3546 lines
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Entry
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- *603283 - TRIADIN; TRDN
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- OMIM
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<p>
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<span class="h4">*603283</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneStructure">Gene Structure</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#animalModel">Animal Model</a>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/603283">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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</li>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</ul>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000186439;t=ENST00000334268" 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=10345" 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=603283" 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=ENSG00000186439;t=ENST00000334268" 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_001251987,NM_001256020,NM_001256021,NM_001256022,NM_001407315,NM_006073" 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_006073" 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=603283" 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=04474&isoform_id=04474_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/TRDN" 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/882223,28950585,34785353,47124553,51476843,104526627,116283491,119568542,146218453,158257166,338817987,354682005,361095116,365192558,365192560,365192563,2246873628" 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/Q13061" 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=10345" 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=ENSG00000186439;t=ENST00000334268" 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=TRDN" 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=TRDN" 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+10345" 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/TRDN" 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:10345" 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/10345" 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=chr6&hgg_gene=ENST00000334268.9&hgg_start=123216339&hgg_end=123636950&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:12261" 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:12261" 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=603283[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=603283[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000186439" 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=TRDN" 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=TRDN" 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=TRDN" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=TRDN&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/PA36941" 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:12261" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
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<div><a href="https://www.mousephenotype.org/data/genes/MGI:1924007" 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/TRDN#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:1924007" 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/10345/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=10345" 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://zfin.org/ZDB-GENE-041014-193" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
|
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:10345" 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=TRDN&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
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<span class="text-danger"><strong>*</strong></span>
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603283
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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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TRIADIN; TRDN
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
|
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</span>
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</p>
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
TRISK
|
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=TRDN" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">TRDN</a></em></strong>
|
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</span>
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</p>
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</div>
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<div>
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<a id="cytogeneticLocation" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
|
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<strong>
|
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<em>
|
|
Cytogenetic location: <a href="/geneMap/6/827?start=-3&limit=10&highlight=827">6q22.31</a>
|
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|
|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr6:123216339-123636950&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'})">6:123,216,339-123,636,950</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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</span>
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</p>
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</div>
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<div>
|
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<br />
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</div>
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<div>
|
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<a id="geneMap" class="mim-anchor"></a>
|
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<div style="margin-bottom: 10px;">
|
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<span class="h4 mim-font">
|
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<strong>Gene-Phenotype Relationships</strong>
|
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</span>
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</div>
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<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
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<thead>
|
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<tr class="active">
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<th>
|
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Location
|
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</th>
|
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<th>
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Phenotype
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</th>
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<th>
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|
Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
|
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Phenotype <br /> mapping key
|
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
|
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<td rowspan="1">
|
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<span class="mim-font">
|
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<a href="/geneMap/6/827?start=-3&limit=10&highlight=827">
|
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6q22.31
|
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</a>
|
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</span>
|
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</td>
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<td>
|
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<span class="mim-font">
|
|
Cardiac arrhythmia syndrome, with or without skeletal muscle weakness
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</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/615441"> 615441 </a>
|
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|
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</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
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</span>
|
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<div class="btn-group">
|
|
<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
|
PheneGene Graphics <span class="caret"></span>
|
|
</button>
|
|
<ul class="dropdown-menu" style="width: 17em;">
|
|
<li><a href="/graph/linear/603283" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/603283" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
|
|
</ul>
|
|
</div>
|
|
<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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</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="text" class="mim-anchor"></a>
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<h4>
|
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|
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<span class="mim-font">
|
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
|
|
<strong>TEXT</strong>
|
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</span>
|
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</span>
|
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</h4>
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<div>
|
|
<a id="description" class="mim-anchor"></a>
|
|
<h4 href="#mimDescriptionFold" id="mimDescriptionToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
|
|
<span id="mimDescriptionToggleTriangle" class="small mimTextToggleTriangle">▼</span>
|
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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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<div id="mimDescriptionFold" class="collapse in ">
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<span class="mim-text-font">
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<p>The triadin gene is alternatively spliced to produce several isoforms that are differentially expressed in skeletal and cardiac muscle. Some isoforms localize to longitudinal regions of the sarcoplasmic reticulum (SR), and others localize to triad junctions, where T-tubules and SR terminal cisternae are in close contact. Triadin isoforms localized to triad junctions appear to have a role in excitation-contraction coupling (summary by <a href="#6" class="mim-tip-reference" title="Oddoux, S., Brocard, J., Schweitzer, A., Szentesi, P., Giannesini, B., Brocard, J., Faure, J., Pernet-Gallay, K., Bendahan, D., Lunardi, J., Csernoch, L., Marty, I. <strong>Triadin deletion induces impaired skeletal muscle function.</strong> J. Biol. Chem. 284: 34918-34929, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19843516/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19843516</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19843516[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/10.1074/jbc.M109.022442" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19843516">Oddoux et al., 2009</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19843516" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 dihydropyridine-sensitive calcium channels (see CACNA2; <a href="/entry/114204">114204</a>) and ryanodine-sensitive calcium channels (RYR1; <a href="/entry/180901">180901</a>) of skeletal muscle play key roles in the generation of calcium transients during excitation/contraction coupling. The coupling of the signal for calcium release between these proteins occurs at highly specialized triadic junctions that separate the T-tubule membrane and the terminal cisternae of the SR. Triadin, a protein found in rabbit triadic junctions, is intrinsic to the terminal cisternae and is closely associated with RYR1. By RT-PCR of human skeletal muscle RNA with primers based on the sequence of a rabbit triadin cDNA, <a href="#11" class="mim-tip-reference" title="Taske, N. L., Eyre, H. J., O'Brien, R. O., Sutherland, G. R., Denborough, M. A., Foster, P. S. <strong>Molecular cloning of the cDNA encoding human skeletal muscle triadin and its localisation to chromosome 6q22-6q23.</strong> Europ. J. Biochem. 233: 258-265, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7588753/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7588753</a>] [<a href="https://doi.org/10.1111/j.1432-1033.1995.258_1.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7588753">Taske et al. (1995)</a> isolated cDNAs encoding human triadin. The predicted 729-amino acid human protein shares 95% identity with rabbit triadin. Like the rabbit protein, human triadin contains a small cytoplasmic domain and a single transmembrane domain. Human triadin has a calculated pI of 9.3 and molecular mass of 82 kD. However, on Western blots, its apparent molecular mass is 117 kD. <a href="#11" class="mim-tip-reference" title="Taske, N. L., Eyre, H. J., O'Brien, R. O., Sutherland, G. R., Denborough, M. A., Foster, P. S. <strong>Molecular cloning of the cDNA encoding human skeletal muscle triadin and its localisation to chromosome 6q22-6q23.</strong> Europ. J. Biochem. 233: 258-265, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7588753/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7588753</a>] [<a href="https://doi.org/10.1111/j.1432-1033.1995.258_1.