+) channels in mouse heart.</strong>
|
|
Proc. Nat. Acad. Sci. 94: 1727-2732, 1997.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9050846/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9050846</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9050846[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=9050846" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1073/pnas.94.5.1727" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="47" class="mim-anchor"></a>
|
|
<a id="Wang2001" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Wang, S.-Q., Song, L.-S., Lakatta, E. G., Cheng, H.
|
|
<strong>Ca(2+) signalling between single L-type Ca(2+) channels and ryanodine receptors in heart cells.</strong>
|
|
Nature 410: 592-596, 2001.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11279498/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11279498</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11279498" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1038/35069083" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="48" class="mim-anchor"></a>
|
|
<a id="Wang2010" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Wang, Y., Deng, X., Mancarella, S., Hendron, E., Eguchi, S., Soboloff, J., Tang, X. D., Gill, D. L.
|
|
<strong>The calcium store sensor, STIM1, reciprocally controls Orai and Ca(v)1.2 channels.</strong>
|
|
Science 330: 105-109, 2010.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20929813/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20929813</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20929813[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=20929813" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1126/science.1191086" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="49" class="mim-anchor"></a>
|
|
<a id="Wemhoner2015" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Wemhoner, K., Friedrich, C., Stallmeyer, B., Coffey, A. J., Grace, A., Zumhagen, S., Seebohm, G., Ortiz-Bonnin, B., Rinne, S., Sachse, F. B., Shulze-Bahr, E., Decher, N.
|
|
<strong>Gain-of-function mutations in the calcium channel CACNA1C (Cav1.2) cause non-syndromic long-QT but not Timothy syndrome.</strong>
|
|
J. Molec. Cell. Cardiol. 80: 186-195, 2015.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25633834/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25633834</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25633834" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1016/j.yjmcc.2015.01.002" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="50" class="mim-anchor"></a>
|
|
<a id="Yazawa2011" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Yazawa, M., Hsueh, B., Jia, X., Pasca, A. M., Bernstein, J. A., Hallmayer, J., Dolmetsch, R. E.
|
|
<strong>Using induced pluripotent stem cells to investigate cardiac phenotypes in Timothy syndrome.</strong>
|
|
Nature 471: 230-234, 2011.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21307850/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21307850</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21307850[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=21307850" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1038/nature09855" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="51" class="mim-anchor"></a>
|
|
<a id="Ye2019" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Ye, D., Tester, D. J., Zhou, W., Papagiannis, J., Ackerman, M. J.
|
|
<strong>A pore-localizing CACNA1C-E1115K missense mutation, identified in a patient with idiopathic QT prolongation, bradycardia, and autism spectrum disorder, converts the L-type calcium channel into a hybrid nonselective monovalent cation channel.</strong>
|
|
Heart Rhythm 16: 270-278, 2019.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30172029/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30172029</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30172029" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1016/j.hrthm.2018.08.030" target="_blank">Full Text</a>]
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<a id="contributors" class="mim-anchor"></a>
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="mim-text-font">
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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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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Marla J. F. O'Neill - updated : 10/06/2022
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</span>
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<div class="row collapse" id="mimCollapseContributors">
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<span class="mim-text-font">
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Marla J. F. O'Neill - updated : 09/29/2022<br>Alan F. Scott - updated : 09/22/2022<br>Cassandra L. Kniffin - updated : 09/13/2022<br>Ada Hamosh - updated : 08/31/2022<br>Ada Hamosh - updated : 06/22/2020<br>Ada Hamosh - updated : 06/05/2019<br>Patricia A. Hartz - updated : 02/17/2017<br>Marla J. F. O'Neill - updated : 08/25/2016<br>Ada Hamosh - updated : 6/14/2011<br>Ada Hamosh - updated : 11/2/2010<br>Marla J. F. O'Neill - updated : 12/9/2009<br>Ada Hamosh - updated : 3/7/2008<br>Marla J. F. O'Neill - updated : 3/4/2008<br>Cassandra L. Kniffin - updated : 7/16/2007<br>Marla J. F. O'Neill - updated : 1/26/2007<br>Stylianos E. Antonarakis - updated : 12/18/2006<br>Ada Hamosh - updated : 1/11/2006<br>Marla J. F. O'Neill - updated : 8/4/2005<br>Ada Hamosh - updated : 1/19/2005<br>Patricia A. Hartz - updated : 10/27/2004<br>Stylianos E. Antonarakis - updated : 10/13/2004<br>Ada Hamosh - updated : 4/29/2004<br>Ada Hamosh - updated : 9/15/2003<br>Dawn Watkins-Chow - updated : 2/27/2003<br>Ada Hamosh - updated : 10/23/2001<br>Ada Hamosh - updated : 4/4/2001<br>Wilson H. Y. Lo - updated : 8/6/1999
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<div>
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<a id="creationDate" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Victor A. McKusick : 2/26/1991
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</span>
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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="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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</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 : 10/28/2024
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</span>
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</div>
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<div class="row collapse" id="mimCollapseEditHistory">
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 01/21/2023<br>alopez : 10/06/2022<br>alopez : 10/06/2022<br>alopez : 09/29/2022<br>alopez : 09/29/2022<br>alopez : 09/29/2022<br>mgross : 09/22/2022<br>carol : 09/15/2022<br>carol : 09/14/2022<br>ckniffin : 09/13/2022<br>carol : 08/06/2021<br>alopez : 06/22/2020<br>alopez : 06/22/2020<br>carol : 06/10/2019<br>carol : 06/06/2019<br>carol : 06/05/2019<br>mgross : 02/17/2017<br>carol : 08/25/2016<br>carol : 08/05/2016<br>carol : 03/19/2014<br>carol : 12/15/2011<br>carol : 11/9/2011<br>alopez : 6/17/2011<br>terry : 6/14/2011<br>alopez : 11/10/2010<br>alopez : 11/10/2010<br>terry : 11/3/2010<br>terry : 11/2/2010<br>carol : 10/4/2010<br>joanna : 1/28/2010<br>wwang : 12/14/2009<br>terry : 12/9/2009<br>alopez : 3/20/2008<br>terry : 3/7/2008<br>wwang : 3/4/2008<br>wwang : 7/31/2007<br>ckniffin : 7/16/2007<br>wwang : 1/26/2007<br>mgross : 12/18/2006<br>terry : 1/11/2006<br>wwang : 8/5/2005<br>wwang : 8/4/2005<br>wwang : 2/1/2005<br>wwang : 1/27/2005<br>terry : 1/19/2005<br>mgross : 11/2/2004<br>mgross : 11/1/2004<br>terry : 10/27/2004<br>mgross : 10/13/2004<br>alopez : 5/4/2004<br>terry : 4/29/2004<br>alopez : 9/15/2003<br>alopez : 9/15/2003<br>tkritzer : 3/3/2003<br>tkritzer : 2/27/2003<br>tkritzer : 2/27/2003<br>carol : 10/24/2001<br>terry : 10/23/2001<br>alopez : 4/5/2001<br>terry : 4/4/2001<br>carol : 8/6/1999<br>dkim : 6/30/1998<br>mark : 6/12/1997<br>mark : 12/29/1996<br>mark : 1/31/1996<br>terry : 1/24/1996<br>carol : 11/18/1994<br>jason : 7/19/1994<br>mimadm : 4/29/1994<br>warfield : 4/7/1994<br>carol : 7/9/1993<br>carol : 1/8/1993
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</span>
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<h3>
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<span class="mim-font">
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<strong>*</strong> 114205
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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, L TYPE, ALPHA-1C SUBUNIT; CACNA1C
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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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<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 1, CARDIAC MUSCLE; CACNL1A1<br />
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CCHL1A1<br />
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CaV1.2<br />
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CALCIUM CHANNEL, CARDIAC DIHYDROPYRIDINE-SENSITIVE, ALPHA-1 SUBUNIT<br />
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DHPR, ALPHA-1 SUBUNIT<br />
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CACH2
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</span>
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</h4>
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</div>
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<br />
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: CACNA1C</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> 1230096008;
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</span>
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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: 12p13.33
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Genomic coordinates <span class="small">(GRCh38)</span> : 12:1,970,780-2,697,950 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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</span>
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</p>
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</div>
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<div>
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<br />
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</h4>
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<div>
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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<tbody>
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<td rowspan="4">
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<span class="mim-font">
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12p13.33
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<span class="mim-font">
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Brugada syndrome 3
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</span>
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</td>
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<td>
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<span class="mim-font">
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611875
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
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Long QT syndrome 8
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</span>
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</td>
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<td>
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<span class="mim-font">
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618447
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
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Neurodevelopmental disorder with hypotonia, language delay, and skeletal defects with or without seizures
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</span>
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</td>
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<td>
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<span class="mim-font">
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620029
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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<tr>
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<td>
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<span class="mim-font">
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Timothy syndrome
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</span>
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</td>
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<td>
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<span class="mim-font">
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601005
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
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</span>
