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<title>
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Entry
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- *605267 - JUNCTOPHILIN 2; JPH2
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- OMIM
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<a href="/search/advanced/entry"> OMIM </a>
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<a href="/search/advanced/clinicalSynopsis"> Clinical Synopses </a>
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<div class="row">
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<p>
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<span class="h4">*605267</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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</li>
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<li role="presentation">
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<li role="presentation">
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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</li>
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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>
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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>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#animalModel">Animal Model</a>
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</li>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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</li>
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<li role="presentation" style="margin-left: 1em">
|
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<a href="/allelicVariants/605267">Table View</a>
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</li>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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</li>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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</li>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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</ul>
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</nav>
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</div>
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</div>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000149596;t=ENST00000372980" 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=57158" 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=605267" 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=ENSG00000149596;t=ENST00000372980" 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_020433,NM_175913,XM_006723833" 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_020433" 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=605267" 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=12006&isoform_id=12006_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/JPH2" 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/6453344,21704281,27805486,29893812,34783626,119596346,119596347,119596348,119596349,194389226,578836085,2462580982" 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/Q9BR39" 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=57158" 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=ENSG00000149596;t=ENST00000372980" 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=JPH2" 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=JPH2" 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+57158" 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/JPH2" 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:57158" 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/57158" 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=chr20&hgg_gene=ENST00000372980.4&hgg_start=44106590&hgg_end=44187188&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">
|
|
<span class="panel-title">
|
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<span class="small">
|
|
<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
|
<div style="display: table-row">
|
|
<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
|
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</a>
|
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</span>
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</span>
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</div>
|
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
|
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:14202" 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=605267[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=605267[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/ENSG00000149596" 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=JPH2" 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=JPH2" 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=JPH2" 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=JPH2&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/PA29999" 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">
|
|
<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">
|
|
<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:14202" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
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<div><a href="https://flybase.org/reports/FBgn0032129.html" class="mim-tip-hint" title="A Database of Drosophila Genes and Genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'FlyBase', 'domain': 'flybase.org'})">FlyBase</a></div>
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<div><a href="https://www.mousephenotype.org/data/genes/MGI:1891496" 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/JPH2#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:1891496" 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/57158/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=57158" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="https://wormbase.org/db/gene/gene?name=WBGene00002179;class=Gene" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name'{'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">Wormbase Gene</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-030131-9848" 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">
|
|
<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
|
|
<span class="panel-title">
|
|
<span class="small">
|
|
<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
|
<div style="display: table-row">
|
|
<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://reactome.org/content/query?q=JPH2&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>
|
|
<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>
|
|
<div class="text-right">
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</div>
|
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<div>
|
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<span class="h3">
|
|
<span class="mim-font mim-tip-hint" title="Gene description">
|
|
<span class="text-danger"><strong>*</strong></span>
|
|
605267
|
|
</span>
|
|
</span>
|
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</div>
|
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</div>
|
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<div>
|
|
<a id="preferredTitle" class="mim-anchor"></a>
|
|
<h3>
|
|
<span class="mim-font">
|
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|
|
JUNCTOPHILIN 2; JPH2
|
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</span>
|
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</h3>
|
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</div>
|
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<div>
|
|
<br />
|
|
</div>
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<div>
|
|
<a id="alternativeTitles" class="mim-anchor"></a>
|
|
<div>
|
|
<p>
|
|
<span class="mim-font">
|
|
<em>Alternative titles; symbols</em>
|
|
</span>
|
|
</p>
|
|
</div>
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
JP2
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
</div>
|
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<div>
|
|
<br />
|
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</div>
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</div>
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<div>
|
|
<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
|
<p>
|
|
<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=JPH2" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">JPH2</a></em></strong>
|
|
</span>
|
|
</p>
|
|
</div>
|
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|
|
<div>
|
|
<a id="cytogeneticLocation" class="mim-anchor"></a>
|
|
<p>
|
|
<span class="mim-text-font">
|
|
<strong>
|
|
<em>
|
|
Cytogenetic location: <a href="/geneMap/20/309?start=-3&limit=10&highlight=309">20q13.12</a>
|
|
|
|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr20:44106590-44187188&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'})">20:44,106,590-44,187,188</a> </span>
|
|
</em>
|
|
</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
|
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|
|
|
|
|
|
</span>
|
|
</p>
|
|
</div>
|
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<div>
|
|
<br />
|
|
</div>
|
|
<div>
|
|
<a id="geneMap" class="mim-anchor"></a>
|
|
<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
|
<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
|
|
<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=619492,613873" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
|
</a>
|
|
</span>
|
|
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="2">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/20/309?start=-3&limit=10&highlight=309">
|
|
20q13.12
|
|
</a>
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
Cardiomyopathy, dilated, 2E
|
|
|
|
</span>
|
|
</td>
|
|
<td>