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7588753">Taske et al. (1995)</a> suggested that triadin has reduced mobility because it is a highly charged protein. Northern blot analysis revealed that triadin is expressed as a 4.8-kb mRNA in human skeletal muscle. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7588753" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By PCR and 3-prime and 5-prime RACE, <a href="#12" class="mim-tip-reference" title="Thevenon, D., Smida-Rezgui, S., Chevessier, F., Groh, S., Henry-Berger, J., Romero, N. B., Villaz, M., DeWaard, M., Marty, I. <strong>Human skeletal muscle triadin: gene organization and cloning of the major isoform, Trisk 51.</strong> Biochem. Biophys. Res. Commun. 303: 669-675, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12659871/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12659871</a>] [<a href="https://doi.org/10.1016/s0006-291x(03)00406-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12659871">Thevenon et al. (2003)</a> cloned 2 triadin isoforms from a skeletal muscle cDNA library. The longer isoform, TRISK95, contains 729 amino acids and has a calculated molecular mass of about 95 kD. The shorter isoform, TRISK51, results from the use of an internal splice site within exon 21. It contains 461 amino acids and has a calculated molecular mass of about 51 kD. The TRISK51 and TRISK95 transcripts are both about 4.5 kb. In rat skeletal muscle, expression of Trisk95 and Trisk51 was roughly equivalent. However, RT-PCR and Western blot analysis of human deltoid and quadriceps muscle indicated that TRISK51 was expressed at high levels, while TRISK95 was expressed at low levels. Immunologic labeling of longitudinal sections of skeletal muscle revealed signal localized to the junctional triad. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12659871" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#3" class="mim-tip-reference" title="Hong, C.-S., Ji, J.-H., Kim, J. P., Jung, D. H., Kim, D. H. <strong>Molecular cloning and characterization of mouse cardiac triadin isoforms.</strong> Gene 278: 193-199, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11707337/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11707337</a>] [<a href="https://doi.org/10.1016/s0378-1119(01)00718-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11707337">Hong et al. (2001)</a> cloned several isoforms of mouse Trdn from skeletal and cardiac muscle. All 3 isoforms have identical N-terminal sequences of 262 amino acids and distinct C-terminal sequences. The isoforms expressed in cardiac muscle were about 1.3, 4.3, and 5.0 kb and corresponded to deglycosylated proteins of 35, 35.5, and 40 kD, respectively. In skeletal muscle, the transcripts sizes were 5.0, 5.5, and 7.0 kb. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11707337" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Shen, X., Franzini-Armstrong, C., Lopez, J. R., Jones, L. R., Kobayashi, Y. M., Wang, Y., Kerrick, W. G. L., Caswell, A. H., Potter, J. D., Miller, T., Allen, P. D., Perez, C. F. <strong>Triadins modulate intracellular Ca2+ homeostasis but are not essential for excitation-contraction coupling in skeletal muscle.</strong> J. Biol. Chem. 282: 37864-37874, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17981799/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17981799</a>] [<a href="https://doi.org/10.1074/jbc.M705702200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17981799">Shen et al. (2007)</a> stated that triadin isoforms of 95 and 60 kD are expressed in triad junctions of mouse skeletal muscle, that isoforms of 32 and 40 kD are expressed in triad junctions of heart, and that nontriad isoforms of 49 and 32 kD are expressed in skeletal muscle. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17981799" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#12" class="mim-tip-reference" title="Thevenon, D., Smida-Rezgui, S., Chevessier, F., Groh, S., Henry-Berger, J., Romero, N. B., Villaz, M., DeWaard, M., Marty, I. <strong>Human skeletal muscle triadin: gene organization and cloning of the major isoform, Trisk 51.</strong> Biochem. Biophys. Res. Commun. 303: 669-675, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12659871/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12659871</a>] [<a href="https://doi.org/10.1016/s0006-291x(03)00406-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12659871">Thevenon et al. (2003)</a> determined that the TRDN gene contains 41 exons and spans 420 kb. Exon 1 contains the initiation codon, and exon 41 contains the stop codon and 1.3 kb of 3-prime untranslated sequence. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12659871" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>By fluorescence in situ hybridization, <a href="#11" class="mim-tip-reference" title="Taske, N. L., Eyre, H. J., O'Brien, R. O., Sutherland, G. R., Denborough, M. A., Foster, P. S. <strong>Molecular cloning of the cDNA encoding human skeletal muscle triadin and its localisation to chromosome 6q22-6q23.</strong> Europ. J. Biochem. 233: 258-265, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7588753/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7588753</a>] [<a href="https://doi.org/10.1111/j.1432-1033.1995.258_1.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7588753">Taske et al. (1995)</a> mapped the triadin gene to 6q22-q23. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7588753" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Using the alpha-myosin heavy chain (<a href="/entry/160710">160710</a>) promoter to drive protein expression, <a href="#4" class="mim-tip-reference" title="Kirchhefer, U., Neumann, J., Baba, H. A., Begrow, F., Kobayashi, Y. M., Reinke, U., Schmitz, W., Jones, L. R. <strong>Cardiac hypertrophy and impaired relaxation in transgenic mice overexpressing triadin 1.</strong> J. Biol. Chem. 276: 4142-4149, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11069905/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11069905</a>] [<a href="https://doi.org/10.1074/jbc.M006443200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11069905">Kirchhefer et al. (2001)</a> developed transgenic mice overexpressing Trdn1, the dominant cardiac isoform of mouse triadin, in the atrium and ventricle. Expression was elevated 5-fold and was accompanied by cardiac hypertrophy. The levels of 2 other junctional SR proteins, RYR2 (<a href="/entry/180902">180902</a>) and junctin (ASPH; <a href="/entry/600582">600582</a>), were reduced by 55% and 73%, respectively. The levels of the junctional SR Ca(2+)-binding protein, calsequestrin (<a href="/entry/114251">114251</a>), and the free SR Ca(2+)-handling proteins, phospholamban (<a href="/entry/172405">172405</a>) and Serca2a (<a href="/entry/180740">180740</a>), were unchanged. The contractile phenotype of hearts from triadin-overexpressing mice included impaired relaxation, blunted contractility with increased pressure loading, and frequency-dependent changes in myocyte shortening. <a href="#4" class="mim-tip-reference" title="Kirchhefer, U., Neumann, J., Baba, H. A., Begrow, F., Kobayashi, Y. M., Reinke, U., Schmitz, W., Jones, L. R. <strong>Cardiac hypertrophy and impaired relaxation in transgenic mice overexpressing triadin 1.</strong> J. Biol. Chem. 276: 4142-4149, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11069905/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11069905</a>] [<a href="https://doi.org/10.1074/jbc.M006443200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11069905">Kirchhefer et al. (2001)</a> concluded that Trdn1 plays an active role in Ca(2+) release, beyond its previously proposed structural role of anchoring calsequestrin to RYR2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11069905" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>From a cohort of 97 patients with catecholaminergic polymorphic ventricular tachycardia (CPVT; see <a href="/entry/604772">604772</a>) in whom mutations in the RYR2 (180902) and CASQ2 (<a href="/entry/114251">114251</a>) genes had been excluded, <a href="#9" class="mim-tip-reference" title="Roux-Buisson, N., Cacheux, M., Fourest-Lieuvin, A., Fauconnier, J., Brocard, J., Denjoy, I., Durand, P., Guicheney, P., Kyndt, F., Leenhardt, A., Le Marec, H., Lucet, V., and 10 others. <strong>Absence of triadin, a protein of the calcium release complex, is responsible for cardiac arrhythmia with sudden death in human.</strong> Hum. Molec. Genet. 21: 2759-2767, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22422768/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22422768</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22422768[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/dds104" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22422768">Roux-Buisson et al. (2012)</a> identified 2 probands with biallelic mutations in the TRDN gene. Both patients had onset of severe cardiac arrhythmias in infancy or early childhood, and 1 also had skeletal muscle weakness (cardiac arrhythmia syndrome with or without skeletal muscle weakness, CARDAR; <a href="/entry/615441">615441</a>). One proband was a 2-year-old boy from the French West Indies who was homozygous for a frameshift mutation (<a href="#0001">603283.0001</a>), and the other was a 26-year-old French man who was compound heterozygous for a missense (T59R; <a href="#0002">603283.0002</a>) and a nonsense (Q205X; <a href="#0003">603283.0003</a>) mutation. The authors noted that the 3 TRDN mutations were located in a region of the gene common to all triadin isoforms, including skeletal muscle isoforms. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22422768" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 10-year-old girl (family 1) with severe cardiac arrhythmias and a prolonged QT interval, who was negative for mutation in known long QT syndrome (LQTS; see <a href="/entry/192500">192500</a>)-associated genes, <a href="#1" class="mim-tip-reference" title="Altmann, H. M., Tester, D. J., Will, M. L., Middha, S., Evans, J. M., Eckloff, B. W., Ackerman, M. J. <strong>Homozygous/compound heterozygous triadin mutations associated with autosomal-recessive long-QT syndrome and pediatric sudden cardiac arrest: elucidation of the triadin knockout syndrome.</strong> Circulation 131: 2051-2060, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25922419/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25922419</a>] [<a href="https://doi.org/10.1161/CIRCULATIONAHA.115.015397" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25922419">Altmann et al. (2015)</a> identified homozygosity for the previously reported 4-bp deletion in the TRDN gene (<a href="#0001">603283.0001</a>). Subsequent analysis of the TRDN gene in 33 unrelated patients with LQTS revealed 4 more children with mutations in TRDN: 3 were homozygous for a 5-bp deletion (<a href="#0004">603283.0004</a>) and 1 was compound heterozygous for the 5-bp deletion and a splicing mutation (<a href="#0005">603283.0005</a>). The mutations segregated with disease in the respective families, and were either not found or were present at very low minor allele frequency in public variant databases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25922419" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 2 sisters from a French family with CPVT, <a href="#7" class="mim-tip-reference" title="Rooryck, C., Kyndt, F., Bozon, D., Roux-Buisson, N., Sacher, F., Probst, V., Thambo, J.-B. <strong>New family with catecholaminergic polymorphic ventricular tachycardia linked to the triadin gene.</strong> J. Cardiovasc. Electrophysiol. 26: 1146-1150, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26200674/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26200674</a>] [<a href="https://doi.org/10.1111/jce.12763" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26200674">Rooryck et al. (2015)</a> identified compound heterozygosity for 2 previously reported mutations in the TRDN gene: Q205X (<a href="#0003">603283.0003</a>) and a splicing mutation (<a href="#0005">603283.0005</a>). Their unaffected parents were each heterozygous for 1 of the mutations; their asymptomatic 3-year-old sister was also compound heterozygous for the variants. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26200674" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 brother and sister with cardiac arrest at age 2 years and possible prolongation of the QT interval on ECG, <a href="#13" class="mim-tip-reference" title="Walsh, M. A., Stuart, A. G., Schlecht, H. B., James, A. F., Hancox, J. C., Newbury-Ecob, R. A. <strong>Compound heterozygous triadin mutation causing cardiac arrest in two siblings.</strong> Pacing Clin. Electrophysiol. 39: 497-501, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26768964/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26768964</a>] [<a href="https://doi.org/10.1111/pace.12813" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26768964">Walsh et al. (2016)</a> identified compound heterozygosity for the previously reported 4-bp deletion (<a href="#0001">603283.0001</a>) and a nonsense mutation in the TRDN gene (E168X; <a href="#0006">603283.0006</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26768964" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#5" class="mim-tip-reference" title="O'Callaghan, B. M., Hancox, J. C., Stuart, A. G., Armstrong, C., Williams, M. M., Hills, A., Pearce, H., Dent, C. L., Gable, M., Walsh, M. A. <strong>A unique triadin exon deletion causing a null phenotype.