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<title>
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Entry
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- *603883 - BAG COCHAPERONE 3; BAG3
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- OMIM
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<input type="hidden" id="mimSearchIndex" name="index" value="entry" />
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<input type="hidden" id="mimSearchLimit" name="limit" value="10" />
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Advanced Search
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<a href="/search/advanced/entry"> OMIM </a>
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<a href="/search/advanced/geneMap"> Gene Map </a>
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*603883</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 role="presentation">
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneStructure">Gene Structure</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#genotypePhenotypeCorrelations">Genotype/Phenotype Correlations</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#animalModel">Animal Model</a>
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<li 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/603883">Table View</a>
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</li>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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</li>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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</ul>
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</nav>
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</div>
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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=ENSG00000151929;t=ENST00000369085" 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=9531" 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=603883" 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=ENSG00000151929;t=ENST00000369085" 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_004281,XM_005270287" 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_004281" 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=603883" 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=04860&isoform_id=04860_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/BAG3" 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/5868898,6724086,6808299,9757714,12643665,13623601,14043024,15779190,62897159,78070354,119569767,119569768,158256102,530394628,1927762116,1927762118,2462521999" 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/O95817" 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=9531" 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=ENSG00000151929;t=ENST00000369085" 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=BAG3" 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=BAG3" 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+9531" 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/BAG3" 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:9531" 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/9531" 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=chr10&hgg_gene=ENST00000369085.8&hgg_start=119651380&hgg_end=119677819&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/gene-dosage/HGNC:939" class="mim-tip-hint" title="A ClinGen curated resource of genes and regions of the genome that are dosage sensitive and should be targeted on a cytogenomic array." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Dosage', 'domain': 'dosage.clinicalgenome.org'})">ClinGen Dosage</a></div>
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:939" 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=603883[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=603883[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
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<div><a href="https://www.deciphergenomics.org/gene/BAG3/overview/clinical-info" class="mim-tip-hint" title="DECIPHER" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'DECIPHER', 'domain': 'DECIPHER'})">DECIPHER</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000151929" 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=BAG3" 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=BAG3" 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=BAG3" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="http://www.LOVD.nl/BAG3" class="mim-tip-hint" title="A gene-specific database of variation." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">Locus Specific DBs</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=BAG3&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/PA25239" class="mim-tip-hint" title="Pharmacogenomics Knowledge Base; curated and annotated information regarding the effects of human genetic variations on drug response." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PharmGKB', 'domain': 'pharmgkb.org'})">PharmGKB</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimAnimalModels">
|
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<span class="panel-title">
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<span class="small">
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<a href="#mimAnimalModelsLinksFold" id="mimAnimalModelsLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimAnimalModelsLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Animal Models</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimAnimalModelsLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.alliancegenome.org/gene/HGNC:939" 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/FBgn0086708.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:1352493" 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/BAG3#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:1352493" 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/9531/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=9531" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-040801-40" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
|
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<span class="panel-title">
|
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<span class="small">
|
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://reactome.org/content/query?q=BAG3&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
|
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<span class="text-danger"><strong>*</strong></span>
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603883
|
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</span>
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</span>
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</div>
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</div>
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<div>
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<a id="preferredTitle" class="mim-anchor"></a>
|
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<h3>
|
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<span class="mim-font">
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<div class="mim-changed mim-change">BAG COCHAPERONE 3; BAG3</div>
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</span>
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</h3>
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</div>
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<div>
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<br />
|
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
|
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<em>Alternative titles; symbols</em>
|
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</span>
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</p>
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</div>
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<div>
|
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<h4>
|
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<span class="mim-font">
|
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<div class="mim-changed mim-change">BCL2-ASSOCIATED ATHANOGENE 3; BAG3</div>
|
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</span>
|
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</h4>
|
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</div>
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</div>
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<div>
|
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<br />
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</div>
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</div>
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<div>
|
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=BAG3" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">BAG3</a></em></strong>
|
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</span>
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</p>
|
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</div>
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<div>
|
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<a id="cytogeneticLocation" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
|
|
<strong>
|
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<em>
|
|
Cytogenetic location: <a href="/geneMap/10/613?start=-3&limit=10&highlight=613">10q26.11</a>
|
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|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr10:119651380-119677819&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'})">10:119,651,380-119,677,819</a> </span>
|
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</em>
|
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</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
|
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</p>
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</div>
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<div>
|
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<br />
|
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</div>
|
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<div>
|
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<a id="geneMap" class="mim-anchor"></a>
|
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<div style="margin-bottom: 10px;">
|
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<span class="h4 mim-font">
|
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<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
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</div>
|
|
<div>
|
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<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
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<thead>
|
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype <br /> MIM number
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<a href="/geneMap/10/613?start=-3&limit=10&highlight=613">
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10q26.11
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?Neuronopathy, distal hereditary motor, autosomal dominant 15
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<a href="/entry/621094"> 621094 </a>
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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Cardiomyopathy, dilated, 1HH
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<a href="/entry/613881"> 613881 </a>
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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Charcot-Marie-Tooth disease, axonal, type 2JJ
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<a href="/entry/621095"> 621095 </a>
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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Myopathy, myofibrillar, 6
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<span class="mim-font">
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<a href="/entry/612954"> 612954 </a>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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PheneGene Graphics <span class="caret"></span>
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</button>
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<li><a href="/graph/linear/603883" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
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<li><a href="/graph/radial/603883" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
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<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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<span class="mim-font">
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
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<strong>TEXT</strong>
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<strong>Description</strong>
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<div class="mim-changed mim-change"><p>The BAG3 gene encodes a member of the chaperone-assisted selective autophagy (CASA) complex, a large complex that identifies misfolded proteins and transfers them to ATP-dependent chaperones such as the Hsp70 family (see <a href="/entry/140550">140550</a>) for refolding or directs them toward ubiquitination and proteasomal degradation. BAG3 binds to HSPB8 (<a href="/entry/608014">608014</a>) and other proteins in the CASA complex (summary by <a href="#1" class="mim-tip-reference" title="Adriaenssens, E., Tedesco, B., Mediani, L., Asselbergh, B., Crippa, V., Antoniani, F., Carra, S., Poletti, A., Timmerman, V. <strong>BAG3 pro209 mutants associated with myopathy and neuropathy relocate chaperones of the CASA-complex to aggresomes.</strong> Sci. Rep. 10: 8755, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32472079/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32472079</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=32472079[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/s41598-020-65664-z" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32472079">Adriaenssens et al., 2020</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32472079" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p></div>