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</h4>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Description</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>The CACNA1C gene encodes multiple isoforms of the pore-forming alpha-1C subunit of the long-lasting (L-type) voltage-gated calcium channel CaV1.2. It is an evolutionarily conserved protein expressed in the heart, lungs, brain, and smooth muscle, and is critical for calcium signaling, cellular and neuronal excitability, muscle contraction, and regulation of gene expression (summary by Bozarth et al., 2018). </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>Activation of voltage-sensitive calcium channels by membrane depolarization triggers key cellular responses such as contraction, secretion, excitation, and electrical signaling (Tsien et al., 1991). The L-type currents produced by voltage-sensitive calcium channels are blocked by 1,4-dihydropyridine (DHP) derivatives; thus, the channels responsible for these currents are referred to as DHP-sensitive. The skeletal muscle DHP-sensitive calcium channel is a complex of 5 subunits: alpha-1, alpha-2, beta, gamma, and delta. The DHP-sensitive calcium channels from cardiac muscle and the brain have pharmacologic and electrophysiologic properties that differ from those of the skeletal muscle channel. Powers et al. (1991) isolated a clone for the human CCHL1A1 gene and partially sequenced it. </p><p>Voltage-dependent calcium channels are made up of 4 repeated domains (I through IV) that each contain at least 6 membrane-spanning regions (S1 through S6), and the 4 domains are connected by linkers of variable length. By PCR of human heart, followed by sequence analysis, Perez-Reyes et al. (1990) identified 3 variants of CACNA1C, which they called CACH2. The variants differed in both the sequence of IVS3 and in the size of the linker between IVS3 and IVS4. </p><p>Soldatov (1992) identified 4 sites of molecular diversity in human fibroblast CACNA1C, which they called HFCC. Three of these involved regions encoding transmembrane segments IIS6, IIIS2, and IVS3, which are important for channel gating, and the fourth was located at the C terminus. </p><p>Schultz et al. (1993) obtained a full-length cDNA encoding CACNA1C by screening human heart cDNA libraries. The deduced 2,180-amino acid protein has a calculated molecular mass of 243.6 kD. CACNA1C contains 5 protein kinase A (see 176911) phosphorylation sites and 4 putative N-glycosylation sites. Human and rabbit CACNA1C share almost 100% homology in the transmembrane regions. The dominant isoform in human heart contains a 71-amino acid insert with a potential CAMK2 (see 607707) consensus sequence. Northern blot analysis detected a 9.4-kb transcript in heart. </p><p>Blumenstein et al. (2002) identified 2 CACNA1C transcripts in human heart that utilize alternative first exons, 1a or 1b. Exon 1a encodes a 46-amino acid N-terminal segment, and exon 1b encodes a 16-amino acid N-terminal segment. </p><p>By ribonuclease protection assay, Saada et al. (2003) found that all smooth muscle-containing tissues examined (bladder, fetal aorta, lung, and intestine) expressed CANCA1C transcripts utilizing exon 1b. Only bladder and fetal aorta also expressed transcripts utilizing exon 1a. Primary cultures of colonic myocytes and coronary artery smooth muscle cells also predominantly expressed transcripts with exon 1b. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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<strong>Gene Structure</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Soldatov (1994) investigated the genomic organization of the CACNL1A1 gene by DNA sequencing of genomic and cDNA clones and PCR products. The gene spans an estimated 150 kb of the human genome and is composed of 44 invariant and 6 alternative exons. Data on cDNA cloning from both human fibroblasts and hippocampus indicated several regions of heterogeneity due to alternative splicing sites of the CACNL1A1 primary transcript. In addition, Southern blotting followed by partial sequencing indicated at least 3 different isoforms of L-type Ca(2+) channels. Soldatov (1994) suggested that the human L-type Ca(2+) channels are genetically regulated through generation of multiple splice variants of the mRNA, some of them in a tissue-specific manner, as well as via expression of different gene isoforms. </p><p>Blumenstein et al. (2002) identified an alternate 5-prime exon, 1a, that lies about 80 kb upstream of the alternate exon 1b in the CACNA1C gene. Saada et al. (2003) demonstrated that exons 1a and 1b have separate functional upstream promoters. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Mapping</strong>
|
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>By constructing oligonucleotides based on the human CCHL1A1 sequence and using them in PCR to amplify specifically this human gene in human-rodent somatic cell hybrids, Powers et al. (1991) assigned the CCHL1A1 gene to 12pter-p12. Using a dinucleotide repeat for linkage analysis in the CEPH panel of families, Powers et al. (1992) narrowed the assignment to 12pter-p13.2. The data placed CACNL1A1 distal to PRB1 (180989). By study of somatic cell hybrids, Sun et al. (1992) likewise assigned the CACNL1A1 gene to 12pter-p13. </p><p>Schultz et al. (1993) localized the CCHL1A1 gene to 12p13.3 by study of a 12p somatic cell hybrid mapping panel and by fluorescence in situ hybridization. </p><p>Studying 2 somatic cell hybrids containing either the der(12) or the der(X) from a mesothelioma with a translocation t(X;12)(q22;p13) as the only chromosomal change and applying PCR analysis based on genomic sequences, Aerssens et al. (1994) mapped the CACNL1A1 gene distal to the 12p13 breakpoint and to VWF (613160). </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Function</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Schultz et al. (1993) found that CACNA1C expressed in Xenopus oocytes produced a large inward Ba(2+) current upon depolarization. The channel opening probability was voltage dependent, and single channel analysis revealed native-like pharmacology and channel properties. </p><p>Soldatov et al. (1997) expressed 3 human hippocampus CACNA1C variants in Xenopus oocytes. The 3 variants were highly sensitive toward DHP, but showed large differences in gating properties. A segment spanning amino acids 1572 to 1651 in the cytoplasmic tail defined the channel inactivation rate, the Ca(2+)-dependent component of inactivation, and the voltage-dependent component of inactivation. </p><p>Klockner et al. (1997) expressed 3 cardiac CACNA1C splice variants encoding proteins with different C termini in Xenopus oocytes and in human embryonic kidney cells. The channels showed insignificant differences in the kinetics and voltage dependence of the induced calcium channel currents. </p><p>By expression in Xenopus oocytes, Blumenstein et al. (2002) found that a protein kinase C (see 176960) activator enhanced the channel activity of the cardiac CACNA1C isoform containing the 46-amino acid N-terminal segment. CACNA1C with the alternate 16-amino acid N-terminal segment was inhibited. </p><p>The mode of calcium entry into a neuron plays a key role in determining which signaling pathways are activated and thus specifies a cellular response to calcium. Calcium influx through L-type voltage-activated channels (LTCs) is particularly effective at activating transcription factors such as CREB (123810) and MEF2 (see 600660). Dolmetsch et al. (2001) developed a functional knockin technique to investigate the features of LTCs that specifically couple them to the signaling pathways that regulate gene expression. They found that an isoleucine-glutamine (IQ) motif in the C terminus of the LTC that binds calcium-calmodulin (114180) is critical for conveying the calcium signaling to the nucleus. Calcium-calmodulin binding to the LTC was necessary for activation of the Ras/mitogen-activated protein kinase (MAPK) pathway, which conveys local calcium signals from the mouth of the LTC to the nucleus. Calmodulin functions as a local calcium sensor at the mouth of the LTC that activates the MAPK pathway and leads to the stimulation of genes that are essential for neuronal survival and plasticity. </p><p>To understand the relationship between the number of calmodulin molecules regulating each L-type calcium channel and the number of calmodulin molecules privy to the local calcium signal from each channel, Mori et al. (2004) fused L-type calcium channels to single calmodulin molecules. These chimeric molecules revealed that a single calmodulin molecule directs L-type channel regulation. Similar fusion molecules were used to estimate the local calmodulin concentration near calcium channels. This estimate indicates marked enrichment of local calmodulin, as if a school of nearby calmodulins were poised to enhance the transduction of local calcium entry into diverse signaling pathways. </p><p>Gomez-Ospina et al. (2006) found that a C-terminal fragment of CaV1.2 that they designated 'calcium channel-associated transcription regulator,' or CCAT, translocated to the nucleus in mouse and rat neurons, rat cardiac myocytes, and human embryonic kidney cells. Nuclear localization of CCAT was regulated both developmentally and by changes in intracellular calcium. CCAT bound to a nuclear protein, Nono (300084), associated with an endogenous promoter, and regulated expression of a wide variety of endogenous genes important for neuronal signaling and excitability in mammalian neurons. Gomez-Ospina et al. (2006) concluded that voltage-gated calcium channels can directly activate transcription. </p><p>Tiwari et al. (2006) studied vascular smooth muscle cells (VSMC) from atherosclerotic and nonatherosclerotic sections of arteries from 6 vascular surgery patients. In VSMC from nonatherosclerotic regions, RT-PCR analysis revealed an extended repertoire of CACNA1C transcripts characterized by the presence of exons 21 and 41A, whereas in VSMC affected by atherosclerosis, expression of CACNA1C was reduced and CACNA1C splice variants were replaced with a unique exon 22 isoform lacking exon 41A. Electrophysiologic studies of the channel splice variants revealed that molecular remodeling of CACNA1C subunits associated with atherosclerosis caused alterations in the kinetics and voltage-dependence of inactivation, recovery from inactivation, and rundown of the Ca(2+) current. Tiwari et al. (2006) suggested that localized changes in cytokine expression generated by inflammation in atherosclerosis affect alternative splicing of the CACNA1C gene in human arteries, resulting in molecular and electrophysiologic remodeling of CACNA1C channels. </p><p>Dick et al. (2008) showed that the spatial calcium ion selectivity of N-lobe calmodulin (114180) regulation is not invariably global but can be switched by a novel calcium ion/calmodulin binding site within the amino terminus of channels (NSCaTE, for N-terminal spatial calcium ion transforming element). Native Ca(v)2.2 channels lack this element and show N-lobe regulation with a global selectivity. On the introduction of NSCaTE into these channels, spatial calcium ion selectivity transforms from a global to local profile. Given this effect, Dick et al. (2008) examined Ca(v)1.2/Ca(v)1.3 channels, which naturally contain NSCaTE, and found that their N-lobe selectivity is indeed local. Disruption of this element produces a global selectivity, confirming the native function of NSCaTE. Thus, Dick et al. (2008) concluded that differences in spatial selectivity between advanced Ca(v)1 and Ca(v)2 channel isoforms are explained by the presence or absence of NSCaTE. Beyond functional effects, the position of NSCaTE on the channel's amino terminus indicates that calmodulin can bridge the amino terminus and carboxy terminus of channels. Finally, the modularity of NSCaTE offers practical means for understanding the basis of global calcium ion selectivity. </p><p>Park et al. (2010) found that stromal interaction molecule-1 (STIM1; 605921), the main activator of store-operated calcium channels, directly suppresses depolarization-induced opening of the voltage-gated calcium channel Ca(v)1.2. STIM1 binds to the C terminus of Ca(v)1.2 through its calcium release-activated calcium activation domain, acutely inhibits gating, and causes long-term internalization of the channel from the membrane. Park et al. (2010) concluded that their results established a theretofore unknown function for STIM1 and provided a molecular mechanism to explain the reciprocal regulation of these 2 channels in cells. </p><p>Wang et al. (2010) revealed a regulatory link between Orai channels (see 610277) and Ca(v)1.2 channels mediated by the ubiquitous calcium-sensing STIM proteins. STIM1 activation by store depletion or mutational modification strongly suppresses voltage-operated calcium (Ca(v)1.2) channels while activating store-operated (Orai) channels. Both actions are mediated by the short STIM-Orai activating region (SOAR) of STIM1. STIM1 interacts with Ca(v)1.2 channels and localizes within discrete endoplasmic reticulum/plasma membrane junctions containing both Ca(v)1.2 and ORAI1 channels. Hence, STIM1 interacts with and reciprocally controls 2 major calcium channels hitherto thought to operate independently. Wang et al. (2010) concluded that such coordinated control of the widely expressed Ca(v)1.2 and Orai channels has major implications for calcium signal generation in excitable and nonexcitable cells. </p><p>Using primary cultures of rat ventricular myocytes, Liu et al. (2014) found that human KCNE2 (603796) coimmunoprecipitated with and colocalized with Cav1.2, predominantly at transverse tubules. KCNE2 overexpression decreased Cav1.2 current magnitude and slightly altered its gating and kinetic properties, but it had no effect on Cav1.2 trafficking or membrane localization. Knockdown of endogenous Kcne2 increased Cav1.2-dependent calcium currents. KCNE2 copurified with the N-terminal inhibitory module of Cav1.2 and appeared to increase its inhibitory function. </p><p>Using mouse brain and human iPSCs from individuals with Timothy syndrome (TS; 601005), Panagiotakos et al. (2019) provided evidence that the CACNA1C G406R mutation (114205.0001) promotes use of alternatively spliced exon 8A and prevents a normal developmental switch in Ca(v)1.2 exon utilization, resulting in persistent expression of gain-of-function mutant channels during neuronal differentiation. In iPSC models, the TS variant reduces the abundance of SATB2-expressing cortical projection neurons, leading to excess CTIP2-positive neurons. Panagiotakos et al. (2019) showed that the expression of the TS-Ca(v)1.2 channels in the embryonic mouse cortex recapitulates these differentiation defects in a calcium-dependent manner and that in utero Ca(v)1.2 gain-and-loss of function reciprocally regulates the abundance of these neuronal populations. </p><p>Liu et al. (2020) identified the mechanism by which beta-adrenergic agonists stimulate voltage-gated calcium channels. Liu et al. (2020) expressed alpha-1C or beta-2B subunits conjugated to ascorbate peroxidase in mouse hearts, and used multiplexed quantitative proteomics to track hundreds of proteins in the proximity of CaV1.2. They observed that the calcium-channel inhibitor Rad (179503) is enriched in the CaV1.2 microenvironment but is depleted during beta-adrenergic stimulation. Phosphorylation by protein kinase A (see 176911) of specific serine residues on Rad decreases its affinity for beta subunits and relieves constitutive inhibition of CaV1.2, observed as an increase in channel open probability. Expression of Rad or its homolog Rem (610388) in HEK293T cells also imparted stimulation of CaV1.3 (CACNA1D; 114206) and CaV2.2 (CACNA1B; 601012) by protein kinase A, revealing an evolutionarily conserved mechanism that confers adrenergic modulation upon voltage-gated calcium channels. </p>
