5361 lines
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Entry
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- *180902 - RYANODINE RECEPTOR 2; RYR2
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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">*180902</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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<ul id="mimFloatingTocMenuItems" class="nav nav-pills nav-stacked mim-floating-toc-padding">
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<li role="presentation">
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<li role="presentation">
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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="#biochemicalFeatures">Biochemical Features</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="#cytogenetics">Cytogenetics</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/180902">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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</nav>
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</div>
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</div>
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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=ENSG00000198626;t=ENST00000366574" 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=6262" 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=180902" 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=ENSG00000198626;t=ENST00000366574" 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_001035,XM_006711802,XM_006711803,XM_006711804,XM_006711805,XM_006711806,XM_006711807,XM_006711808,XM_006711810,XM_017002028,XM_047427317,XM_047427329,XM_047427333,XM_047427336,XM_047427337,XM_047427341,XR_002957299,XR_007062490" 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_001035" 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=180902" 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=01619&isoform_id=01619_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/RYR2" 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/1022321,1526978,1561614,2582749,11878411,112799847,119590475,119590476,119590477,194378330,194387592,299889159,299889161,299889163,299889165,299889167,308153558,444737963,578802297,578802299,578802301,578802303,578802305,578802307,578802309,578802313,1034560884,2217269852,2217269857,2217269859,2217269861,2217269863,2217269865,2462512276,2462512278,2462512280,2462512282,2462512284,2462512286,2462512288,2462512290,2462512292,2462512294,2462512296,2462512298,2462512300,2462512302,2462512306" 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/Q92736" 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=6262" 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=ENSG00000198626;t=ENST00000366574" 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=RYR2" 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=RYR2" 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+6262" 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/RYR2" 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:6262" 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/6262" 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=chr1&hgg_gene=ENST00000366574.7&hgg_start=237042184&hgg_end=237833988&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:10484" 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:10484" 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=180902[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=180902[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/RYR2/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/ENSG00000198626" 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=RYR2" 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=RYR2" 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=RYR2" 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="http://www.fsm.it/cardmoc/" class="mim-tip-hint" title="A gene-specific database of variation." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">Locus Specific DBs</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=RYR2&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/PA300" 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:10484" 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/FBgn0011286.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:99685" 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/RYR2#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:99685" 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/6262/ortholog/" class="mim-tip-hint" title="Orthologous genes at NCBI." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Orthologs', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Orthologs</a></div>
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<div><a href="https://www.orthodb.org/?ncbi=6262" 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=WBGene00006801;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-061226-3" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
|
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<span class="panel-title">
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<span class="small">
|
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
|
<div style="display: table-row">
|
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
|
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</div>
|
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
|
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:6262" 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=RYR2&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
|
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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</div>
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<div>
|
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<span class="h3">
|
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<span class="mim-font mim-tip-hint" title="Gene description">
|
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<span class="text-danger"><strong>*</strong></span>
|
|
180902
|
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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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|
RYANODINE RECEPTOR 2; RYR2
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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">
|
|
<em>Alternative titles; symbols</em>
|
|
</span>
|
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</p>
|
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</div>
|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
RYANODINE RECEPTOR, CARDIAC
|
|
</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>
|
|
<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
|
<p>
|
|
<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=RYR2" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">RYR2</a></em></strong>
|
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</span>
|
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</p>
|
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</div>
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<div>
|
|
<a id="cytogeneticLocation" class="mim-anchor"></a>
|
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<p>
|
|
<span class="mim-text-font">
|
|
<strong>
|
|
<em>
|
|
Cytogenetic location: <a href="/geneMap/1/1830?start=-3&limit=10&highlight=1830">1q43</a>
|
|
|
|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr1:237042184-237833988&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'})">1:237,042,184-237,833,988</a> </span>
|
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</em>
|
|
</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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|
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</span>
|
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</p>
|
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</div>
|
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<div>
|
|
<br />
|
|
</div>
|
|
<div>
|
|
<a id="geneMap" class="mim-anchor"></a>
|
|
<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
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<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
|
|
<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=115000,604772" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
|
</a>
|
|
</span>
|
|
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="2">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/1/1830?start=-3&limit=10&highlight=1830">
|
|
1q43
|
|
</a>
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
Ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/115000"> 115000 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
|
</span>
|
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</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
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</span>
|
|
</td>
|
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</tr>
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Ventricular tachycardia, catecholaminergic polymorphic, 1
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PheneGene Graphics <span class="caret"></span>
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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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<p>RYR2 is the major Ca(2+) channel protein in the membrane of the sarcoplasmic reticulum (SR). SR acts as an intracellular Ca(2+) storage in cardiomyocytes, and Ca(2+) can be released from SR to the cytosol by RYR2 (<a href="#23" class="mim-tip-reference" title="Polonen, R. P., Penttinen, K., Swan, H., Aalto-Setala, K. <strong>Antiarrhythmic effects of carvedilol and flecainide in cardiomyocytes derived from catecholaminergic polymorphic ventricular tachycardia patients.</strong> Stem Cells Int. 2018: 9109503, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29760739/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29760739</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29760739[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/10.1155/2018/9109503" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29760739">Polonen et al., 2018</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29760739" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#22" class="mim-tip-reference" title="Otsu, K., Willard, H. F., Khanna, V. K., Zorzato, F., Green, N. M., MacLennan, D. H. <strong>Molecular cloning of cDNA encoding the Ca2+ release channel (ryanodine receptor) of rabbit cardiac muscle sarcoplasmic reticulum.</strong> J. Biol. Chem. 265: 13472-13483, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2380170/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2380170</a>]" pmid="2380170">Otsu et al. (1990)</a> cloned a cDNA encoding the calcium-release channel (ryanodine receptor) of rabbit cardiac muscle sarcoplasmic reticulum. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2380170" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Zorzato, F., Fujii, J., Otsu, K., Phillips, M., Green, N. M., Lai, F. A., Meissner, G., MacLennan, D. H. <strong>Molecular cloning of cDNA encoding human and rabbit forms of the Ca2+ release channel (ryanodine receptor) of skeletal muscle sarcoplasmic reticulum.</strong> J. Biol. Chem. 265: 2244-2256, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2298749/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2298749</a>]" pmid="2298749">Zorzato et al. (1990)</a> cloned human RYR2 that encodes a 5,032-amino acid protein with a calculated molecular mass of 563.5 kD, which is made without an N-terminal signal sequence. Analysis of RYR2 sequence indicates that 10 potential transmembrane sequences in the C-terminal fifth of the molecule and 2 additional potential transmembrane sequences nearer to the center of the molecule could contribute to the formation of the Ca(2+) conducting pore. The remainder of the molecule is hydrophilic and presumably constitutes the cytoplasmic domain of the protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2298749" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#32" class="mim-tip-reference" title="Tiso, N., Stephan, D. A., Nava, A., Bagattin, A., Devaney, J. M., Stanchi, F., Larderet, G., Brahmbhatt, B., Brown, K., Bauce, B., Muriago, M., Basso, C., Thiene, G., Danieli, G. A., Rampazzo, A. <strong>Identification of mutations in the cardiac ryanodine receptor gene in families affected with arrhythmogenic right ventricular cardiomyopathy type 2 (ARVD2).</strong> Hum. Molec. Genet. 10: 189-194, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11159936/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11159936</a>] [<a href="https://doi.org/10.1093/hmg/10.3.189" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11159936">Tiso et al. (2001)</a> determined that the RYR2 gene encompasses 105 exons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11159936" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#22" class="mim-tip-reference" title="Otsu, K., Willard, H. F., Khanna, V. K., Zorzato, F., Green, N. M., MacLennan, D. H. <strong>Molecular cloning of cDNA encoding the Ca2+ release channel (ryanodine receptor) of rabbit cardiac muscle sarcoplasmic reticulum.</strong> J. Biol. Chem. 265: 13472-13483, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2380170/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2380170</a>]" pmid="2380170">Otsu et al. (1990)</a> located the human cardiac ryanodine receptor on chromosome 1 by analysis of rodent/human somatic cell hybrids. By fluorescence in situ hybridization, <a href="#21" class="mim-tip-reference" title="Otsu, K., Fujii, J., Periasamy, M., Difilippantonio, M., Uppender, M., Ward, D. C., MacLennan, D. H. <strong>Chromosome mapping of five human cardiac and skeletal muscle sarcoplasmic reticulum protein genes.</strong> Genomics 17: 507-509, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8406504/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8406504</a>] [<a href="https://doi.org/10.1006/geno.1993.1357" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8406504">Otsu et al. (1993)</a> demonstrated that the RYR2 gene is located in the interval between 1q42.1 and 1q43. <a href="#18" class="mim-tip-reference" title="Mattei, M. G., Giannini, G., Moscatelli, F., Sorrentino, V. <strong>Chromosomal localization of murine ryanodine receptor genes RYR1, RYR2, and RYR3 by in situ hybridization.</strong> Genomics 22: 202-204, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7959768/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7959768</a>] [<a href="https://doi.org/10.1006/geno.1994.1362" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7959768">Mattei et al. (1994)</a> used in situ hybridization to map the murine Ryr2 gene to 13A1-13A2. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2380170+7959768+8406504" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Crystal Structure</em></strong></p><p>
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<a href="#33" class="mim-tip-reference" title="Tung, C.-C., Lobo, P. A., Kimlicka, L., Van Petegem, F. <strong>The amino-terminal disease hotspot of ryanodine receptors forms a cytoplasmic vestibule.</strong> Nature 468: 585-588, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21048710/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21048710</a>] [<a href="https://doi.org/10.1038/nature09471" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21048710">Tung et al. (2010)</a> showed the 2.5-angstrom resolution crystal structure of a region spanning 3 domains of ryanodine receptor type 1 (RyR1; <a href="/entry/180901">180901</a>), encompassing amino acid residues 1-559. The domains interact with each other through a predominantly hydrophilic interface. Docking in RyR1 electron microscopy maps unambiguously places the domains in the cytoplasmic portion of the channel, forming a 240-kD cytoplasmic vestibule around the 4-fold symmetry axis. <a href="#33" class="mim-tip-reference" title="Tung, C.-C., Lobo, P. A., Kimlicka, L., Van Petegem, F. <strong>The amino-terminal disease hotspot of ryanodine receptors forms a cytoplasmic vestibule.</strong> Nature 468: 585-588, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21048710/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21048710</a>] [<a href="https://doi.org/10.1038/nature09471" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21048710">Tung et al. (2010)</a> pinpointed the exact locations of more than 50 disease-associated mutations in full-length RyR1 and RyR2. The mutations can be classified into 3 groups: those that destabilize the interfaces between the 3 amino-terminal domains, disturb the folding of individual domains, or affect 1 of the 6 interfaces with other parts of the receptor. <a href="#33" class="mim-tip-reference" title="Tung, C.-C., Lobo, P. A., Kimlicka, L., Van Petegem, F. <strong>The amino-terminal disease hotspot of ryanodine receptors forms a cytoplasmic vestibule.</strong> Nature 468: 585-588, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21048710/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21048710</a>] [<a href="https://doi.org/10.1038/nature09471" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21048710">Tung et al. (2010)</a> proposed a model whereby the opening of RyR coincides with allosterically couples motions within the N-terminal domains. This process can be affected by mutations that target various interfaces within and across subunits. <a href="#33" class="mim-tip-reference" title="Tung, C.-C., Lobo, P. A., Kimlicka, L., Van Petegem, F. <strong>The amino-terminal disease hotspot of ryanodine receptors forms a cytoplasmic vestibule.</strong> Nature 468: 585-588, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21048710/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21048710</a>] [<a href="https://doi.org/10.1038/nature09471" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21048710">Tung et al. (2010)</a> proposed that the crystal structure provides a framework to understand the many disease-associated mutations in RyRs that have been studied using functional methods, and would be useful for developing new strategies to modulate RyR function in disease states. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21048710" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Cryoelectron Microscopy</em></strong></p><p>
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<a href="#5" class="mim-tip-reference" title="Gong, D., Chi, X., Wei, J., Zhou, G., Huang, G., Zhang, L., Wang, R., Lei, J., Chen, S. R. W., Yan, N. <strong>Modulation of cardiac ryanodine receptor 2 by calmodulin.</strong> Nature 572: 347-351, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31278385/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31278385</a>] [<a href="https://doi.org/10.1038/s41586-019-1377-y" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31278385">Gong et al. (2019)</a> revealed the regulatory mechanism by which porcine RyR2 is modulated by human calmodulin (see <a href="/entry/114180">114180</a>) through the structural determination of RyR2 under 8 conditions by cryoelectron microscopy. Apo-calmodulin and Ca(2+)-calmodulin bind to distinct but overlapping sites in an elongated cleft formed by the handle, helical, and central domains. The shift in calmodulin-binding sites on RyR2 is controlled by Ca(2+) binding to calmodulin, rather than to RyR2. Ca(2+)-calmodulin induces rotations and intradomain shifts of individual central domains, resulting in pore closure of the PCB95- and Ca(2+)-activated channel. In contrast, the pore of the ATP-, caffeine-, and Ca(2+)-activated channel remains open in the presence of Ca(2+)-calmodulin, which suggests that Ca(2+)-calmodulin is one of the many competing modulators of RyR2 gating. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31278385" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>The ryanodine receptor on the sarcoplasmic reticulum is the major source of calcium required for cardiac muscle excitation-contraction coupling. The channel is a tetramer composed of 4 RYR2 polypeptides and 4 FK506-binding proteins (see FKBP12.6, or FKBP1B; <a href="/entry/600620">600620</a>). <a href="#17" class="mim-tip-reference" title="Marx, S. O., Reiken, S., Hisamatsu, Y., Jayaraman, T., Burkhoff, D., Rosemblit, N., Marks, A. R. <strong>PKA phosphorylation dissociates FKBP12.6 from the calcium release channel (ryanodine receptor): defective regulation in failing hearts.</strong> Cell 101: 365-376, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10830164/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10830164</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)80847-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10830164">Marx et al. (2000)</a> showed that protein kinase A (PKA; see <a href="/entry/176911">176911</a>) phosphorylation of RYR2 dissociates FKBP12.6 and regulates the channel open probability. Using cosedimentation and coimmunoprecipitation, the authors defined a macromolecular complex composed of RYR2, FKBP12.6, PKA, the protein phosphatases PP1 (see <a href="/entry/603771">603771</a>) and PP2A (see <a href="/entry/603113">603113</a>), and an anchoring protein, AKAP6 (<a href="/entry/604691">604691</a>). In failing human hearts, <a href="#17" class="mim-tip-reference" title="Marx, S. O., Reiken, S., Hisamatsu, Y., Jayaraman, T., Burkhoff, D., Rosemblit, N., Marks, A. R. <strong>PKA phosphorylation dissociates FKBP12.6 from the calcium release channel (ryanodine receptor): defective regulation in failing hearts.</strong> Cell 101: 365-376, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10830164/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10830164</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)80847-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10830164">Marx et al. (2000)</a> showed that RYR2 is PKA hyperphosphorylated, resulting in defective channel function due to increased sensitivity to calcium-induced activation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10830164" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using a quantitative yeast 2-hybrid system, <a href="#31" class="mim-tip-reference" title="Tiso, N., Salamon, M., Bagattin, A., Danieli, G. A., Argenton, F., Bortolussi, M. <strong>The binding of the RyR2 calcium channel to its gating protein FKBP12.6 is oppositely affected by ARVD2 and VTSIP mutations.</strong> Biochem. Biophys. Res. Commun. 299: 594-598, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12459180/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12459180</a>] [<a href="https://doi.org/10.1016/s0006-291x(02)02689-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12459180">Tiso et al. (2002)</a> analyzed and compared the interaction between FKBP12.6 and 3 mutated FKBP12.6 binding regions. An RYR2 mutation (R2474S, <a href="#0002">180902.0002</a>) causing catecholaminergic polymorphic ventricular tachycardia (CPVT1; <a href="/entry/604772">604772</a>) markedly increased the binding of RYR2 to FKBP12.6, whereas other RYR2 mutations (N2386I, <a href="#0005">180902.0005</a>; Y2392C) significantly decreased this binding. <a href="#31" class="mim-tip-reference" title="Tiso, N., Salamon, M., Bagattin, A., Danieli, G. A., Argenton, F., Bortolussi, M. <strong>The binding of the RyR2 calcium channel to its gating protein FKBP12.6 is oppositely affected by ARVD2 and VTSIP mutations.