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<div class="mim-changed mim-change"><p>Members of the BAG family, including BAG3, are cytoprotective proteins that bind to and regulate Hsp70 family molecular chaperones (<a href="#20" class="mim-tip-reference" title="Takayama, S., Xie, Z., Reed, J. C. <strong>An evolutionarily conserved family of Hsp70/Hsc70 molecular chaperone regulators.</strong> J. Biol. Chem. 274: 781-786, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9873016/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9873016</a>] [<a href="https://doi.org/10.1074/jbc.274.2.781" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9873016">Takayama et al., 1999</a>; <a href="#7" class="mim-tip-reference" title="Homma, S., Iwasaki, M., Shelton, G. D., Engvall, E., Reed, J. C., Takayama, S. <strong>BAG3 deficiency results in fulminant myopathy and early lethality.</strong> Am. J. Path. 169: 761-773, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16936253/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16936253</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16936253[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/10.2353/ajpath.2006.060250" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16936253">Homma et al., 2006</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16936253+9873016" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p></div>
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<strong>Cloning and Expression</strong>
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<p><a href="#20" class="mim-tip-reference" title="Takayama, S., Xie, Z., Reed, J. C. <strong>An evolutionarily conserved family of Hsp70/Hsc70 molecular chaperone regulators.</strong> J. Biol. Chem. 274: 781-786, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9873016/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9873016</a>] [<a href="https://doi.org/10.1074/jbc.274.2.781" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9873016">Takayama et al. (1999)</a> identified cDNAs corresponding to BAG3 and 3 other BAG1 (<a href="/entry/601497">601497</a>)-like proteins. The partial BAG3 cDNA encodes a protein containing a WW domain in the N-terminal region and a BAG domain in the C-terminal region. <a href="#17" class="mim-tip-reference" title="Selcen, D., Muntoni, F., Burton, B. K., Pegoraro, E., Sewry, C., Bite, A. V., Engel, A. G. <strong>Mutation in BAG3 causes severe dominant childhood muscular dystrophy.</strong> Ann. Neurol. 65: 83-89, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19085932/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19085932</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19085932[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/ana.21553" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19085932">Selcen et al. (2009)</a> noted that BAG3 also contains a C-terminal proline-rich domain that interacts with WW-domain proteins implicated in signal transduction and with SH3-domain proteins. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=19085932+9873016" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 database analysis using BAG4 (<a href="/entry/603884">603884</a>) as query, <a href="#9" class="mim-tip-reference" title="Jiang, Y., Woronicz, J. D., Liu, W., Goeddel, D. V. <strong>Prevention of constitutive TNF receptor 1 signaling by silencer of death domains.</strong> Science 283: 543-546, 1999. Note: Erratum: Science 283: 1852 only, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9915703/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9915703</a>] [<a href="https://doi.org/10.1126/science.283.5401.543" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9915703">Jiang et al. (1999)</a> identified BAG3, which has 61% identity to the C-terminal region of BAG4. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9915703" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>Using Western blot analysis, <a href="#16" class="mim-tip-reference" title="Pagliuca, M. G., Lerose, R., Cagliano, S., Leone, A. <strong>Regulation by heavy metals and temperature of the human BAG-3 gene, a modulator of Hsp70 activity.</strong> FEBS Lett. 541: 11-15, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12706811/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12706811</a>] [<a href="https://doi.org/10.1016/s0014-5793(03)00274-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12706811">Pagliuca et al. (2003)</a> found that BAG3 has an apparent molecular mass of 84 kD. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12706811" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="mim-changed mim-change"><p>BAG3 is highly expressed in cardiomyocytes and skeletal muscle cells (summary by <a href="#1" class="mim-tip-reference" title="Adriaenssens, E., Tedesco, B., Mediani, L., Asselbergh, B., Crippa, V., Antoniani, F., Carra, S., Poletti, A., Timmerman, V. <strong>BAG3 pro209 mutants associated with myopathy and neuropathy relocate chaperones of the CASA-complex to aggresomes.</strong> Sci. Rep. 10: 8755, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32472079/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32472079</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=32472079[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/s41598-020-65664-z" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32472079">Adriaenssens et al., 2020</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32472079" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p></div>
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<p><a href="#17" class="mim-tip-reference" title="Selcen, D., Muntoni, F., Burton, B. K., Pegoraro, E., Sewry, C., Bite, A. V., Engel, A. G. <strong>Mutation in BAG3 causes severe dominant childhood muscular dystrophy.</strong> Ann. Neurol. 65: 83-89, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19085932/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19085932</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19085932[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/ana.21553" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19085932">Selcen et al. (2009)</a> stated that the BAG3 gene contains 4 exons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19085932" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#5" class="mim-tip-reference" title="Gross, M. B. <strong>Personal Communication.</strong> Baltimore, Md. 4/24/2015."None>Gross (2015)</a> mapped the BAG3 gene to chromosome 10q26.11 based on an alignment of the BAG3 sequence (GenBank <a href="https://www.ncbi.nlm.nih.gov/search/all/?term=AF071218" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'GENBANK\', \'domain\': \'ncbi.nlm.nih.gov\'})">AF071218</a>) with the genomic sequence (GRCh38).</p>
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<p><a href="#20" class="mim-tip-reference" title="Takayama, S., Xie, Z., Reed, J. C. <strong>An evolutionarily conserved family of Hsp70/Hsc70 molecular chaperone regulators.</strong> J. Biol. Chem. 274: 781-786, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9873016/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9873016</a>] [<a href="https://doi.org/10.1074/jbc.274.2.781" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9873016">Takayama et al. (1999)</a> demonstrated that BAG1, BAG2 (<a href="/entry/603882">603882</a>), and BAG3 bind with high affinity to the ATPase domain of Hsc70 and inhibit its chaperone activity in a HIP (ST13; <a href="/entry/606796">606796</a>)-repressible manner. These authors concluded that interactions with various BAG family proteins allow opportunities for specification and diversification of Hsp70/Hsc70 (HSPA8; <a href="/entry/600816">600816</a>) chaperone functions. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9873016" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>Using in situ hybridization and immunohistochemical analyses, <a href="#12" class="mim-tip-reference" title="Liao, Q., Ozawa, F., Friess, H., Zimmermann, A., Takayama, S., Reed, J. C., Kleeff, J., Buchler, M. W. <strong>The anti-apoptotic protein BAG-3 is overexpressed in pancreatic cancer and induced by heat stress in pancreatic cancer cell lines.</strong> FEBS Lett. 503: 151-157, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11513873/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11513873</a>] [<a href="https://doi.org/10.1016/s0014-5793(01)02728-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11513873">Liao et al. (2001)</a> detected high BAG3 mRNA and protein expression in the cytoplasm of pancreatic tumor tissue, with little or no expression in adjacent normal pancreatic tissue. BAG3 was not overexpressed in other gastrointestinal cancers. <a href="#12" class="mim-tip-reference" title="Liao, Q., Ozawa, F., Friess, H., Zimmermann, A., Takayama, S., Reed, J. C., Kleeff, J., Buchler, M. W. <strong>The anti-apoptotic protein BAG-3 is overexpressed in pancreatic cancer and induced by heat stress in pancreatic cancer cell lines.</strong> FEBS Lett. 503: 151-157, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11513873/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11513873</a>] [<a href="https://doi.org/10.1016/s0014-5793(01)02728-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11513873">Liao et al. (2001)</a> hypothesized that the antiapoptotic function of BAG3 may contribute to the aggressiveness of pancreatic cancers. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11513873" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>Using Northern and Western blot analyses, <a href="#16" class="mim-tip-reference" title="Pagliuca, M. G., Lerose, R., Cagliano, S., Leone, A. <strong>Regulation by heavy metals and temperature of the human BAG-3 gene, a modulator of Hsp70 activity.</strong> FEBS Lett. 541: 11-15, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12706811/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12706811</a>] [<a href="https://doi.org/10.1016/s0014-5793(03)00274-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12706811">Pagliuca et al. (2003)</a> found that expression of BAG3, together with that of HSP70 and metallothionein (see MT1A; <a href="/entry/156350">156350</a>), was upregulated in HeLa cells exposed to heat or to the heavy metals zinc and cadmium. During heat and metal stress, the intracellular localization of BAG3 changed from a homogeneous cytoplasmic distribution to a reticular perinuclear distribution, where BAG3 colocalized with a rough endoplasmic reticulum (ER) marker. <a href="#16" class="mim-tip-reference" title="Pagliuca, M. G., Lerose, R., Cagliano, S., Leone, A. <strong>Regulation by heavy metals and temperature of the human BAG-3 gene, a modulator of Hsp70 activity.</strong> FEBS Lett. 541: 11-15, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12706811/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12706811</a>] [<a href="https://doi.org/10.1016/s0014-5793(03)00274-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12706811">Pagliuca et al. (2003)</a> noted that the ER is the major organelle in the integration of damage-sensing and proapoptotic stimuli and hypothesized that BAG3 may have a role in the cellular response to environmental stress. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12706811" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="mim-changed mim-change"><p>In skeletal muscle, BAG3 plays a role in cell resilience to mechanical stress through chaperone-associated selected autophagy (CASA), which removes misfolded proteins. Similarly, peripheral nerves are subject to mechanical tension and prone to protein misfolding or aggregation. BAG3 binds to HSPB8 (<a href="/entry/608014">608014</a>) via 2 conserved Ile-Pro-Val (IPV) motifs. This interaction is essential for function of the CASA complex (summary by <a href="#19" class="mim-tip-reference" title="Shy, M., Rebelo, A. P., Feely, S. M. E., Abreu, L. A., Tao, F., Swenson, A., Bacon, C., Zuchner, S. <strong>Mutations in BAG3 cause adult-onset Charcot-Marie-Tooth disease.</strong> J. Neurol. Neurosurg. Psychiat. 89: 313-315, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28754666/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28754666</a>] [<a href="https://doi.org/10.1136/jnnp-2017-315929" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28754666">Shy et al., 2018</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28754666" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p></div>
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<p><strong><em>Myofibrillar Myopathy 6</em></strong>
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<div class="mim-changed mim-change"><p>In 3 unrelated patients with childhood-onset of rapidly progressive myofibrillar myopathy (MFM6; <a href="/entry/612954">612954</a>), <a href="#17" class="mim-tip-reference" title="Selcen, D., Muntoni, F., Burton, B. K., Pegoraro, E., Sewry, C., Bite, A. V., Engel, A. G. <strong>Mutation in BAG3 causes severe dominant childhood muscular dystrophy.</strong> Ann. Neurol. 65: 83-89, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19085932/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19085932</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19085932[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/ana.21553" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19085932">Selcen et al. (2009)</a> identified the same heterozygous mutation in the BAG3 gene (P209L; <a href="#0001">603883.0001</a>). The unaffected parents of 2 patients did not carry the mutation, indicating de novo occurrence; DNA was not available from the unaffected parents of the third patient. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19085932" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p></div>