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<p>Junctional complexes between the plasma membrane (PM) and endoplasmic/sarcoplasmic reticulum (ER/SR) are a common feature of all excitable cell types and mediate cross talk between cell surface and intracellular ion channels. <a href="#11" class="mim-tip-reference" title="Takeshima, H., Komazaki, S., Nishi, M., Iino, M., Kangawa, K. <strong>Junctophilins: a novel family of junctional membrane complex proteins.</strong> Molec. Cell 6: 11-22, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10949023/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10949023</a>] [<a href="https://doi.org/10.1016/s1097-2765(00)00003-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10949023">Takeshima et al. (2000)</a> identified the junctophilins (JPs), a conserved family of proteins that are components of the junctional complexes. JPs are composed of a C-terminal hydrophobic segment spanning the ER/SR membrane and a remaining cytoplasmic domain that shows specific affinity for the PM. In mouse, there are at least 3 JP subtypes: Jp1, Jp2, and Jp3. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10949023" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 screening genomic DNA libraries, <a href="#9" class="mim-tip-reference" title="Nishi, M., Mizushima, A., Nakagawara, K., Takeshima, H. <strong>Characterization of human junctophilin subtype genes.</strong> Biochem. Biophys. Res. Commun. 273: 920-927, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10891348/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10891348</a>] [<a href="https://doi.org/10.1006/bbrc.2000.3011" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10891348">Nishi et al. (2000)</a> isolated the human JP1 (JPH1; <a href="/entry/605266">605266</a>) and JP2 genes, and by screening a brain cDNA library, they isolated a cDNA encoding human JP3 (JPH3; <a href="/entry/605268">605268</a>). The JP2 gene encodes a deduced 696-amino acid protein. The human JPs share an overall sequence identity of 39%, and they share characteristic structural features with their rabbit and mouse counterparts. RNA blot hybridization indicated that the tissue-specific expression patterns of the JP genes in human are essentially the same as those in mouse; JP1 was expressed as a 4.5-kb transcript in skeletal muscle and at low levels in heart, JP2 was expressed as a 4.1-kb transcript in heart and skeletal muscle, and JP3 was expressed as a 4.6-kb transcript in brain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10891348" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using immunoblot analysis, <a href="#3" class="mim-tip-reference" title="Ito, K., Komazaki, S., Sasamoto, K., Yoshida, M., Nishi, M., Kitamura, K., Takeshima, H. <strong>Deficiency of triad junction and contraction in mutant skeletal muscle lacking junctophilin type 1.</strong> J. Cell Biol. 154: 1059-1067, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11535622/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11535622</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11535622[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/10.1083/jcb.200105040" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11535622">Ito et al. (2001)</a> showed that Jp1 was specifically expressed in skeletal muscle in mice, whereas Jp2 was expressed in both skeletal and cardiac muscle. Analysis of mouse hindlimb muscle showed that expression levels of both Jp1 and Jp2 increased significantly during muscle maturation. Histochemical analysis demonstrated that Jp1 and Jp2 colocalized in the triad junction of skeletal muscle. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11535622" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using gradient and Western blot analyses, <a href="#8" class="mim-tip-reference" title="Minamisawa, S., Oshikawa, J., Takeshima, H., Hoshijima, M., Wang, Y., Chien, K. R., Ishikawa, Y., Matsuoka, R. <strong>Junctophilin type 2 is associated with caveolin-3 and is down-regulated in the hypertrophic and dilated cardiomyopathies.</strong> Biochem. Biophys. Res. Commun. 325: 852-856, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15541368/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15541368</a>] [<a href="https://doi.org/10.1016/j.bbrc.2004.10.107" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15541368">Minamisawa et al. (2004)</a> showed that mouse Jp2 localized to low-density membrane fractions in mouse ventricular myocytes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15541368" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#7" class="mim-tip-reference" title="Matsushita, Y., Furukawa, T., Kasanuki, H., Nishibatake, M., Kurihara, Y., Ikeda, A., Kamatani, N., Takeshima, H., Matsuoka, R. <strong>Mutation of junctophilin type 2 associated with hypertrophic cardiomyopathy.</strong> J. Hum. Genet. 52: 543-548, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17476457/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17476457</a>] [<a href="https://doi.org/10.1007/s10038-007-0149-y" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17476457">Matsushita et al. (2007)</a> noted that the JPH2 protein is composed of 6 predicted domains: MORN (membrane occupation and recognition nexus) motif region I (MORN1), joining region, MORN2 motif, putative alpha-helical region, divergent region, and membrane-spanning region. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17476457" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#9" class="mim-tip-reference" title="Nishi, M., Mizushima, A., Nakagawara, K., Takeshima, H. <strong>Characterization of human junctophilin subtype genes.</strong> Biochem. Biophys. Res. Commun. 273: 920-927, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10891348/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10891348</a>] [<a href="https://doi.org/10.1006/bbrc.2000.3011" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10891348">Nishi et al. (2000)</a> determined that the JPH2 gene contains 5 exons, similar to JPH1 and JPH3. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10891348" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>By FISH, <a href="#9" class="mim-tip-reference" title="Nishi, M., Mizushima, A., Nakagawara, K., Takeshima, H. <strong>Characterization of human junctophilin subtype genes.</strong> Biochem. Biophys. Res. Commun. 273: 920-927, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10891348/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10891348</a>] [<a href="https://doi.org/10.1006/bbrc.2000.3011" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10891348">Nishi et al. (2000)</a> mapped the JPH2 gene to chromosome 20q12 and determined that the JPH genes do not cluster on the human genome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10891348" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Stumpf, A. M. <strong>Personal Communication.</strong> Baltimore, Md. 08/18/2021."None>Stumpf (2021)</a> mapped the JPH2 gene to chromosome 20q13.12 based on an alignment of the JPH2 sequence (GenBank <a href="https://www.ncbi.nlm.nih.gov/search/all/?term=BC172751" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'GENBANK\', \'domain\': \'ncbi.nlm.nih.gov\'})">BC172751</a>) with the genomic sequence (GRCh38).</p>
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<p><a href="#11" class="mim-tip-reference" title="Takeshima, H., Komazaki, S., Nishi, M., Iino, M., Kangawa, K. <strong>Junctophilins: a novel family of junctional membrane complex proteins.</strong> Molec. Cell 6: 11-22, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10949023/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10949023</a>] [<a href="https://doi.org/10.1016/s1097-2765(00)00003-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10949023">Takeshima et al. (2000)</a> showed that Jp2 is abundantly expressed in mouse heart, and mutant mice lacking Jp2 exhibited embryonic lethality. Cardiac myocytes from the mutant mice showed deficiency of the junctional membrane complexes and abnormal calcium transients. These results suggested that JPs are important components of junctional membrane complexes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10949023" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 immunoprecipitation and immunoblot analyses, <a href="#8" class="mim-tip-reference" title="Minamisawa, S., Oshikawa, J., Takeshima, H., Hoshijima, M., Wang, Y., Chien, K. R., Ishikawa, Y., Matsuoka, R. <strong>Junctophilin type 2 is associated with caveolin-3 and is down-regulated in the hypertrophic and dilated cardiomyopathies.</strong> Biochem. Biophys. Res. Commun. 325: 852-856, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15541368/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15541368</a>] [<a href="https://doi.org/10.1016/j.bbrc.2004.10.107" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15541368">Minamisawa et al. (2004)</a> showed that Jp2 interacted and colocalized with caveolin-3 (CAV3; <a href="/entry/601253">601253</a>) in membranes of mouse ventricular myocytes. Expression of Jp2 was upregulated during normal development but downregulated in mouse models of hypertrophic and dilated cardiomyopathy. The results suggested that expression levels of Jp2 are likely associated with normal development of junctional membrane complexes and impaired Ca(2+)-induced Ca(2+) release in heart. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15541368" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>After cardiac stress, JP2 is cleaved by the calcium ion-dependent protease calpain (see <a href="/entry/114220">114220</a>), which disrupts the excitation-contraction (E-C) coupling ultrastructural machinery and drives heart failure progression. <a href="#1" class="mim-tip-reference" title="Guo, A., Wang, Y., Chen, B., Wang, Y., Yuan, J., Zhang, L., Hall, D., Wu, J., Shi, Y., Zhu, Q., Chen, C., Thiel, W. H., and 11 others. <strong>E-C coupling structural protein junctophilin-2 encodes a stress-adaptive transcription regulator.