</strong> HeartRhythm Case Rep. 4: 514-518, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30479949/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30479949</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30479949[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.hrcr.2018.07.014" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30479949">O'Callaghan et al. (2018)</a> studied an Omani male infant who experienced cardiac arrest at age 16 months and showed prolonged QTc and T-wave inversion in the anterior precordial leads on ECG. Subsequent ECGs documented torsades de pointes and ventricular fibrillation. Next-generation sequencing targeting 54 cardiac arrhythmia-associated genes revealed mutations in 3 genes: an apparently homozygous deletion of exon 2 of the TRDN gene; a previously reported missense mutation in the KCNE2 gene (I57T; <a href="/entry/603796#0003">603796.0003</a>), associated with long QT syndrome (LQT6; <a href="/entry/613693">613693</a>); and a E3783Q substitution in the RYR2 gene of uncertain significance. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30479949" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In an Afghan family in which 2 sibs had died suddenly and a third child was resuscitated from cardiac arrest, <a href="#8" class="mim-tip-reference" title="Rossi, D., Gigli, L., Gamberucci, A., Bordoni, R., Pietrelli, A., Lorenzini, S., Pierantozzi, E., Peretto, G., De Bellis, G., Della Bella, P., Ferrari, M., Sorrentino, V., Benedetti, S., Sala, S., Di Resta, C. <strong>A novel homozygous mutation in the TRDN gene causes a severe form of pediatric malignant ventricular arrhythmia.</strong> Heart Rhythm 17: 296-304, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31437535/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31437535</a>] [<a href="https://doi.org/10.1016/j.hrthm.2019.08.018" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31437535">Rossi et al. (2020)</a> identified homozygosity for a missense mutation in the TRDN gene (L56P; <a href="#0007">603283.0007</a>) that segregated with disease in the family. Functional analysis suggested that the L56P variant may trigger arrhythmias by altering calcium homeostasis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31437535" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#10" class="mim-tip-reference" title="Shen, X., Franzini-Armstrong, C., Lopez, J. R., Jones, L. R., Kobayashi, Y. M., Wang, Y., Kerrick, W. G. L., Caswell, A. H., Potter, J. D., Miller, T., Allen, P. D., Perez, C. F. <strong>Triadins modulate intracellular Ca2+ homeostasis but are not essential for excitation-contraction coupling in skeletal muscle.</strong> J. Biol. Chem. 282: 37864-37874, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17981799/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17981799</a>] [<a href="https://doi.org/10.1074/jbc.M705702200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17981799">Shen et al. (2007)</a> found that mice with complete knockout of triadin expression appeared normal in their survival, fertility, and movements. Western blot analysis of SR proteins in Trdn -/- skeletal muscle showed downregulation of junctophilin-1 (JPH1; <a href="/entry/605266">605266</a>), junctin (ASPH; <a href="/entry/600582">600582</a>), and calsequestrin (see <a href="/entry/114250">114250</a>). Some calsequestrin was also detected in tubes of the longitudinal SR in Trdn -/- muscle. Expression of junctin and Ryr1 (<a href="/entry/180901">180901</a>) was differentially affected in slow and fast Trdn -/- muscle. Trdn -/- muscle showed reduced amplitude of calcium transients and increased myoplasmic resting free Ca(2+), but it did not show contractile dysfunction. Minor disorganization of triadic junctions was observed in fast-twitch, but not slow-twitch, Trdn -/- muscle fibers. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17981799" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>The calcium release unit is a multiprotein complex whose principal components include the L-type calcium channel Cav1.2 (CACNA1C; <a href="/entry/114205">114205</a>) and Ryr2 (<a href="/entry/180902">180902</a>). <a href="#2" class="mim-tip-reference" title="Chopra, N., Yang, T., Asghari, P., Moore, E. D., Huke, S., Akin, B., Cattolica, R. A., Perez, C. F., Hlaing, T., Knollmann-Ritschel, B. E. C., Jones, L. R., Pessah, I. N., Allen, P. D., Franzini-Armstrong, C., Knollmann, B. C. <strong>Ablation of triadin causes loss of cardiac Ca2+ release units, impaired excitation-contraction coupling, and cardiac arrhythmias.</strong> Proc. Nat. Acad. Sci. 106: 7636-7641, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19383796/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19383796</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19383796[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.0902919106" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19383796">Chopra et al. (2009)</a> found that homozygous deletion of Trdn in mice resulted in defective excitation-contraction coupling in heart, concomitant with significant changes in the structure and protein composition of the cardiac calcium release unit. Electron microscopy of Trdn -/- hearts showed fragmentation and an overall 50% reduction in the contacts between cardiac junctional SR and T-tubules, with reduced colocalization of Cav1.2 with Ryr2. Calcium release unit function was impaired in Trdn -/- myocytes, with reduced SR calcium release and impaired negative feedback of SR calcium release in response to Cav1.2 calcium currents. Beta-adrenergic receptor (see <a href="/entry/109630">109630</a>) stimulation caused ventricular arrhythmias in Trdn -/- mice and spontaneous SR calcium release in isolated Trdn -/- myocytes, likely due to uninhibited calcium influx. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19383796" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Independently, <a href="#6" class="mim-tip-reference" title="Oddoux, S., Brocard, J., Schweitzer, A., Szentesi, P., Giannesini, B., Brocard, J., Faure, J., Pernet-Gallay, K., Bendahan, D., Lunardi, J., Csernoch, L., Marty, I. <strong>Triadin deletion induces impaired skeletal muscle function.</strong> J. Biol. Chem. 284: 34918-34929, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19843516/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19843516</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19843516[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/10.1074/jbc.M109.022442" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19843516">Oddoux et al. (2009)</a> found that deletion of Trdn expression in mice altered the composition of the calcium release complex in fast and slow skeletal muscle, caused abnormal orientation of triads with loss of associated mitochondria, and reduced SR terminal cisternae volume and calcium content. Trdn -/- mice showed reduced strength, and both fast- and slow-twitch muscle from Trdn -/- mice showed reduced twitch and tetanic forces, but improved resistance to fatigue. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19843516" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>.0001 CARDIAC ARRHYTHMIA SYNDROME WITH OR WITHOUT SKELETAL MUSCLE WEAKNESS</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> rs768049331 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs768049331;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/rs768049331?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=rs768049331" 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=rs768049331" 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 2-year-old boy with cardiac arrhythmia syndrome (CARDAR; <a href="/entry/615441">615441</a>) who died after cardiac arrest due to catecholaminergic polymorphic ventricular tachycardia (CPVT), <a href="#9" class="mim-tip-reference" title="Roux-Buisson, N., Cacheux, M., Fourest-Lieuvin, A., Fauconnier, J., Brocard, J., Denjoy, I., Durand, P., Guicheney, P., Kyndt, F., Leenhardt, A., Le Marec, H., Lucet, V., and 10 others. <strong>Absence of triadin, a protein of the calcium release complex, is responsible for cardiac arrhythmia with sudden death in human.</strong> Hum. Molec. Genet. 21: 2759-2767, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22422768/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22422768</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22422768[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/dds104" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22422768">Roux-Buisson et al. (2012)</a> identified homozygosity for a 4-bp deletion (c.53_56delACAG) in exon 2 of the TRDN gene, resulting in a frameshift predicted to result in a premature termination codon (Asp18AlafsTer13) before the transmembrane helix in the cardiac isoform of triadin (TRISK32). The mutation was present in heterozygosity in the proband's unaffected parents and older brother. Haplotype analysis in the family suggested a remote common ancestor. <a href="#9" class="mim-tip-reference" title="Roux-Buisson, N., Cacheux, M., Fourest-Lieuvin, A., Fauconnier, J., Brocard, J., Denjoy, I., Durand, P., Guicheney, P., Kyndt, F., Leenhardt, A., Le Marec, H., Lucet, V., and 10 others. <strong>Absence of triadin, a protein of the calcium release complex, is responsible for cardiac arrhythmia with sudden death in human.</strong> Hum. Molec. Genet. 21: 2759-2767, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22422768/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22422768</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22422768[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/dds104" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22422768">Roux-Buisson et al. (2012)</a> remarked that the young age of the patient precluded detection of skeletal muscle weakness. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22422768" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 10-year-old black girl (family 1) with CARDAR with severe cardiac arrhythmias and a prolonged QT interval, <a href="#1" class="mim-tip-reference" title="Altmann, H. M., Tester, D. J., Will, M. L., Middha, S., Evans, J. M., Eckloff, B. W., Ackerman, M. J. <strong>Homozygous/compound heterozygous triadin mutations associated with autosomal-recessive long-QT syndrome and pediatric sudden cardiac arrest: elucidation of the triadin knockout syndrome.</strong> Circulation 131: 2051-2060, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25922419/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25922419</a>] [<a href="https://doi.org/10.1161/CIRCULATIONAHA.115.015397" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25922419">Altmann et al. (2015)</a> identified homozygosity for the previously reported 4-bp deletion in the TRDN gene (c.53_56delACAG, NM_001256021.1) for which her unaffected parents were heterozygous. The authors noted that the variant was not found in the 1000 Genomes Project database or in white exomes in the NHLBI GO ESP database, but was present in 1 of 1,861 black exomes in GO ESP, and was also present in the ExAC database at an overall minor allele frequency of 0.01%, and in black exomes at 0.14%. Skeletal muscle weakness was noted to be absent. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25922419" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 brother and sister with CARDAR who both experienced cardiac arrest at 2 years of age and showed possible prolongation of the QT interval, <a href="#13" class="mim-tip-reference" title="Walsh, M. A., Stuart, A. G., Schlecht, H. B., James, A. F., Hancox, J. C., Newbury-Ecob, R. A. <strong>Compound heterozygous triadin mutation causing cardiac arrest in two siblings.</strong> Pacing Clin. Electrophysiol. 39: 497-501, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26768964/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26768964</a>] [<a href="https://doi.org/10.1111/pace.12813" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26768964">Walsh et al. (2016)</a> identified compound heterozygosity for the 4-bp deletion in the TRDN gene and a c.502G-T transversion, resulting in a glu168-to-ter (E168X; <a href="#0006">603283.0006</a>) substitution. Their unaffected parents were each heterozygous for 1 of the mutations. <a href="#13" class="mim-tip-reference" title="Walsh, M. A., Stuart, A. G., Schlecht, H. B., James, A. F., Hancox, J. C., Newbury-Ecob, R. A. <strong>Compound heterozygous triadin mutation causing cardiac arrest in two siblings.</strong> Pacing Clin. Electrophysiol. 39: 497-501, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26768964/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26768964</a>] [<a href="https://doi.org/10.1111/pace.12813" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26768964">Walsh et al. (2016)</a> attributed residual generalized weakness in the sister to the mutation, and noted that the gross motor development of the brother was slightly delayed compared to that of his half-sibs. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26768964" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs397515459 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs397515459;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/rs397515459?