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<div class="mim-changed mim-change"><p><a href="#11" class="mim-tip-reference" title="Lee, H. C., Cherk, S. W., Chan, S. K., Wong, S., Tong, T. W., Ho, W. S., Chan, A. Y., Lee, K. C., Mak, C. M. <strong>BAG3-related myofibrillar myopathy in a Chinese family.</strong> Clin. Genet. 81: 394-398, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21361913/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21361913</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2011.01659.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21361913">Lee et al. (2012)</a> identified a de novo heterozygous P209L mutation in a Chinese girl with myofibrillar myopathy. The patient and her father had an R258W missense mutation (<a href="#0009">603883.0009</a>) in the BAG3 gene. The father had no abnormal neuromuscular findings, but asymptomatic prolonged QT interval. It was unclear whether the R258W mutation contributed to the phenotype of either individual. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21361913" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p></div>
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<p>In a man with adult-onset myofibrillar myopathy, <a href="#18" class="mim-tip-reference" title="Semmler, A.-L., Sacconi, S., Bach, J. E., Liebe, C., Burmann, J., Kley, R. A., Ferbert, A., Anderheiden, R., Van den Bergh, P., Martin, J.-J., De Jonghe, P., Neuen-Jacob, E., and 9 others. <strong>Unusual multisystemic involvement and a novel BAG3 mutation revealed by NGS screening in a large cohort of myofibrillar myopathies.</strong> Orphanet J. Rare Dis. 9: 121, 2014. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25208129/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25208129</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25208129[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/10.1186/s13023-014-0121-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25208129">Semmler et al. (2014)</a> identified a de novo heterozygous missense mutation in the BAG3 gene (P209Q; <a href="#0010">603883.0010</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25208129" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="mim-changed mim-change"><p>In a 15-year-old Korean girl with MFM6 and a peripheral axonal sensorimotor neuropathy consistent with Charcot-Marie-Tooth disease, <a href="#10" class="mim-tip-reference" title="Kim, S. J., Nam, S. H., Kanwal, S., Nam, D. E., Yoo, D. H., Chae, J.-H., Suh, Y.-L., Chung, K. W., Choi, B.-O. <strong>BAG3 mutation in a patient with atypical phenotypes of myofibrillar myopathy and Charcot-Marie-Tooth disease.</strong> Genes Genomics 40: 1269-1277, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30145633/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30145633</a>] [<a href="https://doi.org/10.1007/s13258-018-0721-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30145633">Kim et al. (2018)</a> identified a de novo heterozygous P209L mutation in the BAG3 gene. The mutation was found by whole-exome sequencing; functional studies of the variant were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30145633" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p></div>
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<div class="mim-changed mim-change"><p>In a 13-year-old Caucasian girl with MFM6 and a peripheral sensorimotor neuropathy consistent with Charcot-Marie-Tooth disease, <a href="#13" class="mim-tip-reference" title="Malatesta, L., Arya, K., Gokden, M., Stefans, V., Veerapandiyan, A. <strong>BAG3 myopathy presenting with prominent neuropathic phenotype and no cardiac or respiratory involvement: a case report and literature review.</strong> J. Clin. Neuromusc. Dis. 21: 230-239, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32453099/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32453099</a>] [<a href="https://doi.org/10.1097/CND.0000000000000300" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32453099">Malatesta et al. (2020)</a> identified a de novo heterozygous P209L mutation in the BAG3 gene. The mutation was found by trio-based exome sequencing; functional studies of the variant were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32453099" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p></div>
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<div class="mim-changed mim-change"><p>In a Japanese man and his mother with MFM6 and an axonal sensorimotor peripheral neuropathy consistent with Charcot-Marie-Tooth disease, <a href="#6" class="mim-tip-reference" title="Hamaguchi, M., Kokubun, N., Inoue, M., Komagamine, T., Aoki, R., Nishino, I., Hirata, K. <strong>A family with adult-onset myofibrillar myopathy with BAG3 mutation (P470S) presenting with axonal polyneuropathy.</strong> Neuromusc. Disord. 30: 727-731, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32859500/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32859500</a>] [<a href="https://doi.org/10.1016/j.nmd.2020.07.012" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32859500">Hamaguchi et al. (2020)</a> identified a heterozygous missense mutation in the BAG3 gene (P470S; <a href="#0012">603883.0012</a>). The mutation was found by sequencing a MFM-targeted gene panel and confirmed by Sanger sequencing. No other family members were sequenced. Functional studies of the variant were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32859500" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p></div>
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<div class="mim-changed mim-change"><p><strong><em>Charcot-Marie-Tooth Disease Type 2JJ</em></strong>
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<div class="mim-changed mim-change"><p>In 9 affected individuals from 2 large multigenerational families with axonal Charcot-Marie-Tooth disease type 2JJ (CMT2JJ; <a href="/entry/621095">621095</a>), <a href="#19" class="mim-tip-reference" title="Shy, M., Rebelo, A. P., Feely, S. M. E., Abreu, L. A., Tao, F., Swenson, A., Bacon, C., Zuchner, S. <strong>Mutations in BAG3 cause adult-onset Charcot-Marie-Tooth disease.</strong> J. Neurol. Neurosurg. Psychiat. 89: 313-315, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28754666/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28754666</a>] [<a href="https://doi.org/10.1136/jnnp-2017-315929" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28754666">Shy et al. (2018)</a> identified a heterozygous P209S mutation in the BAG3 gene (<a href="#0011">603883.0011</a>). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. The P209S variant occurs at a conserved residue in 1 of the 2 Ile-Pro-Val (IPV) motifs that mediates binding to HSPB8. Functional studies of the variant were not performed, buy <a href="#19" class="mim-tip-reference" title="Shy, M., Rebelo, A. P., Feely, S. M. E., Abreu, L. A., Tao, F., Swenson, A., Bacon, C., Zuchner, S. <strong>Mutations in BAG3 cause adult-onset Charcot-Marie-Tooth disease.</strong> J. Neurol. Neurosurg. Psychiat. 89: 313-315, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28754666/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28754666</a>] [<a href="https://doi.org/10.1136/jnnp-2017-315929" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28754666">Shy et al. (2018)</a> suggested that disruption of the IPV motif could interrupt BAG3-HSPB8 binding and fail to promote clearance of aggregate proteins in peripheral nerves, resulting in damage to the nerves. The patients had no clinical evidence of a myopathy; neither muscle biopsy nor sural nerve biopsy were performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28754666" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p></div>
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<div class="mim-changed mim-change"><p>In a mother and daughter from a nonconsanguineous Chinese family with CMT2JJ, <a href="#4" class="mim-tip-reference" title="Fu, J., Ma, M., Song, J., Pang, M., Li, G., Zhang, J. <strong>BAG3 p.Pro209Ser mutation identified in a Chinese family with Charcot-Marie-Tooth disease.</strong> J. Neurol. 267: 1080-1085, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31853710/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31853710</a>] [<a href="https://doi.org/10.1007/s00415-019-09680-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31853710">Fu et al. (2020)</a> identified a heterozygous P209S mutation in the BAG3 gene. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The variant was not found in the ExAC or gnomAD databases. Functional studies of the variant and studies of patient cells were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31853710" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p></div>
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<div class="mim-changed mim-change"><p><strong><em>Autosomal Dominant Distal Hereditary Motor Neuronopathy 15</em></strong>
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<div class="mim-changed mim-change"><p>In 8 affected members of a Spanish family with autosomal dominant distal hereditary motor neuronopathy-15 (HMND15; <a href="/entry/621094">621094</a>), <a href="#3" class="mim-tip-reference" title="de Fuenmayor-Fernandez de la Hoz, C. P., Lupo, V., Bermejo-Guerrero, L., Martin-Jimenez, P., Hernandez-Lain, A., Olive, M., Gallardo, E., Esteban-Perez, J., Espinos, C., Dominguez-Gonzalez, C. <strong>Distal hereditary motor neuronopathy as a new phenotype associated with variants in BAG3.</strong> J. Neurol. 271: 986-994, 2024.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/37907725/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">37907725</a>] [<a href="https://doi.org/10.1007/s00415-023-12039-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="37907725">de Fuenmayor-Fernandez de la Hoz et al. (2024)</a> identified a heterozygous frameshift in the BAG3 gene (Val505GlyfsTer6; <a href="#0013">603883.0013</a>), thus eliminating the LEAD sequence, a functional caspase recognition and cleavage site. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The variant was not present in public databases, including gnomAD. Western blot analysis of muscle tissue from 2 patients showed presence of a truncated BAG3 protein. Functional studies of the variant were not performed, but the authors noted that mutant caspase-resistant BAG3 cells are able to resist apoptosis in vitro. They suggested that the frameshift mutation in this family, eliminating the LEAD sequence, would decrease apoptosis and result in increased expression of mutant BAG3, possibly causing increased binding to HSPB8 (<a href="/entry/608014">608014</a>), the formation of intracellular aggregates, and disrupted autophagy in lower motor neurons. The patients had no sensory abnormalities. Sural nerve biopsy was not performed; muscle biopsy showed neurogenic changes, but was otherwise normal. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=37907725" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p></div>
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<p><strong><em>Dilated Cardiomyopathy 1HH</em></strong>
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<p>In a large 3-generation family segregating autosomal dominant dilated cardiomyopathy (CMD1HH; <a href="/entry/613881">613881</a>), <a href="#14" class="mim-tip-reference" title="Norton, N., Li, D., Rieder, M. J., Siegfried, J. D., Rampersaud, E., Zuchner, S., Mangos, S., Gonzalez-Quintana, J., Wang, L., McGee, S., Reiser, J., Martin, E., Nickerson, D. A., Hershberger, R. E. <strong>Genome-wide studies of copy number variation and exome sequencing identify rare variants in BAG3 as a cause of dilated cardiomyopathy.</strong> Am. J. Hum. Genet. 88: 273-282, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21353195/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21353195</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21353195[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.ajhg.2011.01.016" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21353195">Norton et al. (2011)</a> performed whole-exome sequencing and genomewide analysis of copy number variation and identified an 8,733-bp deletion in the BAG3 gene (<a href="#0002">603883.0002</a>) that was present in all 7 affected family members and absent from 355 controls. <a href="#14" class="mim-tip-reference" title="Norton, N., Li, D., Rieder, M. J., Siegfried, J. D., Rampersaud, E., Zuchner, S., Mangos, S., Gonzalez-Quintana, J., Wang, L., McGee, S., Reiser, J., Martin, E., Nickerson, D. A., Hershberger, R. E. <strong>Genome-wide studies of copy number variation and exome sequencing identify rare variants in BAG3 as a cause of dilated cardiomyopathy.</strong> Am. J. Hum. Genet. 88: 273-282, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21353195/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21353195</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21353195[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.ajhg.2011.01.016" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21353195">Norton et al. (2011)</a> then sequenced exons 2, 3, and 4 of BAG3 in an additional 311 CMD probands who were negative for mutation in 15 known CMD-associated genes, and identified heterozygous point mutations in 7 unrelated probands that were not found in 2,644 control chromosomes (see, e.g., <a href="#0003">603883.0003</a>-<a href="#0006">603883.0006</a>). Knockdown of bag3 in a zebrafish model recapitulated CMD and heart failure. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21353195" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In 72 Japanese probands with familial CMD, <a href="#2" class="mim-tip-reference" title="Arimura, T., Ishikawa, T., Nunoda, S., Kawai, S., Kimura, A. <strong>Dilated cardiomyopathy-associated BAG3 mutations impair Z-disc assembly and enhance sensitivity to apoptosis in cardiomyocytes.</strong> Hum. Mutat. 32: 1481-1491, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21898660/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21898660</a>] [<a href="https://doi.org/10.1002/humu.21603" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21898660">Arimura et al. (2011)</a> analyzed the BAG3 gene and identified heterozygosity for 2 missense mutations in 2 probands: R218W (<a href="#0007">603883.0007</a>) and L462P (<a href="#0008">603883.0008</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21898660" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In transfected neonatal rat cardiomyocytes (NRCs), <a href="#2" class="mim-tip-reference" title="Arimura, T., Ishikawa, T., Nunoda, S., Kawai, S., Kimura, A. <strong>Dilated cardiomyopathy-associated BAG3 mutations impair Z-disc assembly and enhance sensitivity to apoptosis in cardiomyocytes.</strong> Hum. Mutat. 32: 1481-1491, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21898660/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21898660</a>] [<a href="https://doi.org/10.1002/humu.21603" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21898660">Arimura et al. (2011)</a> demonstrated that the CMD-associated mutations R218W and L462P disturbed the assembly and integrity of Z-discs as well as the nuclear localization of BAG3 protein, whereas such abnormalities were not observed with the P209L myofibrillar myopathy (MFM) mutation. In addition, analysis of transfected C2C12 myoblast cells showed that myotube formation was disturbed by the MFM mutation but not by the CMD mutations. TUNEL assay in NRCs and quantified apoptosis of H9c2 cells also indicated that the CMD-associated mutations R218W and L462P increased susceptibility to stress-induced apoptosis compared to wildtype, whereas the P209L MFM mutation did not. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21898660" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In adult mice, <a href="#7" class="mim-tip-reference" title="Homma, S., Iwasaki, M., Shelton, G. D., Engvall, E., Reed, J. C., Takayama, S. <strong>BAG3 deficiency results in fulminant myopathy and early lethality.</strong> Am. J. Path. 169: 761-773, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16936253/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16936253</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16936253[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/10.2353/ajpath.2006.060250" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16936253">Homma et al. (2006)</a> showed that Bag3 is prominently expressed in striated and cardiac muscle and colocalized with Z-discs, with lesser expression in other tissues. Mice with homozygous disruption of the Bag3 gene developed normally, but deteriorated postnatally with stunted growth evident by 1 to 2 weeks of age, and death by 4 weeks. Bag3-deficient mice developed a fulminant myopathy characterized by noninflammatory myofibrillar degeneration with apoptotic features. Cardiac muscle was also affected. Knockdown of Bag3 expression in cultured myoblasts increased apoptosis on induction of differentiation, suggesting that Bag3 is needed for maintenance of myotube survival and confirming a cell autonomous role for Bag3 in muscle. <a href="#7" class="mim-tip-reference" title="Homma, S., Iwasaki, M., Shelton, G. D., Engvall, E., Reed, J. C., Takayama, S. <strong>BAG3 deficiency results in fulminant myopathy and early lethality.</strong> Am. J. Path. 169: 761-773, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16936253/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16936253</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16936253[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/10.2353/ajpath.2006.060250" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16936253">Homma et al. (2006)</a> concluded that, although BAG3 is not required for muscle development, it appears to be critically important for maintenance of mature skeletal muscle. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16936253" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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=603883[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">rs121918312 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918312;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=rs121918312" 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=rs121918312" 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=RCV000006347 OR RCV000183317 OR RCV000648847 OR RCV001836702 OR RCV002362566" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000006347, RCV000183317, RCV000648847, RCV001836702, RCV002362566" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000006347...</a>
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<div class="mim-changed mim-change"><p>In 3 unrelated patients with late-childhood onset of autosomal dominant myofibrillar myopathy-6 (MFM6; <a href="/entry/612954">612954</a>), <a href="#17" class="mim-tip-reference" title="Selcen, D., Muntoni, F., Burton, B. K., Pegoraro, E., Sewry, C., Bite, A. V., Engel, A. G. <strong>Mutation in BAG3 causes severe dominant childhood muscular dystrophy.</strong> Ann. Neurol. 65: 83-89, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19085932/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19085932</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19085932[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/ana.21553" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19085932">Selcen et al. (2009)</a> identified a heterozygous 626C-T transition in exon 3 of the BAG3, gene, resulting in a pro209-to-leu (P209L) substitution. The mutation was not present in 200 control individuals. The unaffected parents of 2 patients did not carry the mutation, indicating de novo occurrence; DNA was not available from the unaffected parents of the third patient. Patients showed a rapidly progressive myopathy affecting both skeletal and cardiac muscle with severe respiratory insufficiency. In vitro functional expression studies showed that the mutant protein tended to aggregate into small granules, suggesting altered folding. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19085932" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p></div>
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<div class="mim-changed mim-change"><p><a href="#11" class="mim-tip-reference" title="Lee, H. C., Cherk, S. W., Chan, S. K., Wong, S., Tong, T. W., Ho, W. S., Chan, A. Y., Lee, K. C., Mak, C. M. <strong>BAG3-related myofibrillar myopathy in a Chinese family.</strong> Clin. Genet. 81: 394-398, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21361913/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21361913</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2011.01659.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21361913">Lee et al. (2012)</a> identified a de novo heterozygous P209L mutation in a Chinese girl with onset of myofibrillar myopathy at age 6 years. She had slowly progressive muscle weakness, clumsy walking, rapidly progressive contractures of the Achilles tendons, limited spinal movement, mildly restrictive lung disease, hypertrophic cardiomyopathy, prolonged QT interval, and decreased motor nerve conduction velocities, suggesting a neurogenic axonal disease. Electron microscopy of muscle biopsy showed sarcoplasmic accumulations of electron-dense granulofilamentous material and myofibrillar degeneration with minicores. The patient and her father had an R258W missense mutation (<a href="#0009">603883.0009</a>) in the BAG3 gene. Her father had no abnormal neuromuscular findings, but asymptomatic prolonged QT interval. It was unclear whether the R258W mutation contributed to the phenotype of either individual. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21361913" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p></div>
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<p>In 4 patients from 3 unrelated families with MFM6, <a href="#15" class="mim-tip-reference" title="Odgerel, Z., Sarkozy, A., Lee, H.-S., McKenna, C., Rankin, J., Straub, V., Lochmuller, H., Paola, F., D'Amico, A., Bertini, E., Bushby, K., Goldfarb, L. G. <strong>Inheritance patterns and phenotypic features of myofibrillar myopathy associated with a BAG3 mutation.</strong> Neuromusc. Disord. 20: 438-442, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20605452/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20605452</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20605452[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.nmd.2010.05.004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20605452">Odgerel et al. (2010)</a> identified a heterozygous P209L mutation. The mutation occurred de novo in 2 patients. Two brothers inherited the mutation from their unaffected father, who was somatic mosaic for the mutation, with an expression level of 17% in the peripheral blood lymphocytes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20605452" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In 4 patients with MFM6, <a href="#8" class="mim-tip-reference" title="Jaffer, F., Murphy, S. M., Scoto, M., Healy, E., Rossor, A. M., Brandner, S., Phadke, R., Selcen, D., Jungbluth, H., Muntoni, F., Reilly, M. M. <strong>BAG3 mutations: another cause of giant axonal neuropathy.</strong> J. Peripher. Nerv. Syst. 17: 210-216, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22734908/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22734908</a>] [<a href="https://doi.org/10.1111/j.1529-8027.2012.00409.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22734908">Jaffer et al. (2012)</a> identified a heterozygous P209L mutation. One of the patients had a sister who was similarly affected, but DNA was not available. Their father had died of a similar but milder disorder at age 30 years, suggesting that he may have been somatic mosaic for the mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22734908" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="mim-changed mim-change"><p>In a 15-year-old Korean girl with MFM6 and a peripheral axonal sensorimotor neuropathy consistent with Charcot-Marie-Tooth disease, <a href="#10" class="mim-tip-reference" title="Kim, S. J., Nam, S. H., Kanwal, S., Nam, D. E., Yoo, D. H., Chae, J.-H., Suh, Y.-L., Chung, K. W., Choi, B.-O. <strong>BAG3 mutation in a patient with atypical phenotypes of myofibrillar myopathy and Charcot-Marie-Tooth disease.</strong> Genes Genomics 40: 1269-1277, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30145633/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30145633</a>] [<a href="https://doi.org/10.1007/s13258-018-0721-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30145633">Kim et al. (2018)</a> identified a de novo heterozygous P209L mutation in the BAG3 gene. The mutation was found by whole-exome sequencing; functional studies of the variant were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30145633" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p></div>
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<div class="mim-changed mim-change"><p>In a 13-year-old Caucasian girl with MFM6 and a peripheral sensorimotor neuropathy consistent with Charcot-Marie-Tooth disease, <a href="#13" class="mim-tip-reference" title="Malatesta, L., Arya, K., Gokden, M., Stefans, V., Veerapandiyan, A. <strong>BAG3 myopathy presenting with prominent neuropathic phenotype and no cardiac or respiratory involvement: a case report and literature review.</strong> J. Clin. Neuromusc. Dis. 21: 230-239, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32453099/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32453099</a>] [<a href="https://doi.org/10.1097/CND.0000000000000300" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32453099">Malatesta et al. (2020)</a> identified a de novo heterozygous P209L mutation in the BAG3 gene. The mutation was found by trio-based exome sequencing; functional studies of the variant were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32453099" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p></div>
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<p>In 7 affected members of a large 3-generation family segregating autosomal dominant dilated cardiomyopathy (CMD1HH; <a href="/entry/613881">613881</a>), <a href="#14" class="mim-tip-reference" title="Norton, N., Li, D., Rieder, M. J., Siegfried, J. D., Rampersaud, E., Zuchner, S., Mangos, S., Gonzalez-Quintana, J., Wang, L., McGee, S., Reiser, J., Martin, E., Nickerson, D. A., Hershberger, R. E. <strong>Genome-wide studies of copy number variation and exome sequencing identify rare variants in BAG3 as a cause of dilated cardiomyopathy.</strong> Am. J. Hum. Genet. 88: 273-282, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21353195/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21353195</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21353195[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.ajhg.2011.01.016" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21353195">Norton et al. (2011)</a> identified heterozygosity for an 8,733-bp deletion encompassing exon 4 of the BAG3 gene. The mutation, which was also present in 3 unaffected family members, was not found in 355 controls. Two affected individuals died of advanced heart failure at age 38 years and age 44 years, and another underwent heart transplant at age 23 years. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21353195" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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> rs387906874 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906874;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/rs387906874?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=rs387906874" 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=rs387906874" 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=RCV000023349 OR RCV000456156 OR RCV000852638 OR RCV001811196 OR RCV002415426 OR RCV003234916" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000023349, RCV000456156, RCV000852638, RCV001811196, RCV002415426, RCV003234916" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000023349...</a>