</strong> Science 362: eaan3303, 2018. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30409805/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30409805</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30409805[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.aan3303" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30409805">Guo et al. (2018)</a> found that stress-induced proteolysis of JP2 liberates an N-terminal fragment (JP2NT) that translocates to the nucleus, binds to genomic DNA, and controls expression of a spectrum of genes in cardiomyocytes. Transgenic overexpression of JP2NT in mice modifies the transcriptional profile, resulting in attenuated pathologic remodeling in response to cardiac stress. Conversely, loss of nuclear JP2NT function accelerates stress-induced development of hypertrophy and heart failure in mutant mice. <a href="#1" class="mim-tip-reference" title="Guo, A., Wang, Y., Chen, B., Wang, Y., Yuan, J., Zhang, L., Hall, D., Wu, J., Shi, Y., Zhu, Q., Chen, C., Thiel, W. H., and 11 others. <strong>E-C coupling structural protein junctophilin-2 encodes a stress-adaptive transcription regulator.</strong> Science 362: eaan3303, 2018. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30409805/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30409805</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30409805[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.aan3303" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30409805">Guo et al. (2018)</a> concluded that their data revealed a self-protective mechanism in failing cardiomyocytes that transduce mechanical information (E-C uncoupling) into salutary transcriptional reprogramming in the stressed heart. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30409805" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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In 223 unrelated patients with hypertrophic cardiomyopathy (see CMH17, <a href="/entry/613873">613873</a>), who were negative for mutation in 8 myofilament-associated genes and 5 Z disc-associated genes, <a href="#5" class="mim-tip-reference" title="Landstrom, A. P., Weisleder, N., Batalden, K. B., Bos, J. M., Tester, D. J., Ommen, S. R., Wehrens, X. H. T., Claycomb, W. C., Ko, J.-K., Hwang, M., Pan, Z., Ma, J., Ackerman, M. J. <strong>Mutations in JPH2-encoded junctophilin-2 associated with hypertrophic cardiomyopathy in humans.</strong> J. Molec. Cell. Cardiol. 42: 1026-1035, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17509612/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17509612</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17509612[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.yjmcc.2007.04.006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17509612">Landstrom et al. (2007)</a> analyzed the candidate gene JPH2 and identified heterozygosity for 3 different missense mutations in 3 probands (<a href="#0001">605267.0001</a>-<a href="#0003">605267.0003</a>, respectively). Functional analysis demonstrated that the mutations caused protein reorganization of JPH2, perturbations in intracellular calcium signaling, and marked cardiomyocyte hyperplasia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17509612" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Dilated Cardiomyopathy 2E</em></strong></p><p>
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From a cohort of 66 patients with childhood-onset cardiomyopathy who presented to the single center in Finland performing cardiac transplantations, <a href="#13" class="mim-tip-reference" title="Vasilescu, C., Ojala, T. H., Brilhante, V., Ojanen, S., Hinterding, H. M., Palin, E., Alastalo, T.-P., Koskenvuo, J., Hiippala, A., Jokinen, E., Jahnukainen, T., Lohi, J., Pihkala, J., Tyni, T. A., Carroll, C. J., Suomalainen, A. <strong>Genetic basis of severe childhood-onset cardiomyopathies.</strong> J. Am. Coll. Cardiol. 72: 2324-2338, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30384889/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30384889</a>] [<a href="https://doi.org/10.1016/j.jacc.2018.08.2171" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30384889">Vasilescu et al. (2018)</a> identified a 22.5-year-old woman with dilated cardiomyopathy (CMD2E; <a href="/entry/619492">619492</a>) who was homozygous for a nonsense mutation in the JPH2 gene (Q428X; <a href="#0005">605267.0005</a>). The variant segregated fully with disease in the proband's family. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30384889" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>From a cohort of 823 clinical whole-exome sequencing (WES) referrals from Iran, <a href="#4" class="mim-tip-reference" title="Jones, E. G., Mazaheri, N., Maroofian, R., Zamani, M., Seifi, T., Sedaghat, A., Shariati, G., Jamshidi, Y., Allen, H. D., Wehrens, X. H. T., Galehdari, H., Landstrom, A. P. <strong>Analysis of enriched rare variants in JPH2-encoded junctophilin-2 among Greater Middle Eastern individuals reveals a novel homozygous variant associated with neonatal dilated cardiomyopathy.</strong> Sci. Rep. 9: 9038, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31227780/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31227780</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31227780[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/s41598-019-44987-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31227780">Jones et al. (2019)</a> identified 2 consanguineous families with neonatal dilated cardiomyopathy associated with death in early childhood, caused by the same 1-bp duplication in the JPH2 gene (<a href="#0006">605267.0006</a>). The mutation segregated with disease in both families, who shared an identical haplotype containing the JPH2 variant, indicating a founder effect. To characterize ethnicity-dependent genetic variability in the JPH2 gene, the authors analyzed the gnomAD, Greater Middle East (GME) Variome, and Iranome databases, compared to WES referral tests and a cohort of patients with hypertrophic cardiomyopathy (see <a href="/entry/192600">192600</a>). Worldwide, 1.45% of healthy individuals hosted a rare JPH2 variant, with a significantly higher proportion (4.45%) among GME individuals. Loss-of-function (LOF) variants were rare overall (0.04%) yet were most prevalent in GME individuals (0.21%), and this increased prevalence of LOF variants in GME individuals was corroborated in region-specific clinical WES cohorts. The authors concluded that there are ethnicity-specific differences in JPH2 rare variants, with GME individuals being at higher risk of homozygosity for LOF variants. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31227780" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>To circumvent embryonic lethality associated with germline Jph2 knockout in mice, <a href="#12" class="mim-tip-reference" title="van Oort, R. J., Garbino, A., Wang, W., Dixit, S. S., Landstrom, A. P., Gaur, N., De Almeida, A. C., Skapura, D. G., Rudy, Y., Burns, A. R., Ackerman, M. J., Wehrens, X. H. T. <strong>Disrupted junctional membrane complexes and hyperactive ryanodine receptors after acute junctophilin knockdown in mice.</strong> Circulation 123: 979-988, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21339484/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21339484</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21339484[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1161/CIRCULATIONAHA.110.006437" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21339484">van Oort et al. (2011)</a> used short hairpin RNA-mediated interference to generate mutant mice with conditionally reduced Jph2 protein levels. Cardiac-specific Jph2 knockdown resulted in impaired cardiac contractility, which caused heart failure and increased mortality. Jph2 deficiency resulted in loss of excitation-contraction coupling gain, precipitated by a reduction in the number of junctional membrane complexes and increased variability in the plasmalemma-sarcoplasmic reticulum distance. Noting that loss of Jph2 had profound effects on Ca(2+) release channel inactivation, the authors suggested a role for JPH2 in regulating intracellular Ca(2+) release channels in cardiac myocytes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21339484" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=605267[MIM]" class="btn btn-default mim-tip-hint" role="button" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1600482909 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1600482909;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=rs1600482909" 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=rs1600482909" 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 40-year-old man who was diagnosed at age 27 years with hypertrophic cardiomyopathy (CMH17; <a href="/entry/613873">613873</a>), <a href="#5" class="mim-tip-reference" title="Landstrom, A. P., Weisleder, N., Batalden, K. B., Bos, J. M., Tester, D. J., Ommen, S. R., Wehrens, X. H. T., Claycomb, W. C., Ko, J.-K., Hwang, M., Pan, Z., Ma, J., Ackerman, M. J. <strong>Mutations in JPH2-encoded junctophilin-2 associated with hypertrophic cardiomyopathy in humans.</strong> J. Molec. Cell. Cardiol. 