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<strong>Biochemical Features</strong>
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<p>Calcium-induced calcium release is a general mechanism that most cells use to amplify calcium signals. In heart cells, this mechanism is operated between voltage-gated L-type calcium channels (LCCs) in the plasma membrane and calcium release channels, commonly known as ryanodine receptors (see 180901), in the sarcoplasmic reticulum. The calcium influx through LCCs traverses a cleft of roughly 12 nm formed by the cell surface and the sarcoplasmic reticulum membrane, and activates adjacent ryanodine receptors to release calcium in the form of calcium sparks (Cheng et al., 1993). Wang et al. (2001) determined the kinetics, fidelity, and stoichiometry of coupling between LCCs and ryanodine receptors. They showed that the local calcium signal produced by a single opening of an LCC, named a 'calcium sparklet,' can trigger about 4 to 6 ryanodine receptors to generate a calcium spark. The coupling between LCCs and ryanodine receptors is stochastic, as judged by the exponential distribution of the coupling latency. The fraction of sparklets that successfully triggers a spark is less than unity and declines in a use-dependent manner. </p>
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<strong>Molecular Genetics</strong>
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<p><strong><em>Timothy Syndrome</em></strong></p><p>
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Timothy syndrome (TS; 601005) is characterized by multiorgan dysfunction, including lethal arrhythmias, webbing of fingers and toes, congenital heart disease, immune deficiency, intermittent hypoglycemia, cognitive abnormalities, and autism. Splawski et al. (2004) showed that, in all available patients, TS resulted from an identical, de novo missense mutation (G406R; 114205.0001) in the alternatively spliced exon 8A of the CACNA1C gene. They found that CACNA1C was expressed in all tissues affected in TS. Splawski et al. (2004) stated that this likely induces intracellular Ca(2+) overload in multiple cell types. They noted that, in the heart, prolonged Ca(2+) current delays cardiomyocyte repolarization and increases risk of arrhythmia, the ultimate cause of death in TS. These findings established the importance of CACNA1C in human physiology and development and implicated Ca(2+) signaling in autism. </p><p>Splawski et al. (2005) described 2 individuals with a severe variant of TS without syndactyly in whom they identified de novo missense mutations in exon 8 of the CACNA1C gene, G406R and G490R (114205.0002). CACNA1C has alternatively spliced transcripts that are encoded by 2 mutually exclusive exons, 8 and 8A. The authors found that the exon 8-specific transcript was highly expressed in heart and brain, accounting for about 80% of CACNA1C mRNA. In functional studies, both mutations in exon 8 caused reduced channel inactivation, resulting in maintained depolarizing L-type calcium currents. Computer modeling showed prolongation of cardiomyocyte action potentials and delayed afterdepolarizations, factors that increase the risk of arrhythmia. Splawski et al. (2005) concluded that gain-of-function mutations in CACNA1C exons 8 and 8A cause distinct forms of TS. </p><p>In a boy who died at age 3.75 years with QT prolongation and a Timothy syndrome phenotype, in whom analysis of an LQT gene panel was negative, including exons 8, 8A, and 9 of the CACNA1C gene, Boczek et al. (2015) performed whole-exome sequencing and identified heterozygosity for a de novo missense mutation in exon 27 of the CACNA1C gene (I1166T; 114205.0015). Sanger sequencing confirmed the mutation and its absence in his parents; the variant was also not present in public variant databases. Functional analysis revealed a novel electrophysiologic phenotype distinct from that of classic TS mutations, which result in almost complete loss of inactivation of CaV1.2 channels. Instead, the I1166T mutation causes an overall loss of current density with a gain-of-function shift in activation, resulting in an increased window current. The authors noted that although extracardiac differences had been observed across various TS-associated CACNA1C mutations, the cardiac phenotype appeared to be consistent, with QT prolongation, arrhythmias, cardiac hypertrophy, and PDA being commonly reported. </p><p>In 3 families with QT prolongation, hypertrophic cardiomyopathy, congenital heart defects, and/or sudden cardiac death, Boczek et al. (2015) identified heterozygosity for missense mutations at residue 518 in exon 12 of the CACNA1C gene: affected individuals from 2 families were heterozygous for an R518C substitution (114205.0016), whereas an R518H substitution (114205.0017) was found in the third family. None of the affected individuals exhibited extracardiac manifestations of Timothy syndrome. Functional analysis showed that the R518C/H variants result in a complex electrophysiologic phenotype including an overall loss of current density, increased window and late currents, and decelerating voltage-dependent inactivation resulting in constitutively active L-type calcium channels. </p><p>In a 14-year-old Japanese boy with a prolonged QT interval, dysmorphic facial features, intellectual disability, seizures, and autism spectrum disorder, Ozawa et al. (2018) screened a gene panel and identified heterozygosity for a de novo missense mutation in the CACNA1C gene (S643F; 114205.0018). Sanger sequencing confirmed the mutation and familial segregation, and it was not found in public variant databases. Functional analysis demonstrated an increase in late CaV1.2 currents as well as a marked reduction in peak currents with the S643F mutant compared to wildtype CACNA1C. In addition, the S643F channels never reached a fully inactivated state, with an inactivation level of 42% at maximum. </p><p>In a 14-year-old boy with QT prolongation, bradycardia, seizures, and autism spectrum disorder, Ye et al. (2019) analyzed a 13-gene LQTS panel and identified heterozygosity for a missense mutation in the CACNA1C gene (E1115K; 114205.0019). The mutation was not found in his unaffected mother or half sibs, or in the gnomAD database; DNA was unavailable from his father. Functional analysis showed that the mutation eliminates intrinsic calcium channel activity and converts the L-type calcium channel into a nonselective monovalent cation channel, with marked increases in both peak and persistent inward sodium currents and outward potassium/cesium currents. </p><p><strong><em>Brugada Syndrome</em></strong></p><p>
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Antzelevitch et al. (2007) screened 82 consecutive probands with a clinical diagnosis of Brugada syndrome for mutations in 16 ion channel genes. In 2 Brugada probands who exhibited shortened QTc intervals of less than or equal to 360 ms (see BRGDA3, 611875), they identified heterozygosity for mutation in the CACNA1C gene (114205.0003 and 114205.0004). </p><p><strong><em>Long QT Syndrome 8</em></strong></p><p>
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By trio-based whole-exome sequencing in a large multigeneration family segregating long QT syndrome (LQT8; 618447) without mutation in known causative genes, Boczek et al. (2013) identified heterozygosity for a missense mutation in the CACNA1C gene (P857R; 114205.0005) that segregated with the disorder in the family. By sequencing the CACNA1C gene in 102 unrelated patients with LQT without a molecular basis, Boczek et al. (2013) identified 3 patients with heterozygous missense mutations in the CACNA1C gene (see, e.g., 114205.0006-114205.0007). </p><p>By screening 278 Japanese probands with LQT who were negative for mutation in known causative genes, Fukuyama et al. (2014) identified 5 novel CACNA1C variants (see, e.g., R858H, 114205.0008 and A582D, 114205.0009) in 7 probands. The variants were absent in the NHLBI Exome Variant Server database and in 500 reference alleles from 250 Japanese controls. </p><p>By Sanger sequencing of the LQT1 through LQT8 genes in 540 probands with LQT, Wemhoner et al. (2015) identified 6 patients with heterozygous mutations in the CACNA1C gene (see, e.g., I1475M, 114205.0010). The mutations segregated with the phenotype in the families. </p><p>In affected members of a 5-generation European family with LQT8, Gardner et al. (2019) identified heterozygosity for the R858H mutation in the CACNA1C gene that was previously identified by Fukuyama et al. (2014) in Japanese patients. </p><p><strong><em>Neurodevelopmental Disorder with Hypotonia, Language Delay, and Skeletal Defects with or without Seizures</em></strong></p><p>
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In a 5-year-old Japanese girl with neurodevelopmental disorder with hypotonia, language delay, and skeletal defects with seizures (NEDHLSS; 620029), Kosaki et al. (2018) identified a de novo heterozygous missense variant (c.3070A-G, NM_199460.3; R1024G) in exon 24 of the CACNA1C gene. The variant was found by exome sequencing. Functional studies of the variant and studies of patient cells were not performed. </p><p>In an 18-month-old girl, born of unrelated parents, with NEDHLSS, Bozarth et al. (2018) identified a de novo heterozygous missense mutation in the CACNA1C gene (V1363M; 114205.0011). The mutation, which was found by trio-based exome sequencing, was not present in public databases, including gnomAD. Functional studies of the variant and studies of patient cells were not performed. </p><p>In 14 unrelated patients (P1-P14) with NEDHLSS, Rodan et al. (2021) identified de novo heterozygous nontruncating mutations (13 missense and 1 in-frame deletion) in the CACNA1C gene (see, e.g., L614P, 114205.0012; L657F, 114205.0013; and L1408V, 114205.0014). The mutations, which were found by exome sequencing, were not present in the gnomAD database. The patients were ascertained through the GeneMatcher Program after exome sequencing was performed. Electrophysiologic patch-clamp voltage studies in HEK293 cells transfected with a subset of the mutations showed no or variable effects on the channel current, both increased and decreased. The authors noted that their studies used the canonical transcript, but that the CACNA1C gene undergoes extensive splicing and interacts with multiple accessory subunits. They postulated a dominant-negative effect rather than haploinsufficiency. </p><p><strong><em>Associations Pending Confirmation</em></strong></p><p>
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For discussion of a possible association between hyperinsulinemic hypoglycemia (see 256450) and variation in the CACNA1C gene, see 114205.0020.</p><p>Blancard et al. (2018) analyzed the CaV1.2-related genes CACNA1C, CACNB2 (600003), and CACNA2D1 (114204) in 65 probands with Brugada syndrome, short QT syndrome, early repolarization syndrome, or idiopathic ventricular fibrillation, and identified 6 missense variants in the CACNA1C gene in 5 probands. Functional analysis showed no major alterations in channel function with 5 of the variants. The sixth variant, a T1787M substitution (c.5360C-T, NM_000719), was present in 2 probands (cases 1 and 2), both of whom were resuscitated from cardiac arrest. Case 1 was a Franco-Cameroonian man with an early repolarization pattern on electrocardiogram (ECG), and case 2 was a woman from La Reunion, in whom torsades de pointes originating from Purkinje fibers was detected. Both underwent placement of a cardioverter/defibrillator device, with brief or nonsustained ventricular tachycardia detected in the following years. Family history of cardiac events and ECG screening of family members were negative. Case 2 had an asymptomatic daughter who also carried the T1787M variant. The T1787M variant was present in the ExAC database at a minor allele frequency of 0.12%, found mostly in the African population, in heterozygous state in 113 of 3,565 individuals as well as in homozygosity in 1 individual. Both probands also carried a second missense variant in CACNA1C, neither of which was considered to be pathogenic; each had an unaffected son carrying only that second variant, and case 2 had an unaffected sister carrying only the second variant. Patch-clamp studies revealed that the T1787M variant reduces calcium and barium currents by increasing C terminal-mediated autoinhibition, and also increases voltage-dependent inhibition. The authors concluded that T1787M, present in 0.8% of the African population, was a risk factor for ventricular arrhythmia. </p><p>Rodan et al. (2021) identified heterozygous putative truncating mutations in the CACNA1C gene in 11 individuals (P15-P22C) from 8 unrelated families with variable neurologic deficits. The phenotype was not as severe as in those with nontruncating mutations. In 3 families with truncating variants, the variant was paternally inherited with variable penetrance and expressivity. Variants occurred de novo in the other individuals. The variants occurred throughout the gene and included nonsense, frameshift, and splice site, all predicted to result in a truncated protein; all but one were predicted to trigger nonsense-mediated mRNA decay. None of the variants were present in the gnomAD database. Functional studies of the variants and studies of patient cells were not performed. The authors postulated haploinsufficiency as a possible pathogenetic mechanism, but noted that this gene undergoes complex alternative splicing, which presents a challenge in interpreting the effect of the variants. </p><p><strong><em>Exclusion Studies</em></strong></p><p>