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<div class="mim-changed mim-change"><p>In a mother and son who were diagnosed with dilated cardiomyopathy (CMD1HH; <a href="/entry/613881">613881</a>) at ages 59 years and 41 years, respectively, <a href="#14" class="mim-tip-reference" title="Norton, N., Li, D., Rieder, M. J., Siegfried, J. D., Rampersaud, E., Zuchner, S., Mangos, S., Gonzalez-Quintana, J., Wang, L., McGee, S., Reiser, J., Martin, E., Nickerson, D. A., Hershberger, R. E. <strong>Genome-wide studies of copy number variation and exome sequencing identify rare variants in BAG3 as a cause of dilated cardiomyopathy.</strong> Am. J. Hum. Genet. 88: 273-282, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21353195/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21353195</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21353195[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.ajhg.2011.01.016" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21353195">Norton et al. (2011)</a> identified heterozygosity for a c.211C-T transition (c.211C-T, NM_004281.3) in exon 2 of the BAG3 gene, resulting in an arg71-to-trp (R71W) substitution. The mutation was not found in 2,644 control chromosomes. The mother underwent heart transplant at age 65 years. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21353195" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p></div>
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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> rs387906875 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906875;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/rs387906875?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=rs387906875" 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=rs387906875" 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=RCV000023350 OR RCV000211711 OR RCV000247382 OR RCV000254992 OR RCV000627789" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000023350, RCV000211711, RCV000247382, RCV000254992, RCV000627789" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000023350...</a>
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<div class="mim-changed mim-change"><p>In a brother and sister who were diagnosed with dilated cardiomyopathy (CMD1HH; <a href="/entry/613881">613881</a>) at ages 25 years and 34 years, respectively, <a href="#14" class="mim-tip-reference" title="Norton, N., Li, D., Rieder, M. J., Siegfried, J. D., Rampersaud, E., Zuchner, S., Mangos, S., Gonzalez-Quintana, J., Wang, L., McGee, S., Reiser, J., Martin, E., Nickerson, D. A., Hershberger, R. E. <strong>Genome-wide studies of copy number variation and exome sequencing identify rare variants in BAG3 as a cause of dilated cardiomyopathy.</strong> Am. J. Hum. Genet. 88: 273-282, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21353195/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21353195</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21353195[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.ajhg.2011.01.016" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21353195">Norton et al. (2011)</a> identified heterozygosity for a c.367C-T transition (c.367C-T, NM_004281.3) in exon 2 of the BAG3 gene, resulting in an arg123-to-ter (R123X) substitution. The mutation was present in their father, who had undergone a heart transplant for an unknown type of cardiomyopathy at 40 years of age, and was also present in an asymptomatic sister, but was not found in 2,644 control chromosomes. The brother had undergone heart transplant at 26 years of age, but his affected sister had only mild left ventricular dysfunction. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21353195" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p></div>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1589630173 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1589630173;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=rs1589630173" 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=rs1589630173" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<div class="mim-changed mim-change"><p>In a man who was diagnosed with dilated cardiomyopathy (CMD1HH; <a href="/entry/613881">613881</a>) at 47 years of age and died at age 54 years, <a href="#14" class="mim-tip-reference" title="Norton, N., Li, D., Rieder, M. J., Siegfried, J. D., Rampersaud, E., Zuchner, S., Mangos, S., Gonzalez-Quintana, J., Wang, L., McGee, S., Reiser, J., Martin, E., Nickerson, D. A., Hershberger, R. E. <strong>Genome-wide studies of copy number variation and exome sequencing identify rare variants in BAG3 as a cause of dilated cardiomyopathy.</strong> Am. J. Hum. Genet. 88: 273-282, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21353195/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21353195</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21353195[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.ajhg.2011.01.016" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21353195">Norton et al. (2011)</a> identified heterozygosity for a 1-bp deletion (c.652delC, NM_004281.3) in exon 3 of the BAG3 gene, resulting in a frameshift predicted to cause a premature termination codon. The mutation was not found in 2,644 control chromosomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21353195" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p></div>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs387906876 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906876;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=rs387906876" 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=rs387906876" 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=RCV000023352 OR RCV001065815 OR RCV004700271" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000023352, RCV001065815, RCV004700271" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000023352...</a>
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<div class="mim-changed mim-change"><p>In a man who was diagnosed with dilated cardiomyopathy (CMD1HH; <a href="/entry/613881">613881</a>) at 50 years of age and underwent heart transplant within a year, <a href="#14" class="mim-tip-reference" title="Norton, N., Li, D., Rieder, M. J., Siegfried, J. D., Rampersaud, E., Zuchner, S., Mangos, S., Gonzalez-Quintana, J., Wang, L., McGee, S., Reiser, J., Martin, E., Nickerson, D. A., Hershberger, R. E. <strong>Genome-wide studies of copy number variation and exome sequencing identify rare variants in BAG3 as a cause of dilated cardiomyopathy.</strong> Am. J. Hum. Genet. 88: 273-282, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21353195/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21353195</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21353195[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.ajhg.2011.01.016" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21353195">Norton et al. (2011)</a> identified heterozygosity for a c.1430G-A transition (c.1430G-A, NM_004281.3) in exon 4 of the BAG3 gene, resulting in an arg477-to-his (R477H) substitution. The mutation was not found in 2,644 control chromosomes. The proband's affected father was deceased, but the mutation was detected in his paternal uncle, who was diagnosed with CMD at 47 years of age and underwent heart transplant at age 57 years. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21353195" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p></div>
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<strong>.0007 CARDIOMYOPATHY, DILATED, 1HH</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs397514506 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs397514506;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/rs397514506?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=rs397514506" 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=rs397514506" 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=RCV000032660 OR RCV000171829 OR RCV000617935 OR RCV000648836 OR RCV003144117" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000032660, RCV000171829, RCV000617935, RCV000648836, RCV003144117" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000032660...</a>
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<div class="mim-changed mim-change"><p>In a 76-year-old Japanese man who developed dilated cardiomyopathy at age 73 years (CMD1HH; <a href="/entry/613881">613881</a>), <a href="#2" class="mim-tip-reference" title="Arimura, T., Ishikawa, T., Nunoda, S., Kawai, S., Kimura, A. <strong>Dilated cardiomyopathy-associated BAG3 mutations impair Z-disc assembly and enhance sensitivity to apoptosis in cardiomyocytes.</strong> Hum. Mutat. 32: 1481-1491, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21898660/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21898660</a>] [<a href="https://doi.org/10.1002/humu.21603" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21898660">Arimura et al. (2011)</a> identified heterozygosity for a c.652C-T transition (c.652C-T, NM_004281.3) in exon 3 of the BAG3 gene, resulting in an arg218-to-trp (R218W) substitution at a highly conserved residue. The patient had 3 affected sisters, 2 of whom had died suddenly; neither of their deceased parents was known to be affected. DNA was not analyzed from any of these family members. Transfection studies in neonatal rat cardiomyocytes (NRCs) demonstrated that wildtype BAG3 had a striated pattern of assembly and colocalized with the Z-disc markers alpha-actinin (see <a href="/entry/102575">102575</a>) and desmin (<a href="/entry/125660">125660</a>), whereas the R218W mutant did not show a striated pattern, and Z-disc assembly as represented by localization of alpha-actinin and desmin was impaired. TUNEL assay in NRCs and quantification of apoptosis in H9c2 cells both indicated that the R218W mutant increased susceptibility to stress-induced apoptosis compared to wildtype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21898660" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p></div>
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<strong>.0008 CARDIOMYOPATHY, DILATED, 1HH</strong>
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BAG3, LEU462PRO
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs397514507 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs397514507;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=rs397514507" 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=rs397514507" 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=RCV000032661 OR RCV000437344" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000032661, RCV000437344" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000032661...</a>
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<div class="mim-changed mim-change"><p>In a 41-year-old Japanese woman who developed dilated cardiomyopathy at age 34 years (CMD1HH; <a href="/entry/613881">613881</a>), <a href="#2" class="mim-tip-reference" title="Arimura, T., Ishikawa, T., Nunoda, S., Kawai, S., Kimura, A. <strong>Dilated cardiomyopathy-associated BAG3 mutations impair Z-disc assembly and enhance sensitivity to apoptosis in cardiomyocytes.</strong> Hum. Mutat. 32: 1481-1491, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21898660/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21898660</a>] [<a href="https://doi.org/10.1002/humu.21603" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21898660">Arimura et al. (2011)</a> identified heterozygosity for a c.1385T-C transition (c.1385T-C, NM_004281.3) in exon 4 of the BAG3 gene, resulting in a leu462-to-pro (L462P) substitution at a highly conserved residue. The mutation was also detected in the proband's 27-year-old sister, who did not have overt CMD but showed slight systolic dysfunction, with regional hypokinesia in the posterior ventricular wall. However, the mutation was not found in their unaffected father or brother or in 400 Japanese controls. Their affected mother had died suddenly at age 52 years. Electrocardiographic analysis of the 2 affected individuals showed no primary conduction defect, serum creatine kinase levels were not elevated, and neither showed signs of skeletal myopathy or neuropathy. Transfection studies in neonatal rat cardiomyocytes demonstrated that wildtype BAG3 had a striated pattern of assembly and colocalized with the Z-disc markers alpha-actinin (see <a href="/entry/102575">102575</a>) and desmin (<a href="/entry/125660">125660</a>), whereas the L462P mutant did not show a striated pattern, and Z-disc assembly as represented by localization of alpha-actinin and desmin was impaired. TUNEL assay in NRCs and quantification of apoptosis in H9c2 cells both indicated that the L462P mutant increased susceptibility to stress-induced apoptosis compared to wildtype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21898660" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p></div>