42: 1026-1035, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17509612/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17509612</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17509612[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.yjmcc.2007.04.006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17509612">Landstrom et al. (2007)</a> identified heterozygosity for a mutation in exon 1 of the JPH2 gene, resulting in a ser101-to-arg (S101R) substitution in the conserved MORN motif. The mutation was not identified in 1,000 Caucasian reference alleles. Studies in transfected H9c2 cardiomyocytes showed an altered localization pattern with respect to the sarcoplasmic reticulum (SR). Analysis of transfected HL-1 cardiomyocytes indicated decreased spontaneous calcium release from the SR, suggesting that excitation-contraction process was disrupted in cells expressing S101R. The patient, who had dyspnea and had undergone placement of an implantable cardioverter-defibrillator, had a family history of CMH, with 3 first-degree affected relatives and 1 second-degree relative, all of whom declined to participate in the study. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17509612" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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> rs387906897 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906897;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/rs387906897?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=rs387906897" 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=rs387906897" 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 33-year-old man who was diagnosed at age 24 years with hypertrophic cardiomyopathy (CMH17; <a href="/entry/613873">613873</a>), <a href="#5" class="mim-tip-reference" title="Landstrom, A. P., Weisleder, N., Batalden, K. B., Bos, J. M., Tester, D. J., Ommen, S. R., Wehrens, X. H. T., Claycomb, W. C., Ko, J.-K., Hwang, M., Pan, Z., Ma, J., Ackerman, M. J. <strong>Mutations in JPH2-encoded junctophilin-2 associated with hypertrophic cardiomyopathy in humans.</strong> J. Molec. Cell. Cardiol. 42: 1026-1035, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17509612/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17509612</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17509612[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.yjmcc.2007.04.006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17509612">Landstrom et al. (2007)</a> identified heterozygosity for a mutation in exon 2 of the JPH2 gene, resulting in a tyr141-to-his (Y141H) substitution at a conserved residue. The mutation was not identified in 1,000 Caucasian reference alleles. Studies in transfected H9c2 cardiomyocytes showed an altered localization pattern with respect to the sarcoplasmic reticulum (SR) and significant hypertrophy (2- to 3-fold) compared to wildtype. Analysis of transfected HL-1 cardiomyocytes indicated decreased spontaneous calcium release from the SR, suggesting that excitation-contraction process was disrupted in cells expressing Y141H. At presentation, the patient had dyspnea, palpitations, angina, and a non-Q-wave myocardial infarction; he underwent placement of a pacemaker and an implantable cardioverter-defibrillator. There was no family history of CMH or sudden cardiac death. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17509612" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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">rs387906898 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906898;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=rs387906898" 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=rs387906898" 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 58-year-old female who was diagnosed at 30 years of age with hypertrophic cardiomyopathy (CMH17; <a href="/entry/613873">613873</a>), <a href="#5" class="mim-tip-reference" title="Landstrom, A. P., Weisleder, N., Batalden, K. B., Bos, J. M., Tester, D. J., Ommen, S. R., Wehrens, X. H. T., Claycomb, W. C., Ko, J.-K., Hwang, M., Pan, Z., Ma, J., Ackerman, M. J. <strong>Mutations in JPH2-encoded junctophilin-2 associated with hypertrophic cardiomyopathy in humans.</strong> J. Molec. Cell. Cardiol. 42: 1026-1035, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17509612/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17509612</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17509612[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.yjmcc.2007.04.006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17509612">Landstrom et al. (2007)</a> identified heterozygosity for a mutation in exon 2 of the JPH2 gene, resulting in a ser165-to-phe (S165F) substitution at a conserved residue. The mutation was not identified in 1,000 Caucasian reference alleles. Studies in transfected H9c2 cardiomyocytes showed an altered localization pattern with respect to the sarcoplasmic reticulum (SR) and significant hypertrophy (2- to 3-fold) compared to wildtype. Analysis of transfected HL-1 cardiomyocytes indicated decreased spontaneous calcium release from the SR, suggesting that excitation-contraction process was disrupted in cells expressing S165F. At presentation, the patient had dyspnea and subacute bacterial endocarditis; she underwent surgical myectomy. There was no family history of CMH or sudden cardiac death. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17509612" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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> rs140740776 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs140740776;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/rs140740776?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=rs140740776" 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=rs140740776" 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=RCV000023411 OR RCV000082005 OR RCV000205170 OR RCV000244391 OR RCV001719698" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000023411, RCV000082005, RCV000205170, RCV000244391, RCV001719698" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000023411...</a>
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<p>This variant, formerly titled CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC 17, has been reclassified based on the findings of <a href="#6" class="mim-tip-reference" title="Manrai, A. K., Funke, B. H., Rehm, H. L., Olesen, M. S., Maron, B. A., Szolovits, P., Margulies, D. M., Loscalzo, J., Kohane, I. S. <strong>Genetic misdiagnoses and the potential for health disparities.</strong> New Eng. J. Med. 375: 655-665, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27532831/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27532831</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27532831[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/10.1056/NEJMsa1507092" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27532831">Manrai et al. (2016)</a> and <a href="#2" class="mim-tip-reference" title="Hamosh, A. <strong>Personal Communication.</strong> Baltimore, Md. 09/20/2016."None>Hamosh (2016)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27532831" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#7" class="mim-tip-reference" title="Matsushita, Y., Furukawa, T., Kasanuki, H., Nishibatake, M., Kurihara, Y., Ikeda, A., Kamatani, N., Takeshima, H., Matsuoka, R. <strong>Mutation of junctophilin type 2 associated with hypertrophic cardiomyopathy.</strong> J. Hum. Genet. 52: 543-548, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17476457/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17476457</a>] [<a href="https://doi.org/10.1007/s10038-007-0149-y" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17476457">Matsushita et al. (2007)</a> analyzed the candidate gene JPH2 in 148 Japanese probands with CMH and 48 affected family members, as well as 32 patients with dilated cardiomyopathy (CMD; see <a href="/entry/115200">115200</a>) and 8 patients with restrictive cardiomyopathy (RCM; see <a href="/entry/115210">115210</a>). In 4 Japanese probands with hypertrophic cardiomyopathy (CMH17; <a href="/entry/613873">613873</a>), <a href="#7" class="mim-tip-reference" title="Matsushita, Y., Furukawa, T., Kasanuki, H., Nishibatake, M., Kurihara, Y., Ikeda, A., Kamatani, N., Takeshima, H., Matsuoka, R. <strong>Mutation of junctophilin type 2 associated with hypertrophic cardiomyopathy.</strong> J. Hum. Genet. 52: 543-548, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17476457/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17476457</a>] [<a href="https://doi.org/10.1007/s10038-007-0149-y" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17476457">Matsushita et al. (2007)</a> identified heterozygosity for a 1306C-T transition in exon 4 of the JPH2 gene, resulting in a gly505-to-ser (G505S) substitution in the divergent region. The G505S mutation was not found in CMD or RCM patients or in 236 Japanese controls. One of the patients, who was diagnosed with CMH at 14 years of age, had a mother who was diagnosed at 40 years of age and also carried the G505S mutation. His healthy father did not carry the mutation, and a younger sister who had died suddenly at 3 years of age could not be examined. Another proband, who was diagnosed with CMH at 33 years of age, had a family history of CMH involving her grandfather, father, and the father's sibs, who were not available for genetic analysis. Analysis of 15 known CMH-associated genes in the 4 probands carrying the G505S mutation in JPH2 revealed that the female proband also carried 2 missense mutations in the MYH7 gene (see, e.g., <a href="/entry/160760#0016">160760.0016</a>). Her newborn son, who had no signs of CMH on echocardiography at 1 day of age, carried both the JPH2 G505S mutation and 1 of the MYH7 mutations. <a href="#7" class="mim-tip-reference" title="Matsushita, Y., Furukawa, T., Kasanuki, H., Nishibatake, M., Kurihara, Y., Ikeda, A., Kamatani, N., Takeshima, H., Matsuoka, R. <strong>Mutation of junctophilin type 2 associated with hypertrophic cardiomyopathy.</strong> J. Hum. Genet. 52: 543-548, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17476457/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17476457</a>] [<a href="https://doi.org/10.1007/s10038-007-0149-y" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17476457">Matsushita et al. (2007)</a> suggested that mutations in both JPH2 and MYH7 could be associated with the pathogenesis of CMH in this proband. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17476457" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#6" class="mim-tip-reference" title="Manrai, A. K., Funke, B. H., Rehm, H. L., Olesen, M. S., Maron, B. A., Szolovits, P., Margulies, D. M., Loscalzo, J., Kohane, I. S. <strong>Genetic misdiagnoses and the potential for health disparities.</strong> New Eng. J. Med. 375: 655-665, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27532831/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27532831</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27532831[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/10.1056/NEJMsa1507092" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27532831">Manrai et al. (2016)</a> found that the G505S variant in JPH2 has an allele frequency of 0.8% in white Americans and 2.9% in black Americans in the NHLBI Exome Sequencing Project data set. <a href="#6" class="mim-tip-reference" title="Manrai, A. K., Funke, B. H., Rehm, H. L., Olesen, M. S., Maron, B. A., Szolovits, P., Margulies, D. M., Loscalzo, J., Kohane, I. S. <strong>Genetic misdiagnoses and the potential for health disparities.</strong> New Eng. J. Med. 375: 655-665, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27532831/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27532831</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27532831[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/10.1056/NEJMsa1507092" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27532831">Manrai et al. (2016)</a> classified this variant as benign based on its high frequency in control populations and on patient and functional data. <a href="#2" class="mim-tip-reference" title="Hamosh, A. <strong>Personal Communication.</strong> Baltimore, Md. 09/20/2016."None>Hamosh (2016)</a> observed that the G505S variant had an allele frequency of 7.3% in South Asians in the ExAC database on September 20, 2016. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27532831" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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> rs199896820 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs199896820;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/rs199896820?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=rs199896820" 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=rs199896820" 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=RCV000208272 OR RCV001572616 OR RCV002478749 OR RCV003298273" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000208272, RCV001572616, RCV002478749, RCV003298273" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000208272...</a>
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<p>In a 22.5-year-old Finnish woman (P10) who was diagnosed with dilated cardiomyopathy (CMD2E; <a href="/entry/619492">619492</a>) at 3 years of age and underwent cardiac transplantation at age 4, <a href="#13" class="mim-tip-reference" title="Vasilescu, C., Ojala, T. H., Brilhante, V., Ojanen, S., Hinterding, H. M., Palin, E., Alastalo, T.-P., Koskenvuo, J., Hiippala, A., Jokinen, E., Jahnukainen, T., Lohi, J., Pihkala, J., Tyni, T. A., Carroll, C. J., Suomalainen, A. <strong>Genetic basis of severe childhood-onset cardiomyopathies.</strong> J. Am. Coll. Cardiol. 72: 2324-2338, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30384889/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30384889</a>] [<a href="https://doi.org/10.1016/j.jacc.2018.08.2171" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30384889">Vasilescu et al. (2018)</a> identified homozygosity for a c.1282C-T transition in the JPH2 gene, resulting in a gln428-to-ter (Q428X) substitution. Her unaffected parents and 2 unaffected sibs were heterozygous for the mutation. Functional studies of the variant or of patient cells were not performed. The authors' criteria for causative recessive variants were a minor allele frequency of less than or equal to 0.01 in the ExAC, gnomAD, and SISu databases, and presence only in heterozygosity; the exact frequency for this variant was not published. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30384889" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 CARDIOMYOPATHY, DILATED, 2E</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">rs2145838034 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2145838034;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=rs2145838034" 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=rs2145838034" 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=RCV001572617" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001572617" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001572617</a>
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<p>In 2 consanguineous Iranian families with neonatal dilated cardiomyopathy (CMD2E; <a href="/entry/619492">619492</a>), <a href="#4" class="mim-tip-reference" title="Jones, E. G., Mazaheri, N., Maroofian, R., Zamani, M., Seifi, T., Sedaghat, A., Shariati, G., Jamshidi, Y., Allen, H. D., Wehrens, X. H. T., Galehdari, H., Landstrom, A. P. <strong>Analysis of enriched rare variants in JPH2-encoded junctophilin-2 among Greater Middle Eastern individuals reveals a novel homozygous variant associated with neonatal dilated cardiomyopathy.</strong> Sci. Rep. 9: 9038, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31227780/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31227780</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31227780[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/s41598-019-44987-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31227780">Jones et al. (2019)</a> identified homozygosity for a 1-bp duplication (c.1920dupT, NM_020433) in the JPH2 gene, predicted to cause a premature termination codon (glu641-to-ter; E641X) within the divergent region. The mutation segregated with disease in both families: in family 1, the proband was homozygous for the variant, which was present in heterozygosity in 11 unaffected relatives, including his first-cousin parents; in family 2, DNA was unavailable from the 2 deceased brothers, but their unaffected consanguineous parents were each heterozygous for the variant, as were 2 more unaffected relatives. The families were not known to be related, but both were of the Lor ethnic background from southwest Iran and they shared an identical haplotype containing the JPH2 variant, indicating a founder effect. Functional studies of the variant or of patient cells were not performed. The variant was absent from 299,100 reference alleles derived from healthy individuals. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31227780" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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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Guo, A., Wang, Y., Chen, B., Wang, Y., Yuan, J., Zhang, L., Hall, D., Wu, J., Shi, Y., Zhu, Q., Chen, C., Thiel, W. H., and 11 others.
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<strong>E-C coupling structural protein junctophilin-2 encodes a stress-adaptive transcription regulator.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30409805/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30409805</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30409805[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=30409805" 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/10.1126/science.aan3303" target="_blank">Full Text</a>]
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Hamosh, A.
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Ito, K., Komazaki, S., Sasamoto, K., Yoshida, M., Nishi, M., Kitamura, K., Takeshima, H.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11535622/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11535622</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11535622[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=11535622" 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/10.1083/jcb.200105040" target="_blank">Full Text</a>]
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<a id="Jones2019" class="mim-anchor"></a>
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Jones, E. G., Mazaheri, N., Maroofian, R., Zamani, M., Seifi, T., Sedaghat, A., Shariati, G., Jamshidi, Y., Allen, H. D., Wehrens, X. H. T., Galehdari, H., Landstrom, A. P.
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<strong>Analysis of enriched rare variants in JPH2-encoded junctophilin-2 among Greater Middle Eastern individuals reveals a novel homozygous variant associated with neonatal dilated cardiomyopathy.</strong>
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Sci. Rep. 9: 9038, 2019.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31227780/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31227780</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31227780[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=31227780" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/s41598-019-44987-6" target="_blank">Full Text</a>]
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<a id="Landstrom2007" class="mim-anchor"></a>
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Landstrom, A. P., Weisleder, N., Batalden, K. B., Bos, J. M., Tester, D. J., Ommen, S. R., Wehrens, X. H. T., Claycomb, W. C., Ko, J.-K., Hwang, M., Pan, Z., Ma, J., Ackerman, M. J.
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[<a href="https://doi.org/10.1016/j.yjmcc.2007.04.006" target="_blank">Full Text</a>]
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Manrai, A. K., Funke, B. H., Rehm, H. L., Olesen, M. S., Maron, B. A., Szolovits, P., Margulies, D. M., Loscalzo, J., Kohane, I. S.