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O'Brien et al. (1995) found no defects in several functional segments (II-III loop or IS3/IS3-IS4 segment) of this gene in a malignant hyperthermia kindred. </p>
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<p>Valenzuela et al. (1997) generated knockout mice lacking both forms of Go-alpha (139311) by homologous recombination and studied the muscarinic regulation of calcium channels in cardiac muscles in Go-alpha -/- mice and controls. There was no difference in the effect of isoproterenol on the L-type voltage-dependent calcium channel in ventricular myocytes of both groups, but the inhibitory effect of carbamylcholine was almost completely abolished in the Go-alpha -/- group. This demonstrated that, in the heart, Go-alpha is specifically required for transmission of signals from the muscarinic receptor to the L-type voltage-dependent calcium channel. </p><p>Using positional cloning, Rottbauer et al. (2001) found that mutations in the zebrafish homolog of CACNA1C, which they called C-LTCC, are responsible for the embryonic lethal island beat (isl) phenotype. The mutations abolish L-type calcium currents in isl cardiomyocytes and the ventricle consequently fails to grow and is electrically silent. Rottbauer et al. (2001) concluded that calcium signaling via C-LTCC can regulate heart growth independently of contraction and plays distinctive roles in fashioning both form and function of the 2 developing chambers in zebrafish. </p><p>Oudit et al. (2003) hypothesized that in iron-overload disorders, iron accumulation in the heart depends on ferrous iron permeation through the L-type voltage-dependent calcium channel (LVDCC), a promiscuous divalent cation transporter. Iron overload in mice was associated with increased mortality, systolic and diastolic dysfunction, bradycardia, hypotension, increased myocardial fibrosis, and elevated oxidative stress. Treatment with LVDCC blockers (amlodipine and verapamil) at therapeutic levels inhibited the LVDCC current in cardiomyocytes, attenuated myocardial iron accumulation and oxidative stress, improved survival, prevented hypotension, and preserved heart structure and function. Consistent with the role of these channels in myocardial iron uptake, iron-overloaded transgenic mice with cardiac-specific overexpression of Cacna1c had 2-fold higher myocardial iron and oxidative stress levels, as well as greater impairment in cardiac function, compared with littermate controls. LVDCC blockade was again protective. Oudit et al. (2003) concluded that cardiac L-type voltage-dependent calcium channels are key transporters of iron into cardiomyocytes under iron-overload conditions. </p><p>Schulla et al. (2003) noted that Cacna1c-knockout mice die in utero. They found that pancreatic beta cell-specific knockout of Cacna1c in mice decreased whole-cell Ca(2+) current by approximately 45% and caused almost complete loss of first-phase insulin secretion, resulting in systemic glucose intolerance. Loss of insulin secretion was also associated with the disappearance of a rapid component of exocytosis. </p><p>Using RT-PCR, Smedler et al. (2022) found that Cacna1c was upregulated on day 8 of mouse embryonic stem cell differentiation. Deletion of Cacna1c specifically in neurons of developing forebrain in mice disrupted spontaneous calcium activity. Portions of brains of mutant mice were statistically smaller than controls, and these mice displayed anxiety in behavioral tests, mimicking certain human psychiatric phenotypes. Smedler et al. (2022) proposed that Cacna1c acts as a molecular switch and that its disruption during embryogenesis perturbs Ca(2+) handling and neural development. </p>
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<strong>ALLELIC VARIANTS</strong>
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<strong>20 Selected Examples):</strong>
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<strong>.0001 TIMOTHY SYNDROME</strong>
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CACNA1C, GLY406ARG
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SNP: rs79891110,
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ClinVar: RCV000019199, RCV000058285, RCV000170771, RCV000199739, RCV002354166, RCV003224103, RCV003332999, RCV003985262
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<p>In 13 patients with Timothy syndrome (TS; 601005), Splawski et al. (2004) analyzed the alternatively spliced exon 8A of the CACNA1C gene and identified heterozygosity for a de novo c.1216G-A transition, resulting in a gly406-to-arg (G406R) substitution at a highly conserved residue at the C-terminal end of the sixth transmembrane segment of domain I. Functional analysis revealed that the G406R mutation produced maintained inward Ca(2+) currents by causing nearly complete loss of voltage-dependent channel inactivation. The G406R mutation was not identified in 180 ethnically matched control samples. In 1 family with 2 affected children, the clinically unaffected mother was mosaic for the G406R mutation. </p><p>In a girl who died at age 6 years with severe Timothy syndrome (see 601005) without syndactyly, Splawski et al. (2005) identified a G406R mutation in exon 8 of the CACNA1C gene, which is analogous to that previously found in exon 8A (Splawski et al., 2004). The exon 8 splice variant was found to be highly expressed in heart and brain (80% of CACNA1C mRNA), and this patient had a longer average QT interval and more severe arrhythmias than patients with the analogous mutation in exon 8A. She was born by cesarean section at 38 weeks' gestation due to severe bradycardia, and at birth had 2:1 atrioventricular block with a QTc of 730 ms. Despite receiving an implantable pacemaker in the neonatal period, she had multiple episodes of severe arrhythmias requiring cardioversion or resuscitation in infancy. Cervical sympathetic ganglionectomy and ventricular pacemaker placement at 4 months of age were unsuccessful in reducing arrhythmias. She also experienced seizures, static encephalopathy, and severe developmental delay. She died at age 6 years due to ventricular fibrillation. </p><p>In a severely affected infant with Timothy syndrome, Etheridge et al. (2011) identified heterozygosity for the G406R mutation in exon 8 of the CACNA1C gene. The proband's mildly affected father, who had cutaneous syndactyly of the feet and a prolonged QTc of 480 ms, but who had never experienced syncope or seizure, was also heterozygous for G406R; however, he was found to be mosaic for the mutation, showing only a minor peak for the mutant allele. An unrelated, moderately affected 14-year-old girl, who was not symptomatic until adolescence, was also mosaic for G406R, with a minor peak for the mutant allele. </p><p><strong><em>Variant Function</em></strong></p><p>
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By measuring whole-cell currents in transfected HEK293 cells, Barrett and Tsien (2008) demonstrated that the G406R mutation powerfully and selectively slows voltage-dependent inactivation (VDI), while sparing or possibly speeding the kinetics of Ca(2+)-dependent inactivation (CDI). Dissociation of VDI and CDI was further substantiated by measurements of Ca(2+) channel gating currents. In addition, CDI did not proceed to completeness but leveled off at approximately 50%, consistent with a change in gating modes and not an absorbing inactivation process. </p><p>To explore the effect of the Timothy syndrome mutation G406R in the CaV1.2 channel on the electrical activity and contraction of human cardiomyocytes, Yazawa et al. (2011) reprogrammed human skin cells from Timothy syndrome patients to generate induced pluripotent stem cells, and differentiated those cells into cardiomyocytes. Electrophysiologic recording and calcium imaging studies of these cells revealed irregular contraction, excess calcium influx, prolonged action potentials, irregular electrical activity, and abnormal calcium transients in ventricular-like cells. Yazawa et al. (2011) found that roscovitine, a compound that increases the voltage-dependent inactivation of CaV1.2, restored the electrical and calcium signaling properties of cardiomyocytes from Timothy syndrome patients. Yazawa et al. (2011) concluded that their study provided new opportunities for studying the molecular and cellular mechanisms of cardiac arrhythmias in humans and provided a robust assay for developing drugs to treat these diseases. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0002 TIMOTHY SYNDROME</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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CACNA1C, GLY402SER
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<br />
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SNP: rs80315385,
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ClinVar: RCV000019200, RCV000058284, RCV000422493, RCV001851937
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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 21-year-old man with severe Timothy syndrome (601005) without syndactyly, Splawski et al. (2005) identified a 1204G-A transition in exon 8 of the CACNA1C gene, resulting in a gly402-to-ser (G402S) substitution. The exon 8 splice variant was found to be highly expressed in heart and brain (80% of CACNA1C mRNA), and this patient had a longer average QT interval and more severe arrhythmias than patients with a mutation in exon 8A (see 114205.0001). The patient was apparently well until age 4 years, when he experienced cardiac arrest while at play and was diagnosed with long QT syndrome. He continued to have episodes of cardiac arrest, ultimately receiving an automatic defibrillator. At age 21, he was still experiencing weekly nocturnal cardiac arrhythmias that were associated with night terrors. Comparison of mutant peaks in DNA from oral mucosa and blood revealed that the patient was a mosaic; the authors noted that this might account for his relatively milder phenotype compared to the other patient with a mutation in exon 8 (see 114205.0001). </p><p>In a 13-year-old Finnish girl with Timothy syndrome, Hiippala et al. (2015) identified heterozygosity for the G402S mutation in the CACNA1C gene. Her unaffected parents did not carry the mutation. Calculating the ratio of mutated and normal alleles from the next-generation sequencing (NGS) reads revealed that the proband was mosaic for the mutation, with only 37% of the reads representing the mutated allele and 61% showing the normal allele. Sanger sequencing of blood- and saliva-derived DNA confirmed the mutation; in both samples, the mutation peak was slightly weaker than the normal genotype, consistent with the allele distribution detected by NGS. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0003 BRUGADA SYNDROME 3</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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CACNA1C, GLY490ARG
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<br />
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SNP: rs121912775,
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gnomAD: rs121912775,
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ClinVar: RCV000019201, RCV000058286, RCV000170775, RCV000334098, RCV000586094, RCV000618330, RCV001085545, RCV001256682, RCV003944830
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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 41-year-old male of Turkish descent with Brugada syndrome and a shortened QTc interval (BRGDA3; 611875), Antzelevitch et al. (2007) identified a heterozygous 1468G-A transition in exon 10 of the CACNA1C gene, predicted to result in a gly490-to-arg (G490R) substitution in the cytoplasmic linker between domains I and II within a highly conserved region of the protein. The proband also carried 2 polymorphisms in CACNA1C, P1820L and V1821M, which were found in 31 and 27 of 114 healthy controls, respectively. The G490R mutation was also found in his 2 daughters, who had QTc intervals of 360 and 370 ms, respectively; the daughter with the longer QTc interval also carried a known K897T polymorphism in the KCNH2 gene. Patch-clamp experiments in Chinese hamster ovary (CHO) cells demonstrated a marked reduction in current amplitude of mutant channels compared to wildtype, although voltage at peak current was unchanged; confocal microscopy revealed normal trafficking of channels containing G490R CaV1.2 subunits. The G490R mutation was not found in 640 ethnically matched control alleles. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0004 BRUGADA SYNDROME 3</strong>