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=rs397515459" 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=rs397515459" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In 26-year-old dizygotic twin brothers with cardiac arrhythmia syndrome (CARDAR; <a href="/entry/615441">615441</a>), who from infancy experienced exercise-induced syncope due to catecholaminergic polymorphic ventricular tachycardia, <a href="#9" class="mim-tip-reference" title="Roux-Buisson, N., Cacheux, M., Fourest-Lieuvin, A., Fauconnier, J., Brocard, J., Denjoy, I., Durand, P., Guicheney, P., Kyndt, F., Leenhardt, A., Le Marec, H., Lucet, V., and 10 others. <strong>Absence of triadin, a protein of the calcium release complex, is responsible for cardiac arrhythmia with sudden death in human.</strong> Hum. Molec. Genet. 21: 2759-2767, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22422768/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22422768</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22422768[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/dds104" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22422768">Roux-Buisson et al. (2012)</a> identified compound heterozygosity for 2 mutations in the TRDN gene: a c.176C-G transversion in exon 2, resulting in a thr59-to-arg (T59R) substitution at a well-conserved residue within the transmembrane domain of the cardiac isoform of triadin (TRISK32), and a c.613C-T transition in exon 8, resulting in a gln205-to-ter substitution (Q205X; <a href="#0003">603283.0003</a>) before the KEKE region. One of the brothers also had proximal muscle weakness. Unaffected family members who were tested carried 1 or none of the variants. Analysis of TRISK32 in COS-7 cells showed that whereas wildtype TRISK32 was localized in the plasma membrane of 83% of cells and in the endoplasmic reticulum (ER) in 17%, T59R mutant TRISK32 was retained in the ER in 100% of cells and was prone to degradation, most likely via the proteasomal pathway. RT-PCR and Western blot analysis of cardiomyocytes from TRDN-knockout mice after viral transduction of the T59R-TRDN mutant demonstrated that although the mutant transcript is expressed, the protein is absent. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22422768" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs397515458 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs397515458;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/rs397515458?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=rs397515458" 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=rs397515458" 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=RCV000056260 OR RCV000484797 OR RCV002354248 OR RCV002496743 OR RCV003103726 OR RCV004017360" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000056260, RCV000484797, RCV002354248, RCV002496743, RCV003103726, RCV004017360" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000056260...</a>
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<p>For discussion of the c.613C-T transition in the TRDN gene, resulting in a gln205-to-ter (Q205X) substitution, that was found in compound heterozygous state in twin brothers with cardiac arrhythmia syndrome with or without skeletal muscle weakness (CARDAR; <a href="/entry/615441">615441</a>) by <a href="#9" class="mim-tip-reference" title="Roux-Buisson, N., Cacheux, M., Fourest-Lieuvin, A., Fauconnier, J., Brocard, J., Denjoy, I., Durand, P., Guicheney, P., Kyndt, F., Leenhardt, A., Le Marec, H., Lucet, V., and 10 others. <strong>Absence of triadin, a protein of the calcium release complex, is responsible for cardiac arrhythmia with sudden death in human.</strong> Hum. Molec. Genet. 21: 2759-2767, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22422768/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22422768</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22422768[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/dds104" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22422768">Roux-Buisson et al. (2012)</a>, see <a href="#0002">603283.0002</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22422768" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 2 sisters (II.1 and II.2) from a French family with CARDAR manifest as catecholaminergic polymorphic ventricular tachycardia (CPVT), who did not have muscle weakness, <a href="#7" class="mim-tip-reference" title="Rooryck, C., Kyndt, F., Bozon, D., Roux-Buisson, N., Sacher, F., Probst, V., Thambo, J.-B. <strong>New family with catecholaminergic polymorphic ventricular tachycardia linked to the triadin gene.</strong> J. Cardiovasc. Electrophysiol. 26: 1146-1150, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26200674/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26200674</a>] [<a href="https://doi.org/10.1111/jce.12763" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26200674">Rooryck et al. (2015)</a> identified compound heterozygosity for the Q205X mutation in the TRDN gene, and a splicing mutation (c.22+29A-G; <a href="#0005">603283.0005</a>). Their unaffected parents were each heterozygous for 1 of the mutations, which were both found at low minor allele frequency in the ExAC database (0.00003244 and 0.000008339, respectively). Their asymptomatic 3-year-old sister (II.3) was also compound heterozygous for the TRDN mutations. In vitro minigene assay demonstrated that the splicing mutation results in an elongation of exon 1 by 29 bases, causing a frameshift and premature termination codon. (In their article, <a href="#7" class="mim-tip-reference" title="Rooryck, C., Kyndt, F., Bozon, D., Roux-Buisson, N., Sacher, F., Probst, V., Thambo, J.-B. <strong>New family with catecholaminergic polymorphic ventricular tachycardia linked to the triadin gene.</strong> J. Cardiovasc. Electrophysiol. 26: 1146-1150, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26200674/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26200674</a>] [<a href="https://doi.org/10.1111/jce.12763" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26200674">Rooryck et al. (2015)</a> correctly referred to the mutation as Q205X but incorrectly as Glu205Ter.) <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26200674" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs752256846 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs752256846;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/rs752256846?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=rs752256846" 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=rs752256846" 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=RCV000519867 OR RCV003525916 OR RCV003985018 OR RCV004023546" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000519867, RCV003525916, RCV003985018, RCV004023546" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000519867...</a>
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<p>In 3 unrelated children (families 2, 3, and 4) with cardiac arrhythmia syndrome (CARDAR; <a href="/entry/615441">615441</a>) who experienced syncope or cardiac arrest before 3 years of age and had long QT intervals on electrocardiography, <a href="#1" class="mim-tip-reference" title="Altmann, H. M., Tester, D. J., Will, M. L., Middha, S., Evans, J. M., Eckloff, B. W., Ackerman, M. J. <strong>Homozygous/compound heterozygous triadin mutations associated with autosomal-recessive long-QT syndrome and pediatric sudden cardiac arrest: elucidation of the triadin knockout syndrome.</strong> Circulation 131: 2051-2060, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25922419/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25922419</a>] [<a href="https://doi.org/10.1161/CIRCULATIONAHA.115.015397" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25922419">Altmann et al. (2015)</a> identified homozygosity for a 5-bp deletion (c.572_576delTAAGA, NM_001256021.1) in the TRDN gene, resulting in an immediate stop codon (Lys147fsTer0). One child (family 2) also exhibited mild proximal muscle weakness, and another (family 4) showed polymorphic and bidirectional ventricular tachycardia on electrocardiography, in addition to transient QT prolongation. A fourth child (family 5), who experienced cardiac arrest at age 20 months and exhibited mild to moderate skeletal muscle weakness and decreased muscle tone at age 4 years, was compound heterozygous for the 5-bp deletion and a splicing mutation (c.22+29A-G; <a href="#0005">603283.0005</a>). The mutations segregated with disease in the respective families, and were either not found or were present at very low minor allele frequency in public variant databases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25922419" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs774068079 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs774068079;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/rs774068079?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=rs774068079" 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=rs774068079" 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=RCV001580169 OR RCV002432068 OR RCV002499793 OR RCV002550267" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001580169, RCV002432068, RCV002499793, RCV002550267" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001580169...</a>
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<p>For discussion of the c.22+29A-G transition (c.22+29A-G, NM_001256021.1) in intron 1 of the TRDN gene that was found in compound heterozygous state in a 4-year-old boy (family 5) with cardiac arrhythmia syndrome and skeletal muscle weakness (CARDAR; <a href="/entry/615441">615441</a>) by <a href="#1" class="mim-tip-reference" title="Altmann, H. M., Tester, D. J., Will, M. L., Middha, S., Evans, J. M., Eckloff, B. W., Ackerman, M. J. <strong>Homozygous/compound heterozygous triadin mutations associated with autosomal-recessive long-QT syndrome and pediatric sudden cardiac arrest: elucidation of the triadin knockout syndrome.</strong> Circulation 131: 2051-2060, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25922419/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25922419</a>] [<a href="https://doi.org/10.1161/CIRCULATIONAHA.115.015397" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25922419">Altmann et al. (2015)</a>, see <a href="#0004">603283.0004</a>. For discussion of the same splicing mutation found in compound heterozygous state in 3 French sisters with CARDAR without skeletal muscle weakness by <a href="#7" class="mim-tip-reference" title="Rooryck, C., Kyndt, F., Bozon, D., Roux-Buisson, N., Sacher, F., Probst, V., Thambo, J.-B. <strong>New family with catecholaminergic polymorphic ventricular tachycardia linked to the triadin gene.</strong> J. Cardiovasc. Electrophysiol. 26: 1146-1150, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26200674/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26200674</a>] [<a href="https://doi.org/10.1111/jce.12763" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26200674">Rooryck et al. (2015)</a>, see <a href="#0003">603283.0003</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=26200674+25922419" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 CARDIAC ARRHYTHMIA SYNDROME WITH OR WITHOUT SKELETAL MUSCLE WEAKNESS</strong>
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TRDN, GLU168TER
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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> rs545032318 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs545032318;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/rs545032318?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=rs545032318" 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=rs545032318" 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=RCV001580170 OR RCV002551449 OR RCV004031109" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001580170, RCV002551449, RCV004031109" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001580170...</a>
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<p>For discussion of the c.502G-T transversion in the TRDN gene, resulting in a glu168-to-ter (E168X) substitution, that was found in compound heterozygous state in a brother and sister with cardiac arrhythmia syndrome (CARDAR; <a href="/entry/615441">615441</a>) by <a href="#13" class="mim-tip-reference" title="Walsh, M. A., Stuart, A. G., Schlecht, H. B., James, A. F., Hancox, J. C., Newbury-Ecob, R. A. <strong>Compound heterozygous triadin mutation causing cardiac arrest in two siblings.</strong> Pacing Clin. Electrophysiol. 39: 497-501, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26768964/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26768964</a>] [<a href="https://doi.org/10.1111/pace.12813" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26768964">Walsh et al. (2016)</a>, see <a href="#0001">603283.0001</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26768964" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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">rs1060502116 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1060502116;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=rs1060502116" 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=rs1060502116" 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=RCV000786235 OR RCV001580171 OR RCV003103778" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000786235, RCV001580171, RCV003103778" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000786235...</a>