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[<a href="https://doi.org/10.1056/NEJMsa1507092" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/s10038-007-0149-y" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/j.bbrc.2004.10.107" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1006/bbrc.2000.3011" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/s1097-2765(00)00003-4" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1161/CIRCULATIONAHA.110.006437" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30384889/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30384889</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30384889" 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.jacc.2018.08.2171" target="_blank">Full Text</a>]
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Bao Lige - updated : 11/04/2024
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<div class="row collapse" id="mimCollapseContributors">
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<span class="mim-text-font">
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Bao Lige - updated : 09/01/2021<br>Anne M. Stumpf - updated : 08/18/2021<br>Marla J. F. O'Neill - updated : 08/18/2021<br>Ada Hamosh - updated : 01/24/2019<br>Ada Hamosh - updated : 09/21/2016<br>Marla J. F. O'Neill - updated : 4/7/2011
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<a id="creationDate" 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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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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Stylianos E. Antonarakis : 9/14/2000
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</span>
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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mgross : 11/04/2024
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<span class="mim-text-font">
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mgross : 09/01/2021<br>carol : 08/27/2021<br>alopez : 08/18/2021<br>alopez : 08/18/2021<br>alopez : 08/18/2021<br>alopez : 03/16/2021<br>alopez : 01/24/2019<br>carol : 04/27/2018<br>alopez : 09/21/2016<br>alopez : 02/03/2012<br>wwang : 4/8/2011<br>terry : 4/7/2011<br>joanna : 12/8/2000<br>mgross : 9/14/2000
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<span class="mim-font">
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<strong>*</strong> 605267
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<h3>
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<span class="mim-font">
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JUNCTOPHILIN 2; JPH2
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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<span class="mim-font">
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JP2
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: JPH2</em></strong>
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<strong>
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<em>
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Cytogenetic location: 20q13.12
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Genomic coordinates <span class="small">(GRCh38)</span> : 20:44,106,590-44,187,188 </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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<span class="mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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<table class="table table-bordered table-condensed small mim-table-padding">
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Location
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Phenotype
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Phenotype <br /> MIM number
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Inheritance
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Phenotype <br /> mapping key
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<span class="mim-font">
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20q13.12
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<span class="mim-font">
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Cardiomyopathy, dilated, 2E
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<span class="mim-font">
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619492
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<span class="mim-font">
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Autosomal recessive
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<span class="mim-font">
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3
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Cardiomyopathy, hypertrophic, 17
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<span class="mim-font">
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613873
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<span class="mim-font">
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Autosomal dominant
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<span class="mim-font">
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3
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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
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</span>
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</h4>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Description</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Junctional complexes between the plasma membrane (PM) and endoplasmic/sarcoplasmic reticulum (ER/SR) are a common feature of all excitable cell types and mediate cross talk between cell surface and intracellular ion channels. Takeshima et al. (2000) identified the junctophilins (JPs), a conserved family of proteins that are components of the junctional complexes. JPs are composed of a C-terminal hydrophobic segment spanning the ER/SR membrane and a remaining cytoplasmic domain that shows specific affinity for the PM. In mouse, there are at least 3 JP subtypes: Jp1, Jp2, and Jp3. </p>
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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 class="mim-text-font">
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<p>By screening genomic DNA libraries, Nishi et al. (2000) isolated the human JP1 (JPH1; 605266) and JP2 genes, and by screening a brain cDNA library, they isolated a cDNA encoding human JP3 (JPH3; 605268). The JP2 gene encodes a deduced 696-amino acid protein. The human JPs share an overall sequence identity of 39%, and they share characteristic structural features with their rabbit and mouse counterparts. RNA blot hybridization indicated that the tissue-specific expression patterns of the JP genes in human are essentially the same as those in mouse; JP1 was expressed as a 4.5-kb transcript in skeletal muscle and at low levels in heart, JP2 was expressed as a 4.1-kb transcript in heart and skeletal muscle, and JP3 was expressed as a 4.6-kb transcript in brain. </p><p>Using immunoblot analysis, Ito et al. (2001) showed that Jp1 was specifically expressed in skeletal muscle in mice, whereas Jp2 was expressed in both skeletal and cardiac muscle. Analysis of mouse hindlimb muscle showed that expression levels of both Jp1 and Jp2 increased significantly during muscle maturation. Histochemical analysis demonstrated that Jp1 and Jp2 colocalized in the triad junction of skeletal muscle. </p><p>Using gradient and Western blot analyses, Minamisawa et al. (2004) showed that mouse Jp2 localized to low-density membrane fractions in mouse ventricular myocytes. </p><p>Matsushita et al. (2007) noted that the JPH2 protein is composed of 6 predicted domains: MORN (membrane occupation and recognition nexus) motif region I (MORN1), joining region, MORN2 motif, putative alpha-helical region, divergent region, and membrane-spanning region. </p>
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</span>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Structure</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Nishi et al. (2000) determined that the JPH2 gene contains 5 exons, similar to JPH1 and JPH3. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Mapping</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>By FISH, Nishi et al. (2000) mapped the JPH2 gene to chromosome 20q12 and determined that the JPH genes do not cluster on the human genome. </p><p>Stumpf (2021) mapped the JPH2 gene to chromosome 20q13.12 based on an alignment of the JPH2 sequence (GenBank BC172751) with the genomic sequence (GRCh38).</p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Function</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Takeshima et al. (2000) showed that Jp2 is abundantly expressed in mouse heart, and mutant mice lacking Jp2 exhibited embryonic lethality. Cardiac myocytes from the mutant mice showed deficiency of the junctional membrane complexes and abnormal calcium transients. These results suggested that JPs are important components of junctional membrane complexes. </p><p>By immunoprecipitation and immunoblot analyses, Minamisawa et al. (2004) showed that Jp2 interacted and colocalized with caveolin-3 (CAV3; 601253) in membranes of mouse ventricular myocytes. Expression of Jp2 was upregulated during normal development but downregulated in mouse models of hypertrophic and dilated cardiomyopathy. The results suggested that expression levels of Jp2 are likely associated with normal development of junctional membrane complexes and impaired Ca(2+)-induced Ca(2+) release in heart. </p><p>After cardiac stress, JP2 is cleaved by the calcium ion-dependent protease calpain (see 114220), which disrupts the excitation-contraction (E-C) coupling ultrastructural machinery and drives heart failure progression. Guo et al. (2018) found that stress-induced proteolysis of JP2 liberates an N-terminal fragment (JP2NT) that translocates to the nucleus, binds to genomic DNA, and controls expression of a spectrum of genes in cardiomyocytes. Transgenic overexpression of JP2NT in mice modifies the transcriptional profile, resulting in attenuated pathologic remodeling in response to cardiac stress. Conversely, loss of nuclear JP2NT function accelerates stress-induced development of hypertrophy and heart failure in mutant mice. Guo et al. (2018) concluded that their data revealed a self-protective mechanism in failing cardiomyocytes that transduce mechanical information (E-C uncoupling) into salutary transcriptional reprogramming in the stressed heart. </p>
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</span>
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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>Molecular Genetics</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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<p><strong><em>Hypertrophic Cardiomyopathy 17</em></strong></p><p>
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In 223 unrelated patients with hypertrophic cardiomyopathy (see CMH17, 613873), who were negative for mutation in 8 myofilament-associated genes and 5 Z disc-associated genes, Landstrom et al. (2007) analyzed the candidate gene JPH2 and identified heterozygosity for 3 different missense mutations in 3 probands (605267.0001-605267.0003, respectively). Functional analysis demonstrated that the mutations caused protein reorganization of JPH2, perturbations in intracellular calcium signaling, and marked cardiomyocyte hyperplasia. </p><p><strong><em>Dilated Cardiomyopathy 2E</em></strong></p><p>
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|
From a cohort of 66 patients with childhood-onset cardiomyopathy who presented to the single center in Finland performing cardiac transplantations, Vasilescu et al. (2018) identified a 22.5-year-old woman with dilated cardiomyopathy (CMD2E; 619492) who was homozygous for a nonsense mutation in the JPH2 gene (Q428X; 605267.0005). The variant segregated fully with disease in the proband's family. </p><p>From a cohort of 823 clinical whole-exome sequencing (WES) referrals from Iran, Jones et al. (2019) identified 2 consanguineous families with neonatal dilated cardiomyopathy associated with death in early childhood, caused by the same 1-bp duplication in the JPH2 gene (605267.0006). The mutation segregated with disease in both families, who shared an identical haplotype containing the JPH2 variant, indicating a founder effect. To characterize ethnicity-dependent genetic variability in the JPH2 gene, the authors analyzed the gnomAD, Greater Middle East (GME) Variome, and Iranome databases, compared to WES referral tests and a cohort of patients with hypertrophic cardiomyopathy (see 192600). Worldwide, 1.45% of healthy individuals hosted a rare JPH2 variant, with a significantly higher proportion (4.45%) among GME individuals. Loss-of-function (LOF) variants were rare overall (0.04%) yet were most prevalent in GME individuals (0.21%), and this increased prevalence of LOF variants in GME individuals was corroborated in region-specific clinical WES cohorts. The authors concluded that there are ethnicity-specific differences in JPH2 rare variants, with GME individuals being at higher risk of homozygosity for LOF variants. </p>