</strong> Biochem. Biophys. Res. Commun. 299: 594-598, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12459180/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12459180</a>] [<a href="https://doi.org/10.1016/s0006-291x(02)02689-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12459180">Tiso et al. (2002)</a> suggested that the latter mutations increase RYR2-mediated calcium release to the cytoplasm, whereas others do not significantly affect cytosolic calcium levels, and that this might explain the clinical differences among patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12459180" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 animals with heart failure and in patients with inherited forms of exercise-induced sudden cardiac death, depletion of the channel-stabilizing protein calstabin-2 (FKBP1B) from the ryanodine receptor-calcium release channel complex causes an intracellular calcium leak that can trigger fatal cardiac arrhythmias. <a href="#35" class="mim-tip-reference" title="Wehrens, X. H. T., Lehnart, S. E., Reiken, S. R., Deng, S.-X., Vest, J. A., Cervantes, D., Coromilas, J., Landry, D. W., Marks, A. R. <strong>Protection from cardiac arrhythmia through ryanodine receptor-stabilizing protein calstabin2.</strong> Science 304: 292-296, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15073377/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15073377</a>] [<a href="https://doi.org/10.1126/science.1094301" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15073377">Wehrens et al. (2004)</a> found that a derivative of 1,4-benzothiazepine increased the affinity of calstabin-2 for RYR2, which stabilized the closed state of RYR2 and prevented the calcium leak that triggers arrhythmias. <a href="#35" class="mim-tip-reference" title="Wehrens, X. H. T., Lehnart, S. E., Reiken, S. R., Deng, S.-X., Vest, J. A., Cervantes, D., Coromilas, J., Landry, D. W., Marks, A. R. <strong>Protection from cardiac arrhythmia through ryanodine receptor-stabilizing protein calstabin2.</strong> Science 304: 292-296, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15073377/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15073377</a>] [<a href="https://doi.org/10.1126/science.1094301" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15073377">Wehrens et al. (2004)</a> postulated that enhancing the binding of calstabin-2 to RYR2 may be a therapeutic strategy for common ventricular arrhythmias. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15073377" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#34" class="mim-tip-reference" title="Wehrens, X. H. T., Lehnart, S. E., Huang, F., Vest, J. A., Reiken, S. R., Mohler, P. J., Sun, J., Guatimosim, S., Song, L.-S., Rosemblit, N., D'Armiento, J. M., Napolitano, C., Memmi, M., Priori, S. G., Lederer, W. J., Marks, A. R. <strong>FKBP12.6 deficiency and defective calcium release channel (ryanodine receptor) function linked to exercise-induced sudden cardiac death.</strong> Cell 113: 829-840, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12837242/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12837242</a>] [<a href="https://doi.org/10.1016/s0092-8674(03)00434-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12837242">Wehrens et al. (2003)</a> found that during exercise, RYR2 phosphorylation by PKA partially dissociated FKBP12.6 from the RYR2 channel, increasing intracellular Ca(2+) release and cardiac contractility. Fkbp12.6 -/- mice consistently exhibited exercise-induced cardiac ventricular arrhythmias that caused sudden cardiac death. Mutations in RYR2 linked to exercise-induced arrhythmias in patients with CPVT, also known as stress-induced polymorphic ventricular tachycardia, reduced the affinity of FKBP12.6 for RYR2 and increased single-channel activity under conditions that simulated exercise. These data suggested that 'leaky' RYR2 channels can trigger fatal cardiac arrhythmias, providing a possible explanation for CPVT. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12837242" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#8" class="mim-tip-reference" title="Jiang, D., Xiao, B., Li, X., Chen, S. R. W. <strong>Smooth muscle tissues express a major dominant negative splice variant of the type 3 Ca(2+) release channel (ryanodine receptor).</strong> J. Biol. Chem. 278: 4763-4769, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12471029/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12471029</a>] [<a href="https://doi.org/10.1074/jbc.M210410200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12471029">Jiang et al. (2003)</a> characterized several rabbit Ryr3 (<a href="/entry/180903">180903</a>) splice variants. One variant lacking a predicted transmembrane helix formed a heteromeric channel with Ryr2 when coexpressed in HEK293 cells and had a dominant-negative effect on Ryr2 channel activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12471029" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Lehnart, S. E., Wehrens, X. H. T., Marks, A. R. <strong>Calstabin deficiency, ryanodine receptors, and sudden cardiac death.</strong> Biochem. Biophys. Res. Commun. 322: 1267-1279, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15336974/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15336974</a>] [<a href="https://doi.org/10.1016/j.bbrc.2004.08.032" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15336974">Lehnart et al. (2004)</a> reviewed the RYR2-FKBP1B interaction and its role in heart failure and genetic forms of arrhythmias. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15336974" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 experimentally induced failing hearts of beagle dogs, <a href="#37" class="mim-tip-reference" title="Yamamoto, T., Yano, M., Xu, X., Uchinoumi, H., Tateishi, H., Mochizuki, M., Oda, T., Kobayashi, S., Ikemoto, N., Matsuzaki, M. <strong>Identification of target domains of the cardiac ryanodine receptor to correct channel disorder in failing hearts.</strong> Circulation 117: 762-772, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18227387/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18227387</a>] [<a href="https://doi.org/10.1161/CIRCULATIONAHA.107.718957" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18227387">Yamamoto et al. (2008)</a> previously demonstrated that defective interdomain interaction between the N-terminal domain (residues 1 to 600) and the central domain (residues 2000 to 2500) resulted in domain unzipping, Ca(2+) leak through the Ryr2 channel, and both cAMP-dependent hyperphosphorylation and Fkbp12.6 dissociation of Ryr2. Further studies showed that K201, a 1,4-benzothiazepine derivative, bound to residues 2114 to 2149, and that K201 interrupted interaction of domain(2114-2149) with residues 2234 to 2750, which appeared to mediate stabilization of Ryr2 and inhibit Ca(2+) leak. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18227387" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In affected members of 2 large multiply consanguineous Amish families with exercise-associated syncope, cardiac arrest, or sudden unexplained death, <a href="#30" class="mim-tip-reference" title="Tester, D. J., Bombei, H. M., Fitzgerald, K. K., Giudicessi, J. R., Pitel, B. A., Thorland, E. C., Russell, B. G., Hamrick, S. K., Kim, C. S. J., Haglund-Turnquist, C. M., Johnsrude, C. L., Atkins, D. L., Ochoa Nunez, L. A., Law, I., Temple, J., Ackerman, M. J. <strong>Identification of a novel homozygous multi-exon duplication in RYR2 among children with exertion-related unexplained sudden deaths in the Amish community.</strong> JAMA Cardiol. 5: 13-18, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31913406/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31913406</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31913406[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/10.1001/jamacardio.2019.5400" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31913406">Tester et al. (2020)</a> identified homozygosity for a 344-kb tandem duplication (chr1:237,205,452-237,519,546, GRCh38) involving approximately 26,000 bp of intergenic sequence, the 5-prime UTR/promoter region of the RYR2 gene, and exons 1 through 4 of RYR2. The duplication segregated fully with disease in both families. Although a common ancestor was not identified despite pedigree expansion over several generations, the authors stated that the duplication likely represents a founder mutation in the Amish community. The authors noted that the phenotype did not appear to be distinct from autosomal dominant RYR2-mediated CPVT. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31913406" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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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Stress-induced polymorphic ventricular tachycardia occurs in the structurally intact heart with onset of manifestations in childhood and adolescence. Affected individuals present with syncopal events and with a distinctive pattern of highly reproducible, stress-related, bidirectional ventricular tachycardia in the absence of either structural heart disease or a prolonged QT interval. Because this disorder had been shown to map to 1q42-q43, the same region as RYR2, and because of the likelihood that delayed afterdepolarizations underlie arrhythmia in this disorder, <a href="#25" class="mim-tip-reference" title="Priori, S. G., Napolitano, C., Tiso, N., Memmi, M., Vignati, G., Bloise, R., Sorrentino, V., Danieli, G. A. <strong>Mutations in the cardiac ryanodine receptor gene (hRyR2) underlie catecholaminergic polymorphic ventricular tachycardia.</strong> Circulation 103: 196-200, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11208676/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11208676</a>] [<a href="https://doi.org/10.1161/01.cir.103.2.196" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11208676">Priori et al. (2001)</a> hypothesized that mutations in the RYR2 gene may be responsible. They studied 12 probands presenting with bidirectional ventricular tachycardia that was reproducibly induced by exercise stress testing and/or isoproterenol infusion and identified heterozygous missense mutations in 4 (see <a href="#0001">180902.0001</a>-<a href="#0004">180902.0004</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11208676" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 4 unrelated Italian families segregating autosomal dominant exercise-induced ventricular arrhythmias, <a href="#32" class="mim-tip-reference" title="Tiso, N., Stephan, D. A., Nava, A., Bagattin, A., Devaney, J. M., Stanchi, F., Larderet, G., Brahmbhatt, B., Brown, K., Bauce, B., Muriago, M., Basso, C., Thiene, G., Danieli, G. A., Rampazzo, A. <strong>Identification of mutations in the cardiac ryanodine receptor gene in families affected with arrhythmogenic right ventricular cardiomyopathy type 2 (ARVD2).</strong> Hum. Molec. Genet. 10: 189-194, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11159936/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11159936</a>] [<a href="https://doi.org/10.1093/hmg/10.3.189" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11159936">Tiso et al. (2001)</a> identified heterozygous missense mutations in the RYR2 gene (see, e.g., <a href="#0005">180902.0005</a>-<a href="#0006">180902.0006</a>). The patients were originally diagnosed as having an unusual localized form of arrhythmogenic right ventricular dysplasia (ARVD; see <a href="/entry/107970">107970</a>), with clinical findings that differed from those reported in other ARVD families (<a href="#1" class="mim-tip-reference" title="Bauce, B., Nava, A., Rampazzo, A., Daliento, L., Muriago, M., Basso, C., Thiene, G., Danieli, G. A. <strong>Familial effort polymorphic ventricular arrhythmias in arrhythmogenic right ventricular cardiomyopathy map to chromosome 1q42-q43.</strong> Am. J. Cardiol. 85: 573-579, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11078270/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11078270</a>] [<a href="https://doi.org/10.1016/s0002-9149(99)00814-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11078270">Bauce et al., 2000</a>); the disorder was later designated to be catecholamine-induced ventricular tachycardia (<a href="#12" class="mim-tip-reference" title="Karmouch, J., Protonotarios, A., Syrris, P. <strong>Genetic basis of arrhythmogenic cardiomyopathy.</strong> Curr. Opin. Cardiol. 33: 276-281, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29543670/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29543670</a>] [<a href="https://doi.org/10.1097/HCO.0000000000000509" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29543670">Karmouch et al., 2018</a>). The mutations occurred at highly conserved residues and segregated fully with disease in each family. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11078270+29543670+11159936" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#24" class="mim-tip-reference" title="Priori, S. G., Napolitano, C., Memmi, M., Colombi, B., Drago, F., Gasparini, M., DeSimone, L., Coltorti, F., Bloise, R., Keegan, R., Cruz Filho, F. E. S., Vignati, G., Benatar, A., DeLogu, A. <strong>Clinical and molecular characterization of patients with catecholaminergic polymorphic ventricular tachycardia.</strong> Circulation 106: 69-74, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12093772/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12093772</a>] [<a href="https://doi.org/10.1161/01.cir.0000020013.73106.d8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12093772">Priori et al. (2002)</a> analyzed the RYR2 gene in 26 probands with CPVT in whom mutations had been excluded in the KCNQ1 (<a href="/entry/607542">607542</a>), KCNH2 (<a href="/entry/152427">152427</a>), SCN5A (<a href="/entry/600163">600163</a>), KCNE1 (<a href="/entry/176261">176261</a>), and KCNE2 (<a href="/entry/603796">603796</a>) genes and identified 9 different mutations in 10 probands, respectively (see, e.g., <a href="#0001">180902.0001</a> and <a href="#0010">180902.0010</a>). With the inclusion of 4 previously reported mutation-positive families (<a href="#25" class="mim-tip-reference" title="Priori, S. G., Napolitano, C., Tiso, N., Memmi, M., Vignati, G., Bloise, R., Sorrentino, V., Danieli, G. A. <strong>Mutations in the cardiac ryanodine receptor gene (hRyR2) underlie catecholaminergic polymorphic ventricular tachycardia.</strong> Circulation 103: 196-200, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11208676/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11208676</a>] [<a href="https://doi.org/10.1161/01.cir.103.2.196" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11208676">Priori et al., 2001</a>) in this study, <a href="#24" class="mim-tip-reference" title="Priori, S. G., Napolitano, C., Memmi, M., Colombi, B., Drago, F., Gasparini, M., DeSimone, L., Coltorti, F., Bloise, R., Keegan, R., Cruz Filho, F. E. S., Vignati, G., Benatar, A., DeLogu, A. <strong>Clinical and molecular characterization of patients with catecholaminergic polymorphic ventricular tachycardia.</strong> Circulation 106: 69-74, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12093772/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12093772</a>] [<a href="https://doi.org/10.1161/01.cir.0000020013.73106.d8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12093772">Priori et al. (2002)</a> found 9 family members who were RYR2 mutation carriers, 5 of whom had exercise-induced arrhythmias at clinical evaluation and 4 of whom were phenotypically silent (incomplete penetrance). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11208676+12093772" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#4" class="mim-tip-reference" title="George, C. H., Higgs, G. V., Lai, F. A. <strong>Ryanodine receptor mutations associated with stress-induced ventricular tachycardia mediate increased calcium release in stimulated cardiomyocytes.</strong> Circ. Res. 93: 531-540, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12919952/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12919952</a>] [<a href="https://doi.org/10.1161/01.RES.0000091335.07574.86" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12919952">George et al. (2003)</a> expressed 3 CPVT1-linked RYR2 mutations in a cardiomyocyte cell line. They found that phenotypic characteristics in resting cells expressing mutant RYR2 were indistinguishable from those expressing the wildtype. However, Ca(2+) release was augmented in cells expressing mutant RYR2 after RYR activation (caffeine or 4-chloro-m-cresol) or beta-adrenergic stimulation (isoproterenol). Interaction between RYR2 and FKBP1A remained intact after caffeine or 4-chloro-m-cresol activation, but was dramatically disrupted by isoproterenol or forskolin, both of which elevated cAMP to similar magnitudes in all cells and were associated with equivalent hyperphosphorylation of mutant and wildtype RYR2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12919952" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Similar mortality rates of approximately 33% by age 35 years and a threshold heart rate of 130 bpm, above which exercise induces ventricular arrhythmias, are observed in Finnish families with stress-induced polymorphic ventricular tachycardia caused by a pro2328-to-ser (P2328S; <a href="#0007">180902.0007</a>), val4653-to-phe (V4653F; <a href="#0008">180902.0008</a>), or gln4201-to-arg (Q4201R; <a href="#0009">180902.0009</a>) mutation in the RYR2 gene. Exercise activates the sympathetic nervous system, increasing cardiac performance as part of the 'fight or flight' stress response. <a href="#15" class="mim-tip-reference" title="Lehnart, S. E., Wehrens, X. H. T., Laitinen, P. J., Reiken, S. R., Deng, S.-X., Cheng, Z., Landry, D. W., Kontula, K., Swan, H., Marks, A. R. <strong>Sudden death in familial polymorphic ventricular tachycardia associated with calcium release channel (ryanodine receptor) leak.</strong> Circulation 109: 3208-3214, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15197150/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15197150</a>] [<a href="https://doi.org/10.1161/01.CIR.0000132472.98675.EC" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15197150">Lehnart et al. (2004)</a> simulated the effects of exercise on mutant RYR2 channels using PKA phosphorylation. All 3 RYR2 mutations exhibited decreased binding of calstabin-2, a subunit that stabilizes the closed state of the channel. After PKA phosphorylation, these mutants showed a significant gain-of-function defect consistent with leaky calcium release channels and a significant rightward shift in the half-maximal inhibitory magnesium concentration. Treatment with an experimental drug enhanced the binding of calstabin-2 to RYR2 and normalized channel function. <a href="#15" class="mim-tip-reference" title="Lehnart, S. E., Wehrens, X. H. T., Laitinen, P. J., Reiken, S. R., Deng, S.-X., Cheng, Z., Landry, D. W., Kontula, K., Swan, H., Marks, A. R. <strong>Sudden death in familial polymorphic ventricular tachycardia associated with calcium release channel (ryanodine receptor) leak.</strong> Circulation 109: 3208-3214, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15197150/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15197150</a>] [<a href="https://doi.org/10.1161/01.CIR.0000132472.98675.EC" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15197150">Lehnart et al. (2004)</a> suggested that stabilization of the RYR2 channel complex may represent a molecular target for the treatment and prevention of exercise-induced arrhythmias and sudden death in these patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15197150" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#9" class="mim-tip-reference" title="Jiang, D., Xiao, B., Yang, D., Wang, R., Choi, P., Zhang, L., Cheng, H., Chen, S. R. W. <strong>RyR2 mutations linked to ventricular tachycardia and sudden death reduce the threshold for store-overload-induced Ca(2+) release (SOICR).</strong> Proc. Nat. Acad. Sci. 101: 13062-13067, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15322274/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15322274</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15322274[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.0402388101" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15322274">Jiang et al. (2004)</a> studied 3 mutations in the RYR2 gene linked to ventricular tachycardia and sudden death, including N4104K (<a href="#0003">180902.0003</a>) and characterized their effects on store-overload-induced Ca(2+) release (SOICR) in human embryonic kidney cells. SOICR refers to the spontaneous Ca(2+) release that occurs when the sarcoplasmic reticulum store Ca(2+) content reaches a critical level. They demonstrated that the 3 mutations markedly increased the occurrence of SOICR. At the molecular level, they showed that these mutations increased the sensitivity of single RyR2 channels to activation by luminal Ca(2+). <a href="#9" class="mim-tip-reference" title="Jiang, D., Xiao, B., Yang, D., Wang, R., Choi, P., Zhang, L., Cheng, H., Chen, S. R. W. <strong>RyR2 mutations linked to ventricular tachycardia and sudden death reduce the threshold for store-overload-induced Ca(2+) release (SOICR).</strong> Proc. Nat. Acad. Sci. 101: 13062-13067, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15322274/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15322274</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15322274[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.0402388101" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15322274">Jiang et al. (2004)</a> concluded that the increased sensitivity reduced the threshold for SOICR, thereby increasing the propensity for triggered arrhythmia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15322274" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#7" class="mim-tip-reference" title="Jiang, D., Wang, R., Xiao, B., Kong, H., Hunt, D. J., Choi, P., Zhang, L., Chen, S. R. W. <strong>Enhanced store overload-induced Ca(2+) release and channel sensitivity to luminal Ca(2+) activation are common defects of RyR2 mutations linked to ventricular tachycardia and sudden death.</strong> Circ. Res. 97: 1173-1181, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16239587/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16239587</a>] [<a href="https://doi.org/10.1161/01.RES.0000192146.85173.4b" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16239587">Jiang et al. (2005)</a> showed that CPVT/ARVD2-associated mutations throughout the RYR2 sequence enhanced the propensity for SOICR in HEK293 cells compared with wildtype. The same effect was observed in HL-1 cardiac cells for several of the mutations. Single RYR2 channel analysis revealed that the mutations augmented SOICR by primarily increasing channel sensitivity to luminal, but not cytosolic, Ca(2+) activation. Further analysis demonstrated that C-terminal RYR2 mutations did not alter Ca(2+) dependence of ryanodine binding to RYR2, and none of the mutations tested altered interaction of RYR2 with FKBP12.6. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16239587" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 studies in HEK293 cells, <a href="#6" class="mim-tip-reference" title="Jiang, D., Chen, W., Wang, R., Zhang, L., Chen, S. R. W. <strong>Loss of luminal Ca(2+) activation in the cardiac ryanodine receptor is associated with ventricular fibrillation and sudden death.</strong> Proc. Nat. Acad. Sci. 104: 18309-18314, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17984046/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17984046</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17984046[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.0706573104" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17984046">Jiang et al. (2007)</a> found that, in contrast to all other disease-linked RYR2 mutations characterized previously, the catecholaminergic idiopathic ventricular fibrillation-associated A4860G mutation (<a href="#0010">180902.0010</a>) diminished the response of RYR2 to activation by luminal Ca(2+) but had little effect on the sensitivity of the channel to activation by cytosolic Ca(2+), and the transfected cells exhibited no SOICR. <a href="#6" class="mim-tip-reference" title="Jiang, D., Chen, W., Wang, R., Zhang, L., Chen, S. R. W. <strong>Loss of luminal Ca(2+) activation in the cardiac ryanodine receptor is associated with ventricular fibrillation and sudden death.</strong> Proc. Nat. Acad. Sci. 104: 18309-18314, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17984046/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17984046</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17984046[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.0706573104" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17984046">Jiang et al. (2007)</a> concluded that loss of luminal Ca(2+) activation and SOICR activity can cause ventricular fibrillation and sudden death. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17984046" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 individuals from 2 families with CPVT associated with sinoatrial and atrioventricular node dysfunction, atrial arrhythmias, and dilated cardiomyopathy, <a href="#3" class="mim-tip-reference" title="Bhuiyan, Z. A., van den Berg, M. P., van Tintelen, J. P., Bink-Boelkens, M. T. E., Wiesfeld, A. C. P., Alders, M., Postma, A. V., van Langen, I., Mannens, M. M. A. M., Wilde, A. A. M. <strong>Expanding spectrum of human RYR2-related disease: new electrocardiographic, structural, and genetic features.</strong> Circulation 116: 1569-1576, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17875969/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17875969</a>] [<a href="https://doi.org/10.1161/CIRCULATIONAHA.107.711606" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17875969">Bhuiyan et al. (2007)</a> identified a heterozygous deletion of exon 3 of the RYR2 gene (<a href="#0011">180902.0011</a>). The authors noted that these families expanded the phenotypic spectrum of human RYR2-related diseases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17875969" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#19" class="mim-tip-reference" title="Medeiros-Domingo, A., Bhuiyan, Z. A., Tester, D. J., Hofman, N., Bikker, H., van Tintelen, J. P., Mannens, M. M. A. M., Wilde, A. A. M., Ackerman, M. J. <strong>The RYR2-encoded ryanodine receptor/calcium release channel in patients diagnosed previously with either catecholaminergic polymorphic ventricular tachycardia or genotype negative, exercise-induced long QT syndrome.</strong> J. Am. Coll. Cardiol. 54: 2065-2074, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19926015/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19926015</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19926015[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.jacc.2009.08.022" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19926015">Medeiros-Domingo et al. (2009)</a> analyzed all 105 RYR2 exons using PCR, HPLC, and sequencing in 110 unrelated patients with a clinical diagnosis of CPVT and in 45 additional unrelated patients with an initial diagnosis of exercise-induced long QT syndrome (LQTS; see <a href="/entry/192500">192500</a>) but who had a QTc of less than 480 ms and who were negative for mutation in 12 genes known to cause LQTS. The authors identified 63 possible CPVT1-associated mutations that were not found in 400 reference alleles in 73 (47%) of the 155 patients; 13 new mutation-containing exons were identified, with two-thirds of the patients having mutations in 1 of 16 exons. Three large genomic rearrangements involving exon 3 were detected in 3 unrelated cases. <a href="#19" class="mim-tip-reference" title="Medeiros-Domingo, A., Bhuiyan, Z. A., Tester, D. J., Hofman, N., Bikker, H., van Tintelen, J. P., Mannens, M. M. A. M., Wilde, A. A. M., Ackerman, M. J. <strong>The RYR2-encoded ryanodine receptor/calcium release channel in patients diagnosed previously with either catecholaminergic polymorphic ventricular tachycardia or genotype negative, exercise-induced long QT syndrome.</strong> J. Am. Coll. Cardiol. 54: 2065-2074, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19926015/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19926015</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19926015[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.jacc.2009.08.022" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19926015">Medeiros-Domingo et al. (2009)</a> stated that 45 of the 105 translated exons of the RYR2 gene were now known to host possible mutations, but that a tiered targeting strategy for CPVT should be considered, since approximately 65% of CPVT1-positive cases would be discovered by selective analysis of just 16 exons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19926015" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 CPVT patient-specific induced pluripotent stem cell-derived cardiac muscle (iPSC-CM) cell lines carrying different RYR2 mutations, <a href="#23" class="mim-tip-reference" title="Polonen, R. P., Penttinen, K., Swan, H., Aalto-Setala, K. <strong>Antiarrhythmic effects of carvedilol and flecainide in cardiomyocytes derived from catecholaminergic polymorphic ventricular tachycardia patients.</strong> Stem Cells Int. 2018: 9109503, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29760739/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29760739</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29760739[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/10.1155/2018/9109503" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29760739">Polonen et al. (2018)</a> evaluated the antiarrhythmic efficacy of carvedilol and flecainide. Adrenaline induced arrhythmias in all CPVT iPSC-CM cell lines examined, but it abolished arrhythmias in control cells. Both carvedilol and flecainide were equally effective in treating arrhythmias, as both drugs lowered intracellular Ca(2+) level and beating rate of cardiomyocytes significantly in all CPVT iPSC-CM cell lines. However, flecainide caused abnormal Ca(2+) transients in 61% of control cells compared with 26% of those treated with carvedilol. CPVT cardiomyocytes carrying the exon 3 deletion had the most severe Ca(2+) abnormalities, but they had the best response to drug therapies. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29760739" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Ventricular Arrhythmias due to Cardiac Ryanodine Receptor Calcium Release Deficiency Syndrome</em></strong></p><p>
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In 6 families in which the proband experienced sudden cardiac death (SCD) or aborted SCD (aSCD) resulting from ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome (VACRDS; <a href="/entry/115000">115000</a>), <a href="#28" class="mim-tip-reference" title="Sun, B., Yao, J., Ni, M., Wei, J., Zhong, X., Guo, W., Zhang, L., Wang, R., Belke, D., Chen, Y.-X., Lieve, K. V. V., Broendberg, A. K., and 19 others. <strong>Cardiac ryanodine receptor calcium release deficiency syndrome.</strong> Sci. Transl. Med. 13: eaba7287, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33536282/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33536282</a>] [<a href="https://doi.org/10.1126/scitranslmed.aba7287" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33536282">Sun et al. (2021)</a> identified heterozygosity for missense mutations in the RYR2 gene (see, e.g., <a href="#0012">180902.0012</a>-<a href="#0014">180902.0014</a>). Combining these families with 4 previously reported families with RYR2 missense mutations, including a family studied by <a href="#24" class="mim-tip-reference" title="Priori, S. G., Napolitano, C., Memmi, M., Colombi, B., Drago, F., Gasparini, M., DeSimone, L., Coltorti, F., Bloise, R., Keegan, R., Cruz Filho, F. E. S., Vignati, G., Benatar, A., DeLogu, A. <strong>Clinical and molecular characterization of patients with catecholaminergic polymorphic ventricular tachycardia.</strong> Circulation 106: 69-74, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12093772/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12093772</a>] [<a href="https://doi.org/10.1161/01.cir.0000020013.73106.d8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12093772">Priori et al. (2002)</a> (<a href="#0010">180902.0010</a>), revealed that 31 (67%) of 46 mutation carriers experienced SCD or aSCD, whereas none of the 46 mutation-negative individuals had life-threatening ventricular arrhythmias. All of the missense mutations showed loss-of-function effects, including marked suppression of caffeine-induced Ca(2+) release and increased threshold for store overload-induced Ca(2+) release and/or RYR2-mediated fractional Ca(2+) release, as well as impairment of cytosolic and luminal Ca(2+) activation of RYR2 channels in some cases. A knockin mouse model with the D4646A mutation (see <a href="#0012">180902.0012</a>) suggested that RYR2 loss-of-function mutations may cause ventricular arrhythmias via an early afterdepolarization-mediated mechanism. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=33536282+12093772" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Reviews</em></strong></p><p>
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<a href="#2" class="mim-tip-reference" title="Benkusky, N. A., Farrell, E. F., Valdivia, H. H. <strong>Ryanodine receptor channelopathies.</strong> Biochem. Biophys. Res. Commun. 322: 1280-1285, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15336975/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15336975</a>] [<a href="https://doi.org/10.1016/j.bbrc.2004.08.033" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15336975">Benkusky et al. (2004)</a> reviewed RYR1 and RYR2 mutations and their role in muscle and heart disease, respectively. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15336975" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#29" class="mim-tip-reference" title="Takeshima, H., Komazaki, S., Hirose, K., Nishi, M., Noda, T., Iino, M. <strong>Embryonic lethality and abnormal cardiac myocytes in mice lacking ryanodine receptor type 2.</strong> EMBO J. 17: 3309-3316, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9628868/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9628868</a>] [<a href="https://doi.org/10.1093/emboj/17.12.3309" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9628868">Takeshima et al. (1998)</a> generated Ryr2 -/- mice, which died at approximately embryonic day 10 with morphologic abnormalities in the heart tube. Prior to embryonic death, large vacuolate sarcoplasmic reticula and structurally abnormal mitochondria began to develop in the mutant cardiac myocytes, and the vacuolate sarcoplasmic reticula appeared to contain high concentrations of Ca(2+). A Ca(2+) transient evoked by caffeine was abolished in mutant cardiac myocytes. Treatment with ryanodine did not exert a major effect on spontaneous Ca(2+) transients in control cardiac myocytes at embryonic days 9.5-11.5. <a href="#29" class="mim-tip-reference" title="Takeshima, H., Komazaki, S., Hirose, K., Nishi, M., Noda, T., Iino, M. <strong>Embryonic lethality and abnormal cardiac myocytes in mice lacking ryanodine receptor type 2.</strong> EMBO J. 17: 3309-3316, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9628868/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9628868</a>] [<a href="https://doi.org/10.1093/emboj/17.12.3309" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9628868">Takeshima et al. (1998)</a> proposed that RYR2 does not participate principally in Ca(2+) signaling during excitation-contraction coupling in the embryonic heart but functions as a major Ca(2+) leak channel to maintain the normal range of luminal Ca(2+) levels in the developing sarcoplasmic reticulum. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9628868" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#10" class="mim-tip-reference" title="Jiang, D., Xiao, B., Zhang, L., Chen, S. R. W. <strong>Enhanced basal activity of a cardiac Ca(2+) release channel (ryanodine receptor) mutant associated with ventricular tachycardia and sudden death.</strong> Circ. Res. 91: 218-225, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12169647/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12169647</a>] [<a href="https://doi.org/10.1161/01.res.0000028455.36940.5e" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12169647">Jiang et al. (2002)</a> characterized the properties of an R4496C mutation in mouse Ryr2, which is equivalent to the disease-causing human RYR2 mutation R4497C (<a href="#0004">180902.0004</a>). Binding studies in HEK293 cells using tritium-labeled ryanodine revealed that the R4496C mutation resulted in an increase in RYR2 channel activity, particularly at low concentrations, and enhanced the sensitivity of RYR2 to activation by Ca(2+) and by caffeine. HEK293 cells transfected with R4496C Ryr2 displayed spontaneous Ca(2+) oscillations more frequently than cells transfected with wildtype Ryr2. Substitution of a negatively charged glutamate for the positively charged R4496 further enhanced basal channel activity, whereas replacement of R4496 by a positively charged lysine had no significant effect on basal activity. <a href="#10" class="mim-tip-reference" title="Jiang, D., Xiao, B., Zhang, L., Chen, S. R. W. <strong>Enhanced basal activity of a cardiac Ca(2+) release channel (ryanodine receptor) mutant associated with ventricular tachycardia and sudden death.</strong> Circ. Res. 91: 218-225, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12169647/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12169647</a>] [<a href="https://doi.org/10.1161/01.res.0000028455.36940.5e" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12169647">Jiang et al. (2002)</a> concluded that charge and polarity at residue 4496 play an essential role in RYR2 channel gating, and that enhanced basal activity of RYR2 may underlie an arrhythmogenic mechanism for effort-induced ventricular tachycardia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12169647" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Wehrens, X. H. T., Lehnart, S. E., Reiken, S., Vest, J. A., Wronska, A., Marks, A. R. <strong>Ryanodine receptor/calcium release channel PKA phosphorylation: a critical mediator of heart failure progression.</strong> Proc. Nat. Acad. Sci. 103: 511-518, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16407108/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16407108</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16407108[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.0510113103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16407108">Wehrens et al. (2006)</a> generated transgenic mice with a ser2808-to-ala substitution (S2808A) of the Ryr2 gene. In vitro and in vivo studies showed that the Ryr2 alanine-2808 channels could not be phosphorylated by protein kinase A, indicating that serine-2808 is the dominant functional phosphorylation site on Ryr2 channels. Transgenic mice with heart failure induced by ligation of the left anterior descending artery showed a higher ejection fraction and improved cardiac function compared to wildtype mice with induced heart failure. <a href="#36" class="mim-tip-reference" title="Wehrens, X. H. T., Lehnart, S. E., Reiken, S., Vest, J. A., Wronska, A., Marks, A. R. <strong>Ryanodine receptor/calcium release channel PKA phosphorylation: a critical mediator of heart failure progression.</strong> Proc. Nat. Acad. Sci. 103: 511-518, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16407108/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16407108</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16407108[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.0510113103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16407108">Wehrens et al. (2006)</a> concluded that PKA-mediated hyperphosphorylation of serine-2808 on the Ryr2 channel is a critical mediator of progressive cardiac dysfunction after myocardial infarction. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16407108" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Kannankeril, P. J., Mitchell, B. M., Goonasekera, S. A., Chelu, M. G., Zhang, W., Sood, S., Kearney, D. L., Danila, C. I., De Biasi, M., Wehrens, X. H. T., Pautler, R. G., Roden, D. M., Taffet, G. E., Dirksen, R. T., Anderson, M. E., Hamilton, S. L. <strong>Mice with the R176Q cardiac ryanodine receptor mutation exhibit catecholamine-induced ventricular tachycardia and cardiomyopathy.</strong> Proc. Nat. Acad. Sci. 103: 12179-12184, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16873551/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16873551</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16873551[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.0600268103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16873551">Kannankeril et al. (2006)</a> generated mice heterozygous for the human disease-associated arg176-to-gln (R176Q) mutation in the Ryr2 gene and observed no fibrofatty infiltration or structural abnormalities characteristic of arrhythmogenic right ventricular dysplasia, but right ventricular end-diastolic volume was decreased in the mutant mice compared to controls. Ventricular tachycardia was observed after caffeine and epinephrine injection in Ryr2 R176Q heterozygotes but not in wildtype mice. Isoproterenol administration during intracardiac programmed stimulation increased the number and duration of ventricular tachycardia episodes in mutants but not controls. Isolated cardiomyocytes from Ryr2 R176Q heterozygous mice exhibited a higher incidence of spontaneous Ca(2+) oscillations in the absence and presence of isoproterenol compared with controls. <a href="#11" class="mim-tip-reference" title="Kannankeril, P. J., Mitchell, B. M., Goonasekera, S. A., Chelu, M. G., Zhang, W., Sood, S., Kearney, D. L., Danila, C. I., De Biasi, M., Wehrens, X. H. T., Pautler, R. G., Roden, D. M., Taffet, G. E., Dirksen, R. T., Anderson, M. E., Hamilton, S. L. <strong>Mice with the R176Q cardiac ryanodine receptor mutation exhibit catecholamine-induced ventricular tachycardia and cardiomyopathy.</strong> Proc. Nat. Acad. Sci. 103: 12179-12184, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16873551/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16873551</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16873551[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.0600268103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16873551">Kannankeril et al. (2006)</a> suggested that the R176Q mutation in RYR2 predisposes the heart to catecholamine-induced oscillatory calcium-release events that trigger a calcium-dependent ventricular arrhythmia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16873551" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#14" class="mim-tip-reference" title="Lehnart, S. E., Mongillo, M., Bellinger, A., Lindegger, N., Chen, B.-X., Hsueh, W., Reiken, S., Wronska, A., Drew, L. J., Ward, C. W., Lederer, W. J., Kass, R. S., Morley, G., Marks, A. R. <strong>Leaky Ca(2+) release channel/ryanodine receptor 2 causes seizures and sudden cardiac death in mice.</strong> J. Clin. Invest. 118: 2230-2245, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18483626/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18483626</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18483626[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI35346" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18483626">Lehnart et al. (2008)</a> found that mice heterozygous for the human CPVT-associated mutation R2474S in Ryr2 exhibited spontaneous generalized tonic-clonic seizures (which occurred in the absence of cardiac arrhythmias), exercise-induced ventricular arrhythmias, and sudden cardiac death. Treatment with an Ryr2-specific compound that enhanced binding of calstabin-2 to the mutant receptor inhibited channel leak, prevented cardiac arrhythmias, and raised the seizure threshold. <a href="#14" class="mim-tip-reference" title="Lehnart, S. E., Mongillo, M., Bellinger, A., Lindegger, N., Chen, B.-X., Hsueh, W., Reiken, S., Wronska, A., Drew, L. J., Ward, C. W., Lederer, W. J., Kass, R. S., Morley, G., Marks, A. R. <strong>Leaky Ca(2+) release channel/ryanodine receptor 2 causes seizures and sudden cardiac death in mice.</strong> J. Clin. Invest. 118: 2230-2245, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18483626/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18483626</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18483626[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI35346" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18483626">Lehnart et al. (2008)</a> concluded that CPVT is a combined neurocardiac disorder in which leaky RYR2 channels in brain cause epilepsy and in heart cause exercise-induced sudden death. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18483626" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Zhao, Y.-T., Valdivia, C. R., Gurrola, G. B., Powers, P. P., Willis, B. C., Moss, R. L., Jalife, J., Valdivia, H. H. <strong>Arrhythmogenesis in a catecholaminergic polymorphic ventricular tachycardia mutation that depresses ryanodine receptor function.</strong> Proc. Nat. Acad. Sci. 112: E1669-E1677, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25775566/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25775566</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25775566[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.1419795112" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25775566">Zhao et al. (2015)</a> found that hearts from knockin mice heterozygous for the Ryr2 A4860G mutation expressed Ryr2 protein at the same level as wildtype and showed no cardiac structural alterations or major hemodynamic parameters. However, heterozygous mutant mice exhibited basal bradycardia, and no homozygote mutants were detected at birth, suggesting a lethal phenotype. Sympathetic stimulation elicited malignant arrhythmias in heterozygous mutant hearts, recapitulating the main proarrhythmogenic features reported in a human patient with the same mutation. In isoproterenol-stimulated ventricular myocytes, the A4860G mutation decreased the peak of Ca(2+) release during systole, gradually overloading the sarcoplasmic reticulum with Ca(2+). The resultant Ca(2+) overload then randomly caused bursts of prolonged Ca(2+) release, activating electrogenic Na(+)-Ca(2+) exchanger activity and triggering early afterdepolarizations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25775566" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#27" class="mim-tip-reference" title="Shan, J., Xie, W., Betzenhauser, M., Reiken, S., Chen, B.-X., Wronska, A., Marks, A. R. <strong>Calcium leak through ryanodine receptors leads to atrial fibrillation in 3 mouse models of catecholaminergic polymorphic ventricular tachycardia.</strong> Circ. Res. 111: 708-717, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22828895/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22828895</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22828895[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/CIRCRESAHA.112.273342" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22828895">Shan et al. (2012)</a> found that 3 knockin mouse lines heterozygous for the CPVT-linked Ryr2 mutations R2474S, R2386I, or L433P (<a href="#0006">180902.0006</a>) displayed atrial burst pacing-induced atrial fibrillation (AF) due to increased diastolic SR Ca(2+) leak in atrial myocytes compared with wildtype. Increased diastolic SR Ca(2+) leak in atrial myocytes from mice heterozygous for R2474S was associated with Ryr2 oxidation and decreased Fkbp12.6 binding to Ryr2. Only atrial, and not ventricular, burst pacing increased resting diastolic SR Ca(2+) leak and induced arrhythmias in R2474S-heterozygous mice. The small molecule Rycal S107 stabilized Ryr2-Fkbp12.6 interactions in the channel complex by inhibiting oxidation/phosphorylation of Ryr2 and significantly decreased the diastolic SR Ca(2+) leak in R2474S-heterozygous mice at the cellular level and prevented burst pacing-induced AF in vivo. Fkbp12.6-knockout mice showed increased atrial burst pacing-induced AF, but it was not prevented by S107 treatment, indicating that the action of S107 was dependent on the presence of Fkbp12.6. The authors found that Camk2 (see <a href="/entry/114078">114078</a>) phosphorylation of Ryr2 did not play a pivotal role in atrial burst pacing-induced AF, and that activation of sympathetic system did not appear to play an important role in triggering AF in CPVT mice. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22828895" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="/allelicVariants/180902" class="btn btn-default" role="button"> Table View </a>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=180902[MIM]" class="btn btn-default mim-tip-hint" role="button" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a>