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<strong>.0009 VARIANT OF UNKNOWN SIGNIFICANCE</strong>
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BAG3, ARG258TRP
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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> rs117671123 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs117671123;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/rs117671123?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=rs117671123" 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=rs117671123" 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=RCV000032662 OR RCV000037897 OR RCV000490529 OR RCV000590218 OR RCV000618102 OR RCV001081302 OR RCV001107316 OR RCV003486548" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000032662, RCV000037897, RCV000490529, RCV000590218, RCV000618102, RCV001081302, RCV001107316, RCV003486548" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000032662...</a>
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<span class="mim-text-font">
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<p>This variant is classified as a variant of unknown significance because its contribution to cardiac or muscle disease has not been confirmed.</p>
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<div class="mim-changed mim-change"><p><a href="#11" class="mim-tip-reference" title="Lee, H. C., Cherk, S. W., Chan, S. K., Wong, S., Tong, T. W., Ho, W. S., Chan, A. Y., Lee, K. C., Mak, C. M. <strong>BAG3-related myofibrillar myopathy in a Chinese family.</strong> Clin. Genet. 81: 394-398, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21361913/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21361913</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2011.01659.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21361913">Lee et al. (2012)</a> identified a heterozygous c.772C-T transition (c.772C-T, NM_004281.3) in the BAG3 gene, resulting in an arg258-to-trp (R258W) substitution at a highly conserved residue in a Chinese father and daughter with prolonged QT interval. The variant was found in 2 of 286 control chromosomes (allele frequency of 0.007). Functional studies were not performed. The variant was identified by study of the daughter, who had myofibrillar myopathy (MFM6; <a href="/entry/612954">612954</a>) caused by a de novo heterozygous known pathogenic mutation in the BAG3 gene (P209L; <a href="#0001">603883.0001</a>). The father had no abnormal neuromuscular findings, and his prolonged QT interval was asymptomatic. It was unclear whether the R258W variant contributed to the phenotype in either individual. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21361913" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p></div>
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<strong>.0010 MYOPATHY, MYOFIBRILLAR, 6</strong>
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BAG3, PRO209GLN
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121918312 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918312;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=rs121918312" 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=rs121918312" 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=RCV000144684 OR RCV001849971" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000144684, RCV001849971" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000144684...</a>
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<div class="mim-changed mim-change"><p>In a man with adult-onset myofibrillar myopathy-6 (MFM6; <a href="/entry/612954">612954</a>), <a href="#18" class="mim-tip-reference" title="Semmler, A.-L., Sacconi, S., Bach, J. E., Liebe, C., Burmann, J., Kley, R. A., Ferbert, A., Anderheiden, R., Van den Bergh, P., Martin, J.-J., De Jonghe, P., Neuen-Jacob, E., and 9 others. <strong>Unusual multisystemic involvement and a novel BAG3 mutation revealed by NGS screening in a large cohort of myofibrillar myopathies.</strong> Orphanet J. Rare Dis. 9: 121, 2014. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25208129/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25208129</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25208129[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/10.1186/s13023-014-0121-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25208129">Semmler et al. (2014)</a> identified a de novo heterozygous c.626C-A transversion (c.626C-A, NM_004281.3) in exon 3 of the BAG3 gene, resulting in a pro209-to-gln (P209Q) substitution. The mutation was not found in the 1000 Genomes Project or Exome Sequencing Project databases or in either unaffected parent. Functional studies of the variant were not performed, but a different mutation at this codon (P209L; <a href="#0001">603883.0001</a>) has been found in multiple patients with MFM6. The patient developed distal lower limb weakness at age 34 years, which progressed to proximal muscle weakness affecting the upper and lower limbs. Muscle biopsy showed vacuoles, core-like lesions, and some necrotic fibers; ultrastructural examination showed tubulofilamentous accumulations, Z-disc streaming, and the accumulation of granulofilamentous material. He also had an axonal sensorimotor polyneuropathy manifest as decreased vibration sense and ataxic gait, but sural nerve biopsy did not show giant axons. He did not have cardiac or respiratory muscle involvement, indicating a relatively mild phenotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25208129" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p></div>
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<strong><div class="mim-changed mim-change">.0011 CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2JJ</div></strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV005065323" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV005065323" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV005065323</a>
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<div class="mim-changed mim-change"><p>In 9 affected individuals from 2 large multigenerational families with axonal Charcot-Marie-Tooth disease type 2JJ (CMT2JJ; <a href="/entry/621095">621095</a>), <a href="#19" class="mim-tip-reference" title="Shy, M., Rebelo, A. P., Feely, S. M. E., Abreu, L. A., Tao, F., Swenson, A., Bacon, C., Zuchner, S. <strong>Mutations in BAG3 cause adult-onset Charcot-Marie-Tooth disease.</strong> J. Neurol. Neurosurg. Psychiat. 89: 313-315, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28754666/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28754666</a>] [<a href="https://doi.org/10.1136/jnnp-2017-315929" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28754666">Shy et al. (2018)</a> identified a heterozygous c.625C-T transition in exon 3 of the BAG3 gene, resulting in a pro209-to-ser (P209S) substitution at a conserved residue in 1 of the 2 Ile-Pro-Val (IPV) motifs that mediates binding to HSPB8 (<a href="/entry/608014">608014</a>). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. The patients had no clinical evidence of a myopathy; neither muscle biopsy nor sural nerve biopsy were performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28754666" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a mother and daughter from a nonconsanguineous Chinese family with CMT2JJ, <a href="#4" class="mim-tip-reference" title="Fu, J., Ma, M., Song, J., Pang, M., Li, G., Zhang, J. <strong>BAG3 p.Pro209Ser mutation identified in a Chinese family with Charcot-Marie-Tooth disease.</strong> J. Neurol. 267: 1080-1085, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31853710/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31853710</a>] [<a href="https://doi.org/10.1007/s00415-019-09680-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31853710">Fu et al. (2020)</a> identified a heterozygous P209S mutation (c.625C-T, NM_004281) in the BAG3 gene. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The variant was not found in the ExAC or gnomAD databases. Functional studies of the variant and studies of patient cells were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31853710" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p></div>
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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> rs756020699 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs756020699;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/rs756020699?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=rs756020699" 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=rs756020699" 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=RCV001046418 OR RCV003339442" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001046418, RCV003339442" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001046418...</a>
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<div class="mim-changed mim-change"><p>In a Japanese man and his mother with adult-onset myofibrillar myopathy-6 (MFM6; <a href="/entry/612954">612954</a>) and an axonal sensorimotor peripheral neuropathy consistent with Charcot-Marie-Tooth disease, <a href="#6" class="mim-tip-reference" title="Hamaguchi, M., Kokubun, N., Inoue, M., Komagamine, T., Aoki, R., Nishino, I., Hirata, K. <strong>A family with adult-onset myofibrillar myopathy with BAG3 mutation (P470S) presenting with axonal polyneuropathy.</strong> Neuromusc. Disord. 30: 727-731, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32859500/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32859500</a>] [<a href="https://doi.org/10.1016/j.nmd.2020.07.012" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32859500">Hamaguchi et al. (2020)</a> identified a heterozygous c.1408C-T transition (c.1408C-T, NM_004281.3) in the BAG3 gene, resulting in a pro470-to-ser (P470S) substitution. The mutation was found by sequencing a MFM-targeted gene panel and confirmed by Sanger sequencing. No other family members were sequenced. Functional studies of the variant were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32859500" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p></div>
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<strong><div class="mim-changed mim-change">.0013 NEURONOPATHY, DISTAL HEREDITARY MOTOR, AUTOSOMAL DOMINANT 15 (1 family)</div></strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV005065324" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV005065324" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV005065324</a>
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<div class="mim-changed mim-change"><p>In 8 affected members of a Spanish family with autosomal dominant distal hereditary motor neuronopathy-15 (HMND15; <a href="/entry/621094">621094</a>), <a href="#3" class="mim-tip-reference" title="de Fuenmayor-Fernandez de la Hoz, C. P., Lupo, V., Bermejo-Guerrero, L., Martin-Jimenez, P., Hernandez-Lain, A., Olive, M., Gallardo, E., Esteban-Perez, J., Espinos, C., Dominguez-Gonzalez, C. <strong>Distal hereditary motor neuronopathy as a new phenotype associated with variants in BAG3.</strong> J. Neurol. 271: 986-994, 2024.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/37907725/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">37907725</a>] [<a href="https://doi.org/10.1007/s00415-023-12039-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="37907725">de Fuenmayor-Fernandez de la Hoz et al. (2024)</a> identified a heterozygous 4-bp insertion (c.1513_1514insGGAC, NM_004281.3) in the BAG3 gene, predicted to result in a frameshift and premature termination (Val505GlyfsTer6) that would eliminate the LEAD sequence, a functional caspase recognition and cleavage site. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The variant was not present in public databases, including gnomAD. Western blot analysis of muscle tissue from 2 patients showed presence of a truncated BAG3 protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=37907725" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p></div>
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Adriaenssens, E., Tedesco, B., Mediani, L., Asselbergh, B., Crippa, V., Antoniani, F., Carra, S., Poletti, A., Timmerman, V.
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<strong>BAG3 pro209 mutants associated with myopathy and neuropathy relocate chaperones of the CASA-complex to aggresomes.</strong>
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Sci. Rep. 10: 8755, 2020.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32472079/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32472079</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=32472079[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=32472079" 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/s41598-020-65664-z" target="_blank">Full Text</a>]
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Arimura, T., Ishikawa, T., Nunoda, S., Kawai, S., Kimura, A.
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<strong>Dilated cardiomyopathy-associated BAG3 mutations impair Z-disc assembly and enhance sensitivity to apoptosis in cardiomyocytes.</strong>
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Hum. Mutat. 32: 1481-1491, 2011.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21898660/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21898660</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21898660" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/humu.21603" target="_blank">Full Text</a>]
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<a id="de Fuenmayor-Fernandez de la Hoz2024" class="mim-anchor"></a>
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de Fuenmayor-Fernandez de la Hoz, C. P., Lupo, V., Bermejo-Guerrero, L., Martin-Jimenez, P., Hernandez-Lain, A., Olive, M., Gallardo, E., Esteban-Perez, J., Espinos, C., Dominguez-Gonzalez, C.