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</span>
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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>To circumvent embryonic lethality associated with germline Jph2 knockout in mice, van Oort et al. (2011) used short hairpin RNA-mediated interference to generate mutant mice with conditionally reduced Jph2 protein levels. Cardiac-specific Jph2 knockdown resulted in impaired cardiac contractility, which caused heart failure and increased mortality. Jph2 deficiency resulted in loss of excitation-contraction coupling gain, precipitated by a reduction in the number of junctional membrane complexes and increased variability in the plasmalemma-sarcoplasmic reticulum distance. Noting that loss of Jph2 had profound effects on Ca(2+) release channel inactivation, the authors suggested a role for JPH2 in regulating intracellular Ca(2+) release channels in cardiac myocytes. </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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<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>6 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 CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC 17</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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JPH2, SER101ARG
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<br />
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SNP: rs1600482909,
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ClinVar: RCV000023408
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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 40-year-old man who was diagnosed at age 27 years with hypertrophic cardiomyopathy (CMH17; 613873), Landstrom et al. (2007) identified heterozygosity for a mutation in exon 1 of the JPH2 gene, resulting in a ser101-to-arg (S101R) substitution in the conserved MORN motif. The mutation was not identified in 1,000 Caucasian reference alleles. Studies in transfected H9c2 cardiomyocytes showed an altered localization pattern with respect to the sarcoplasmic reticulum (SR). Analysis of transfected HL-1 cardiomyocytes indicated decreased spontaneous calcium release from the SR, suggesting that excitation-contraction process was disrupted in cells expressing S101R. The patient, who had dyspnea and had undergone placement of an implantable cardioverter-defibrillator, had a family history of CMH, with 3 first-degree affected relatives and 1 second-degree relative, all of whom declined to participate in the study. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0002 CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC 17</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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JPH2, TYR141HIS
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<br />
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SNP: rs387906897,
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gnomAD: rs387906897,
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ClinVar: RCV000023409, RCV001256951, RCV001781303, RCV002326683
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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 33-year-old man who was diagnosed at age 24 years with hypertrophic cardiomyopathy (CMH17; 613873), Landstrom et al. (2007) identified heterozygosity for a mutation in exon 2 of the JPH2 gene, resulting in a tyr141-to-his (Y141H) substitution at a conserved residue. The mutation was not identified in 1,000 Caucasian reference alleles. Studies in transfected H9c2 cardiomyocytes showed an altered localization pattern with respect to the sarcoplasmic reticulum (SR) and significant hypertrophy (2- to 3-fold) compared to wildtype. Analysis of transfected HL-1 cardiomyocytes indicated decreased spontaneous calcium release from the SR, suggesting that excitation-contraction process was disrupted in cells expressing Y141H. At presentation, the patient had dyspnea, palpitations, angina, and a non-Q-wave myocardial infarction; he underwent placement of a pacemaker and an implantable cardioverter-defibrillator. There was no family history of CMH or sudden cardiac death. </p>
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</span>
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</div>
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<div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0003 CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC 17</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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JPH2, SER165PHE
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<br />
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SNP: rs387906898,
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ClinVar: RCV000023410
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</span>
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<div>
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<span class="mim-text-font">
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<p>In a 58-year-old female who was diagnosed at 30 years of age with hypertrophic cardiomyopathy (CMH17; 613873), Landstrom et al. (2007) identified heterozygosity for a mutation in exon 2 of the JPH2 gene, resulting in a ser165-to-phe (S165F) substitution at a conserved residue. The mutation was not identified in 1,000 Caucasian reference alleles. Studies in transfected H9c2 cardiomyocytes showed an altered localization pattern with respect to the sarcoplasmic reticulum (SR) and significant hypertrophy (2- to 3-fold) compared to wildtype. Analysis of transfected HL-1 cardiomyocytes indicated decreased spontaneous calcium release from the SR, suggesting that excitation-contraction process was disrupted in cells expressing S165F. At presentation, the patient had dyspnea and subacute bacterial endocarditis; she underwent surgical myectomy. There was no family history of CMH or sudden cardiac death. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0004 RECLASSIFIED - VARIANT OF UNKNOWN SIGNIFICANCE</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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JPH2, GLY505SER
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<br />
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SNP: rs140740776,
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gnomAD: rs140740776,
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ClinVar: RCV000023411, RCV000082005, RCV000205170, RCV000244391, RCV001719698
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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>This variant, formerly titled CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC 17, has been reclassified based on the findings of Manrai et al. (2016) and Hamosh (2016). </p><p>Matsushita et al. (2007) analyzed the candidate gene JPH2 in 148 Japanese probands with CMH and 48 affected family members, as well as 32 patients with dilated cardiomyopathy (CMD; see 115200) and 8 patients with restrictive cardiomyopathy (RCM; see 115210). In 4 Japanese probands with hypertrophic cardiomyopathy (CMH17; 613873), Matsushita et al. (2007) identified heterozygosity for a 1306C-T transition in exon 4 of the JPH2 gene, resulting in a gly505-to-ser (G505S) substitution in the divergent region. The G505S mutation was not found in CMD or RCM patients or in 236 Japanese controls. One of the patients, who was diagnosed with CMH at 14 years of age, had a mother who was diagnosed at 40 years of age and also carried the G505S mutation. His healthy father did not carry the mutation, and a younger sister who had died suddenly at 3 years of age could not be examined. Another proband, who was diagnosed with CMH at 33 years of age, had a family history of CMH involving her grandfather, father, and the father's sibs, who were not available for genetic analysis. Analysis of 15 known CMH-associated genes in the 4 probands carrying the G505S mutation in JPH2 revealed that the female proband also carried 2 missense mutations in the MYH7 gene (see, e.g., 160760.0016). Her newborn son, who had no signs of CMH on echocardiography at 1 day of age, carried both the JPH2 G505S mutation and 1 of the MYH7 mutations. Matsushita et al. (2007) suggested that mutations in both JPH2 and MYH7 could be associated with the pathogenesis of CMH in this proband. </p><p>Manrai et al. (2016) found that the G505S variant in JPH2 has an allele frequency of 0.8% in white Americans and 2.9% in black Americans in the NHLBI Exome Sequencing Project data set. Manrai et al. (2016) classified this variant as benign based on its high frequency in control populations and on patient and functional data. Hamosh (2016) observed that the G505S variant had an allele frequency of 7.3% in South Asians in the ExAC database on September 20, 2016. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0005 CARDIOMYOPATHY, DILATED, 2E</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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JPH2, GLN428TER
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<br />
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SNP: rs199896820,
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gnomAD: rs199896820,
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ClinVar: RCV000208272, RCV001572616, RCV002478749, RCV003298273
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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 22.5-year-old Finnish woman (P10) who was diagnosed with dilated cardiomyopathy (CMD2E; 619492) at 3 years of age and underwent cardiac transplantation at age 4, Vasilescu et al. (2018) identified homozygosity for a c.1282C-T transition in the JPH2 gene, resulting in a gln428-to-ter (Q428X) substitution. Her unaffected parents and 2 unaffected sibs were heterozygous for the mutation. Functional studies of the variant or of patient cells were not performed. The authors' criteria for causative recessive variants were a minor allele frequency of less than or equal to 0.01 in the ExAC, gnomAD, and SISu databases, and presence only in heterozygosity; the exact frequency for this variant was not published. </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 CARDIOMYOPATHY, DILATED, 2E</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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JPH2, 1-BP DUP, 1920T
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<br />
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SNP: rs2145838034,
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ClinVar: RCV001572617
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In 2 consanguineous Iranian families with neonatal dilated cardiomyopathy (CMD2E; 619492), Jones et al. (2019) identified homozygosity for a 1-bp duplication (c.1920dupT, NM_020433) in the JPH2 gene, predicted to cause a premature termination codon (glu641-to-ter; E641X) within the divergent region. The mutation segregated with disease in both families: in family 1, the proband was homozygous for the variant, which was present in heterozygosity in 11 unaffected relatives, including his first-cousin parents; in family 2, DNA was unavailable from the 2 deceased brothers, but their unaffected consanguineous parents were each heterozygous for the variant, as were 2 more unaffected relatives. The families were not known to be related, but both were of the Lor ethnic background from southwest Iran and they shared an identical haplotype containing the JPH2 variant, indicating a founder effect. Functional studies of the variant or of patient cells were not performed. The variant was absent from 299,100 reference alleles derived from healthy individuals. </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>REFERENCES</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<ol>
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<li>
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<p class="mim-text-font">
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Guo, A., Wang, Y., Chen, B., Wang, Y., Yuan, J., Zhang, L., Hall, D., Wu, J., Shi, Y., Zhu, Q., Chen, C., Thiel, W. H., and 11 others.