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<p>In an Afghan family with cardiac arrhythmia syndrome (CARDAR; <a href="/entry/615441">615441</a>) in which 2 sibs had died suddenly at ages 2 years and 3 years, and a third child was resuscitated from cardiac arrest at age 14 months and showed prolongation of the QT interval on electrocardiography, <a href="#8" class="mim-tip-reference" title="Rossi, D., Gigli, L., Gamberucci, A., Bordoni, R., Pietrelli, A., Lorenzini, S., Pierantozzi, E., Peretto, G., De Bellis, G., Della Bella, P., Ferrari, M., Sorrentino, V., Benedetti, S., Sala, S., Di Resta, C. <strong>A novel homozygous mutation in the TRDN gene causes a severe form of pediatric malignant ventricular arrhythmia.</strong> Heart Rhythm 17: 296-304, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31437535/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31437535</a>] [<a href="https://doi.org/10.1016/j.hrthm.2019.08.018" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31437535">Rossi et al. (2020)</a> identified homozygosity for a c.167T-C transition (c.167T-C, NM_006073.3) in the TRDN gene, resulting in a leu56-to-pro (L56P) substitution at a highly conserved residue within the transmembrane helix domain. The variant segregated with disease in the family and was not found in the 1000 Genomes Project or gnomAD databases. Functional analysis in transfected HeLa cells showed that the mobile fraction with the L56P variant was significantly higher than that with the wildtype protein, suggesting that the L56P mutation increases triadin mobility in the endoplasmic reticulum membrane. In addition, HEK293T cells expressing RYR2 (<a href="/entry/180902">180902</a>) channels showed a peak magnitude of caffeine-stimulated calcium release that was significantly reduced with the L56P mutant compared to wildtype TRDN. <a href="#8" class="mim-tip-reference" title="Rossi, D., Gigli, L., Gamberucci, A., Bordoni, R., Pietrelli, A., Lorenzini, S., Pierantozzi, E., Peretto, G., De Bellis, G., Della Bella, P., Ferrari, M., Sorrentino, V., Benedetti, S., Sala, S., Di Resta, C. <strong>A novel homozygous mutation in the TRDN gene causes a severe form of pediatric malignant ventricular arrhythmia.</strong> Heart Rhythm 17: 296-304, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31437535/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31437535</a>] [<a href="https://doi.org/10.1016/j.hrthm.2019.08.018" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31437535">Rossi et al. (2020)</a> noted that while the index case in this family did not show signs of myopathy, this could be due to his very young age, and could not exclude future muscular involvement. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31437535" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>REFERENCES</strong>
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<a id="Altmann2015" class="mim-anchor"></a>
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Altmann, H. M., Tester, D. J., Will, M. L., Middha, S., Evans, J. M., Eckloff, B. W., Ackerman, M. J.
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<strong>Homozygous/compound heterozygous triadin mutations associated with autosomal-recessive long-QT syndrome and pediatric sudden cardiac arrest: elucidation of the triadin knockout syndrome.</strong>
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Circulation 131: 2051-2060, 2015.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25922419/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25922419</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25922419" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1161/CIRCULATIONAHA.115.015397" target="_blank">Full Text</a>]
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Chopra, N., Yang, T., Asghari, P., Moore, E. D., Huke, S., Akin, B., Cattolica, R. A., Perez, C. F., Hlaing, T., Knollmann-Ritschel, B. E. C., Jones, L. R., Pessah, I. N., Allen, P. D., Franzini-Armstrong, C., Knollmann, B. C.
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<strong>Ablation of triadin causes loss of cardiac Ca2+ release units, impaired excitation-contraction coupling, and cardiac arrhythmias.</strong>
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Proc. Nat. Acad. Sci. 106: 7636-7641, 2009.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19383796/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19383796</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19383796[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=19383796" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1073/pnas.0902919106" target="_blank">Full Text</a>]
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Hong, C.-S., Ji, J.-H., Kim, J. P., Jung, D. H., Kim, D. H.
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<strong>Molecular cloning and characterization of mouse cardiac triadin isoforms.</strong>
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Gene 278: 193-199, 2001.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11707337/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11707337</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11707337" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/s0378-1119(01)00718-1" target="_blank">Full Text</a>]
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Kirchhefer, U., Neumann, J., Baba, H. A., Begrow, F., Kobayashi, Y. M., Reinke, U., Schmitz, W., Jones, L. R.
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<strong>Cardiac hypertrophy and impaired relaxation in transgenic mice overexpressing triadin 1.</strong>
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J. Biol. Chem. 276: 4142-4149, 2001.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11069905/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11069905</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11069905" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1074/jbc.M006443200" target="_blank">Full Text</a>]
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O'Callaghan, B. M., Hancox, J. C., Stuart, A. G., Armstrong, C., Williams, M. M., Hills, A., Pearce, H., Dent, C. L., Gable, M., Walsh, M. A.
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<strong>A unique triadin exon deletion causing a null phenotype.</strong>
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HeartRhythm Case Rep. 4: 514-518, 2018.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30479949/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30479949</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30479949[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=30479949" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.hrcr.2018.07.014" target="_blank">Full Text</a>]
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Oddoux, S., Brocard, J., Schweitzer, A., Szentesi, P., Giannesini, B., Brocard, J., Faure, J., Pernet-Gallay, K., Bendahan, D., Lunardi, J., Csernoch, L., Marty, I.
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<strong>Triadin deletion induces impaired skeletal muscle function.</strong>
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J. Biol. Chem. 284: 34918-34929, 2009.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19843516/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19843516</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19843516[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=19843516" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1074/jbc.M109.022442" target="_blank">Full Text</a>]
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<a id="7" class="mim-anchor"></a>
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<a id="Rooryck2015" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Rooryck, C., Kyndt, F., Bozon, D., Roux-Buisson, N., Sacher, F., Probst, V., Thambo, J.-B.
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<strong>New family with catecholaminergic polymorphic ventricular tachycardia linked to the triadin gene.</strong>
|
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J. Cardiovasc. Electrophysiol. 26: 1146-1150, 2015.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26200674/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26200674</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26200674" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1111/jce.12763" target="_blank">Full Text</a>]
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</p>
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<a id="8" class="mim-anchor"></a>
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<a id="Rossi2020" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Rossi, D., Gigli, L., Gamberucci, A., Bordoni, R., Pietrelli, A., Lorenzini, S., Pierantozzi, E., Peretto, G., De Bellis, G., Della Bella, P., Ferrari, M., Sorrentino, V., Benedetti, S., Sala, S., Di Resta, C.
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<strong>A novel homozygous mutation in the TRDN gene causes a severe form of pediatric malignant ventricular arrhythmia.</strong>
|
|
Heart Rhythm 17: 296-304, 2020.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31437535/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31437535</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31437535" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.hrthm.2019.08.018" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="9" class="mim-anchor"></a>
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<a id="Roux-Buisson2012" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Roux-Buisson, N., Cacheux, M., Fourest-Lieuvin, A., Fauconnier, J., Brocard, J., Denjoy, I., Durand, P., Guicheney, P., Kyndt, F., Leenhardt, A., Le Marec, H., Lucet, V., and 10 others.
|
|
<strong>Absence of triadin, a protein of the calcium release complex, is responsible for cardiac arrhythmia with sudden death in human.</strong>
|
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Hum. Molec. Genet. 21: 2759-2767, 2012.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22422768/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22422768</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22422768[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=22422768" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/dds104" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="10" class="mim-anchor"></a>
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<a id="Shen2007" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Shen, X., Franzini-Armstrong, C., Lopez, J. R., Jones, L. R., Kobayashi, Y. M., Wang, Y., Kerrick, W. G. L., Caswell, A. H., Potter, J. D., Miller, T., Allen, P. D., Perez, C. F.
|
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<strong>Triadins modulate intracellular Ca2+ homeostasis but are not essential for excitation-contraction coupling in skeletal muscle.</strong>
|
|
J. Biol. Chem. 282: 37864-37874, 2007.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17981799/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17981799</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17981799" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1074/jbc.M705702200" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="11" class="mim-anchor"></a>
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<a id="Taske1995" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Taske, N. L., Eyre, H. J., O'Brien, R. O., Sutherland, G. R., Denborough, M. A., Foster, P. S.
|
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<strong>Molecular cloning of the cDNA encoding human skeletal muscle triadin and its localisation to chromosome 6q22-6q23.</strong>
|
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Europ. J. Biochem. 233: 258-265, 1995.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7588753/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7588753</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7588753" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1111/j.1432-1033.1995.258_1.x" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="12" class="mim-anchor"></a>
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<a id="Thevenon2003" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Thevenon, D., Smida-Rezgui, S., Chevessier, F., Groh, S., Henry-Berger, J., Romero, N. B., Villaz, M., DeWaard, M., Marty, I.
|
|
<strong>Human skeletal muscle triadin: gene organization and cloning of the major isoform, Trisk 51.</strong>
|
|
Biochem. Biophys. Res. Commun. 303: 669-675, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12659871/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12659871</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12659871" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/s0006-291x(03)00406-6" target="_blank">Full Text</a>]
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</p>
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</div>
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<li>
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<a id="13" class="mim-anchor"></a>
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<a id="Walsh2016" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Walsh, M. A., Stuart, A. G., Schlecht, H. B., James, A. F., Hancox, J. C., Newbury-Ecob, R. A.