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<strong>.0001 VENTRICULAR TACHYCARDIA, CATECHOLAMINERGIC POLYMORPHIC, 1</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121918597 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918597;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=rs121918597" 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=rs121918597" 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=RCV000013820 OR RCV000182746 OR RCV001798004 OR RCV003298032" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013820, RCV000182746, RCV001798004, RCV003298032" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013820...</a>
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<p><a href="#25" class="mim-tip-reference" title="Priori, S. G., Napolitano, C., Tiso, N., Memmi, M., Vignati, G., Bloise, R., Sorrentino, V., Danieli, G. A. <strong>Mutations in the cardiac ryanodine receptor gene (hRyR2) underlie catecholaminergic polymorphic ventricular tachycardia.</strong> Circulation 103: 196-200, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11208676/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11208676</a>] [<a href="https://doi.org/10.1161/01.cir.103.2.196" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11208676">Priori et al. (2001)</a> identified a heterozygous ser2246-to-leu (S2246L) mutation of the RYR2 gene in an 8-year-old boy with stress-induced polymorphic ventricular tachycardia (CPVT1; <a href="/entry/604772">604772</a>). The boy had had recurrent syncopal events since the age of 3 years. The events were invariably induced by exercise. Resting ECG of the proband was normal. Ventricular arrhythmias (isolated premature ventricular beats, couplets, and runs of bidirectional ventricular tachycardia) could be reproducibly induced during exercise testing and progressively worsened as the workload increased. Electrical stimulation induced no repetitive arrhythmias, but isoproterenol infusion induced bidirectional ventricular tachycardia. The patient was treated with nadolol, and an implantable cardiac defibrillator was implanted. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11208676" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 male patient with bidirectional ventricular tachycardia who developed symptoms of CPVT at 2 years of age, <a href="#24" class="mim-tip-reference" title="Priori, S. G., Napolitano, C., Memmi, M., Colombi, B., Drago, F., Gasparini, M., DeSimone, L., Coltorti, F., Bloise, R., Keegan, R., Cruz Filho, F. E. S., Vignati, G., Benatar, A., DeLogu, A. <strong>Clinical and molecular characterization of patients with catecholaminergic polymorphic ventricular tachycardia.</strong> Circulation 106: 69-74, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12093772/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12093772</a>] [<a href="https://doi.org/10.1161/01.cir.0000020013.73106.d8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12093772">Priori et al. (2002)</a> identified a de novo S2246L mutation in the RYR2 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12093772" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<span class="mim-font">
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<strong>.0002 VENTRICULAR TACHYCARDIA, CATECHOLAMINERGIC POLYMORPHIC, 1</strong>
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RYR2, ARG2474SER
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121918598 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918598;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=rs121918598" 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=rs121918598" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000013821" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013821" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013821</a>
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<p><a href="#25" class="mim-tip-reference" title="Priori, S. G., Napolitano, C., Tiso, N., Memmi, M., Vignati, G., Bloise, R., Sorrentino, V., Danieli, G. A. <strong>Mutations in the cardiac ryanodine receptor gene (hRyR2) underlie catecholaminergic polymorphic ventricular tachycardia.</strong> Circulation 103: 196-200, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11208676/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11208676</a>] [<a href="https://doi.org/10.1161/01.cir.103.2.196" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11208676">Priori et al. (2001)</a> identified a heterozygous arg2474-to-ser (R2474S) mutation of the RYR2 gene in an 8-year-old boy with stress-induced polymorphic ventricular tachycardia (CPVT1; <a href="/entry/604772">604772</a>). The boy had had repeated syncopal episodes. His identical twin had a history of repeated syncopal events and died suddenly at 7 years of age; autopsy failed to demonstrate abnormal findings, and death was attributed to cardiac arrest. The parents were asymptomatic. The patient was treated with atenolol, and adequate control of the arrhythmias was achieved with no recurrence of syncope through 6 years of follow-up. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11208676" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="0003" class="mim-anchor"></a>
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<span class="mim-font">
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<strong>.0003 VENTRICULAR TACHYCARDIA, CATECHOLAMINERGIC POLYMORPHIC, 1</strong>
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<span class="mim-text-font">
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RYR2, ASN4104LYS
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121918599 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918599;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=rs121918599" 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=rs121918599" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000013822" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013822" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013822</a>
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<span class="mim-text-font">
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<p><a href="#25" class="mim-tip-reference" title="Priori, S. G., Napolitano, C., Tiso, N., Memmi, M., Vignati, G., Bloise, R., Sorrentino, V., Danieli, G. A. <strong>Mutations in the cardiac ryanodine receptor gene (hRyR2) underlie catecholaminergic polymorphic ventricular tachycardia.</strong> Circulation 103: 196-200, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11208676/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11208676</a>] [<a href="https://doi.org/10.1161/01.cir.103.2.196" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11208676">Priori et al. (2001)</a> identified a heterozygous asn4104-to-lys (N4104K) mutation of the RYR2 gene in a 14-year-old boy with stress-induced polymorphic ventricular tachycardia (CPVT1; <a href="/entry/604772">604772</a>). The boy had been referred because of frequent episodes of loss of consciousness during exercise, beginning at age 7 years. There was no family history of sudden cardiac death and/or syncopal episodes. The parents were asymptomatic, with normal hearts and no exercise-induced arrhythmias. The patient was treated with atenolol, which prevented recurrence of syncope and ventricular arrhythmias during 9 years of follow-up. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11208676" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="0004" class="mim-anchor"></a>
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<span class="mim-font">
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<strong>.0004 VENTRICULAR TACHYCARDIA, CATECHOLAMINERGIC POLYMORPHIC, 1</strong>
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RYR2, ARG4497CYS
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121918600 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918600;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=rs121918600" 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=rs121918600" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000013823 OR RCV000478561 OR RCV000617445 OR RCV003149571" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013823, RCV000478561, RCV000617445, RCV003149571" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013823...</a>
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<p><a href="#25" class="mim-tip-reference" title="Priori, S. G., Napolitano, C., Tiso, N., Memmi, M., Vignati, G., Bloise, R., Sorrentino, V., Danieli, G. A. <strong>Mutations in the cardiac ryanodine receptor gene (hRyR2) underlie catecholaminergic polymorphic ventricular tachycardia.</strong> Circulation 103: 196-200, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11208676/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11208676</a>] [<a href="https://doi.org/10.1161/01.cir.103.2.196" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11208676">Priori et al. (2001)</a> identified a heterozygous arg4497-to-cys (R4497C) mutation of the RYR2 gene in a 30-year-old woman with catecholaminergic polymorphic ventricular tachycardia (CPVT1; <a href="/entry/604772">604772</a>) and a family history of sudden cardiac death. Testing showed bidirectional ventricular tachycardia developing during exercise stress testing in the woman, her mother, in 2 of her sisters, and in her brother; 2 other sisters had died at ages 14 and 16 years, respectively, one while being tested at school and the second while climbing stairs. During 1 year of follow-up after placement of an implantable cardiac defibrillator, the patient experienced 2 appropriate shocks that successfully terminated ventricular fibrillation. On both occasions, emotional stress preceded the events; the first episode occurred while she was being fired by her boss; the second while she was acting in a play at the local school. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11208676" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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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<span class="mim-font">
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<strong>.0005 VENTRICULAR TACHYCARDIA, CATECHOLAMINERGIC POLYMORPHIC, 1</strong>
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RYR2, ASN2386ILE
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121918601 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918601;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=rs121918601" 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=rs121918601" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV003151726" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV003151726" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV003151726</a>
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<p>In two 3-generation families (families 102 and 123) with exercise-induced ventricular arrhythmias (CPVT1; <a href="/entry/604772">604772</a>), one of which (102) was originally reported by <a href="#26" class="mim-tip-reference" title="Rampazzo, A., Nava, A., Erne, P., Eberhard, M., Vian, E., Slomp, P., Tiso, N., Thiene, G., Danieli, G. A. <strong>A new locus for arrhythmogenic right ventricular cardiomyopathy (ARVD2) maps to chromosome 1q42-q43.</strong> Hum. Molec. Genet. 4: 2151-2154, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8589694/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8589694</a>] [<a href="https://doi.org/10.1093/hmg/4.11.2151" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8589694">Rampazzo et al. (1995)</a>, <a href="#32" class="mim-tip-reference" title="Tiso, N., Stephan, D. A., Nava, A., Bagattin, A., Devaney, J. M., Stanchi, F., Larderet, G., Brahmbhatt, B., Brown, K., Bauce, B., Muriago, M., Basso, C., Thiene, G., Danieli, G. A., Rampazzo, A. <strong>Identification of mutations in the cardiac ryanodine receptor gene in families affected with arrhythmogenic right ventricular cardiomyopathy type 2 (ARVD2).</strong> Hum. Molec. Genet. 10: 189-194, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11159936/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11159936</a>] [<a href="https://doi.org/10.1093/hmg/10.3.189" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11159936">Tiso et al. (2001)</a> detected a 7157A-T transversion in exon 47 of the RYR2 gene, resulting in an asn2386-to-ile (N2386I) mutation at a highly conserved residue in the 12-kD FK506-binding domain. The mutation segregated fully with disease in both families and was not found in 120 healthy Italian controls. Both families were from Monselice, a small town close to Padua, and haplotype analysis suggested the existence of a relatively recent common ancestor for the 2 apparently independent families. The phenotype, which was originally diagnosed as an unusual localized form of arrhythmogenic right ventricular dysplasia (ARVD; see <a href="/entry/107970">107970</a>), was later designated to be catecholamine-induced ventricular tachycardia (<a href="#12" class="mim-tip-reference" title="Karmouch, J., Protonotarios, A., Syrris, P. <strong>Genetic basis of arrhythmogenic cardiomyopathy.</strong> Curr. Opin. Cardiol. 33: 276-281, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29543670/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29543670</a>] [<a href="https://doi.org/10.1097/HCO.0000000000000509" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29543670">Karmouch et al., 2018</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=29543670+8589694+11159936" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 VENTRICULAR TACHYCARDIA, CATECHOLAMINERGIC POLYMORPHIC, 1</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121918602 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918602;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=rs121918602" 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=rs121918602" 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=RCV000151756 OR RCV000190229 OR RCV000780694 OR RCV003151727" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000151756, RCV000190229, RCV000780694, RCV003151727" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000151756...</a>
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<p>In a 3-generation family (family 122) with exercise-induced ventricular arrhythmias (CPVT1; <a href="/entry/604772">604772</a>), <a href="#32" class="mim-tip-reference" title="Tiso, N., Stephan, D. A., Nava, A., Bagattin, A., Devaney, J. M., Stanchi, F., Larderet, G., Brahmbhatt, B., Brown, K., Bauce, B., Muriago, M., Basso, C., Thiene, G., Danieli, G. A., Rampazzo, A. <strong>Identification of mutations in the cardiac ryanodine receptor gene in families affected with arrhythmogenic right ventricular cardiomyopathy type 2 (ARVD2).</strong> Hum. Molec. Genet. 10: 189-194, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11159936/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11159936</a>] [<a href="https://doi.org/10.1093/hmg/10.3.189" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11159936">Tiso et al. (2001)</a> detected a T-to-C transition at nucleotide 1298 in exon 15 of the RYR2 gene, resulting in a leu433-to-pro (L433P) substitution at a highly conserved residue in the cytosolic portion of the protein. The L433P variant segregated fully with disease in the family and was not found in 120 healthy Italian controls. The authors noted that the affected family members also carried a known RYR2 polymorphism, G1885E, on the same allele as the L433P variant. The phenotype, which was originally diagnosed as an unusual localized form of arrhythmogenic right ventricular dysplasia (ARVD; see <a href="/entry/107970">107970</a>), was later designated to be catecholamine-induced ventricular tachycardia (<a href="#12" class="mim-tip-reference" title="Karmouch, J., Protonotarios, A., Syrris, P. <strong>Genetic basis of arrhythmogenic cardiomyopathy.</strong> Curr. Opin. Cardiol. 33: 276-281, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29543670/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29543670</a>] [<a href="https://doi.org/10.1097/HCO.0000000000000509" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29543670">Karmouch et al., 2018</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=29543670+11159936" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#20" class="mim-tip-reference" title="Olubando, D., Hopton, C., Eden, J., Caswell, R., Thomas, N. L., Roberts, S. A., Morris-Rosendahl, D., Venetucci, L., Newman, W. G. <strong>Classification and correlation of RYR2 missense variants in individuals with catecholaminergic polymorphic ventricular tachycardia reveals phenotypic relationships.</strong> J. Hum. Genet. 65: 531-539, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32152366/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32152366</a>] [<a href="https://doi.org/10.1038/s10038-020-0738-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32152366">Olubando et al. (2020)</a> reviewed mutations according to ACMG criteria and considered the L33P mutation to be a variant of uncertain significance (1 strong, 1 moderate, and 1 supporting). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32152366" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>.0007 VENTRICULAR TACHYCARDIA, CATECHOLAMINERGIC POLYMORPHIC, 1</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121918603 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918603;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=rs121918603" 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=rs121918603" 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=RCV000013826" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013826" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013826</a>
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<p><a href="#13" class="mim-tip-reference" title="Laitinen, P. J., Brown, K. M., Piippo, K., Swan, H., Devaney, J. M., Brahmbhatt, B., Donarum, E. A., Marino, M., Tiso, N., Viitasalo, M., Toivonen, L., Stephan, D. A., Kontula, K. <strong>Mutations of the cardiac ryanodine receptor (RyR2) gene in familial polymorphic ventricular tachycardia.</strong> Circulation 103: 485-490, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11157710/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11157710</a>] [<a href="https://doi.org/10.1161/01.cir.103.4.485" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11157710">Laitinen et al. (2001)</a> reported a pro2328-to-ser (P2328S) missense mutation in the RYR2 gene in a large Finnish family with a history of stress-induced ventricular tachycardia (CPVT1; <a href="/entry/604772">604772</a>) and sudden unexplained death. This mutation was located in the large cytoplasmic domain of the cardiac ryanodine receptor. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11157710" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Lehnart, S. E., Wehrens, X. H. T., Laitinen, P. J., Reiken, S. R., Deng, S.-X., Cheng, Z., Landry, D. W., Kontula, K., Swan, H., Marks, A. R. <strong>Sudden death in familial polymorphic ventricular tachycardia associated with calcium release channel (ryanodine receptor) leak.</strong> Circulation 109: 3208-3214, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15197150/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15197150</a>] [<a href="https://doi.org/10.1161/01.CIR.0000132472.98675.EC" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15197150">Lehnart et al. (2004)</a> simulated the effects of exercise on mutant RYR2 channels using PKA phosphorylation. The P2328S mutant exhibited decreased binding of calstabin-2, a subunit that stabilizes the closed state of the channel. After PKA phosphorylation, the mutant showed a significant gain-of-function defect consistent with leaky Ca(2+)-release channels and a significant rightward shift in the half-maximal inhibitory magnesium concentration. Treatment with an experimental drug enhanced the binding of calstabin-2 to RYR2 and normalized channel function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15197150" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>.0008 VENTRICULAR TACHYCARDIA, CATECHOLAMINERGIC POLYMORPHIC, 1</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121918604 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918604;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/rs121918604?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=rs121918604" 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=rs121918604" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p><a href="#13" class="mim-tip-reference" title="Laitinen, P. J., Brown, K. M., Piippo, K., Swan, H., Devaney, J. M., Brahmbhatt, B., Donarum, E. A., Marino, M., Tiso, N., Viitasalo, M., Toivonen, L., Stephan, D. A., Kontula, K. <strong>Mutations of the cardiac ryanodine receptor (RyR2) gene in familial polymorphic ventricular tachycardia.</strong> Circulation 103: 485-490, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11157710/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11157710</a>] [<a href="https://doi.org/10.1161/01.cir.103.4.485" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11157710">Laitinen et al. (2001)</a> reported a val4653-to-phe (V4653F) mutation in the RYR2 gene in a large Finnish family with a history of stress-induced ventricular tachycardia (CPVT1; <a href="/entry/604772">604772</a>) and sudden unexplained death. This mutation was located in the carboxy-terminal part of the cardiac ryanodine receptor, which contains several membrane-spanning domains. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11157710" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Lehnart, S. E., Wehrens, X. H. T., Laitinen, P. J., Reiken, S. R., Deng, S.-X., Cheng, Z., Landry, D. W., Kontula, K., Swan, H., Marks, A. R. <strong>Sudden death in familial polymorphic ventricular tachycardia associated with calcium release channel (ryanodine receptor) leak.</strong> Circulation 109: 3208-3214, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15197150/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15197150</a>] [<a href="https://doi.org/10.1161/01.CIR.0000132472.98675.EC" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15197150">Lehnart et al. (2004)</a> simulated the effects of exercise on mutant RYR2 channels using PKA phosphorylation. The V4653F mutant exhibited decreased binding of calstabin-2, a subunit that stabilizes the closed state of the channel. After PKA phosphorylation, the mutant showed a significant gain-of-function defect consistent with leaky Ca(2+)-release channels and a significant rightward shift in the half-maximal inhibitory magnesium concentration. Treatment with an experimental drug enhanced the binding of calstabin-2 to RYR2 and normalized channel function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15197150" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0009 VENTRICULAR TACHYCARDIA, CATECHOLAMINERGIC POLYMORPHIC, 1</strong>