|
|
</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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CACNA1C, ALA39VAL
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<br />
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SNP: rs121912776,
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ClinVar: RCV000019202, RCV000058283
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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 44-year-old white male of European descent with Brugada syndrome and a shortened QTc interval (BRGDA3; 611875), Antzelevitch et al. (2007) identified a heterozygous 116C-T transition in exon 2 of the CACNA1C gene, predicted to result in an ala39-to-val (A39V) substitution near the N terminus within a highly conserved region of the protein. The mutation was not found in 404 ethnically matched control alleles. Patch-clamp experiments in CHO cells demonstrated a marked reduction in current amplitude of mutant channels compared to wildtype, although voltage at peak current was unchanged; confocal microscopy revealed a defect in trafficking of A39V CaV1.2 channels. </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>.0005 LONG QT SYNDROME 8</strong>
|
|
</span>
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</h4>
|
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</div>
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<div>
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<span class="mim-text-font">
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|
CACNA1C, PRO857ARG
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<br />
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SNP: rs750835733,
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|
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gnomAD: rs750835733,
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|
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ClinVar: RCV000782177, RCV001856203
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|
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</span>
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>By trio-based whole-exome sequencing in a large multigeneration family segregating long QT syndrome (LQT8; 618447) without mutation in known causative genes, Boczek et al. (2013) identified heterozygosity for a c.2570C-G transition in the CACNA1C gene, resulting in a pro857-to-arg (P857R) substitution in the PEST domain. The mutation segregated with the disease in the family and was not found in the 1000 Genomes Project or NHLBI ESP databases or in 200 Danish Beijing Genomics Institute exomes or an additional 680 ethnically matched controls. Functional studies of the variant revealed a 113% increase in peak current amplitude and an increase in surface expression of the Cav1.2 channel compared to wildtype, consistent with a gain of function. </p>
|
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0006 LONG QT SYNDROME 8</strong>
|
|
</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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|
|
|
CACNA1C, PRO857LEU
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|
|
|
|
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<br />
|
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|
|
SNP: rs750835733,
|
|
|
|
|
|
gnomAD: rs750835733,
|
|
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|
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ClinVar: RCV000208178, RCV000782178
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|
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</span>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>By sequencing the CACNA1C gene in an asymptomatic 15-year-old boy who was diagnosed with long QT syndrome (LQT8; 618447) following the unexplained death of his 12-year-old sister during sleep, Boczek et al. (2013) identified a c.2570C-T transition, resulting in a pro857-to-leu (P857L) substitution in the PEST domain. No mutations in previously identified causative genes had been found, and the mutation segregated with the phenotype in available family members tested, including the unaffected father and affected mother and maternal grandmother. The variant was not found in the 1000 Genomes Project or NHLBI Exome Sequencing project databases or in 680 controls. No functional studies were reported. </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>.0007 LONG QT SYNDROME 8</strong>
|
|
</span>
|
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</h4>
|
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
CACNA1C, LYS834GLU
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|
|
|
<br />
|
|
|
|
SNP: rs1555836187,
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|
|
|
|
|
|
|
ClinVar: RCV000782179, RCV005092337
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>By sequencing the CACNA1C gene in a 15-year-old girl with long QT syndrome-8 (LQT8; 618447), who had a personal history of syncope, QTc of 475 ms, and a negative family history, Boczek et al. (2013) identified a c.2500A-G transition, resulting in a lys834-to-glu (K834E) substitution in the PEST domain. The variant was not found in the 1000 Genomes Project or NHLBI Exome Sequencing project databases or in 680 controls. No functional studies were reported. </p>
|
|
</span>
|
|
</div>
|
|
|
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<div>
|
|
<br />
|
|
</div>
|
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|
|
</div>
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|
|
|
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<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0008 LONG QT SYNDROME 8</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
CACNA1C, ARG858HIS ({dbSNP rs786205753})
|
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|
|
<br />
|
|
|
|
SNP: rs786205753,
|
|
|
|
|
|
|
|
ClinVar: RCV000550877, RCV000782180, RCV001509415, RCV002453577
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members of 3 Japanese families (families 4, 5 and 6) with long QT syndrome (LQT8; 618447), Fukuyama et al. (2014) identified heterozygosity for a c.2573G-A transition in the CACNA1C gene, resulting in an arg858-to-his (R858H) substitution. Functional studies showed that the peak calcium currents in R858H mutant channels were significantly larger than those of wildtype. Activation of the R858H channel showed an approximately 2 mV negative shift compared with wildtype, whereas inactivation of the mutant channel showed an approximately 2 mV positive shift, consistent with a gain-of-function effect. The variant was not found in the NHLBI Exome Variant Server database or in 500 reference alleles from 250 Japanese controls. </p><p>Gardner et al. (2019) identified heterozygosity for a c.2573G-A transition (c.2573G-A, NM_000719.6) in the CACNA1C gene, resulting in the R858H substitution, in affected members of a 5-generation European family segregating long QT. The R858H variant was not found in the ExAC database. No functional studies were performed. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0009 LONG QT SYNDROME 8</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
CACNA1C, ALA582ASP
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1568469857,
|
|
|
|
|
|
|
|
ClinVar: RCV000782181
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 12-year-old girl and her mother with long QT syndrome (LQT8; 618447), Fukuyama et al. (2014) identified heterozygosity for a c.1745C-A transition in the CACNA1C gene, resulting in an ala582-to-asp (A582D) substitution. The A582D mutant channel displayed significantly slower inactivation compared with wildtype. Inactivation of the mutant A582D channel showed an approximately 2 mV positive shift compared to wildtype, indicating a gain-of-function effect. The variant was not found in the NHLBI Exome Variant Server database or in 500 reference alleles from 250 Japanese controls. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
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|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 LONG QT SYNDROME 8</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
CACNA1C, ILE1475MET
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1569139160,
|
|
|
|
|
|
|
|
ClinVar: RCV000782182
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 14-year-old girl with long QT syndrome (LQT8; 618447), Wemhoner et al. (2015) identified heterozygosity for a c.4425C-G transition in the CACNA1C gene, resulting in an ile1475-to-met (I1475M) substitution. The I1475M mutation showed a leftward shift in the peak current amplitude compared to wildtype, indicating a gain-of-function effect. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
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|
|
</div>
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|
|
|
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<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0011 NEURODEVELOPMENTAL DISORDER WITH HYPOTONIA, LANGUAGE DELAY, AND SKELETAL DEFECTS WITH SEIZURES</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
CACNA1C, VAL1363MET
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1555968941,
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|
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|
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|
|
ClinVar: RCV000523935, RCV002283488, RCV003985375
|
|
|
|
|
|
</span>
|
|
</div>
|
|
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In an 18-month-old girl, born of unrelated parents, with neurodevelopmental disorder with hypotonia, language delay, and skeletal defects with seizures (NEDHLSS; 620029), Bozarth et al. (2018) identified a de novo heterozygous c.4087G-A transition (c.4087G-A, NM_000719.6) in the CACNA1C gene, resulting in a val1363-to-met (V1363M) substitution at a highly conserved residue in the fifth transmembrane helix in domain IV. The mutation, which was found by trio-based exome sequencing, was not present in public databases, including gnomAD. Functional studies of the variant and studies of patient cells were not performed. The patient had poor overall growth, hypotonia, severe global developmental delay with inability to track visually, mild distal skeletal anomalies, and early-onset refractory seizures. She did not have cardiac involvement. </p>
|
|
</span>
|
|
</div>
|
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<div>
|
|
<br />
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|
</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>.0012 NEURODEVELOPMENTAL DISORDER WITH HYPOTONIA, LANGUAGE DELAY, AND SKELETAL DEFECTS WITH SEIZURES</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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|
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<div>
|
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<span class="mim-text-font">
|
|
|
|
CACNA1C, LEU614PRO
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|
|
|
|
|
<br />
|
|
|
|
SNP: rs1057518994,
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|
|
|
|
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|
|
ClinVar: RCV000415023, RCV002283478
|
|
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|
|
|
</span>
|
|
</div>
|
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|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 24-year-old man (P8) with neurodevelopmental disorder with hypotonia, language delay, and skeletal defects with seizures (NEDHLSS; 620029), Rodan et al. (2021) a de novo heterozygous c.1841T-C transition (c.1841T-C, NM_000719) in the CACNA1C gene, resulting in a leu614-to-pro (L614P) substitution. The mutation, which was found by exome sequencing, was not present in the gnomAD database. Electrophysiologic patch-clamp voltage studies in transfected HEK293 cells showed that the CACNA1C L614P tended to cause a current increase, suggesting a gain of function, but the differences were not statistically significant. The patient had no cardiac involvement. </p>
|
|
</span>
|
|
</div>
|
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<div>
|
|
<br />
|
|
</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>.0013 NEURODEVELOPMENTAL DISORDER WITH HYPOTONIA, LANGUAGE DELAY, AND SKELETAL DEFECTS WITH SEIZURES</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
CACNA1C, LEU657PHE
|
|
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<br />
|
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|
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|
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|
|
ClinVar: RCV002284054
|
|
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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 15-year-old girl (P9) with neurodevelopmental disorder with hypotonia, language delay, and skeletal defects with seizures (NEDHLSS; 620029), Rodan et al. (2021) identified a de novo heterozygous c.1969C-T transition (c.1969C-T, NM_000719) in the CACNA1C gene, resulting in a leu657-to-phe (L657F) substitution. The mutation, which was found by exome sequencing, was not present in the gnomAD database. Compared to wildtype, the L657F variant was associated with increased CACNA1C protein levels. Electrophysiologic patch-clamp voltage studies in transfected HEK293 cells showed that the L657F mutation resulted in a dramatic increase in calcium current compared to controls, suggesting a gain-of-function effect. The patient had no cardiac involvement. </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>.0014 NEURODEVELOPMENTAL DISORDER WITH HYPOTONIA, LANGUAGE DELAY, AND SKELETAL DEFECTS WITH SEIZURES</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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CACNA1C, LEU1408VAL