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<strong>Compound heterozygous triadin mutation causing cardiac arrest in two siblings.</strong>
|
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Pacing Clin. Electrophysiol. 39: 497-501, 2016.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26768964/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26768964</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26768964" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1111/pace.12813" target="_blank">Full Text</a>]
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</p>
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</ol>
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<div>
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<br />
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</div>
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</div>
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<a id="contributors" class="mim-anchor"></a>
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<div class="row">
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<span class="mim-text-font">
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Marla J. F. O'Neill - updated : 08/23/2021
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseContributors">
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<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Patricia A. Hartz - updated : 1/10/2014<br>Marla J. F. O'Neill - updated : 9/30/2013<br>Patricia A. Hartz - updated : 5/20/2003
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="creationDate" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Rebekah S. Rasooly : 11/12/1998
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="editHistory" class="mim-anchor"></a>
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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alopez : 09/16/2021
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseEditHistory">
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 08/24/2021<br>alopez : 08/23/2021<br>alopez : 08/23/2021<br>carol : 07/21/2021<br>mcolton : 06/09/2015<br>mgross : 1/10/2014<br>mcolton : 1/7/2014<br>carol : 10/1/2013<br>tpirozzi : 9/30/2013<br>terry : 4/9/2004<br>mgross : 5/20/2003<br>mgross : 5/20/2003<br>carol : 12/21/1999<br>alopez : 11/12/1998
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</span>
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</div>
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</div>
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</div>
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<div class="container visible-print-block">
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<div>
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<div>
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<h3>
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<span class="mim-font">
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<strong>*</strong> 603283
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</span>
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</h3>
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</div>
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<div>
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<h3>
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<span class="mim-font">
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TRIADIN; TRDN
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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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<div >
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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TRISK
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: TRDN</em></strong>
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</span>
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</p>
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong>
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<em>
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Cytogenetic location: 6q22.31
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Genomic coordinates <span class="small">(GRCh38)</span> : 6:123,216,339-123,636,950 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</h4>
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<div>
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
|
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</tr>
|
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</thead>
|
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<tbody>
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|
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<tr>
|
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<td rowspan="1">
|
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<span class="mim-font">
|
|
6q22.31
|
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</span>
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</td>
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<td>
|
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<span class="mim-font">
|
|
Cardiac arrhythmia syndrome, with or without skeletal muscle weakness
|
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</span>
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
615441
|
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</span>
|
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</td>
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<td>
|
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<span class="mim-font">
|
|
Autosomal recessive
|
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</span>
|
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</td>
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<td>
|
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<span class="mim-font">
|
|
3
|
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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<strong>TEXT</strong>
|
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</span>
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</h4>
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<div>
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<h4>
|
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<span class="mim-font">
|
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<strong>Description</strong>
|
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</span>
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</h4>
|
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</div>
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<span class="mim-text-font">
|
|
<p>The triadin gene is alternatively spliced to produce several isoforms that are differentially expressed in skeletal and cardiac muscle. Some isoforms localize to longitudinal regions of the sarcoplasmic reticulum (SR), and others localize to triad junctions, where T-tubules and SR terminal cisternae are in close contact. Triadin isoforms localized to triad junctions appear to have a role in excitation-contraction coupling (summary by Oddoux et al., 2009). </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>The dihydropyridine-sensitive calcium channels (see CACNA2; 114204) and ryanodine-sensitive calcium channels (RYR1; 180901) of skeletal muscle play key roles in the generation of calcium transients during excitation/contraction coupling. The coupling of the signal for calcium release between these proteins occurs at highly specialized triadic junctions that separate the T-tubule membrane and the terminal cisternae of the SR. Triadin, a protein found in rabbit triadic junctions, is intrinsic to the terminal cisternae and is closely associated with RYR1. By RT-PCR of human skeletal muscle RNA with primers based on the sequence of a rabbit triadin cDNA, Taske et al. (1995) isolated cDNAs encoding human triadin. The predicted 729-amino acid human protein shares 95% identity with rabbit triadin. Like the rabbit protein, human triadin contains a small cytoplasmic domain and a single transmembrane domain. Human triadin has a calculated pI of 9.3 and molecular mass of 82 kD. However, on Western blots, its apparent molecular mass is 117 kD. Taske et al. (1995) suggested that triadin has reduced mobility because it is a highly charged protein. Northern blot analysis revealed that triadin is expressed as a 4.8-kb mRNA in human skeletal muscle. </p><p>By PCR and 3-prime and 5-prime RACE, Thevenon et al. (2003) cloned 2 triadin isoforms from a skeletal muscle cDNA library. The longer isoform, TRISK95, contains 729 amino acids and has a calculated molecular mass of about 95 kD. The shorter isoform, TRISK51, results from the use of an internal splice site within exon 21. It contains 461 amino acids and has a calculated molecular mass of about 51 kD. The TRISK51 and TRISK95 transcripts are both about 4.5 kb. In rat skeletal muscle, expression of Trisk95 and Trisk51 was roughly equivalent. However, RT-PCR and Western blot analysis of human deltoid and quadriceps muscle indicated that TRISK51 was expressed at high levels, while TRISK95 was expressed at low levels. Immunologic labeling of longitudinal sections of skeletal muscle revealed signal localized to the junctional triad. </p><p>Hong et al. (2001) cloned several isoforms of mouse Trdn from skeletal and cardiac muscle. All 3 isoforms have identical N-terminal sequences of 262 amino acids and distinct C-terminal sequences. The isoforms expressed in cardiac muscle were about 1.3, 4.3, and 5.0 kb and corresponded to deglycosylated proteins of 35, 35.5, and 40 kD, respectively. In skeletal muscle, the transcripts sizes were 5.0, 5.5, and 7.0 kb. </p><p>Shen et al. (2007) stated that triadin isoforms of 95 and 60 kD are expressed in triad junctions of mouse skeletal muscle, that isoforms of 32 and 40 kD are expressed in triad junctions of heart, and that nontriad isoforms of 49 and 32 kD are expressed in skeletal muscle. </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>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>Thevenon et al. (2003) determined that the TRDN gene contains 41 exons and spans 420 kb. Exon 1 contains the initiation codon, and exon 41 contains the stop codon and 1.3 kb of 3-prime untranslated sequence. </p>
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</span>
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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>Mapping</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>By fluorescence in situ hybridization, Taske et al. (1995) mapped the triadin gene to 6q22-q23. </p>
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<br />
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene 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>Using the alpha-myosin heavy chain (160710) promoter to drive protein expression, Kirchhefer et al. (2001) developed transgenic mice overexpressing Trdn1, the dominant cardiac isoform of mouse triadin, in the atrium and ventricle. Expression was elevated 5-fold and was accompanied by cardiac hypertrophy. The levels of 2 other junctional SR proteins, RYR2 (180902) and junctin (ASPH; 600582), were reduced by 55% and 73%, respectively. The levels of the junctional SR Ca(2+)-binding protein, calsequestrin (114251), and the free SR Ca(2+)-handling proteins, phospholamban (172405) and Serca2a (180740), were unchanged. The contractile phenotype of hearts from triadin-overexpressing mice included impaired relaxation, blunted contractility with increased pressure loading, and frequency-dependent changes in myocyte shortening. Kirchhefer et al. (2001) concluded that Trdn1 plays an active role in Ca(2+) release, beyond its previously proposed structural role of anchoring calsequestrin to RYR2. </p>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>From a cohort of 97 patients with catecholaminergic polymorphic ventricular tachycardia (CPVT; see 604772) in whom mutations in the RYR2 (180902) and CASQ2 (114251) genes had been excluded, Roux-Buisson et al. (2012) identified 2 probands with biallelic mutations in the TRDN gene. Both patients had onset of severe cardiac arrhythmias in infancy or early childhood, and 1 also had skeletal muscle weakness (cardiac arrhythmia syndrome with or without skeletal muscle weakness, CARDAR; 615441). One proband was a 2-year-old boy from the French West Indies who was homozygous for a frameshift mutation (603283.0001), and the other was a 26-year-old French man who was compound heterozygous for a missense (T59R; 603283.0002) and a nonsense (Q205X; 603283.0003) mutation. The authors noted that the 3 TRDN mutations were located in a region of the gene common to all triadin isoforms, including skeletal muscle isoforms. </p><p>In a 10-year-old girl (family 1) with severe cardiac arrhythmias and a prolonged QT interval, who was negative for mutation in known long QT syndrome (LQTS; see 192500)-associated genes, Altmann et al. (2015) identified homozygosity for the previously reported 4-bp deletion in the TRDN gene (603283.0001). Subsequent analysis of the TRDN gene in 33 unrelated