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<strong>Distal hereditary motor neuronopathy as a new phenotype associated with variants in BAG3.</strong>
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J. Neurol. 271: 986-994, 2024.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/37907725/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">37907725</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=37907725" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Fu, J., Ma, M., Song, J., Pang, M., Li, G., Zhang, J.
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<strong>BAG3 p.Pro209Ser mutation identified in a Chinese family with Charcot-Marie-Tooth disease.</strong>
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J. Neurol. 267: 1080-1085, 2020.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31853710/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31853710</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31853710" 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/10.1007/s00415-019-09680-8" target="_blank">Full Text</a>]
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Gross, M. B.
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<strong>Personal Communication.</strong>
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Baltimore, Md. 4/24/2015.
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[<a href="https://doi.org/10.1016/j.nmd.2020.07.012" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.2353/ajpath.2006.060250" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1111/j.1529-8027.2012.00409.x" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1126/science.283.5401.543" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/s13258-018-0721-1" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1111/j.1399-0004.2011.01659.x" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/s0014-5793(01)02728-4" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1097/CND.0000000000000300" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/j.ajhg.2011.01.016" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/j.nmd.2010.05.004" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/s0014-5793(03)00274-6" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ana.21553" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1186/s13023-014-0121-9" target="_blank">Full Text</a>]
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Shy, M., Rebelo, A. P., Feely, S. M. E., Abreu, L. A., Tao, F., Swenson, A., Bacon, C., Zuchner, S.
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[<a href="https://doi.org/10.1136/jnnp-2017-315929" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1074/jbc.274.2.781" target="_blank">Full Text</a>]
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<span class="mim-text-font">
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Cassandra L. Kniffin - updated : 02/10/2025
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<span class="mim-text-font">
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Matthew B. Gross - updated : 04/24/2015<br>Cassandra L. Kniffin - updated : 10/14/2014<br>Cassandra L. Kniffin - updated : 6/2/2014<br>Cassandra L. Kniffin - updated : 1/2/2013<br>Marla J. F. O'Neill - updated : 11/20/2012<br>Marla J. F. O'Neill - updated : 4/8/2011<br>Patricia A. Hartz - updated : 8/2/2010<br>Cassandra L. Kniffin - updated : 8/10/2009
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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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Rebekah S. Rasooly : 6/7/1999
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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alopez : 02/10/2025
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ckniffin : 02/10/2025<br>carol : 12/21/2017<br>carol : 12/18/2017<br>mgross : 04/24/2015<br>carol : 10/17/2014<br>mcolton : 10/15/2014<br>ckniffin : 10/14/2014<br>ckniffin : 6/2/2014<br>carol : 1/10/2013<br>ckniffin : 1/2/2013<br>alopez : 11/21/2012<br>terry : 11/20/2012<br>alopez : 11/19/2012<br>carol : 4/8/2011<br>mgross : 8/11/2010<br>terry : 8/2/2010<br>wwang : 8/28/2009<br>ckniffin : 8/10/2009<br>alopez : 6/7/1999
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<h3>
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<span class="mim-font">
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<strong>*</strong> 603883
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<h3>
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<span class="mim-font">
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BAG COCHAPERONE 3; BAG3
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<br />
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<em>Alternative titles; symbols</em>
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<h4>
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<span class="mim-font">
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BCL2-ASSOCIATED ATHANOGENE 3; BAG3
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: BAG3</em></strong>
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</span>
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<strong>
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<em>
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Cytogenetic location: 10q26.11
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Genomic coordinates <span class="small">(GRCh38)</span> : 10:119,651,380-119,677,819 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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</span>
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</p>
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<span class="mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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<div>
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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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</th>
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<th>
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Phenotype <br /> MIM number
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Inheritance
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<th>
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Phenotype <br /> mapping key
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<span class="mim-font">
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10q26.11
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<span class="mim-font">
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?Neuronopathy, distal hereditary motor, autosomal dominant 15
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</span>
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</td>
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<td>
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<span class="mim-font">
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621094
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</span>
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<td>
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<span class="mim-font">
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Autosomal dominant
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</span>
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<td>
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<span class="mim-font">
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3
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<span class="mim-font">
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Cardiomyopathy, dilated, 1HH
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<span class="mim-font">
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613881
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<span class="mim-font">
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Autosomal dominant
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<td>
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<span class="mim-font">
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3
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<tr>
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<td>
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<span class="mim-font">
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Charcot-Marie-Tooth disease, axonal, type 2JJ
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</span>
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</td>
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<td>
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<span class="mim-font">
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621095
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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<span class="mim-font">
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Myopathy, myofibrillar, 6
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</td>
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<td>
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<span class="mim-font">
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612954
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
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</span>
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</h4>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Description</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>The BAG3 gene encodes a member of the chaperone-assisted selective autophagy (CASA) complex, a large complex that identifies misfolded proteins and transfers them to ATP-dependent chaperones such as the Hsp70 family (see 140550) for refolding or directs them toward ubiquitination and proteasomal degradation. BAG3 binds to HSPB8 (608014) and other proteins in the CASA complex (summary by Adriaenssens et al., 2020). </p><p>Members of the BAG family, including BAG3, are cytoprotective proteins that bind to and regulate Hsp70 family molecular chaperones (Takayama et al., 1999; Homma et al., 2006). </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Takayama et al. (1999) identified cDNAs corresponding to BAG3 and 3 other BAG1 (601497)-like proteins. The partial BAG3 cDNA encodes a protein containing a WW domain in the N-terminal region and a BAG domain in the C-terminal region. Selcen et al. (2009) noted that BAG3 also contains a C-terminal proline-rich domain that interacts with WW-domain proteins implicated in signal transduction and with SH3-domain proteins. </p><p>By database analysis using BAG4 (603884) as query, Jiang et al. (1999) identified BAG3, which has 61% identity to the C-terminal region of BAG4. </p><p>Using Western blot analysis, Pagliuca et al. (2003) found that BAG3 has an apparent molecular mass of 84 kD. </p><p>BAG3 is highly expressed in cardiomyocytes and skeletal muscle cells (summary by Adriaenssens et al., 2020). </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Structure</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Selcen et al. (2009) stated that the BAG3 gene contains 4 exons. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Mapping</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Gross (2015) mapped the BAG3 gene to chromosome 10q26.11 based on an alignment of the BAG3 sequence (GenBank AF071218) 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>Takayama et al. (1999) demonstrated that BAG1, BAG2 (603882), and BAG3 bind with high affinity to the ATPase domain of Hsc70 and inhibit its chaperone activity in a HIP (ST13; 606796)-repressible manner. These authors concluded that interactions with various BAG family proteins allow opportunities for specification and diversification of Hsp70/Hsc70 (HSPA8; 600816) chaperone functions. </p><p>Using in situ hybridization and immunohistochemical analyses, Liao et al. (2001) detected high BAG3 mRNA and protein expression in the cytoplasm of pancreatic tumor tissue, with little or no expression in adjacent normal pancreatic tissue. BAG3 was not overexpressed in other gastrointestinal cancers. Liao et al. (2001) hypothesized that the antiapoptotic function of BAG3 may contribute to the aggressiveness of pancreatic cancers. </p><p>Using Northern and Western blot analyses, Pagliuca et al. (2003) found that expression of BAG3, together with that of HSP70 and metallothionein (see MT1A; 156350), was upregulated in HeLa cells exposed to heat or to the heavy metals zinc and cadmium. During heat and metal stress, the intracellular localization of BAG3 changed from a homogeneous cytoplasmic distribution to a reticular perinuclear distribution, where BAG3 colocalized with a rough endoplasmic reticulum (ER) marker. Pagliuca et al. (2003) noted that the ER is the major organelle in the integration of damage-sensing and proapoptotic stimuli and hypothesized that BAG3 may have a role in the cellular response to environmental stress. </p><p>In skeletal muscle, BAG3 plays a role in cell resilience to mechanical stress through chaperone-associated selected autophagy (CASA), which removes misfolded proteins. Similarly, peripheral nerves are subject to mechanical tension and prone to protein misfolding or aggregation. BAG3 binds to HSPB8 (608014) via 2 conserved Ile-Pro-Val (IPV) motifs. This interaction is essential for function of the CASA complex (summary by Shy et al., 2018). </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p><strong><em>Myofibrillar Myopathy 6</em></strong></p><p>