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<br />
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ClinVar: RCV002284055
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a 6.8-year-old girl (P12) with neurodevelopmental disorder with hypotonia, language delay, and skeletal defects with seizures (NEDHLSS; 620029), Rodan et al. (2021) identified a de novo heterozygous c.4222C-G transversion (c.4222C-G, NM_000719) in the CACNA1C gene, resulting in a leu1408-to-val (L1408V) substitution. The mutation, which was found by exome sequencing, was not present in the gnomAD database. Additional variants in other genes were also identified, including in CACNA1G (604065). Electrophysiologic patch-clamp voltage studies in transfected HEK293 cells showed that the CACNA1C L1408V mutation resulted in an overall reduction in current density compared to controls, with unaltered activation kinetics. The patient had possible cardiac ventricular conduction delay and trace cardiac valvular regurgitation. </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>.0015 TIMOTHY SYNDROME</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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CACNA1C, ILE1166THR
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<br />
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SNP: rs797044881,
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ClinVar: RCV000190696, RCV001795308
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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 boy who died at age 3.75 years with QT prolongation and a Timothy syndrome phenotype (TS; 601005), Boczek et al. (2015) identified heterozygosity for a de novo c.3497T-C transition in exon 27 of the CACNA1C gene, resulting in an ile1166-to-thr (I1166T) substitution at a highly conserved residue within the third repeat. Sanger sequencing confirmed the mutation and its absence in his parents; the variant was also not present in the 1000 Genomes Project or NHLBI EVS databases. Whole-cell patch-clamp analysis of the heterologously expressed L-type calcium channel revealed that the I1166T mutation causes an overall loss of current density with a gain-of-function shift in activation, resulting in an increased window current. </p>
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</span>
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</div>
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<div>
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</div>
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</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>.0016 TIMOTHY SYNDROME</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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CACNA1C, ARG518CYS
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<br />
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SNP: rs786205748,
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ClinVar: RCV000170780, RCV000232889, RCV002250585, RCV002287377, RCV002399602
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In affected individuals from 2 families (pedigrees 1 and 2) with QT prolongation, hypertrophic cardiomyopathy, congenital heart defects, and/or sudden cardiac death (TS; 601005), Boczek et al. (2015) identified heterozygosity for a c.1552C-T transition in exon 12 of the CACNA1C gene, resulting in an arg518-to-cys (R58C) substitution that segregated with disease. None of the affected individuals exhibited extracardiac manifestations of Timothy syndrome. Functional analysis demonstrated that the R518C variant results in a complex electrophysiologic phenotype including an overall approximately 60% loss of current density, increased window and late currents, and decelerating voltage-dependent inactivation resulting in constitutively active L-type calcium channels. In addition, confocal imaging showed a higher proportion of mutant channels in the center versus the periphery of the cell compared to wildtype channels, suggesting the possibility of a trafficking defect. </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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<h4>
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<span class="mim-font">
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<strong>.0017 TIMOTHY SYNDROME</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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CACNA1C, ARG518HIS
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<br />
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SNP: rs1057517711,
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gnomAD: rs1057517711,
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ClinVar: RCV000412828, RCV000584800, RCV000631664, RCV001808785, RCV002230228, RCV002288982, RCV002402099
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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 sisters and a female cousin (pedigree 3) with QT prolongation, hypertrophic cardiomyopathy, congenital heart defects, and/or sudden cardiac death (TS; 601005), Boczek et al. (2015) identified heterozygosity for a variant in exon 12 of the CACNA1C gene, resulting in an arg518-to-his (R518H) substitution. DNA was unavailable from their affected mothers and maternal grandfather. None of the affected individuals in this family exhibited extracardiac manifestations of Timothy syndrome. Functional analysis demonstrated that the R518H variant results in a complex electrophysiologic phenotype including an overall approximately 60% loss of current density as well as increased window and late currents. </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>.0018 TIMOTHY SYNDROME</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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CACNA1C, SER643PHE
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<br />
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ClinVar: RCV002286523, RCV004697202
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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 14-year-old Japanese boy with a prolonged QT interval, dysmorphic facial features, intellectual disability, seizures, and autism spectrum disorder (TS; 601005), Ozawa et al. (2018) screened a gene panel and identified heterozygosity for a de novo ser643-to-phe (S643F) substitution in the CACNA1C gene, at a highly conserved residue within the S4-S5 linker of domain II. Sanger sequencing confirmed the mutation and its absence in his unaffected parents and sibs, and it was not present in the 1000 Genomes Project or NHLBI EVS databases. The patient experienced cardiac arrest at age 13 years, followed by recurrent episodes of torsades de pointes and ventricular fibrillation, and he underwent placement of a cardioverter-defibrillator device. Functional analysis in a heterologous expression system demonstrated an increase in late CaV1.2 currents as well as a marked reduction in peak currents with the S643F mutant compared to wildtype CACNA1C. Evaluation of inactivation gating showed an extraordinary decrease in voltage-dependent inactivation with the S643F channels, which exhibited inactivation levels of 38 to 42% at maximum and never reached a fully inactivated state. </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>.0019 TIMOTHY SYNDROME</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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CACNA1C, GLU1115LYS
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<br />
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SNP: rs199473391,
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ClinVar: RCV000058287, RCV000475353, RCV001795047, RCV002490650, RCV004786338
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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 14-year-old boy with QT prolongation, bradycardia, seizures, and autism spectrum disorder (TS; 601005), Ye et al. (2019) analyzed a 13-gene long-QT syndrome panel and identified heterozygosity for a glu1115-to-lys (E1115K) substitution the CACNA1C gene, at a highly conserved residue within the DIII-S5/S6 pore region. The mutation was not found in his unaffected mother or half sibs, or in the gnomAD database; DNA was unavailable from his father. Functional analysis showed that the mutation eliminates intrinsic calcium channel activity and converts the L-type calcium channel into a nonselective monovalent cation channel, with marked increases in both peak and persistent inward sodium currents and outward potassium/cesium currents. </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>.0020 VARIANT OF UNKNOWN SIGNIFICANCE</strong>
|
|
</span>
|
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</h4>
|
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</div>
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<div>
|
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<span class="mim-text-font">
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CACNA1C, LEU566PRO
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<br />
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ClinVar: RCV002287885
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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>This variant is classified as a variant of unknown significance because its contribution to hyperinsulinemic hypoglycemia (see 256450) has not been confirmed.</p><p>In a 17-year-old girl with nonsyndromic congenital hyperinsulinemic hypoglycemia, Kummer et al. (2022) identified heterozygosity for a c.1679T-C transition (c.1679T-C, NM_000719.6) in exon 13 of the CACNA1C gene, resulting in a leu566-to-pro (L566P) substitution at a highly conserved residue within the S2-S3 linker of the second domain. The mutation was not found in the proband's unaffected mother or in the 1000 Genomes Project or gnomAD databases; DNA was unavailable from the deceased father. Sanger sequencing of DNA from blood and buccal swabs from the proband showed no indication of low-grade mosaicism restricted to particular tissues. The proband also carried 2 heterozygous variants of unknown significance in genes associated with disturbed glucose regulation, ALMS1 (606844) and ETFB (130410). The proband had a generalized seizure after overnight fasting at 8 months of age; during the subsequent hospitalization recurrent episodes of hypoglycemia were documented, and metabolic evaluation showed a typical profile for hyperinsulinemic hypoglycemia. Echocardiography was normal and remained so. Electrocardiography showed QTc intervals in the normal or upper normal range, with QTc prolongation on only 2 occasions, once during treatment with nifedipine; there were no signs of cardiac arrhythmias. Electrophysiologic characterization of CACNA1C L566P mutant channels by voltage-clamp recordings in Xenopus oocytes revealed loss of function due to reduced peak current amplitudes, as well as diverse gain-of-function effects due to impaired voltage-dependent inactivation, including a slowing of the rate, an altered voltage dependence, and a reduced steady-state of inactivation. Technical difficulties prevented the establishment of a beta-cell model for validating the consequences of the mutant channels. The authors reviewed the medical records of 5 patients who had Timothy syndrome (601005) and reported hypoglycemic episodes, but noted that those episodes appeared to be biochemically more diverse than congenital hyperinsulinism. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>REFERENCES</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<ol>
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<li>
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<p class="mim-text-font">
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Aerssens, J., Chaffanet, M., Baens, M., Matthijs, G., Van Den Berghe, H., Cassiman, J.-J., Marynen, P.
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<strong>Regional assignment of seven loci to 12p13.2-pter by PCR analysis of somatic cell hybrids containing the der(12) or the der(X) chromosome from a mesothelioma showing t(X;12)(q22;p13).</strong>
|
|
Genomics 20: 119-121, 1994.
|
|
|
|
|
|
[PubMed: 8020938]
|
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|
|
|
|
[Full Text: https://doi.org/10.1006/geno.1994.1136]
|
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|
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</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
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Antzelevitch, C., Pollevick, G. D., Cordeiro, J. M., Casis, O., Sanguinetti, M. C., Aizawa, Y., Guerchicoff, A., Pfeiffer, R., Oliva, A., Wollnik, B., Gelber, P., Bonaros, E. P., Jr., and 11 others.
|
|
<strong>Loss-of-function mutations in the cardiac calcium channel underlie a new clinical entity characterized by ST-segment elevation, short QT intervals, and sudden cardiac death.</strong>
|
|
Circulation 115: 442-449, 2007.
|
|
|
|
|
|
[PubMed: 17224476]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1161/CIRCULATIONAHA.106.668392]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
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Barrett, C. F., Tsien, R. W.