patients with LQTS revealed 4 more children with mutations in TRDN: 3 were homozygous for a 5-bp deletion (603283.0004) and 1 was compound heterozygous for the 5-bp deletion and a splicing mutation (603283.0005). The mutations segregated with disease in the respective families, and were either not found or were present at very low minor allele frequency in public variant databases. </p><p>In 2 sisters from a French family with CPVT, Rooryck et al. (2015) identified compound heterozygosity for 2 previously reported mutations in the TRDN gene: Q205X (603283.0003) and a splicing mutation (603283.0005). Their unaffected parents were each heterozygous for 1 of the mutations; their asymptomatic 3-year-old sister was also compound heterozygous for the variants. </p><p>In a brother and sister with cardiac arrest at age 2 years and possible prolongation of the QT interval on ECG, Walsh et al. (2016) identified compound heterozygosity for the previously reported 4-bp deletion (603283.0001) and a nonsense mutation in the TRDN gene (E168X; 603283.0006). </p><p>O'Callaghan et al. (2018) studied an Omani male infant who experienced cardiac arrest at age 16 months and showed prolonged QTc and T-wave inversion in the anterior precordial leads on ECG. Subsequent ECGs documented torsades de pointes and ventricular fibrillation. Next-generation sequencing targeting 54 cardiac arrhythmia-associated genes revealed mutations in 3 genes: an apparently homozygous deletion of exon 2 of the TRDN gene; a previously reported missense mutation in the KCNE2 gene (I57T; 603796.0003), associated with long QT syndrome (LQT6; 613693); and a E3783Q substitution in the RYR2 gene of uncertain significance. </p><p>In an Afghan family in which 2 sibs had died suddenly and a third child was resuscitated from cardiac arrest, Rossi et al. (2020) identified homozygosity for a missense mutation in the TRDN gene (L56P; 603283.0007) that segregated with disease in the family. Functional analysis suggested that the L56P variant may trigger arrhythmias by altering calcium homeostasis. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Animal Model</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Shen et al. (2007) found that mice with complete knockout of triadin expression appeared normal in their survival, fertility, and movements. Western blot analysis of SR proteins in Trdn -/- skeletal muscle showed downregulation of junctophilin-1 (JPH1; 605266), junctin (ASPH; 600582), and calsequestrin (see 114250). Some calsequestrin was also detected in tubes of the longitudinal SR in Trdn -/- muscle. Expression of junctin and Ryr1 (180901) was differentially affected in slow and fast Trdn -/- muscle. Trdn -/- muscle showed reduced amplitude of calcium transients and increased myoplasmic resting free Ca(2+), but it did not show contractile dysfunction. Minor disorganization of triadic junctions was observed in fast-twitch, but not slow-twitch, Trdn -/- muscle fibers. </p><p>The calcium release unit is a multiprotein complex whose principal components include the L-type calcium channel Cav1.2 (CACNA1C; 114205) and Ryr2 (180902). Chopra et al. (2009) found that homozygous deletion of Trdn in mice resulted in defective excitation-contraction coupling in heart, concomitant with significant changes in the structure and protein composition of the cardiac calcium release unit. Electron microscopy of Trdn -/- hearts showed fragmentation and an overall 50% reduction in the contacts between cardiac junctional SR and T-tubules, with reduced colocalization of Cav1.2 with Ryr2. Calcium release unit function was impaired in Trdn -/- myocytes, with reduced SR calcium release and impaired negative feedback of SR calcium release in response to Cav1.2 calcium currents. Beta-adrenergic receptor (see 109630) stimulation caused ventricular arrhythmias in Trdn -/- mice and spontaneous SR calcium release in isolated Trdn -/- myocytes, likely due to uninhibited calcium influx. </p><p>Independently, Oddoux et al. (2009) found that deletion of Trdn expression in mice altered the composition of the calcium release complex in fast and slow skeletal muscle, caused abnormal orientation of triads with loss of associated mitochondria, and reduced SR terminal cisternae volume and calcium content. Trdn -/- mice showed reduced strength, and both fast- and slow-twitch muscle from Trdn -/- mice showed reduced twitch and tetanic forces, but improved resistance to fatigue. </p>
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</span>
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<div>
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<br />
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>7 Selected Examples):</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0001 CARDIAC ARRHYTHMIA SYNDROME WITH OR WITHOUT SKELETAL MUSCLE WEAKNESS</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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TRDN, 4-BP DEL, 53ACAG
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<br />
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SNP: rs768049331,
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gnomAD: rs768049331,
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ClinVar: RCV000056259, RCV002223180, RCV002345363, RCV002513732
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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 2-year-old boy with cardiac arrhythmia syndrome (CARDAR; 615441) who died after cardiac arrest due to catecholaminergic polymorphic ventricular tachycardia (CPVT), Roux-Buisson et al. (2012) identified homozygosity for a 4-bp deletion (c.53_56delACAG) in exon 2 of the TRDN gene, resulting in a frameshift predicted to result in a premature termination codon (Asp18AlafsTer13) before the transmembrane helix in the cardiac isoform of triadin (TRISK32). The mutation was present in heterozygosity in the proband's unaffected parents and older brother. Haplotype analysis in the family suggested a remote common ancestor. Roux-Buisson et al. (2012) remarked that the young age of the patient precluded detection of skeletal muscle weakness. </p><p>In a 10-year-old black girl (family 1) with CARDAR with severe cardiac arrhythmias and a prolonged QT interval, Altmann et al. (2015) identified homozygosity for the previously reported 4-bp deletion in the TRDN gene (c.53_56delACAG, NM_001256021.1) for which her unaffected parents were heterozygous. The authors noted that the variant was not found in the 1000 Genomes Project database or in white exomes in the NHLBI GO ESP database, but was present in 1 of 1,861 black exomes in GO ESP, and was also present in the ExAC database at an overall minor allele frequency of 0.01%, and in black exomes at 0.14%. Skeletal muscle weakness was noted to be absent. </p><p>In a brother and sister with CARDAR who both experienced cardiac arrest at 2 years of age and showed possible prolongation of the QT interval, Walsh et al. (2016) identified compound heterozygosity for the 4-bp deletion in the TRDN gene and a c.502G-T transversion, resulting in a glu168-to-ter (E168X; 603283.0006) substitution. Their unaffected parents were each heterozygous for 1 of the mutations. Walsh et al. (2016) attributed residual generalized weakness in the sister to the mutation, and noted that the gross motor development of the brother was slightly delayed compared to that of his half-sibs. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0002 CARDIAC ARRHYTHMIA SYNDROME WITH OR WITHOUT SKELETAL MUSCLE WEAKNESS</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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TRDN, THR59ARG
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<br />
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SNP: rs397515459,
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gnomAD: rs397515459,
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ClinVar: RCV000056261
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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 26-year-old dizygotic twin brothers with cardiac arrhythmia syndrome (CARDAR; 615441), who from infancy experienced exercise-induced syncope due to catecholaminergic polymorphic ventricular tachycardia, Roux-Buisson et al. (2012) identified compound heterozygosity for 2 mutations in the TRDN gene: a c.176C-G transversion in exon 2, resulting in a thr59-to-arg (T59R) substitution at a well-conserved residue within the transmembrane domain of the cardiac isoform of triadin (TRISK32), and a c.613C-T transition in exon 8, resulting in a gln205-to-ter substitution (Q205X; 603283.0003) before the KEKE region. One of the brothers also had proximal muscle weakness. Unaffected family members who were tested carried 1 or none of the variants. Analysis of TRISK32 in COS-7 cells showed that whereas wildtype TRISK32 was localized in the plasma membrane of 83% of cells and in the endoplasmic reticulum (ER) in 17%, T59R mutant TRISK32 was retained in the ER in 100% of cells and was prone to degradation, most likely via the proteasomal pathway. RT-PCR and Western blot analysis of cardiomyocytes from TRDN-knockout mice after viral transduction of the T59R-TRDN mutant demonstrated that although the mutant transcript is expressed, the protein is absent. </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>.0003 CARDIAC ARRHYTHMIA SYNDROME WITH OR WITHOUT SKELETAL MUSCLE WEAKNESS</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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TRDN, GLN205TER
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<br />
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SNP: rs397515458,
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gnomAD: rs397515458,
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ClinVar: RCV000056260, RCV000484797, RCV002354248, RCV002496743, RCV003103726, RCV004017360
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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|
<p>For discussion of the c.613C-T transition in the TRDN gene, resulting in a gln205-to-ter (Q205X) substitution, that was found in compound heterozygous state in twin brothers with cardiac arrhythmia syndrome with or without skeletal muscle weakness (CARDAR; 615441) by Roux-Buisson et al. (2012), see 603283.0002. </p><p>In 2 sisters (II.1 and II.2) from a French family with CARDAR manifest as catecholaminergic polymorphic ventricular tachycardia (CPVT), who did not have muscle weakness, Rooryck et al. (2015) identified compound heterozygosity for the Q205X mutation in the TRDN gene, and a splicing mutation (c.22+29A-G; 603283.0005). Their unaffected parents were each heterozygous for 1 of the mutations, which were both found at low minor allele frequency in the ExAC database (0.00003244 and 0.000008339, respectively). Their asymptomatic 3-year-old sister (II.3) was also compound heterozygous for the TRDN mutations. In vitro minigene assay demonstrated that the splicing mutation results in an elongation of exon 1 by 29 bases, causing a frameshift and premature termination codon. (In their article, Rooryck et al. (2015) correctly referred to the mutation as Q205X but incorrectly as Glu205Ter.) </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0004 CARDIAC ARRHYTHMIA SYNDROME WITH OR WITHOUT SKELETAL MUSCLE WEAKNESS</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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TRDN, 5-BP DEL, 572TAAGA
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<br />
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SNP: rs752256846,
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gnomAD: rs752256846,
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ClinVar: RCV000519867, RCV003525916, RCV003985018, RCV004023546
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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 unrelated children (families 2, 3, and 4) with cardiac arrhythmia syndrome (CARDAR; 615441) who experienced syncope or cardiac arrest before 3 years of age and had long QT intervals on electrocardiography, Altmann et al. (2015) identified homozygosity for a 5-bp deletion (c.572_576delTAAGA, NM_001256021.1) in the TRDN gene, resulting in an immediate stop codon (Lys147fsTer0). One child (family 2) also exhibited mild proximal muscle weakness, and another (family 4) showed polymorphic and bidirectional ventricular tachycardia on electrocardiography, in addition to transient QT prolongation. A fourth child (family 5), who experienced cardiac arrest at age 20 months and exhibited mild to moderate skeletal muscle weakness and decreased muscle tone at age 4 years, was compound heterozygous for the 5-bp deletion and a splicing mutation (c.22+29A-G; 603283.0005). The mutations segregated with disease in the respective families, and were either not found or were present at very low minor allele frequency in public variant databases. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>.0005 CARDIAC ARRHYTHMIA SYNDROME WITH OR WITHOUT SKELETAL MUSCLE WEAKNESS</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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TRDN, IVS1, A-G, +29