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<p><a href="#13" class="mim-tip-reference" title="Laitinen, P. J., Brown, K. M., Piippo, K., Swan, H., Devaney, J. M., Brahmbhatt, B., Donarum, E. A., Marino, M., Tiso, N., Viitasalo, M., Toivonen, L., Stephan, D. A., Kontula, K. <strong>Mutations of the cardiac ryanodine receptor (RyR2) gene in familial polymorphic ventricular tachycardia.</strong> Circulation 103: 485-490, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11157710/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11157710</a>] [<a href="https://doi.org/10.1161/01.cir.103.4.485" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11157710">Laitinen et al. (2001)</a> reported a gln4201-to-arg (Q4201R) mutation in the RYR2 gene in a Finnish family with a history of stress-induced ventricular tachycardia (CPVT1; <a href="/entry/604772">604772</a>) and sudden unexplained death. This mutation was located in the C-terminal part of the RYR2 receptor, which contains several membrane-spanning domains. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11157710" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Lehnart, S. E., Wehrens, X. H. T., Laitinen, P. J., Reiken, S. R., Deng, S.-X., Cheng, Z., Landry, D. W., Kontula, K., Swan, H., Marks, A. R. <strong>Sudden death in familial polymorphic ventricular tachycardia associated with calcium release channel (ryanodine receptor) leak.</strong> Circulation 109: 3208-3214, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15197150/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15197150</a>] [<a href="https://doi.org/10.1161/01.CIR.0000132472.98675.EC" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15197150">Lehnart et al. (2004)</a> simulated the effects of exercise on mutant RYR2 channels using PKA phosphorylation. The Q4201R mutant exhibited decreased binding of calstabin-2, a subunit that stabilizes the closed state of the channel. After PKA phosphorylation, the mutant showed a significant gain-of-function defect consistent with leaky Ca(2+)-release channels and a significant rightward shift in the half-maximal inhibitory magnesium concentration. Treatment with an experimental drug enhanced the binding of calstabin-2 to RYR2 and normalized channel function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15197150" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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">rs121918606 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918606;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=rs121918606" 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=rs121918606" 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 female patient with ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome (VACRDS; <a href="/entry/115000">115000</a>), <a href="#24" class="mim-tip-reference" title="Priori, S. G., Napolitano, C., Memmi, M., Colombi, B., Drago, F., Gasparini, M., DeSimone, L., Coltorti, F., Bloise, R., Keegan, R., Cruz Filho, F. E. S., Vignati, G., Benatar, A., DeLogu, A. <strong>Clinical and molecular characterization of patients with catecholaminergic polymorphic ventricular tachycardia.</strong> Circulation 106: 69-74, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12093772/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12093772</a>] [<a href="https://doi.org/10.1161/01.cir.0000020013.73106.d8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12093772">Priori et al. (2002)</a> identified a heterozygous ala4860-to-gly (A4860G) substitution at a highly conserved transmembrane residue of the RYR2 gene. Her mother and a maternal uncle had unexplained sudden cardiac death at 38 years and 22 years of age, respectively; her sister was an asymptomatic carrier of the mutation. The mutation was not found in 350 unrelated controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12093772" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 A4860G-transfected human embryonic kidney cells, <a href="#6" class="mim-tip-reference" title="Jiang, D., Chen, W., Wang, R., Zhang, L., Chen, S. R. W. <strong>Loss of luminal Ca(2+) activation in the cardiac ryanodine receptor is associated with ventricular fibrillation and sudden death.</strong> Proc. Nat. Acad. Sci. 104: 18309-18314, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17984046/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17984046</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17984046[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.0706573104" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17984046">Jiang et al. (2007)</a> found that the mutation diminished the response of RYR2 to activation by luminal Ca(2+) but had little effect on the sensitivity of the channel to activation by cytosolic Ca(2+). Stable, inducible HEK293 cells expressing the A4860G mutant showed caffeine-induced Ca(2+) release but exhibited no store-overload-induced Ca(2+) release (SOICR), and HL1 cardiac cells transfected with the A4860G mutant displayed attenuated SOICR activity compared to cells transfected with wildtype RYR2. <a href="#6" class="mim-tip-reference" title="Jiang, D., Chen, W., Wang, R., Zhang, L., Chen, S. R. W. <strong>Loss of luminal Ca(2+) activation in the cardiac ryanodine receptor is associated with ventricular fibrillation and sudden death.</strong> Proc. Nat. Acad. Sci. 104: 18309-18314, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17984046/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17984046</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17984046[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.0706573104" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17984046">Jiang et al. (2007)</a> concluded that loss of luminal Ca(2+) activation and SOICR activity can cause ventricular fibrillation and sudden death. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17984046" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 site-directed mutagenesis, <a href="#38" class="mim-tip-reference" title="Zhao, Y.-T., Valdivia, C. R., Gurrola, G. B., Powers, P. P., Willis, B. C., Moss, R. L., Jalife, J., Valdivia, H. H. <strong>Arrhythmogenesis in a catecholaminergic polymorphic ventricular tachycardia mutation that depresses ryanodine receptor function.</strong> Proc. Nat. Acad. Sci. 112: E1669-E1677, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25775566/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25775566</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25775566[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.1419795112" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25775566">Zhao et al. (2015)</a> showed that the A4860G mutation in mouse Ryr2 did not affect the expression level of the protein, but it severely inhibited Ryr2 channel activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25775566" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Sun, B., Yao, J., Ni, M., Wei, J., Zhong, X., Guo, W., Zhang, L., Wang, R., Belke, D., Chen, Y.-X., Lieve, K. V. V., Broendberg, A. K., and 19 others. <strong>Cardiac ryanodine receptor calcium release deficiency syndrome.</strong> Sci. Transl. Med. 13: eaba7287, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33536282/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33536282</a>] [<a href="https://doi.org/10.1126/scitranslmed.aba7287" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33536282">Sun et al. (2021)</a> restudied the patient originally reported by <a href="#24" class="mim-tip-reference" title="Priori, S. G., Napolitano, C., Memmi, M., Colombi, B., Drago, F., Gasparini, M., DeSimone, L., Coltorti, F., Bloise, R., Keegan, R., Cruz Filho, F. E. S., Vignati, G., Benatar, A., DeLogu, A. <strong>Clinical and molecular characterization of patients with catecholaminergic polymorphic ventricular tachycardia.</strong> Circulation 106: 69-74, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12093772/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12093772</a>] [<a href="https://doi.org/10.1161/01.cir.0000020013.73106.d8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12093772">Priori et al. (2002)</a>, noting that she had no trigger for her original event, which involved an aborted sudden cardiac death (aSCD) at age 7 years, with documented ventricular fibrillation. An exercise stress test performed 1 week after the event was unremarkable with no arrhythmias elicited; similarly, programmed electrical stimulation and isoproterenol administration did not induce arrhythmias. <a href="#28" class="mim-tip-reference" title="Sun, B., Yao, J., Ni, M., Wei, J., Zhong, X., Guo, W., Zhang, L., Wang, R., Belke, D., Chen, Y.-X., Lieve, K. V. V., Broendberg, A. K., and 19 others. <strong>Cardiac ryanodine receptor calcium release deficiency syndrome.</strong> Sci. Transl. Med. 13: eaba7287, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33536282/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33536282</a>] [<a href="https://doi.org/10.1126/scitranslmed.aba7287" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33536282">Sun et al. (2021)</a> classified the patient as having RYR2 Ca(2+) release deficiency syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=33536282+12093772" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In affected individuals from 2 families with catecholaminergic polymorphic ventricular tachycardia associated with sinoatrial and atrioventricular node dysfunction, atrial arrhythmias, and dilated cardiomyopathy (CPVT1; <a href="/entry/604772">604772</a>), <a href="#3" class="mim-tip-reference" title="Bhuiyan, Z. A., van den Berg, M. P., van Tintelen, J. P., Bink-Boelkens, M. T. E., Wiesfeld, A. C. P., Alders, M., Postma, A. V., van Langen, I., Mannens, M. M. A. M., Wilde, A. A. M. <strong>Expanding spectrum of human RYR2-related disease: new electrocardiographic, structural, and genetic features.</strong> Circulation 116: 1569-1576, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17875969/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17875969</a>] [<a href="https://doi.org/10.1161/CIRCULATIONAHA.107.711606" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17875969">Bhuiyan et al. (2007)</a> identified a heterozygous 1.1-kb deletion comprising all of exon 3 and part of the flanking introns 2 and 3 (161-236_272+781del1126) of the RYR2 gene, resulting in loss of 35 amino acids. Several patients in both families gradually developed depressed left ventricular function, and 1 patient who died suddenly at 30 years of age had left ventricular dilation on echocardiography. At autopsy, myocardial biopsy of the left interventricular septum showed mild myocyte hypertrophy and interstitial fibrosis; there were no inflammatory or fibrolipomatous changes of the right ventricular endocardium. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17875969" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#19" class="mim-tip-reference" title="Medeiros-Domingo, A., Bhuiyan, Z. A., Tester, D. J., Hofman, N., Bikker, H., van Tintelen, J. P., Mannens, M. M. A. M., Wilde, A. A. M., Ackerman, M. J. <strong>The RYR2-encoded ryanodine receptor/calcium release channel in patients diagnosed previously with either catecholaminergic polymorphic ventricular tachycardia or genotype negative, exercise-induced long QT syndrome.</strong> J. Am. Coll. Cardiol. 54: 2065-2074, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19926015/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19926015</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19926015[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.jacc.2009.08.022" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19926015">Medeiros-Domingo et al. (2009)</a> identified 3 large genomic rearrangements comprising exon 3 of the RYR2 gene in 3 unrelated patients with CPVT1, involving a 3.6-kb deletion in 1 case and a 1.1-kb deletion in 2 cases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19926015" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV001814262 OR RCV002553827" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001814262, RCV002553827" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001814262...</a>
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<p>In a 3-generation family with sudden cardiac death (SCD) or aborted SCD resulting from ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome (VACRDS; <a href="/entry/115000">115000</a>), <a href="#28" class="mim-tip-reference" title="Sun, B., Yao, J., Ni, M., Wei, J., Zhong, X., Guo, W., Zhang, L., Wang, R., Belke, D., Chen, Y.-X., Lieve, K. V. V., Broendberg, A. K., and 19 others. <strong>Cardiac ryanodine receptor calcium release deficiency syndrome.</strong> Sci. Transl. Med. 13: eaba7287, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33536282/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33536282</a>] [<a href="https://doi.org/10.1126/scitranslmed.aba7287" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33536282">Sun et al. (2021)</a> identified heterozygosity for a c.13937A-C transversion in exon 96 of the RYR2 gene, resulting in an asp4646-to-ala (D4646A) substitution. The 51-year-old proband experienced syncope and aborted SCD at age 39 years, with ventricular fibrillation observed on the ambulance monitor. In the ICU, polymorphic ventricular tachycardia was observed and treated with direct-current (DC) shock. No arrhythmias were elicited on exercise stress test, and she underwent placement of an implantable cardioverter-defibrillator (ICD), which later discharged appropriately when she experienced syncope during an episode of acute emotional stress. Family history revealed 4 more cases of SCD in the maternal branch of the family, occurring between 16 and 43 years of age, triggered by acute emotional stress. The D4646A mutation was found in a maternal aunt who died with SCD, as well as in the proband's asymptomatic 17-year-old son and in an asymptomatic first cousin once removed whose father and paternal grandfather both had SCD, but the variant was not present in the proband's asymptomatic sister or in 3 asymptomatic male cousins. Functional analysis demonstrated that the D4646A mutation markedly suppressed caffeine-induced Ca(2+) release and store overload-induced Ca(2+) release (SOICR) without altering the store capacity. In addition, the SOICR termination threshold and RYR2-mediated fractional Ca(2+) release were both significantly increased with the mutant compared to wildtype RYR2. The D4646A mutant also impaired the cytosolic Ca(2+) activation and diminished the luminal Ca(2+) activation of single RYR2 channels. The authors generated a knockin mouse model and observed that the D4646A mutation abolished abnormal diastolic spontaneous Ca(2+) release from the sarcoplasmic reticulum in intact mouse hearts, completely protecting them against delayed afterdepolarization-driven ventricular arrhythmias. There was substantial electrophysiologic remodeling in the mutant mouse hearts, increasing the transient outward K+ current, the L-type Ca(2+) channel current, and the Na+/Ca(2+) exchange current. This altered the action potential waveform (shortened APD50 and lengthened APD90) and increased the propensity for arrhythmogenic early afterdepolarizations in the mutant hearts. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33536282" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 VENTRICULAR ARRHYTHMIAS DUE TO CARDIAC RYANODINE RECEPTOR CALCIUM RELEASE DEFICIENCY 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">rs2149352030 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2149352030;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=rs2149352030" 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=rs2149352030" 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=RCV001814321" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001814321" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001814321</a>
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<p>In a 3-generation family with sudden cardiac death (SCD) or aborted SCD resulting from ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome (VACRDS; <a href="/entry/115000">115000</a>), <a href="#28" class="mim-tip-reference" title="Sun, B., Yao, J., Ni, M., Wei, J., Zhong, X., Guo, W., Zhang, L., Wang, R., Belke, D., Chen, Y.-X., Lieve, K. V. V., Broendberg, A. K., and 19 others. <strong>Cardiac ryanodine receptor calcium release deficiency syndrome.</strong> Sci. Transl. Med. 13: eaba7287, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33536282/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33536282</a>] [<a href="https://doi.org/10.1126/scitranslmed.aba7287" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33536282">Sun et al. (2021)</a> identified heterozygosity for a c.11983A-C transversion in the RYR2 gene, resulting in an ile3995-to-val (I3995V) substitution. The variant was initially identified in the family after 2 cousins had SCD at ages 28 and 32 years. The 60-year-old female proband was a known carrier of the I3995V mutation who experienced syncope at age 52 while watching television. Cardiac evaluation, including an exercise stress test, was negative, but given the family history, an implantable cardioverter-defibrillator (ICD) was placed. The device recorded nonsustained polymorphic ventricular tachycardia/ventricular fibrillation during follow-up, when proband had presyncopal episodes. Her brother and her 2 children were asymptomatic carriers of the variant. Functional analysis demonstrated that the I3995V mutation markedly suppressed caffeine-induced Ca(2+) release and store overload-induced Ca(2+) release (SOICR) without altering the store capacity. In addition, the SOICR termination threshold and RYR2-mediated fractional Ca(2+) release were both significantly increased with the mutant compared to wildtype RYR2. The I3995V mutant also impaired the cytosolic Ca(2+) activation and diminished the luminal Ca(2+) activation of single RYR2 channels. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33536282" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 VENTRICULAR ARRHYTHMIAS DUE TO CARDIAC RYANODINE RECEPTOR CALCIUM RELEASE DEFICIENCY 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">rs2149354389 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2149354389;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=rs2149354389" 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=rs2149354389" 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=RCV001814322 OR RCV002557515" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001814322, RCV002557515" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001814322...</a>
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<p>In 3 sibs with sudden cardiac death (SCD) or aborted SCD resulting from ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome (VACRDS; <a href="/entry/115000">115000</a>), <a href="#28" class="mim-tip-reference" title="Sun, B., Yao, J., Ni, M., Wei, J., Zhong, X., Guo, W., Zhang, L., Wang, R., Belke, D., Chen, Y.-X., Lieve, K. V. V., Broendberg, A. K., and 19 others. <strong>Cardiac ryanodine receptor calcium release deficiency syndrome.</strong> Sci. Transl. Med. 13: eaba7287, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33536282/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33536282</a>] [<a href="https://doi.org/10.1126/scitranslmed.aba7287" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33536282">Sun et al. (2021)</a> identified heterozygosity for a c.12587C-T transition in the RYR2 gene, resulting in a thr4196-to-ile (T4196I) substitution. The proband had recurrent episodes of syncope on exertion at age 17 years, but cardiac evaluation was normal, including exercise stress testing. She died suddenly at age 19 while running. Cardiac screening of her 4 sibs, including exercise stress testing, was negative. However, 12 years later, the proband's 33-year-old sister collapsed while running on a treadmill and was found to be in ventricular fibrillation by paramedics, who performed successful cardioversion to normal sinus rhythm. Another brother later died suddenly while running during a baseball game. The remaining 2 sibs and the 33-year-old sister's 3 asymptomatic children did not carry the mutation. Functional analysis demonstrated that the T4196I mutation markedly suppressed caffeine- and store overload-induced Ca(2+) release without altering the store capacity. In addition, RYR2-mediated fractional Ca(2+) release was significantly increased with the mutant compared to wildtype RYR2. The T4196I mutant also impaired the cytosolic Ca(2+) activation and diminished the luminal Ca(2+) activation of single RYR2 channels. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33536282" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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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Bauce, B., Nava, A., Rampazzo, A., Daliento, L., Muriago, M., Basso, C., Thiene, G., Danieli, G. A.