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<strong>The Timothy syndrome mutation differentially affects voltage- and calcium-dependent inactivation of Ca(V)1.2 L-type calcium channels.</strong>
|
|
Proc. Nat. Acad. Sci. 105: 2157-2162, 2008.
|
|
|
|
|
|
[PubMed: 18250309]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1073/pnas.0710501105]
|
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|
|
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</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
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Blancard, M., Debbiche, A., Kato, K., Cardin, C., Sabrina, G., Gandjbakhch, E., Probst, V., Haissaguerre, M., Extramiana, F., Hocini, M., Olivier, G., Leenhardt, A., Guicheney, P., Rougier, J.-S.
|
|
<strong>An African loss-of-function CACNA1C variant p.T1787M associated with a risk of ventricular fibrillation.</strong>
|
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Sci. Rep. 8: 14619, 2018.
|
|
|
|
|
|
[PubMed: 30279520]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/s41598-018-32867-4]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Blumenstein, Y., Kanevsky, N., Sahar, G., Barzilai, R., Ivanina, T., Dascal, N.
|
|
<strong>A novel long N-terminal isoform of human L-type Ca(2+) channel is up-regulated by protein kinase C.</strong>
|
|
J. Biol. Chem. 277: 3419-3423, 2002.
|
|
|
|
|
|
[PubMed: 11741969]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1074/jbc.C100642200]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Boczek, N. J., Best, J. M., Tester, D. J., Giudicessi, J. R., Middha, S., Evans, J. M., Kamp, T. J., Ackerman, M. J.
|
|
<strong>Exome sequencing and systems biology converge to identify novel mutations in the L-type calcium channel, CACNA1C, linked to autosomal dominant long QT syndrome.</strong>
|
|
Circ. Cardiovasc. Genet. 6: 279-289, 2013.
|
|
|
|
|
|
[PubMed: 23677916]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1161/CIRCGENETICS.113.000138]
|
|
|
|
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|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Boczek, N. J., Miller, E. M., Ye, D., Nesterenko, V. V., Tester, D. J., Antzelevitch, C., Czosek, R. J., Ackerman, M. J., Ware, S. M.
|
|
<strong>Novel Timothy syndrome mutation leading to increase in CACNA1C window current.</strong>
|
|
Heart Rhythm 12: 211-219, 2015.
|
|
|
|
|
|
[PubMed: 25260352]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1016/j.hrthm.2014.09.051]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Boczek, N. J., Ye, D., Jin, F., Tester, D. J., Huseby, A., Bos, J. M., Johnson, A. J., Kanter, R., Ackerman, M. J.
|
|
<strong>Identification and functional characterization of a novel CACNA1C-mediated cardiac disorder characterized by prolonged QT intervals with hypertrophic cardiomyopathy, congenital heart defects, and sudden cardiac death.</strong>
|
|
Circ. Arrhythm. Electrophysiol. 8: 1122-1132, 2015.
|
|
|
|
|
|
[PubMed: 26253506]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1161/CIRCEP.115.002745]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Bozarth, X., Dines, J. N., Cong, Q., Mirzaa, G. M., Foss, K., Lawrence Merritt, J., Thies, J., Mefford, H. C., Novotny, E.
|
|
<strong>Expanding clinical phenotype in CACNA1C related disorders: From neonatal onset severe epileptic encephalopathy to late-onset epilepsy.</strong>
|
|
Am. J. Med. Genet. 176A: 2733-2739, 2018.
|
|
|
|
|
|
[PubMed: 30513141]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1002/ajmg.a.40657]
|
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|
</p>
|
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</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
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Cheng, H., Lederer, W. J., Cannell, M. B.
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|
<strong>Calcium sparks: elementary events underlying excitation-contraction coupling in heart muscle.</strong>
|
|
Science 262: 740-744, 1993.
|
|
|
|
|
|
[PubMed: 8235594]
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|
[Full Text: https://doi.org/10.1126/science.8235594]
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</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Dick, I. E., Tadross, M. R., Liang, H., Tay, L. H., Yang, W., Yue, D. T.
|
|
<strong>A modular switch for spatial Ca(2+) selectivity in the calmodulin regulation of Ca(v) channels.</strong>
|
|
Nature 451: 830-834, 2008.
|
|
|
|
|
|
[PubMed: 18235447]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/nature06529]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Dolmetsch, R. E., Pajvani, U., Fife, K., Spotts, J. M., Greenberg, M. E.
|
|
<strong>Signaling to the nucleus by an L-type calcium channel-calmodulin complex through the MAP kinase pathway.</strong>
|
|
Science 294: 333-339, 2001.
|
|
|
|
|
|
[PubMed: 11598293]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1126/science.1063395]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Etheridge, S. P., Bowles, N. E., Arrington, C. B., Pilcher, T., Rope, A., Wilde, A. A. M., Alders, M., Saarel, E. V., Tavernier, R., Timothy, K. W., Tristani-Firouzi, M.
|
|
<strong>Somatic mosaicism contributes to phenotypic variation in Timothy syndrome.</strong>
|
|
Am. J. Med. Genet. 155A: 2578-2583, 2011.
|
|
|
|
|
|
[PubMed: 21910241]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1002/ajmg.a.34223]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Fukuyama, M., Wang, Q., Kato, K., Ohno, S., Ding, W.-G., Toyoda, F., Itoh, H., Kimura, H., Makiyama, T., Ito, M., Matsuura, H., Horie, M.
|
|
<strong>Long QT syndrome type 8: novel CACNA2C mutations causing QT prolongation and variant phenotypes.</strong>
|
|
Europace 16: 1828-1837, 2014.
|
|
|
|
|
|
[PubMed: 24728418]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1093/europace/euu063]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Gardner, R. J. M., Crozier, I. G., Binfield, A. L., Love, D. R., Lehnert, K., Gibson, K., Lintott, C. J., Snell, R. G., Jacobsen, J. C., Jones, P. P., Waddell-Smith, K. E., Kennedy, M. A., Skinner, J. R.
|
|
<strong>Penetrance and expressivity of the R858H CACNA1C variant in a five-generation pedigree segregating an arrhythmogenic channelopathy.</strong>
|
|
Molec. Genet. Genomic Med. 7: e00476, 2019. Note: Electronic Article.
|
|
|
|
|
|
[PubMed: 30345660]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1002/mgg3.476]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Gomez-Ospina, N., Tsuruta, F., Barreto-Chang, O., Hu, L., Dolmetsch, R.
|
|
<strong>The C terminus of the L-type voltage-gated calcium channel Ca(V)1.2 encodes a transcription factor.</strong>
|
|
Cell 127: 591-606, 2006.
|
|
|
|
|
|
[PubMed: 17081980]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1016/j.cell.2006.10.017]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Hiippala, A., Tallila, J., Myllykangas, S., Koskenvuo, J. W., Alastalo, T.-P.
|
|
<strong>Expanding the phenotype of Timothy syndrome type 2: an adolescent with ventricular fibrillation but normal development.</strong>
|
|
Am. J. Med. Genet. 167A: 629-634, 2015.
|
|
|
|
|
|
[PubMed: 25691416]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1002/ajmg.a.36924]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Klockner, U., Mikala, G., Eisfeld, J., Iles, D. E., Strobeck, M., Mershon, J. L., Schwartz, A., Varadi, G.
|
|
<strong>Properties of three COOH-terminal splice variants of a human cardiac L-type Ca(2+)-channel alpha-1-subunit.</strong>
|
|
Am. J. Physiol. 272: H1372-H1381, 1997.
|
|
|
|
|
|
[PubMed: 9087614]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1152/ajpheart.1997.272.3.H1372]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Kosaki, R., Ono, H., Terashima, H., Kosaki, K.
|
|
<strong>Timothy syndrome-like condition with syndactyly but without prolongation of the QT interval.</strong>
|
|
Am. J. Med. Genet. 176A: 1657-1661, 2018.
|
|
|
|
|
|
[PubMed: 29736926]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1002/ajmg.a.38833]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Kummer, S., Rinne, S., Seemann, G., Bachmann, N., Timothy, K., Thornton, P. S., Pillekamp, F., Mayatepek, E., Bergmann, C., Meissner, T., Decher, N.
|
|
<strong>Hyperinsulinemic hypoglycemia associated with a CaV1.2 variant with mixed gain- and loss-of-function effects.</strong>
|
|
Int. J. Molec. Sci. 23: 8097, 2022.
|
|
|
|
|
|
[PubMed: 35897673]
|
|
|
|
|
|
[Full Text: https://doi.org/10.3390/ijms23158097]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Liu, G., Papa, A., Katchman, A. N., Zakharov, S. I., Roybal, D., Hennessey, J. A., Kushner, J., Yang, L., Chen, B.-X., Kushnir, A., Dangas, K., Gygi, S. P., Pitt, G. S., Colecraft, H. M., Ben-Johny, M., Kalocsay, M., Marx, S. O.
|
|
<strong>Mechanism of adrenergic Ca(V)1.2 stimulation revealed by proximity proteomics.</strong>
|
|
Nature 577: 695-700, 2020.
|
|
|
|
|
|
[PubMed: 31969708]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/s41586-020-1947-z]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Liu, W., Deng, J., Wang, G., Zhang, C., Luo, X., Yan, D., Su, Q., Liu, J.
|
|
<strong>KCNE2 modulates cardiac L-type Ca(2+) channel.</strong>
|
|
J. Molec. Cell. Cardiol. 72: 208-218, 2014.
|
|
|
|
|
|
[PubMed: 24681347]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1016/j.yjmcc.2014.03.013]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Mori, M. X., Erickson, M. G., Yue, D. T.
|
|
<strong>Functional stoichiometry and local enrichment of calmodulin interacting with Ca(2+) channels.</strong>
|
|
Science 304: 432-435, 2004.
|
|
|
|
|
|
[PubMed: 15087548]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1126/science.1093490]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
O'Brien, R. O., Taske, N. L., Hansbro, P. M., Matthaei, K. I., Hogan, S. P., Denborough, M. A., Foster, P. S.
|
|
<strong>Exclusion of defects in the skeletal muscle specific regions of the DHPR alpha-1 subunit as frequent causes of malignant hyperthermia.</strong>
|
|
J. Med. Genet. 32: 913-914, 1995.
|
|
|
|
|
|
[PubMed: 8592342]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1136/jmg.32.11.913]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Oudit, G. Y., Sun, H., Trivieri, M. G., Koch, S. E., Dawood, F., Ackerley, C., Yazdanpanah, M., Wilson, G. J., Schwartz, A., Liu, P. P., Backx, P. H.
|
|
<strong>L-type Ca(2+) channels provide a major pathway for iron entry into cardiomyocytes in iron-overload cardiomyopathy.</strong>
|
|
Nature Med. 9: 1187-1194, 2003.
|
|
|
|
|
|
[PubMed: 12937413]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/nm920]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Ozawa, J., Ohno, S., Saito, H., Saitoh, A., Matsuura, H., Horie, M.
|
|
<strong>A novel CACNA1C mutation identified in a patient with Timothy syndrome without syndactyly exerts both marked loss- and gain-of-function effects.</strong>
|
|
HeartRhythm Case Rep. 4: 273-277, 2018.
|
|
|
|
|
|
[PubMed: 30023270]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1016/j.hrcr.2018.03.003]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Panagiotakos, G., Haveles, C., Arjun, A., Petrova, R., Rana, A., Portmann, T., Pasca, S. P., Palmer, T. D., Dolmetsch, R. E.
|
|
<strong>Aberrant calcium channel splicing drives defects in cortical differentiation in Timothy syndrome.</strong>
|
|
eLife 8: e51037, 2019.
|
|
|
|
|
|
[PubMed: 31868578]
|
|
|
|
|
|
[Full Text: https://doi.org/10.7554/eLife.51037]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Park, C. Y., Shcheglovitov, A., Dolmetsch, R.