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<br />
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SNP: rs774068079,
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gnomAD: rs774068079,
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ClinVar: RCV001580169, RCV002432068, RCV002499793, RCV002550267
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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|
<p>For discussion of the c.22+29A-G transition (c.22+29A-G, NM_001256021.1) in intron 1 of the TRDN gene that was found in compound heterozygous state in a 4-year-old boy (family 5) with cardiac arrhythmia syndrome and skeletal muscle weakness (CARDAR; 615441) by Altmann et al. (2015), see 603283.0004. For discussion of the same splicing mutation found in compound heterozygous state in 3 French sisters with CARDAR without skeletal muscle weakness by Rooryck et al. (2015), see 603283.0003. </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 CARDIAC ARRHYTHMIA SYNDROME WITH OR WITHOUT SKELETAL MUSCLE WEAKNESS</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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TRDN, GLU168TER
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<br />
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SNP: rs545032318,
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gnomAD: rs545032318,
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ClinVar: RCV001580170, RCV002551449, RCV004031109
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
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<p>For discussion of the c.502G-T transversion in the TRDN gene, resulting in a glu168-to-ter (E168X) substitution, that was found in compound heterozygous state in a brother and sister with cardiac arrhythmia syndrome (CARDAR; 615441) by Walsh et al. (2016), see 603283.0001. </p>
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</span>
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</div>
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<span class="mim-font">
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<strong>.0007 CARDIAC ARRHYTHMIA SYNDROME WITH OR WITHOUT SKELETAL MUSCLE WEAKNESS</strong>
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TRDN, LEU56PRO
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<br />
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SNP: rs1060502116,
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ClinVar: RCV000786235, RCV001580171, RCV003103778
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<p>In an Afghan family with cardiac arrhythmia syndrome (CARDAR; 615441) in which 2 sibs had died suddenly at ages 2 years and 3 years, and a third child was resuscitated from cardiac arrest at age 14 months and showed prolongation of the QT interval on electrocardiography, Rossi et al. (2020) identified homozygosity for a c.167T-C transition (c.167T-C, NM_006073.3) in the TRDN gene, resulting in a leu56-to-pro (L56P) substitution at a highly conserved residue within the transmembrane helix domain. The variant segregated with disease in the family and was not found in the 1000 Genomes Project or gnomAD databases. Functional analysis in transfected HeLa cells showed that the mobile fraction with the L56P variant was significantly higher than that with the wildtype protein, suggesting that the L56P mutation increases triadin mobility in the endoplasmic reticulum membrane. In addition, HEK293T cells expressing RYR2 (180902) channels showed a peak magnitude of caffeine-stimulated calcium release that was significantly reduced with the L56P mutant compared to wildtype TRDN. Rossi et al. (2020) noted that while the index case in this family did not show signs of myopathy, this could be due to his very young age, and could not exclude future muscular involvement. </p>
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<h4>
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<span class="mim-font">
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<strong>REFERENCES</strong>
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</span>
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</h4>
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<p />
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Altmann, H. M., Tester, D. J., Will, M. L., Middha, S., Evans, J. M., Eckloff, B. W., Ackerman, M. J.
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<strong>Homozygous/compound heterozygous triadin mutations associated with autosomal-recessive long-QT syndrome and pediatric sudden cardiac arrest: elucidation of the triadin knockout syndrome.</strong>
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Circulation 131: 2051-2060, 2015.
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[PubMed: 25922419]
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[Full Text: https://doi.org/10.1161/CIRCULATIONAHA.115.015397]
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</li>
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Chopra, N., Yang, T., Asghari, P., Moore, E. D., Huke, S., Akin, B., Cattolica, R. A., Perez, C. F., Hlaing, T., Knollmann-Ritschel, B. E. C., Jones, L. R., Pessah, I. N., Allen, P. D., Franzini-Armstrong, C., Knollmann, B. C.
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<strong>Ablation of triadin causes loss of cardiac Ca2+ release units, impaired excitation-contraction coupling, and cardiac arrhythmias.</strong>
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Proc. Nat. Acad. Sci. 106: 7636-7641, 2009.
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[PubMed: 19383796]
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[Full Text: https://doi.org/10.1073/pnas.0902919106]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Hong, C.-S., Ji, J.-H., Kim, J. P., Jung, D. H., Kim, D. H.
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<strong>Molecular cloning and characterization of mouse cardiac triadin isoforms.</strong>
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Gene 278: 193-199, 2001.
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[PubMed: 11707337]
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[Full Text: https://doi.org/10.1016/s0378-1119(01)00718-1]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Kirchhefer, U., Neumann, J., Baba, H. A., Begrow, F., Kobayashi, Y. M., Reinke, U., Schmitz, W., Jones, L. R.
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<strong>Cardiac hypertrophy and impaired relaxation in transgenic mice overexpressing triadin 1.</strong>
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J. Biol. Chem. 276: 4142-4149, 2001.
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[PubMed: 11069905]
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[Full Text: https://doi.org/10.1074/jbc.M006443200]
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O'Callaghan, B. M., Hancox, J. C., Stuart, A. G., Armstrong, C., Williams, M. M., Hills, A., Pearce, H., Dent, C. L., Gable, M., Walsh, M. A.
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<strong>A unique triadin exon deletion causing a null phenotype.</strong>
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HeartRhythm Case Rep. 4: 514-518, 2018.
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[PubMed: 30479949]
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[Full Text: https://doi.org/10.1016/j.hrcr.2018.07.014]
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<p class="mim-text-font">
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Oddoux, S., Brocard, J., Schweitzer, A., Szentesi, P., Giannesini, B., Brocard, J., Faure, J., Pernet-Gallay, K., Bendahan, D., Lunardi, J., Csernoch, L., Marty, I.
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<strong>Triadin deletion induces impaired skeletal muscle function.</strong>
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J. Biol. Chem. 284: 34918-34929, 2009.
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[PubMed: 19843516]
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[Full Text: https://doi.org/10.1074/jbc.M109.022442]
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Rooryck, C., Kyndt, F., Bozon, D., Roux-Buisson, N., Sacher, F., Probst, V., Thambo, J.-B.
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<strong>New family with catecholaminergic polymorphic ventricular tachycardia linked to the triadin gene.</strong>
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J. Cardiovasc. Electrophysiol. 26: 1146-1150, 2015.
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[PubMed: 26200674]
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[Full Text: https://doi.org/10.1111/jce.12763]
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Rossi, D., Gigli, L., Gamberucci, A., Bordoni, R., Pietrelli, A., Lorenzini, S., Pierantozzi, E., Peretto, G., De Bellis, G., Della Bella, P., Ferrari, M., Sorrentino, V., Benedetti, S., Sala, S., Di Resta, C.
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<strong>A novel homozygous mutation in the TRDN gene causes a severe form of pediatric malignant ventricular arrhythmia.</strong>
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Heart Rhythm 17: 296-304, 2020.
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[PubMed: 31437535]
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[Full Text: https://doi.org/10.1016/j.hrthm.2019.08.018]
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Roux-Buisson, N., Cacheux, M., Fourest-Lieuvin, A., Fauconnier, J., Brocard, J., Denjoy, I., Durand, P., Guicheney, P., Kyndt, F., Leenhardt, A., Le Marec, H., Lucet, V., and 10 others.
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<strong>Absence of triadin, a protein of the calcium release complex, is responsible for cardiac arrhythmia with sudden death in human.</strong>
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Hum. Molec. Genet. 21: 2759-2767, 2012.
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[PubMed: 22422768]
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[Full Text: https://doi.org/10.1093/hmg/dds104]
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</p>
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<p class="mim-text-font">
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Shen, X., Franzini-Armstrong, C., Lopez, J. R., Jones, L. R., Kobayashi, Y. M., Wang, Y., Kerrick, W. G. L., Caswell, A. H., Potter, J. D., Miller, T., Allen, P. D., Perez, C. F.
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<strong>Triadins modulate intracellular Ca2+ homeostasis but are not essential for excitation-contraction coupling in skeletal muscle.</strong>
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J. Biol. Chem. 282: 37864-37874, 2007.
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[PubMed: 17981799]
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[Full Text: https://doi.org/10.1074/jbc.M705702200]
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Taske, N. L., Eyre, H. J., O'Brien, R. O., Sutherland, G. R., Denborough, M. A., Foster, P. S.
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<strong>Molecular cloning of the cDNA encoding human skeletal muscle triadin and its localisation to chromosome 6q22-6q23.</strong>
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Europ. J. Biochem. 233: 258-265, 1995.
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[PubMed: 7588753]
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[Full Text: https://doi.org/10.1111/j.1432-1033.1995.258_1.x]
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<p class="mim-text-font">
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Thevenon, D., Smida-Rezgui, S., Chevessier, F., Groh, S., Henry-Berger, J., Romero, N. B., Villaz, M., DeWaard, M., Marty, I.
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<strong>Human skeletal muscle triadin: gene organization and cloning of the major isoform, Trisk 51.</strong>
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Biochem. Biophys. Res. Commun. 303: 669-675, 2003.
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[PubMed: 12659871]
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[Full Text: https://doi.org/10.1016/s0006-291x(03)00406-6]
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Walsh, M. A., Stuart, A. G., Schlecht, H. B., James, A. F., Hancox, J. C., Newbury-Ecob, R. A.
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<strong>Compound heterozygous triadin mutation causing cardiac arrest in two siblings.</strong>
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Pacing Clin. Electrophysiol. 39: 497-501, 2016.
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[PubMed: 26768964]
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[Full Text: https://doi.org/10.1111/pace.12813]
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Marla J. F. O'Neill - updated : 08/23/2021<br>Patricia A. Hartz - updated : 1/10/2014<br>Marla J. F. O'Neill - updated : 9/30/2013<br>Patricia A. Hartz - updated : 5/20/2003
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