|
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<strong>E-C coupling structural protein junctophilin-2 encodes a stress-adaptive transcription regulator.</strong>
|
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Science 362: eaan3303, 2018. Note: Electronic Article.
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[PubMed: 30409805]
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[Full Text: https://doi.org/10.1126/science.aan3303]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Hamosh, A.
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<strong>Personal Communication.</strong>
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Baltimore, Md. 09/20/2016.
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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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Ito, K., Komazaki, S., Sasamoto, K., Yoshida, M., Nishi, M., Kitamura, K., Takeshima, H.
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<strong>Deficiency of triad junction and contraction in mutant skeletal muscle lacking junctophilin type 1.</strong>
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J. Cell Biol. 154: 1059-1067, 2001.
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[PubMed: 11535622]
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[Full Text: https://doi.org/10.1083/jcb.200105040]
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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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Jones, E. G., Mazaheri, N., Maroofian, R., Zamani, M., Seifi, T., Sedaghat, A., Shariati, G., Jamshidi, Y., Allen, H. D., Wehrens, X. H. T., Galehdari, H., Landstrom, A. P.
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|
<strong>Analysis of enriched rare variants in JPH2-encoded junctophilin-2 among Greater Middle Eastern individuals reveals a novel homozygous variant associated with neonatal dilated cardiomyopathy.</strong>
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Sci. Rep. 9: 9038, 2019.
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[PubMed: 31227780]
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[Full Text: https://doi.org/10.1038/s41598-019-44987-6]
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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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Landstrom, A. P., Weisleder, N., Batalden, K. B., Bos, J. M., Tester, D. J., Ommen, S. R., Wehrens, X. H. T., Claycomb, W. C., Ko, J.-K., Hwang, M., Pan, Z., Ma, J., Ackerman, M. J.
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<strong>Mutations in JPH2-encoded junctophilin-2 associated with hypertrophic cardiomyopathy in humans.</strong>
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J. Molec. Cell. Cardiol. 42: 1026-1035, 2007.
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[PubMed: 17509612]
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[Full Text: https://doi.org/10.1016/j.yjmcc.2007.04.006]
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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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Manrai, A. K., Funke, B. H., Rehm, H. L., Olesen, M. S., Maron, B. A., Szolovits, P., Margulies, D. M., Loscalzo, J., Kohane, I. S.
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<strong>Genetic misdiagnoses and the potential for health disparities.</strong>
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New Eng. J. Med. 375: 655-665, 2016.
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[PubMed: 27532831]
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[Full Text: https://doi.org/10.1056/NEJMsa1507092]
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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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Matsushita, Y., Furukawa, T., Kasanuki, H., Nishibatake, M., Kurihara, Y., Ikeda, A., Kamatani, N., Takeshima, H., Matsuoka, R.
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<strong>Mutation of junctophilin type 2 associated with hypertrophic cardiomyopathy.</strong>
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J. Hum. Genet. 52: 543-548, 2007.
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[PubMed: 17476457]
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[Full Text: https://doi.org/10.1007/s10038-007-0149-y]
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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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Minamisawa, S., Oshikawa, J., Takeshima, H., Hoshijima, M., Wang, Y., Chien, K. R., Ishikawa, Y., Matsuoka, R.
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<strong>Junctophilin type 2 is associated with caveolin-3 and is down-regulated in the hypertrophic and dilated cardiomyopathies.</strong>
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Biochem. Biophys. Res. Commun. 325: 852-856, 2004.
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[PubMed: 15541368]
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[Full Text: https://doi.org/10.1016/j.bbrc.2004.10.107]
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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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Nishi, M., Mizushima, A., Nakagawara, K., Takeshima, H.
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<strong>Characterization of human junctophilin subtype genes.</strong>
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Biochem. Biophys. Res. Commun. 273: 920-927, 2000.
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[PubMed: 10891348]
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[Full Text: https://doi.org/10.1006/bbrc.2000.3011]
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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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Stumpf, A. M.
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<strong>Personal Communication.</strong>
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Baltimore, Md. 08/18/2021.
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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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Takeshima, H., Komazaki, S., Nishi, M., Iino, M., Kangawa, K.
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<strong>Junctophilins: a novel family of junctional membrane complex proteins.</strong>
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Molec. Cell 6: 11-22, 2000.
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[PubMed: 10949023]
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[Full Text: https://doi.org/10.1016/s1097-2765(00)00003-4]
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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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van Oort, R. J., Garbino, A., Wang, W., Dixit, S. S., Landstrom, A. P., Gaur, N., De Almeida, A. C., Skapura, D. G., Rudy, Y., Burns, A. R., Ackerman, M. J., Wehrens, X. H. T.
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<strong>Disrupted junctional membrane complexes and hyperactive ryanodine receptors after acute junctophilin knockdown in mice.</strong>
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Circulation 123: 979-988, 2011.
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[PubMed: 21339484]
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[Full Text: https://doi.org/10.1161/CIRCULATIONAHA.110.006437]
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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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Vasilescu, C., Ojala, T. H., Brilhante, V., Ojanen, S., Hinterding, H. M., Palin, E., Alastalo, T.-P., Koskenvuo, J., Hiippala, A., Jokinen, E., Jahnukainen, T., Lohi, J., Pihkala, J., Tyni, T. A., Carroll, C. J., Suomalainen, A.
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<strong>Genetic basis of severe childhood-onset cardiomyopathies.</strong>
|
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J. Am. Coll. Cardiol. 72: 2324-2338, 2018.
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[PubMed: 30384889]
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[Full Text: https://doi.org/10.1016/j.jacc.2018.08.2171]
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</li>
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<div>
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<div class="col-lg-1 col-md-1 col-sm-2 col-xs-2">
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<span class="text-nowrap mim-text-font">
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Contributors:
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</span>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Bao Lige - updated : 11/04/2024<br>Bao Lige - updated : 09/01/2021<br>Anne M. Stumpf - updated : 08/18/2021<br>Marla J. F. O'Neill - updated : 08/18/2021<br>Ada Hamosh - updated : 01/24/2019<br>Ada Hamosh - updated : 09/21/2016<br>Marla J. F. O'Neill - updated : 4/7/2011
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Creation Date:
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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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Stylianos E. Antonarakis : 9/14/2000
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