|
|
<strong>The CRAC channel activator STIM1 binds and inhibits L-type voltage-gated calcium channels.</strong>
|
|
Science 330: 101-105, 2010.
|
|
|
|
|
|
[PubMed: 20929812]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1126/science.1191027]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Perez-Reyes, E., Wei, X., Castellano, A., Birnbaumer, L.
|
|
<strong>Molecular diversity of L-type calcium channels: evidence for alternative splicing of the transcripts of three non-allelic genes.</strong>
|
|
J. Biol. Chem. 265: 20430-20436, 1990.
|
|
|
|
|
|
[PubMed: 2173707]
|
|
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Powers, P. A., Gregg, R. G., Hogan, K.
|
|
<strong>Linkage mapping of the human gene for the alpha-1 subunit of the cardiac DHP-sensitive Ca(2+) channel (CACNL1A1) to chromosome 12p13.2-pter using a dinucleotide repeat.</strong>
|
|
Genomics 14: 206-207, 1992.
|
|
|
|
|
|
[PubMed: 1330882]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1016/s0888-7543(05)80312-x]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Powers, P. A., Gregg, R. G., Lalley, P. A., Liao, M., Hogan, K.
|
|
<strong>Assignment of the human gene for the alpha-1 subunit of the cardiac DHP-sensitive Ca(2+) channel (CCHL1A1) to chromosome 12p12-pter.</strong>
|
|
Genomics 10: 835-839, 1991.
|
|
|
|
|
|
[PubMed: 1653763]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1016/0888-7543(91)90471-p]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Rodan, L. H., Spillmann, R. C., Kurata, H. T., Lamothe, S. M., Maghera, J., Jamra, R. A., Alkelai, A., Antonarakis, S. E., Atallah, I., Bar-Yosef, O., Bilan, F., Bjorgo, K., and 46 others.
|
|
<strong>Phenotypic expansion of CACNA1C-associated disorders to include isolated neurological manifestations.</strong>
|
|
Genet. Med. 23: 1922-1932, 2021. Note: Erratum: Genet. Med. 23: 2016 only, 2021.
|
|
|
|
|
|
[PubMed: 34163037]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/s41436-021-01232-8]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Rottbauer, W., Baker, K., Wo, Z. G., Mohideen, M.-A. P. K., Cantiello, H. F., Fishman, M. C.
|
|
<strong>Growth and function of the embryonic heart depend upon the cardiac-specific L-type calcium channel alpha-1 subunit.</strong>
|
|
Dev. Cell 1: 265-275, 2001.
|
|
|
|
|
|
[PubMed: 11702785]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1016/s1534-5807(01)00023-5]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Saada, N., Dai, B., Echetebu, C., Sarna, S. K., Palade, P.
|
|
<strong>Smooth muscle uses another promoter to express primarily a form of human Ca(v)1.2 L-type calcium channel different from the principal heart form.</strong>
|
|
Biochem. Biophys. Res. Commun. 302: 23-28, 2003.
|
|
|
|
|
|
[PubMed: 12593842]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1016/s0006-291x(03)00097-4]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Schulla, V., Renstrom, E., Feil, R., Feil, S., Franklin, I., Gjinovci, A., Jing, X. J., Laux, D., Lundquist, I., Magnuson, M. A., Obermuller, S., Olofsson, C. S., Salehi, A., Wendt, A., Klugbauer, N., Wollheim, C. B., Rorsman, P., Hofmann, F.
|
|
<strong>Impaired insulin secretion and glucose tolerance in beta cell-selective Ca(v)1.2 Ca(2+) channel null mice.</strong>
|
|
EMBO J. 22: 3844-3854, 2003.
|
|
|
|
|
|
[PubMed: 12881419]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1093/emboj/cdg389]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Schultz, D., Mikala, G., Yatani, A., Engle, D. B., Iles, D. E., Segers, B., Sinke, R. J., Weghuis, D. O., Klockner, U., Wakamori, M., Wang, J.-J., Melvin, D., Varadi, G., Schwartz, A.
|
|
<strong>Cloning, chromosomal localization, and functional expression of the alpha-1 subunit of the L-type voltage-dependent calcium channel from normal human heart.</strong>
|
|
Proc. Nat. Acad. Sci. 90: 6228-6232, 1993.
|
|
|
|
|
|
[PubMed: 8392192]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1073/pnas.90.13.6228]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Smedler, E., Louhivuori, L., Romanov, R. A., Masini, D., Dehnisch Ellstrom, I., Wang, C., Caramia, M., West, Z., Zhang, S., Rebellato, P., Malmersjo, S., Brusini, I., Kanatani, S., Fisone, G., Harkany, T., Uhlen, P.
|
|
<strong>Disrupted Cacna1c gene expression perturbs spontaneous Ca(2+) activity causing abnormal brain development and increased anxiety.</strong>
|
|
Proc. Nat. Acad. Sci. 119: e2108768119, 2022.
|
|
|
|
|
|
[PubMed: 35135875]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1073/pnas.2108768119]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Soldatov, N. M., Zuhlke, R. D., Bouron, A., Reuter, H.
|
|
<strong>Molecular structures involved in L-type calcium channel inactivation: role of the carboxyl-terminal region encoded by exons 40-42 in alpha-1C subunit in the kinetics and Ca(2+) dependence of inactivation.</strong>
|
|
J. Biol. Chem. 272: 3560-3566, 1997.
|
|
|
|
|
|
[PubMed: 9013606]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1074/jbc.272.6.3560]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Soldatov, N. M.
|
|
<strong>Molecular diversity of L-type Ca(2+) channel transcripts in human fibroblasts.</strong>
|
|
Proc. Nat. Acad. Sci. 89: 4628-4632, 1992.
|
|
|
|
|
|
[PubMed: 1316612]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1073/pnas.89.10.4628]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Soldatov, N. M.
|
|
<strong>Genomic structure of human L-type Ca(2+) channel.</strong>
|
|
Genomics 22: 77-87, 1994.
|
|
|
|
|
|
[PubMed: 7959794]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1006/geno.1994.1347]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Splawski, I., Timothy, K. W., Decher, N., Kumar, P., Sachse, F. B., Beggs, A. H., Sanguinetti, M. C., Keating, M. T.
|
|
<strong>Severe arrhythmia disorder caused by cardiac L-type calcium channel mutations.</strong>
|
|
Proc. Nat. Acad. Sci. 102: 8089-8096, 2005.
|
|
|
|
|
|
[PubMed: 15863612]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1073/pnas.0502506102]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Splawski, I., Timothy, K. W., Sharpe, L. M., Decher, N., Kumar, P., Bloise, R., Napolitano, C., Schwartz, P. J., Joseph, R. M., Condouris, K., Tager-Flusberg, H., Priori, S. G., Sanguinetti, M. C., Keating, M. T.
|
|
<strong>Ca(V)1.2 calcium channel dysfunction causes a multisystem disorder including arrhythmia and autism.</strong>
|
|
Cell 119: 19-31, 2004.
|
|
|
|
|
|
[PubMed: 15454078]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1016/j.cell.2004.09.011]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Sun, W., McPherson, J. D., Hoang, D. Q., Wasmuth, J. J., Evans, G. A., Montal, M.
|
|
<strong>Mapping of a human brain voltage-gated calcium channel to human chromosome 12p13-pter.</strong>
|
|
Genomics 14: 1092-1094, 1992.
|
|
|
|
|
|
[PubMed: 1335957]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1016/s0888-7543(05)80135-1]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Tiwari, S., Zhang, Y., Heller, J., Abernethy, D. R., Soldatov, N. M.
|
|
<strong>Atherosclerosis-related molecular alteration of the human Ca(V)1.2 calcium channel alpha-1C subunit.</strong>
|
|
Proc. Nat. Acad. Sci. 103: 17024-17029, 2006.
|
|
|
|
|
|
[PubMed: 17071743]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1073/pnas.0606539103]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Tsien, R. W., Ellinor, P. T., Horne, W. A.
|
|
<strong>Molecular diversity of voltage-dependent Ca(2+) channels.</strong>
|
|
Trends Pharm. Sci. 12: 349-354, 1991.
|
|
|
|
|
|
[PubMed: 1659003]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1016/0165-6147(91)90595-j]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Valenzuela, D., Han, X., Mende, U., Fankhauser, C., Mashimo, H., Huang, P., Pfeffer, J., Neer, E. J., Fishman, M. C.
|
|
<strong>G-alpha-o is necessary for muscarinic regulation of Ca(2+) channels in mouse heart.</strong>
|
|
Proc. Nat. Acad. Sci. 94: 1727-2732, 1997.
|
|
|
|
|
|
[PubMed: 9050846]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1073/pnas.94.5.1727]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Wang, S.-Q., Song, L.-S., Lakatta, E. G., Cheng, H.
|
|
<strong>Ca(2+) signalling between single L-type Ca(2+) channels and ryanodine receptors in heart cells.</strong>
|
|
Nature 410: 592-596, 2001.
|
|
|
|
|
|
[PubMed: 11279498]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/35069083]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Wang, Y., Deng, X., Mancarella, S., Hendron, E., Eguchi, S., Soboloff, J., Tang, X. D., Gill, D. L.
|
|
<strong>The calcium store sensor, STIM1, reciprocally controls Orai and Ca(v)1.2 channels.</strong>
|
|
Science 330: 105-109, 2010.
|
|
|
|
|
|
[PubMed: 20929813]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1126/science.1191086]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Wemhoner, K., Friedrich, C., Stallmeyer, B., Coffey, A. J., Grace, A., Zumhagen, S., Seebohm, G., Ortiz-Bonnin, B., Rinne, S., Sachse, F. B., Shulze-Bahr, E., Decher, N.
|
|
<strong>Gain-of-function mutations in the calcium channel CACNA1C (Cav1.2) cause non-syndromic long-QT but not Timothy syndrome.</strong>
|
|
J. Molec. Cell. Cardiol. 80: 186-195, 2015.
|
|
|
|
|
|
[PubMed: 25633834]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1016/j.yjmcc.2015.01.002]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Yazawa, M., Hsueh, B., Jia, X., Pasca, A. M., Bernstein, J. A., Hallmayer, J., Dolmetsch, R. E.
|
|
<strong>Using induced pluripotent stem cells to investigate cardiac phenotypes in Timothy syndrome.</strong>
|
|
Nature 471: 230-234, 2011.
|
|
|
|
|
|
[PubMed: 21307850]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/nature09855]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Ye, D., Tester, D. J., Zhou, W., Papagiannis, J., Ackerman, M. J.
|
|
<strong>A pore-localizing CACNA1C-E1115K missense mutation, identified in a patient with idiopathic QT prolongation, bradycardia, and autism spectrum disorder, converts the L-type calcium channel into a hybrid nonselective monovalent cation channel.</strong>
|
|
Heart Rhythm 16: 270-278, 2019.
|
|
|
|
|
|
[PubMed: 30172029]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1016/j.hrthm.2018.08.030]
|
|
|
|
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|
</p>
|
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|
|
|
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