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<strong>Familial effort polymorphic ventricular arrhythmias in arrhythmogenic right ventricular cardiomyopathy map to chromosome 1q42-q43.</strong>
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[<a href="https://doi.org/10.1016/s0002-9149(99)00814-0" target="_blank">Full Text</a>]
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<strong>Ryanodine receptor channelopathies.</strong>
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Biochem. Biophys. Res. Commun. 322: 1280-1285, 2004.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15336975/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15336975</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15336975" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Bhuiyan, Z. A., van den Berg, M. P., van Tintelen, J. P., Bink-Boelkens, M. T. E., Wiesfeld, A. C. P., Alders, M., Postma, A. V., van Langen, I., Mannens, M. M. A. M., Wilde, A. A. M.
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<strong>Expanding spectrum of human RYR2-related disease: new electrocardiographic, structural, and genetic features.</strong>
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Circulation 116: 1569-1576, 2007.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17875969/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17875969</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17875969" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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<strong>Ryanodine receptor mutations associated with stress-induced ventricular tachycardia mediate increased calcium release in stimulated cardiomyocytes.</strong>
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Circ. Res. 93: 531-540, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12919952/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12919952</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12919952" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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<strong>Modulation of cardiac ryanodine receptor 2 by calmodulin.</strong>
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Nature 572: 347-351, 2019.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31278385/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31278385</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31278385" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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<strong>Loss of luminal Ca(2+) activation in the cardiac ryanodine receptor is associated with ventricular fibrillation and sudden death.</strong>
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Proc. Nat. Acad. Sci. 104: 18309-18314, 2007.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17984046/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17984046</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17984046[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=17984046" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Jiang, D., Wang, R., Xiao, B., Kong, H., Hunt, D. J., Choi, P., Zhang, L., Chen, S. R. W.
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<strong>Enhanced store overload-induced Ca(2+) release and channel sensitivity to luminal Ca(2+) activation are common defects of RyR2 mutations linked to ventricular tachycardia and sudden death.</strong>
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Circ. Res. 97: 1173-1181, 2005.
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[<a href="https://doi.org/10.1161/01.RES.0000192146.85173.4b" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1074/jbc.M210410200" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1073/pnas.0402388101" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1161/01.res.0000028455.36940.5e" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1073/pnas.0600268103" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1097/HCO.0000000000000509" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1161/01.cir.103.4.485" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1172/JCI35346" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1161/01.CIR.0000132472.98675.EC" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/j.bbrc.2004.08.032" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1006/geno.1994.1362" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/j.jacc.2009.08.022" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1155/2018/9109503" target="_blank">Full Text</a>]
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<a id="39" class="mim-anchor"></a>
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<a id="Zorzato1990" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Zorzato, F., Fujii, J., Otsu, K., Phillips, M., Green, N. M., Lai, F. A., Meissner, G., MacLennan, D. H.
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<strong>Molecular cloning of cDNA encoding human and rabbit forms of the Ca2+ release channel (ryanodine receptor) of skeletal muscle sarcoplasmic reticulum.</strong>
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J. Biol. Chem. 265: 2244-2256, 1990.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2298749/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2298749</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2298749" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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</p>
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<a id="contributors" class="mim-anchor"></a>
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Marla J. F. O'Neill - updated : 03/07/2023
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</span>
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</div>
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<div class="row collapse" id="mimCollapseContributors">
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<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Marla J. F. O'Neill - updated : 01/13/2022<br>Bao Lige - updated : 06/14/2021<br>Marla J. F. O'Neill - updated : 05/21/2021<br>Ada Hamosh - updated : 05/07/2021<br>Marla J. F. O'Neill - updated : 03/18/2021<br>Ada Hamosh - updated : 12/03/2019<br>Marla J. F. O'Neill - updated : 5/26/2011<br>Ada Hamosh - updated : 2/2/2011<br>Marla J. F. O'Neill - updated : 3/5/2010<br>Patricia A. Hartz - updated : 8/20/2008<br>Marla J. F. O'Neill - updated : 4/8/2008<br>Marla J. F. O'Neill - updated : 9/15/2006<br>Cassandra L. Kniffin - updated : 2/27/2006<br>Marla J. F. O'Neill - updated : 7/29/2005<br>Victor A. McKusick - updated : 2/22/2005<br>Cassandra L. Kniffin - updated : 12/17/2004<br>Stylianos E. Antonarakis - updated : 11/24/2004<br>Victor A. McKusick - updated : 10/4/2004<br>Ada Hamosh - updated : 4/20/2004<br>Patricia A. Hartz - updated : 7/10/2003<br>Paul Brennan - updated : 4/17/2002<br>Victor A. McKusick - updated : 12/20/2001<br>George E. Tiller - updated : 4/16/2001<br>Victor A. McKusick - updated : 1/2/2001<br>Stylianos E. Antonarakis - updated : 6/7/2000
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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 : 8/20/1991
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</span>
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</div>
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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alopez : 03/07/2023
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</span>
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<div class="row collapse" id="mimCollapseEditHistory">
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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alopez : 03/07/2023<br>carol : 01/13/2022<br>mgross : 06/14/2021<br>carol : 05/22/2021<br>alopez : 05/21/2021<br>carol : 05/07/2021<br>alopez : 03/23/2021<br>carol : 03/23/2021<br>carol : 03/22/2021<br>alopez : 03/18/2021<br>carol : 01/08/2020<br>alopez : 12/03/2019<br>wwang : 06/02/2011<br>terry : 5/26/2011<br>wwang : 5/25/2011<br>alopez : 2/7/2011<br>terry : 2/2/2011<br>wwang : 3/9/2010<br>terry : 3/5/2010<br>mgross : 8/25/2008<br>terry : 8/20/2008<br>wwang : 4/8/2008<br>wwang : 9/19/2006<br>terry : 9/15/2006<br>wwang : 3/21/2006<br>ckniffin : 2/27/2006<br>terry : 8/12/2005<br>terry : 7/29/2005<br>wwang : 3/9/2005<br>terry : 2/22/2005<br>ckniffin : 12/17/2004<br>mgross : 11/24/2004<br>mgross : 11/24/2004<br>tkritzer : 10/7/2004<br>terry : 10/4/2004<br>alopez : 4/20/2004<br>terry : 4/20/2004<br>tkritzer : 3/11/2004<br>mgross : 7/10/2003<br>alopez : 4/17/2002<br>alopez : 4/17/2002<br>carol : 12/21/2001<br>terry : 12/20/2001<br>cwells : 5/9/2001<br>cwells : 4/26/2001<br>cwells : 4/16/2001<br>cwells : 1/5/2001<br>cwells : 1/5/2001<br>terry : 1/2/2001<br>mgross : 6/7/2000<br>dkim : 7/14/1998<br>carol : 10/18/1994<br>carol : 9/14/1993<br>carol : 8/23/1993<br>supermim : 3/16/1992<br>carol : 9/4/1991<br>carol : 8/20/1991
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</span>
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<h3>
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<span class="mim-font">
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<strong>*</strong> 180902
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</h3>
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<div>
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<h3>
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<span class="mim-font">
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RYANODINE RECEPTOR 2; RYR2
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</h3>
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</div>
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<div>
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<br />
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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<div>
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<h4>
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<span class="mim-font">
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RYANODINE RECEPTOR, CARDIAC
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: RYR2</em></strong>
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</span>
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<strong>
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<em>
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Cytogenetic location: 1q43
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Genomic coordinates <span class="small">(GRCh38)</span> : 1:237,042,184-237,833,988 </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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<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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Location
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Phenotype
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</th>
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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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<span class="mim-font">
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1q43
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<td>
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<span class="mim-font">
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Ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome
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</td>
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<td>
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<span class="mim-font">
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115000
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<td>
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<span class="mim-font">
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Autosomal dominant
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<td>
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<span class="mim-font">
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3
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<span class="mim-font">
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Ventricular tachycardia, catecholaminergic polymorphic, 1
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</td>
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<td>
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<span class="mim-font">
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604772
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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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</table>
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<div>
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<br />
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<div>
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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
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</span>
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</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>RYR2 is the major Ca(2+) channel protein in the membrane of the sarcoplasmic reticulum (SR). SR acts as an intracellular Ca(2+) storage in cardiomyocytes, and Ca(2+) can be released from SR to the cytosol by RYR2 (Polonen 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>Otsu et al. (1990) cloned a cDNA encoding the calcium-release channel (ryanodine receptor) of rabbit cardiac muscle sarcoplasmic reticulum. </p><p>Zorzato et al. (1990) cloned human RYR2 that encodes a 5,032-amino acid protein with a calculated molecular mass of 563.5 kD, which is made without an N-terminal signal sequence. Analysis of RYR2 sequence indicates that 10 potential transmembrane sequences in the C-terminal fifth of the molecule and 2 additional potential transmembrane sequences nearer to the center of the molecule could contribute to the formation of the Ca(2+) conducting pore. The remainder of the molecule is hydrophilic and presumably constitutes the cytoplasmic domain of the protein. </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>Tiso et al. (2001) determined that the RYR2 gene encompasses 105 exons. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Mapping</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Otsu et al. (1990) located the human cardiac ryanodine receptor on chromosome 1 by analysis of rodent/human somatic cell hybrids. By fluorescence in situ hybridization, Otsu et al. (1993) demonstrated that the RYR2 gene is located in the interval between 1q42.1 and 1q43. Mattei et al. (1994) used in situ hybridization to map the murine Ryr2 gene to 13A1-13A2. </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>Biochemical Features</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p><strong><em>Crystal Structure</em></strong></p><p>
|
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Tung et al. (2010) showed the 2.5-angstrom resolution crystal structure of a region spanning 3 domains of ryanodine receptor type 1 (RyR1; 180901), encompassing amino acid residues 1-559. The domains interact with each other through a predominantly hydrophilic interface. Docking in RyR1 electron microscopy maps unambiguously places the domains in the cytoplasmic portion of the channel, forming a 240-kD cytoplasmic vestibule around the 4-fold symmetry axis. Tung et al. (2010) pinpointed the exact locations of more than 50 disease-associated mutations in full-length RyR1 and RyR2. The mutations can be classified into 3 groups: those that destabilize the interfaces between the 3 amino-terminal domains, disturb the folding of individual domains, or affect 1 of the 6 interfaces with other parts of the receptor. Tung et al. (2010) proposed a model whereby the opening of RyR coincides with allosterically couples motions within the N-terminal domains. This process can be affected by mutations that target various interfaces within and across subunits. Tung et al. (2010) proposed that the crystal structure provides a framework to understand the many disease-associated mutations in RyRs that have been studied using functional methods, and would be useful for developing new strategies to modulate RyR function in disease states. </p><p><strong><em>Cryoelectron Microscopy</em></strong></p><p>
|
|
Gong et al. (2019) revealed the regulatory mechanism by which porcine RyR2 is modulated by human calmodulin (see 114180) through the structural determination of RyR2 under 8 conditions by cryoelectron microscopy. Apo-calmodulin and Ca(2+)-calmodulin bind to distinct but overlapping sites in an elongated cleft formed by the handle, helical, and central domains. The shift in calmodulin-binding sites on RyR2 is controlled by Ca(2+) binding to calmodulin, rather than to RyR2. Ca(2+)-calmodulin induces rotations and intradomain shifts of individual central domains, resulting in pore closure of the PCB95- and Ca(2+)-activated channel. In contrast, the pore of the ATP-, caffeine-, and Ca(2+)-activated channel remains open in the presence of Ca(2+)-calmodulin, which suggests that Ca(2+)-calmodulin is one of the many competing modulators of RyR2 gating. </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>The ryanodine receptor on the sarcoplasmic reticulum is the major source of calcium required for cardiac muscle excitation-contraction coupling. The channel is a tetramer composed of 4 RYR2 polypeptides and 4 FK506-binding proteins (see FKBP12.6, or FKBP1B; 600620). Marx et al. (2000) showed that protein kinase A (PKA; see 176911) phosphorylation of RYR2 dissociates FKBP12.6 and regulates the channel open probability. Using cosedimentation and coimmunoprecipitation, the authors defined a macromolecular complex composed of RYR2, FKBP12.6, PKA, the protein phosphatases PP1 (see 603771) and PP2A (see 603113), and an anchoring protein, AKAP6 (604691). In failing human hearts, Marx et al. (2000) showed that RYR2 is PKA hyperphosphorylated, resulting in defective channel function due to increased sensitivity to calcium-induced activation. </p><p>Using a quantitative yeast 2-hybrid system, Tiso et al. (2002) analyzed and compared the interaction between FKBP12.6 and 3 mutated FKBP12.6 binding regions. An RYR2 mutation (R2474S, 180902.0002) causing catecholaminergic polymorphic ventricular tachycardia (CPVT1; 604772) markedly increased the binding of RYR2 to FKBP12.6, whereas other RYR2 mutations (N2386I, 180902.0005; Y2392C) significantly decreased this binding. Tiso et al. (2002) suggested that the latter mutations increase RYR2-mediated calcium release to the cytoplasm, whereas others do not significantly affect cytosolic calcium levels, and that this might explain the clinical differences among patients. </p><p>In animals with heart failure and in patients with inherited forms of exercise-induced sudden cardiac death, depletion of the channel-stabilizing protein calstabin-2 (FKBP1B) from the ryanodine receptor-calcium release channel complex causes an intracellular calcium leak that can trigger fatal cardiac arrhythmias. Wehrens et al. (2004) found that a derivative of 1,4-benzothiazepine increased the affinity of calstabin-2 for RYR2, which stabilized the closed state of RYR2 and prevented the calcium leak that triggers arrhythmias. Wehrens et al. (2004) postulated that enhancing the binding of calstabin-2 to RYR2 may be a therapeutic strategy for common ventricular arrhythmias. </p><p>Wehrens et al. (2003) found that during exercise, RYR2 phosphorylation by PKA partially dissociated FKBP12.6 from the RYR2 channel, increasing intracellular Ca(2+) release and cardiac contractility. Fkbp12.6 -/- mice consistently exhibited exercise-induced cardiac ventricular arrhythmias that caused sudden cardiac death. Mutations in RYR2 linked to exercise-induced arrhythmias in patients with CPVT, also known as stress-induced polymorphic ventricular tachycardia, reduced the affinity of FKBP12.6 for RYR2 and increased single-channel activity under conditions that simulated exercise. These data suggested that 'leaky' RYR2 channels can trigger fatal cardiac arrhythmias, providing a possible explanation for CPVT. </p><p>Jiang et al. (2003) characterized several rabbit Ryr3 (180903) splice variants. One variant lacking a predicted transmembrane helix formed a heteromeric channel with Ryr2 when coexpressed in HEK293 cells and had a dominant-negative effect on Ryr2 channel activity. </p><p>Lehnart et al. (2004) reviewed the RYR2-FKBP1B interaction and its role in heart failure and genetic forms of arrhythmias. </p><p>In experimentally induced failing hearts of beagle dogs, Yamamoto et al. (2008) previously demonstrated that defective interdomain interaction between the N-terminal domain (residues 1 to 600) and the central domain (residues 2000 to 2500) resulted in domain unzipping, Ca(2+) leak through the Ryr2 channel, and both cAMP-dependent hyperphosphorylation and Fkbp12.6 dissociation of Ryr2. Further studies showed that K201, a 1,4-benzothiazepine derivative, bound to residues 2114 to 2149, and that K201 interrupted interaction of domain(2114-2149) with residues 2234 to 2750, which appeared to mediate stabilization of Ryr2 and inhibit Ca(2+) leak. </p>
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<h4>
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<span class="mim-font">
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<strong>Cytogenetics</strong>
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</h4>
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<p>In affected members of 2 large multiply consanguineous Amish families with exercise-associated syncope, cardiac arrest, or sudden unexplained death, Tester et al. (2020) identified homozygosity for a 344-kb tandem duplication (chr1:237,205,452-237,519,546, GRCh38) involving approximately 26,000 bp of intergenic sequence, the 5-prime UTR/promoter region of the RYR2 gene, and exons 1 through 4 of RYR2. The duplication segregated fully with disease in both families. Although a common ancestor was not identified despite pedigree expansion over several generations, the authors stated that the duplication likely represents a founder mutation in the Amish community. The authors noted that the phenotype did not appear to be distinct from autosomal dominant RYR2-mediated CPVT. </p>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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</h4>
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<p><strong><em>Ventricular Tachycardia, Catecholaminergic Polymorphic, 1</em></strong></p><p>
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Stress-induced polymorphic ventricular tachycardia occurs in the structurally intact heart with onset of manifestations in childhood and adolescence. Affected individuals present with syncopal events and with a distinctive pattern of highly reproducible, stress-related, bidirectional ventricular tachycardia in the absence of either structural heart disease or a prolonged QT interval. Because this disorder had been shown to map to 1q42-q43, the same region as RYR2, and because of the likelihood that delayed afterdepolarizations underlie arrhythmia in this disorder, Priori et al. (2001) hypothesized that mutations in the RYR2 gene may be responsible. They studied 12 probands presenting with bidirectional ventricular tachycardia that was reproducibly induced by exercise stress testing and/or isoproterenol infusion and identified heterozygous missense mutations in 4 (see 180902.0001-180902.0004). </p><p>In 4 unrelated Italian families segregating autosomal dominant exercise-induced ventricular arrhythmias, Tiso et al. (2001) identified heterozygous missense mutations in the RYR2 gene (see, e.g., 180902.0005-180902.0006). The patients were originally diagnosed as having an unusual localized form of arrhythmogenic right ventricular dysplasia (ARVD; see 107970), with clinical findings that differed from those reported in other ARVD families (Bauce et al., 2000); the disorder was later designated to be catecholamine-induced ventricular tachycardia (Karmouch et al., 2018). The mutations occurred at highly conserved residues and segregated fully with disease in each family. </p><p>Priori et al. (2002) analyzed the RYR2 gene in 26 probands with CPVT in whom mutations had been excluded in the KCNQ1 (607542), KCNH2 (152427), SCN5A (600163), KCNE1 (176261), and KCNE2 (603796) genes and identified 9 different mutations in 10 probands, respectively (see, e.g., 180902.0001 and 180902.0010). With the inclusion of 4 previously reported mutation-positive families (Priori et al., 2001) in this study, Priori et al. (2002) found 9 family members who were RYR2 mutation carriers, 5 of whom had exercise-induced arrhythmias at clinical evaluation and 4 of whom were phenotypically silent (incomplete penetrance). </p><p>George et al. (2003) expressed 3 CPVT1-linked RYR2 mutations in a cardiomyocyte cell line. They found that phenotypic characteristics in resting cells expressing mutant RYR2 were indistinguishable from those expressing the wildtype. However, Ca(2+) release was augmented in cells expressing mutant RYR2 after RYR activation (caffeine or 4-chloro-m-cresol) or beta-adrenergic stimulation (isoproterenol). Interaction between RYR2 and FKBP1A remained intact after caffeine or 4-chloro-m-cresol activation, but was dramatically disrupted by isoproterenol or forskolin, both of which elevated cAMP to similar magnitudes in all cells and were associated with equivalent hyperphosphorylation of mutant and wildtype RYR2. </p><p>Similar mortality rates of approximately 33% by age 35 years and a threshold heart rate of 130 bpm, above which exercise induces ventricular arrhythmias, are observed in Finnish families with stress-induced polymorphic ventricular tachycardia caused by a pro2328-to-ser (P2328S; 180902.0007), val4653-to-phe (V4653F; 180902.0008), or gln4201-to-arg (Q4201R; 180902.0009) mutation in the RYR2 gene. Exercise activates the sympathetic nervous system, increasing cardiac performance as part of the 'fight or flight' stress response. Lehnart et al. (2004) simulated the effects of exercise on mutant RYR2 channels using PKA phosphorylation. All 3 RYR2 mutations exhibited decreased binding of calstabin-2, a subunit that stabilizes the closed state of the channel. After PKA phosphorylation, these mutants showed a significant gain-of-function defect consistent with leaky calcium release channels and a significant rightward shift in the half-maximal inhibitory magnesium concentration. Treatment with an experimental drug enhanced the binding of calstabin-2 to RYR2 and normalized channel function. Lehnart et al. (2004) suggested that stabilization of the RYR2 channel complex may represent a molecular target for the treatment and prevention of exercise-induced arrhythmias and sudden death in these patients. </p><p>Jiang et al. (2004) studied 3 mutations in the RYR2 gene linked to ventricular tachycardia and sudden death, including N4104K (180902.0003) and characterized their effects on store-overload-induced Ca(2+) release (SOICR) in human embryonic kidney cells. SOICR refers to the spontaneous Ca(2+) release that occurs when the sarcoplasmic reticulum store Ca(2+) content reaches a critical level. They demonstrated that the 3 mutations markedly increased the occurrence of SOICR. At the molecular level, they showed that these mutations increased the sensitivity of single RyR2 channels to activation by luminal Ca(2+). Jiang et al. (2004) concluded that the increased sensitivity reduced the threshold for SOICR, thereby increasing the propensity for triggered arrhythmia. </p><p>Jiang et al. (2005) showed that CPVT/ARVD2-associated mutations throughout the RYR2 sequence enhanced the propensity for SOICR in HEK293 cells compared with wildtype. The same effect was observed in HL-1 cardiac cells for several of the mutations. Single RYR2 channel analysis revealed that the mutations augmented SOICR by primarily increasing channel sensitivity to luminal, but not cytosolic, Ca(2+) activation. Further analysis demonstrated that C-terminal RYR2 mutations did not alter Ca(2+) dependence of ryanodine binding to RYR2, and none of the mutations tested altered interaction of RYR2 with FKBP12.6. </p><p>In studies in HEK293 cells, Jiang et al. (2007) found that, in contrast to all other disease-linked RYR2 mutations characterized previously, the catecholaminergic idiopathic ventricular fibrillation-associated A4860G mutation (180902.0010) diminished the response of RYR2 to activation by luminal Ca(2+) but had little effect on the sensitivity of the channel to activation by cytosolic Ca(2+), and the transfected cells exhibited no SOICR. Jiang et al. (2007) concluded that loss of luminal Ca(2+) activation and SOICR activity can cause ventricular fibrillation and sudden death. </p><p>In affected individuals from 2 families with CPVT associated with sinoatrial and atrioventricular node dysfunction, atrial arrhythmias, and dilated cardiomyopathy, Bhuiyan et al. (2007) identified a heterozygous deletion of exon 3 of the RYR2 gene (180902.0011). The authors noted that these families expanded the phenotypic spectrum of human RYR2-related diseases. </p><p>Medeiros-Domingo et al. (2009) analyzed all 105 RYR2 exons using PCR, HPLC, and sequencing in 110 unrelated patients with a clinical diagnosis of CPVT and in 45 additional unrelated patients with an initial diagnosis of exercise-induced long QT syndrome (LQTS; see 192500) but who had a QTc of less than 480 ms and who were negative for mutation in 12 genes known to cause LQTS. The authors identified 63 possible CPVT1-associated mutations that were not found in 400 reference alleles in 73 (47%) of the 155 patients; 13 new mutation-containing exons were identified, with two-thirds of the patients having mutations in 1 of 16 exons. Three large genomic rearrangements involving exon 3 were detected in 3 unrelated cases. Medeiros-Domingo et al. (2009) stated that 45 of the 105 translated exons of the RYR2 gene were now known to host possible mutations, but that a tiered targeting strategy for CPVT should be considered, since approximately 65% of CPVT1-positive cases would be discovered by selective analysis of just 16 exons. </p><p>Using CPVT patient-specific induced pluripotent stem cell-derived cardiac muscle (iPSC-CM) cell lines carrying different RYR2 mutations, Polonen et al. (2018) evaluated the antiarrhythmic efficacy of carvedilol and flecainide. Adrenaline induced arrhythmias in all CPVT iPSC-CM cell lines examined, but it abolished arrhythmias in control cells. Both carvedilol and flecainide were equally effective in treating arrhythmias, as both drugs lowered intracellular Ca(2+) level and beating rate of cardiomyocytes significantly in all CPVT iPSC-CM cell lines. However, flecainide caused abnormal Ca(2+) transients in 61% of control cells compared with 26% of those treated with carvedilol. CPVT cardiomyocytes carrying the exon 3 deletion had the most severe Ca(2+) abnormalities, but they had the best response to drug therapies. </p><p><strong><em>Ventricular Arrhythmias due to Cardiac Ryanodine Receptor Calcium Release Deficiency Syndrome</em></strong></p><p>
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In 6 families in which the proband experienced sudden cardiac death (SCD) or aborted SCD (aSCD) resulting from ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome (VACRDS; 115000), Sun et al. (2021) identified heterozygosity for missense mutations in the RYR2 gene (see, e.g., 180902.0012-180902.0014). Combining these families with 4 previously reported families with RYR2 missense mutations, including a family studied by Priori et al. (2002) (180902.0010), revealed that 31 (67%) of 46 mutation carriers experienced SCD or aSCD, whereas none of the 46 mutation-negative individuals had life-threatening ventricular arrhythmias. All of the missense mutations showed loss-of-function effects, including marked suppression of caffeine-induced Ca(2+) release and increased threshold for store overload-induced Ca(2+) release and/or RYR2-mediated fractional Ca(2+) release, as well as impairment of cytosolic and luminal Ca(2+) activation of RYR2 channels in some cases. A knockin mouse model with the D4646A mutation (see 180902.0012) suggested that RYR2 loss-of-function mutations may cause ventricular arrhythmias via an early afterdepolarization-mediated mechanism. </p><p><strong><em>Reviews</em></strong></p><p>
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Benkusky et al. (2004) reviewed RYR1 and RYR2 mutations and their role in muscle and heart disease, respectively. </p>
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</span>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Animal Model</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Takeshima et al. (1998) generated Ryr2 -/- mice, which died at approximately embryonic day 10 with morphologic abnormalities in the heart tube. Prior to embryonic death, large vacuolate sarcoplasmic reticula and structurally abnormal mitochondria began to develop in the mutant cardiac myocytes, and the vacuolate sarcoplasmic reticula appeared to contain high concentrations of Ca(2+). A Ca(2+) transient evoked by caffeine was abolished in mutant cardiac myocytes. Treatment with ryanodine did not exert a major effect on spontaneous Ca(2+) transients in control cardiac myocytes at embryonic days 9.5-11.5. Takeshima et al. (1998) proposed that RYR2 does not participate principally in Ca(2+) signaling during excitation-contraction coupling in the embryonic heart but functions as a major Ca(2+) leak channel to maintain the normal range of luminal Ca(2+) levels in the developing sarcoplasmic reticulum. </p><p>Jiang et al. (2002) characterized the properties of an R4496C mutation in mouse Ryr2, which is equivalent to the disease-causing human RYR2 mutation R4497C (180902.0004). Binding studies in HEK293 cells using tritium-labeled ryanodine revealed that the R4496C mutation resulted in an increase in RYR2 channel activity, particularly at low concentrations, and enhanced the sensitivity of RYR2 to activation by Ca(2+) and by caffeine. HEK293 cells transfected with R4496C Ryr2 displayed spontaneous Ca(2+) oscillations more frequently than cells transfected with wildtype Ryr2. Substitution of a negatively charged glutamate for the positively charged R4496 further enhanced basal channel activity, whereas replacement of R4496 by a positively charged lysine had no significant effect on basal activity. Jiang et al. (2002) concluded that charge and polarity at residue 4496 play an essential role in RYR2 channel gating, and that enhanced basal activity of RYR2 may underlie an arrhythmogenic mechanism for effort-induced ventricular tachycardia. </p><p>Wehrens et al. (2006) generated transgenic mice with a ser2808-to-ala substitution (S2808A) of the Ryr2 gene. In vitro and in vivo studies showed that the Ryr2 alanine-2808 channels could not be phosphorylated by protein kinase A, indicating that serine-2808 is the dominant functional phosphorylation site on Ryr2 channels. Transgenic mice with heart failure induced by ligation of the left anterior descending artery showed a higher ejection fraction and improved cardiac function compared to wildtype mice with induced heart failure. Wehrens et al. (2006) concluded that PKA-mediated hyperphosphorylation of serine-2808 on the Ryr2 channel is a critical mediator of progressive cardiac dysfunction after myocardial infarction. </p><p>Kannankeril et al. (2006) generated mice heterozygous for the human disease-associated arg176-to-gln (R176Q) mutation in the Ryr2 gene and observed no fibrofatty infiltration or structural abnormalities characteristic of arrhythmogenic right ventricular dysplasia, but right ventricular end-diastolic volume was decreased in the mutant mice compared to controls. Ventricular tachycardia was observed after caffeine and epinephrine injection in Ryr2 R176Q heterozygotes but not in wildtype mice. Isoproterenol administration during intracardiac programmed stimulation increased the number and duration of ventricular tachycardia episodes in mutants but not controls. Isolated cardiomyocytes from Ryr2 R176Q heterozygous mice exhibited a higher incidence of spontaneous Ca(2+) oscillations in the absence and presence of isoproterenol compared with controls. Kannankeril et al. (2006) suggested that the R176Q mutation in RYR2 predisposes the heart to catecholamine-induced oscillatory calcium-release events that trigger a calcium-dependent ventricular arrhythmia. </p><p>Lehnart et al. (2008) found that mice heterozygous for the human CPVT-associated mutation R2474S in Ryr2 exhibited spontaneous generalized tonic-clonic seizures (which occurred in the absence of cardiac arrhythmias), exercise-induced ventricular arrhythmias, and sudden cardiac death. Treatment with an Ryr2-specific compound that enhanced binding of calstabin-2 to the mutant receptor inhibited channel leak, prevented cardiac arrhythmias, and raised the seizure threshold. Lehnart et al. (2008) concluded that CPVT is a combined neurocardiac disorder in which leaky RYR2 channels in brain cause epilepsy and in heart cause exercise-induced sudden death. </p><p>Zhao et al. (2015) found that hearts from knockin mice heterozygous for the Ryr2 A4860G mutation expressed Ryr2 protein at the same level as wildtype and showed no cardiac structural alterations or major hemodynamic parameters. However, heterozygous mutant mice exhibited basal bradycardia, and no homozygote mutants were detected at birth, suggesting a lethal phenotype. Sympathetic stimulation elicited malignant arrhythmias in heterozygous mutant hearts, recapitulating the main proarrhythmogenic features reported in a human patient with the same mutation. In isoproterenol-stimulated ventricular myocytes, the A4860G mutation decreased the peak of Ca(2+) release during systole, gradually overloading the sarcoplasmic reticulum with Ca(2+). The resultant Ca(2+) overload then randomly caused bursts of prolonged Ca(2+) release, activating electrogenic Na(+)-Ca(2+) exchanger activity and triggering early afterdepolarizations. </p><p>Shan et al. (2012) found that 3 knockin mouse lines heterozygous for the CPVT-linked Ryr2 mutations R2474S, R2386I, or L433P (180902.0006) displayed atrial burst pacing-induced atrial fibrillation (AF) due to increased diastolic SR Ca(2+) leak in atrial myocytes compared with wildtype. Increased diastolic SR Ca(2+) leak in atrial myocytes from mice heterozygous for R2474S was associated with Ryr2 oxidation and decreased Fkbp12.6 binding to Ryr2. Only atrial, and not ventricular, burst pacing increased resting diastolic SR Ca(2+) leak and induced arrhythmias in R2474S-heterozygous mice. The small molecule Rycal S107 stabilized Ryr2-Fkbp12.6 interactions in the channel complex by inhibiting oxidation/phosphorylation of Ryr2 and significantly decreased the diastolic SR Ca(2+) leak in R2474S-heterozygous mice at the cellular level and prevented burst pacing-induced AF in vivo. Fkbp12.6-knockout mice showed increased atrial burst pacing-induced AF, but it was not prevented by S107 treatment, indicating that the action of S107 was dependent on the presence of Fkbp12.6. The authors found that Camk2 (see 114078) phosphorylation of Ryr2 did not play a pivotal role in atrial burst pacing-induced AF, and that activation of sympathetic system did not appear to play an important role in triggering AF in CPVT mice. </p>
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<h4>
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<span class="mim-font">
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>14 Selected Examples):</strong>
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</span>
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</h4>
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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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<strong>.0001 VENTRICULAR TACHYCARDIA, CATECHOLAMINERGIC POLYMORPHIC, 1</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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RYR2, SER2246LEU
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<br />
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SNP: rs121918597,
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ClinVar: RCV000013820, RCV000182746, RCV001798004, RCV003298032
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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>Priori et al. (2001) identified a heterozygous ser2246-to-leu (S2246L) mutation of the RYR2 gene in an 8-year-old boy with stress-induced polymorphic ventricular tachycardia (CPVT1; 604772). The boy had had recurrent syncopal events since the age of 3 years. The events were invariably induced by exercise. Resting ECG of the proband was normal. Ventricular arrhythmias (isolated premature ventricular beats, couplets, and runs of bidirectional ventricular tachycardia) could be reproducibly induced during exercise testing and progressively worsened as the workload increased. Electrical stimulation induced no repetitive arrhythmias, but isoproterenol infusion induced bidirectional ventricular tachycardia. The patient was treated with nadolol, and an implantable cardiac defibrillator was implanted. </p><p>In a male patient with bidirectional ventricular tachycardia who developed symptoms of CPVT at 2 years of age, Priori et al. (2002) identified a de novo S2246L mutation in the RYR2 gene. </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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<h4>
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<span class="mim-font">
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<strong>.0002 VENTRICULAR TACHYCARDIA, CATECHOLAMINERGIC POLYMORPHIC, 1</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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RYR2, ARG2474SER
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<br />
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SNP: rs121918598,
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ClinVar: RCV000013821
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</span>
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<span class="mim-text-font">
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<p>Priori et al. (2001) identified a heterozygous arg2474-to-ser (R2474S) mutation of the RYR2 gene in an 8-year-old boy with stress-induced polymorphic ventricular tachycardia (CPVT1; 604772). The boy had had repeated syncopal episodes. His identical twin had a history of repeated syncopal events and died suddenly at 7 years of age; autopsy failed to demonstrate abnormal findings, and death was attributed to cardiac arrest. The parents were asymptomatic. The patient was treated with atenolol, and adequate control of the arrhythmias was achieved with no recurrence of syncope through 6 years of follow-up. </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>.0003 VENTRICULAR TACHYCARDIA, CATECHOLAMINERGIC POLYMORPHIC, 1</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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RYR2, ASN4104LYS
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<br />
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SNP: rs121918599,
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ClinVar: RCV000013822
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</span>
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<span class="mim-text-font">
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<p>Priori et al. (2001) identified a heterozygous asn4104-to-lys (N4104K) mutation of the RYR2 gene in a 14-year-old boy with stress-induced polymorphic ventricular tachycardia (CPVT1; 604772). The boy had been referred because of frequent episodes of loss of consciousness during exercise, beginning at age 7 years. There was no family history of sudden cardiac death and/or syncopal episodes. The parents were asymptomatic, with normal hearts and no exercise-induced arrhythmias. The patient was treated with atenolol, which prevented recurrence of syncope and ventricular arrhythmias during 9 years of follow-up. </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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<h4>
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<span class="mim-font">
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<strong>.0004 VENTRICULAR TACHYCARDIA, CATECHOLAMINERGIC POLYMORPHIC, 1</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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RYR2, ARG4497CYS
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<br />
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SNP: rs121918600,
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ClinVar: RCV000013823, RCV000478561, RCV000617445, RCV003149571
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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>Priori et al. (2001) identified a heterozygous arg4497-to-cys (R4497C) mutation of the RYR2 gene in a 30-year-old woman with catecholaminergic polymorphic ventricular tachycardia (CPVT1; 604772) and a family history of sudden cardiac death. Testing showed bidirectional ventricular tachycardia developing during exercise stress testing in the woman, her mother, in 2 of her sisters, and in her brother; 2 other sisters had died at ages 14 and 16 years, respectively, one while being tested at school and the second while climbing stairs. During 1 year of follow-up after placement of an implantable cardiac defibrillator, the patient experienced 2 appropriate shocks that successfully terminated ventricular fibrillation. On both occasions, emotional stress preceded the events; the first episode occurred while she was being fired by her boss; the second while she was acting in a play at the local school. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>.0005 VENTRICULAR TACHYCARDIA, CATECHOLAMINERGIC POLYMORPHIC, 1</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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RYR2, ASN2386ILE
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<br />
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SNP: rs121918601,
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ClinVar: RCV003151726
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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 two 3-generation families (families 102 and 123) with exercise-induced ventricular arrhythmias (CPVT1; 604772), one of which (102) was originally reported by Rampazzo et al. (1995), Tiso et al. (2001) detected a 7157A-T transversion in exon 47 of the RYR2 gene, resulting in an asn2386-to-ile (N2386I) mutation at a highly conserved residue in the 12-kD FK506-binding domain. The mutation segregated fully with disease in both families and was not found in 120 healthy Italian controls. Both families were from Monselice, a small town close to Padua, and haplotype analysis suggested the existence of a relatively recent common ancestor for the 2 apparently independent families. The phenotype, which was originally diagnosed as an unusual localized form of arrhythmogenic right ventricular dysplasia (ARVD; see 107970), was later designated to be catecholamine-induced ventricular tachycardia (Karmouch et al., 2018). </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>.0006 VENTRICULAR TACHYCARDIA, CATECHOLAMINERGIC POLYMORPHIC, 1</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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RYR2, LEU433PRO
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<br />
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SNP: rs121918602,
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ClinVar: RCV000151756, RCV000190229, RCV000780694, RCV003151727
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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 3-generation family (family 122) with exercise-induced ventricular arrhythmias (CPVT1; 604772), Tiso et al. (2001) detected a T-to-C transition at nucleotide 1298 in exon 15 of the RYR2 gene, resulting in a leu433-to-pro (L433P) substitution at a highly conserved residue in the cytosolic portion of the protein. The L433P variant segregated fully with disease in the family and was not found in 120 healthy Italian controls. The authors noted that the affected family members also carried a known RYR2 polymorphism, G1885E, on the same allele as the L433P variant. The phenotype, which was originally diagnosed as an unusual localized form of arrhythmogenic right ventricular dysplasia (ARVD; see 107970), was later designated to be catecholamine-induced ventricular tachycardia (Karmouch et al., 2018). </p><p>Olubando et al. (2020) reviewed mutations according to ACMG criteria and considered the L33P mutation to be a variant of uncertain significance (1 strong, 1 moderate, and 1 supporting). </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>.0007 VENTRICULAR TACHYCARDIA, CATECHOLAMINERGIC POLYMORPHIC, 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
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<span class="mim-text-font">
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RYR2, PRO2328SER
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<br />
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SNP: rs121918603,
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|
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ClinVar: RCV000013826
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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>Laitinen et al. (2001) reported a pro2328-to-ser (P2328S) missense mutation in the RYR2 gene in a large Finnish family with a history of stress-induced ventricular tachycardia (CPVT1; 604772) and sudden unexplained death. This mutation was located in the large cytoplasmic domain of the cardiac ryanodine receptor. </p><p>Lehnart et al. (2004) simulated the effects of exercise on mutant RYR2 channels using PKA phosphorylation. The P2328S mutant exhibited decreased binding of calstabin-2, a subunit that stabilizes the closed state of the channel. After PKA phosphorylation, the mutant showed a significant gain-of-function defect consistent with leaky Ca(2+)-release channels and a significant rightward shift in the half-maximal inhibitory magnesium concentration. Treatment with an experimental drug enhanced the binding of calstabin-2 to RYR2 and normalized channel 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>
|
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<span class="mim-font">
|
|
<strong>.0008 VENTRICULAR TACHYCARDIA, CATECHOLAMINERGIC POLYMORPHIC, 1</strong>
|
|
</span>
|
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</h4>
|
|
</div>
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<div>
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<span class="mim-text-font">
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RYR2, VAL4653PHE
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<br />
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SNP: rs121918604,
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gnomAD: rs121918604,
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|
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ClinVar: RCV000013827
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|
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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|
<p>Laitinen et al. (2001) reported a val4653-to-phe (V4653F) mutation in the RYR2 gene in a large Finnish family with a history of stress-induced ventricular tachycardia (CPVT1; 604772) and sudden unexplained death. This mutation was located in the carboxy-terminal part of the cardiac ryanodine receptor, which contains several membrane-spanning domains. </p><p>Lehnart et al. (2004) simulated the effects of exercise on mutant RYR2 channels using PKA phosphorylation. The V4653F mutant exhibited decreased binding of calstabin-2, a subunit that stabilizes the closed state of the channel. After PKA phosphorylation, the mutant showed a significant gain-of-function defect consistent with leaky Ca(2+)-release channels and a significant rightward shift in the half-maximal inhibitory magnesium concentration. Treatment with an experimental drug enhanced the binding of calstabin-2 to RYR2 and normalized channel function. </p>
|
|
</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0009 VENTRICULAR TACHYCARDIA, CATECHOLAMINERGIC POLYMORPHIC, 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
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<span class="mim-text-font">
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RYR2, GLN4201ARG
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<br />
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|
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SNP: rs121918605,
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|
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ClinVar: RCV000013828
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|
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>Laitinen et al. (2001) reported a gln4201-to-arg (Q4201R) mutation in the RYR2 gene in a Finnish family with a history of stress-induced ventricular tachycardia (CPVT1; 604772) and sudden unexplained death. This mutation was located in the C-terminal part of the RYR2 receptor, which contains several membrane-spanning domains. </p><p>Lehnart et al. (2004) simulated the effects of exercise on mutant RYR2 channels using PKA phosphorylation. The Q4201R mutant exhibited decreased binding of calstabin-2, a subunit that stabilizes the closed state of the channel. After PKA phosphorylation, the mutant showed a significant gain-of-function defect consistent with leaky Ca(2+)-release channels and a significant rightward shift in the half-maximal inhibitory magnesium concentration. Treatment with an experimental drug enhanced the binding of calstabin-2 to RYR2 and normalized channel function. </p>
|
|
</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 VENTRICULAR ARRHYTHMIAS DUE TO CARDIAC RYANODINE RECEPTOR CALCIUM RELEASE DEFICIENCY SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
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</div>
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<div>
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<span class="mim-text-font">
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|
RYR2, ALA4860GLY
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<br />
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SNP: rs121918606,
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|
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ClinVar: RCV001813980, RCV003525856
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</span>
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a female patient with ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome (VACRDS; 115000), Priori et al. (2002) identified a heterozygous ala4860-to-gly (A4860G) substitution at a highly conserved transmembrane residue of the RYR2 gene. Her mother and a maternal uncle had unexplained sudden cardiac death at 38 years and 22 years of age, respectively; her sister was an asymptomatic carrier of the mutation. The mutation was not found in 350 unrelated controls. </p><p>In A4860G-transfected human embryonic kidney cells, Jiang et al. (2007) found that the mutation diminished the response of RYR2 to activation by luminal Ca(2+) but had little effect on the sensitivity of the channel to activation by cytosolic Ca(2+). Stable, inducible HEK293 cells expressing the A4860G mutant showed caffeine-induced Ca(2+) release but exhibited no store-overload-induced Ca(2+) release (SOICR), and HL1 cardiac cells transfected with the A4860G mutant displayed attenuated SOICR activity compared to cells transfected with wildtype RYR2. Jiang et al. (2007) concluded that loss of luminal Ca(2+) activation and SOICR activity can cause ventricular fibrillation and sudden death. </p><p>Using site-directed mutagenesis, Zhao et al. (2015) showed that the A4860G mutation in mouse Ryr2 did not affect the expression level of the protein, but it severely inhibited Ryr2 channel activity. </p><p>Sun et al. (2021) restudied the patient originally reported by Priori et al. (2002), noting that she had no trigger for her original event, which involved an aborted sudden cardiac death (aSCD) at age 7 years, with documented ventricular fibrillation. An exercise stress test performed 1 week after the event was unremarkable with no arrhythmias elicited; similarly, programmed electrical stimulation and isoproterenol administration did not induce arrhythmias. Sun et al. (2021) classified the patient as having RYR2 Ca(2+) release deficiency syndrome. </p>
|
|
</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0011 VENTRICULAR TACHYCARDIA, CATECHOLAMINERGIC POLYMORPHIC, 1, WITH OR WITHOUT ATRIAL DYSFUNCTION AND DILATED CARDIOMYOPATHY</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
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<span class="mim-text-font">
|
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|
|
RYR2, 1.1-KB DEL, EX3
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|
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<br />
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ClinVar: RCV000022760
|
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</span>
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</div>
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<div>
|
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<span class="mim-text-font">
|
|
<p>In affected individuals from 2 families with catecholaminergic polymorphic ventricular tachycardia associated with sinoatrial and atrioventricular node dysfunction, atrial arrhythmias, and dilated cardiomyopathy (CPVT1; 604772), Bhuiyan et al. (2007) identified a heterozygous 1.1-kb deletion comprising all of exon 3 and part of the flanking introns 2 and 3 (161-236_272+781del1126) of the RYR2 gene, resulting in loss of 35 amino acids. Several patients in both families gradually developed depressed left ventricular function, and 1 patient who died suddenly at 30 years of age had left ventricular dilation on echocardiography. At autopsy, myocardial biopsy of the left interventricular septum showed mild myocyte hypertrophy and interstitial fibrosis; there were no inflammatory or fibrolipomatous changes of the right ventricular endocardium. </p><p>Medeiros-Domingo et al. (2009) identified 3 large genomic rearrangements comprising exon 3 of the RYR2 gene in 3 unrelated patients with CPVT1, involving a 3.6-kb deletion in 1 case and a 1.1-kb deletion in 2 cases. </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>.0012 VENTRICULAR ARRHYTHMIAS DUE TO CARDIAC RYANODINE RECEPTOR CALCIUM RELEASE DEFICIENCY SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
RYR2, ASP4646ALA
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|
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|
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<br />
|
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|
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SNP: rs1658967336,
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|
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|
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ClinVar: RCV001814262, RCV002553827
|
|
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|
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</span>
|
|
</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In a 3-generation family with sudden cardiac death (SCD) or aborted SCD resulting from ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome (VACRDS; 115000), Sun et al. (2021) identified heterozygosity for a c.13937A-C transversion in exon 96 of the RYR2 gene, resulting in an asp4646-to-ala (D4646A) substitution. The 51-year-old proband experienced syncope and aborted SCD at age 39 years, with ventricular fibrillation observed on the ambulance monitor. In the ICU, polymorphic ventricular tachycardia was observed and treated with direct-current (DC) shock. No arrhythmias were elicited on exercise stress test, and she underwent placement of an implantable cardioverter-defibrillator (ICD), which later discharged appropriately when she experienced syncope during an episode of acute emotional stress. Family history revealed 4 more cases of SCD in the maternal branch of the family, occurring between 16 and 43 years of age, triggered by acute emotional stress. The D4646A mutation was found in a maternal aunt who died with SCD, as well as in the proband's asymptomatic 17-year-old son and in an asymptomatic first cousin once removed whose father and paternal grandfather both had SCD, but the variant was not present in the proband's asymptomatic sister or in 3 asymptomatic male cousins. Functional analysis demonstrated that the D4646A mutation markedly suppressed caffeine-induced Ca(2+) release and store overload-induced Ca(2+) release (SOICR) without altering the store capacity. In addition, the SOICR termination threshold and RYR2-mediated fractional Ca(2+) release were both significantly increased with the mutant compared to wildtype RYR2. The D4646A mutant also impaired the cytosolic Ca(2+) activation and diminished the luminal Ca(2+) activation of single RYR2 channels. The authors generated a knockin mouse model and observed that the D4646A mutation abolished abnormal diastolic spontaneous Ca(2+) release from the sarcoplasmic reticulum in intact mouse hearts, completely protecting them against delayed afterdepolarization-driven ventricular arrhythmias. There was substantial electrophysiologic remodeling in the mutant mouse hearts, increasing the transient outward K+ current, the L-type Ca(2+) channel current, and the Na+/Ca(2+) exchange current. This altered the action potential waveform (shortened APD50 and lengthened APD90) and increased the propensity for arrhythmogenic early afterdepolarizations in the mutant hearts. </p>
|
|
</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0013 VENTRICULAR ARRHYTHMIAS DUE TO CARDIAC RYANODINE RECEPTOR CALCIUM RELEASE DEFICIENCY SYNDROME</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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RYR2, ILE3995VAL
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<br />
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SNP: rs2149352030,
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ClinVar: RCV001814321
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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 3-generation family with sudden cardiac death (SCD) or aborted SCD resulting from ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome (VACRDS; 115000), Sun et al. (2021) identified heterozygosity for a c.11983A-C transversion in the RYR2 gene, resulting in an ile3995-to-val (I3995V) substitution. The variant was initially identified in the family after 2 cousins had SCD at ages 28 and 32 years. The 60-year-old female proband was a known carrier of the I3995V mutation who experienced syncope at age 52 while watching television. Cardiac evaluation, including an exercise stress test, was negative, but given the family history, an implantable cardioverter-defibrillator (ICD) was placed. The device recorded nonsustained polymorphic ventricular tachycardia/ventricular fibrillation during follow-up, when proband had presyncopal episodes. Her brother and her 2 children were asymptomatic carriers of the variant. Functional analysis demonstrated that the I3995V mutation markedly suppressed caffeine-induced Ca(2+) release and store overload-induced Ca(2+) release (SOICR) without altering the store capacity. In addition, the SOICR termination threshold and RYR2-mediated fractional Ca(2+) release were both significantly increased with the mutant compared to wildtype RYR2. The I3995V mutant also impaired the cytosolic Ca(2+) activation and diminished the luminal Ca(2+) activation of single RYR2 channels. </p>
|
|
</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0014 VENTRICULAR ARRHYTHMIAS DUE TO CARDIAC RYANODINE RECEPTOR CALCIUM RELEASE DEFICIENCY SYNDROME</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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RYR2, THR4196ILE
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<br />
|
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SNP: rs2149354389,
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ClinVar: RCV001814322, RCV002557515
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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 3 sibs with sudden cardiac death (SCD) or aborted SCD resulting from ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome (VACRDS; 115000), Sun et al. (2021) identified heterozygosity for a c.12587C-T transition in the RYR2 gene, resulting in a thr4196-to-ile (T4196I) substitution. The proband had recurrent episodes of syncope on exertion at age 17 years, but cardiac evaluation was normal, including exercise stress testing. She died suddenly at age 19 while running. Cardiac screening of her 4 sibs, including exercise stress testing, was negative. However, 12 years later, the proband's 33-year-old sister collapsed while running on a treadmill and was found to be in ventricular fibrillation by paramedics, who performed successful cardioversion to normal sinus rhythm. Another brother later died suddenly while running during a baseball game. The remaining 2 sibs and the 33-year-old sister's 3 asymptomatic children did not carry the mutation. Functional analysis demonstrated that the T4196I mutation markedly suppressed caffeine- and store overload-induced Ca(2+) release without altering the store capacity. In addition, RYR2-mediated fractional Ca(2+) release was significantly increased with the mutant compared to wildtype RYR2. The T4196I mutant also impaired the cytosolic Ca(2+) activation and diminished the luminal Ca(2+) activation of single RYR2 channels. </p>
|
|
</span>
|
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</div>
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<div>
|
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<br />
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