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In 3 unrelated patients with childhood-onset of rapidly progressive myofibrillar myopathy (MFM6; 612954), Selcen et al. (2009) identified the same heterozygous mutation in the BAG3 gene (P209L; 603883.0001). The unaffected parents of 2 patients did not carry the mutation, indicating de novo occurrence; DNA was not available from the unaffected parents of the third patient. </p><p>Lee et al. (2012) identified a de novo heterozygous P209L mutation in a Chinese girl with myofibrillar myopathy. The patient and her father had an R258W missense mutation (603883.0009) in the BAG3 gene. The father had no abnormal neuromuscular findings, but asymptomatic prolonged QT interval. It was unclear whether the R258W mutation contributed to the phenotype of either individual. </p><p>In a man with adult-onset myofibrillar myopathy, Semmler et al. (2014) identified a de novo heterozygous missense mutation in the BAG3 gene (P209Q; 603883.0010). </p><p>In a 15-year-old Korean girl with MFM6 and a peripheral axonal sensorimotor neuropathy consistent with Charcot-Marie-Tooth disease, Kim et al. (2018) identified a de novo heterozygous P209L mutation in the BAG3 gene. The mutation was found by whole-exome sequencing; functional studies of the variant were not performed. </p><p>In a 13-year-old Caucasian girl with MFM6 and a peripheral sensorimotor neuropathy consistent with Charcot-Marie-Tooth disease, Malatesta et al. (2020) identified a de novo heterozygous P209L mutation in the BAG3 gene. The mutation was found by trio-based exome sequencing; functional studies of the variant were not performed. </p><p>In a Japanese man and his mother with MFM6 and an axonal sensorimotor peripheral neuropathy consistent with Charcot-Marie-Tooth disease, Hamaguchi et al. (2020) identified a heterozygous missense mutation in the BAG3 gene (P470S; 603883.0012). The mutation was found by sequencing a MFM-targeted gene panel and confirmed by Sanger sequencing. No other family members were sequenced. Functional studies of the variant were not performed. </p><p><strong><em>Charcot-Marie-Tooth Disease Type 2JJ</em></strong></p><p>
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In 9 affected individuals from 2 large multigenerational families with axonal Charcot-Marie-Tooth disease type 2JJ (CMT2JJ; 621095), Shy et al. (2018) identified a heterozygous P209S mutation in the BAG3 gene (603883.0011). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. The P209S variant occurs at a conserved residue in 1 of the 2 Ile-Pro-Val (IPV) motifs that mediates binding to HSPB8. Functional studies of the variant were not performed, buy Shy et al. (2018) suggested that disruption of the IPV motif could interrupt BAG3-HSPB8 binding and fail to promote clearance of aggregate proteins in peripheral nerves, resulting in damage to the nerves. The patients had no clinical evidence of a myopathy; neither muscle biopsy nor sural nerve biopsy were performed. </p><p>In a mother and daughter from a nonconsanguineous Chinese family with CMT2JJ, Fu et al. (2020) identified a heterozygous P209S mutation in the BAG3 gene. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The variant was not found in the ExAC or gnomAD databases. Functional studies of the variant and studies of patient cells were not performed. </p><p><strong><em>Autosomal Dominant Distal Hereditary Motor Neuronopathy 15</em></strong></p><p>
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In 8 affected members of a Spanish family with autosomal dominant distal hereditary motor neuronopathy-15 (HMND15; 621094), de Fuenmayor-Fernandez de la Hoz et al. (2024) identified a heterozygous frameshift in the BAG3 gene (Val505GlyfsTer6; 603883.0013), thus eliminating the LEAD sequence, a functional caspase recognition and cleavage site. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The variant was not present in public databases, including gnomAD. Western blot analysis of muscle tissue from 2 patients showed presence of a truncated BAG3 protein. Functional studies of the variant were not performed, but the authors noted that mutant caspase-resistant BAG3 cells are able to resist apoptosis in vitro. They suggested that the frameshift mutation in this family, eliminating the LEAD sequence, would decrease apoptosis and result in increased expression of mutant BAG3, possibly causing increased binding to HSPB8 (608014), the formation of intracellular aggregates, and disrupted autophagy in lower motor neurons. The patients had no sensory abnormalities. Sural nerve biopsy was not performed; muscle biopsy showed neurogenic changes, but was otherwise normal. </p><p><strong><em>Dilated Cardiomyopathy 1HH</em></strong></p><p>
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In a large 3-generation family segregating autosomal dominant dilated cardiomyopathy (CMD1HH; 613881), Norton et al. (2011) performed whole-exome sequencing and genomewide analysis of copy number variation and identified an 8,733-bp deletion in the BAG3 gene (603883.0002) that was present in all 7 affected family members and absent from 355 controls. Norton et al. (2011) then sequenced exons 2, 3, and 4 of BAG3 in an additional 311 CMD probands who were negative for mutation in 15 known CMD-associated genes, and identified heterozygous point mutations in 7 unrelated probands that were not found in 2,644 control chromosomes (see, e.g., 603883.0003-603883.0006). Knockdown of bag3 in a zebrafish model recapitulated CMD and heart failure. </p><p>In 72 Japanese probands with familial CMD, Arimura et al. (2011) analyzed the BAG3 gene and identified heterozygosity for 2 missense mutations in 2 probands: R218W (603883.0007) and L462P (603883.0008). </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>Genotype/Phenotype Correlations</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>In transfected neonatal rat cardiomyocytes (NRCs), Arimura et al. (2011) demonstrated that the CMD-associated mutations R218W and L462P disturbed the assembly and integrity of Z-discs as well as the nuclear localization of BAG3 protein, whereas such abnormalities were not observed with the P209L myofibrillar myopathy (MFM) mutation. In addition, analysis of transfected C2C12 myoblast cells showed that myotube formation was disturbed by the MFM mutation but not by the CMD mutations. TUNEL assay in NRCs and quantified apoptosis of H9c2 cells also indicated that the CMD-associated mutations R218W and L462P increased susceptibility to stress-induced apoptosis compared to wildtype, whereas the P209L MFM mutation did not. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Animal Model</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>In adult mice, Homma et al. (2006) showed that Bag3 is prominently expressed in striated and cardiac muscle and colocalized with Z-discs, with lesser expression in other tissues. Mice with homozygous disruption of the Bag3 gene developed normally, but deteriorated postnatally with stunted growth evident by 1 to 2 weeks of age, and death by 4 weeks. Bag3-deficient mice developed a fulminant myopathy characterized by noninflammatory myofibrillar degeneration with apoptotic features. Cardiac muscle was also affected. Knockdown of Bag3 expression in cultured myoblasts increased apoptosis on induction of differentiation, suggesting that Bag3 is needed for maintenance of myotube survival and confirming a cell autonomous role for Bag3 in muscle. Homma et al. (2006) concluded that, although BAG3 is not required for muscle development, it appears to be critically important for maintenance of mature skeletal muscle. </p>
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</span>
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<div>
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<br />
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>13 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 MYOPATHY, MYOFIBRILLAR, 6</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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BAG3, PRO209LEU
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<br />
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SNP: rs121918312,
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ClinVar: RCV000006347, RCV000183317, RCV000648847, RCV001836702, RCV002362566
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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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<div class="mim-changed mim-change"><p>In 3 unrelated patients with late-childhood onset of autosomal dominant myofibrillar myopathy-6 (MFM6; 612954), Selcen et al. (2009) identified a heterozygous 626C-T transition in exon 3 of the BAG3, gene, resulting in a pro209-to-leu (P209L) substitution. The mutation was not present in 200 control individuals. The unaffected parents of 2 patients did not carry the mutation, indicating de novo occurrence; DNA was not available from the unaffected parents of the third patient. Patients showed a rapidly progressive myopathy affecting both skeletal and cardiac muscle with severe respiratory insufficiency. In vitro functional expression studies showed that the mutant protein tended to aggregate into small granules, suggesting altered folding. </p></div>
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<div class="mim-changed mim-change"><p>Lee et al. (2012) identified a de novo heterozygous P209L mutation in a Chinese girl with onset of myofibrillar myopathy at age 6 years. She had slowly progressive muscle weakness, clumsy walking, rapidly progressive contractures of the Achilles tendons, limited spinal movement, mildly restrictive lung disease, hypertrophic cardiomyopathy, prolonged QT interval, and decreased motor nerve conduction velocities, suggesting a neurogenic axonal disease. Electron microscopy of muscle biopsy showed sarcoplasmic accumulations of electron-dense granulofilamentous material and myofibrillar degeneration with minicores. The patient and her father had an R258W missense mutation (603883.0009) in the BAG3 gene. Her father had no abnormal neuromuscular findings, but asymptomatic prolonged QT interval. It was unclear whether the R258W mutation contributed to the phenotype of either individual. </p></div>
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<p>In 4 patients from 3 unrelated families with MFM6, Odgerel et al. (2010) identified a heterozygous P209L mutation. The mutation occurred de novo in 2 patients. Two brothers inherited the mutation from their unaffected father, who was somatic mosaic for the mutation, with an expression level of 17% in the peripheral blood lymphocytes. </p>
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<p>In 4 patients with MFM6, Jaffer et al. (2012) identified a heterozygous P209L mutation. One of the patients had a sister who was similarly affected, but DNA was not available. Their father had died of a similar but milder disorder at age 30 years, suggesting that he may have been somatic mosaic for the mutation. </p>
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<div class="mim-changed mim-change"><p>In a 15-year-old Korean girl with MFM6 and a peripheral axonal sensorimotor neuropathy consistent with Charcot-Marie-Tooth disease, Kim et al. (2018) identified a de novo heterozygous P209L mutation in the BAG3 gene. The mutation was found by whole-exome sequencing; functional studies of the variant were not performed. </p></div>
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<div class="mim-changed mim-change"><p>In a 13-year-old Caucasian girl with MFM6 and a peripheral sensorimotor neuropathy consistent with Charcot-Marie-Tooth disease, Malatesta et al. (2020) identified a de novo heterozygous P209L mutation in the BAG3 gene. The mutation was found by trio-based exome sequencing; functional studies of the variant were not performed. </p></div>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0002 CARDIOMYOPATHY, DILATED, 1HH</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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BAG3, EX4DEL
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<br />
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ClinVar: RCV000023348
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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 7 affected members of a large 3-generation family segregating autosomal dominant dilated cardiomyopathy (CMD1HH; 613881), Norton et al. (2011) identified heterozygosity for an 8,733-bp deletion encompassing exon 4 of the BAG3 gene. The mutation, which was also present in 3 unaffected family members, was not found in 355 controls. Two affected individuals died of advanced heart failure at age 38 years and age 44 years, and another underwent heart transplant at age 23 years. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0003 CARDIOMYOPATHY, DILATED, 1HH</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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BAG3, ARG71TRP
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<br />
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SNP: rs387906874,
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gnomAD: rs387906874,
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ClinVar: RCV000023349, RCV000456156, RCV000852638, RCV001811196, RCV002415426, RCV003234916
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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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<div class="mim-changed mim-change"><p>In a mother and son who were diagnosed with dilated cardiomyopathy (CMD1HH; 613881) at ages 59 years and 41 years, respectively, Norton et al. (2011) identified heterozygosity for a c.211C-T transition (c.211C-T, NM_004281.3) in exon 2 of the BAG3 gene, resulting in an arg71-to-trp (R71W) substitution. The mutation was not found in 2,644 control chromosomes. The mother underwent heart transplant at age 65 years. </p></div>
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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>.0004 CARDIOMYOPATHY, DILATED, 1HH</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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BAG3, ARG123TER
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<br />
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SNP: rs387906875,
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gnomAD: rs387906875,
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ClinVar: RCV000023350, RCV000211711, RCV000247382, RCV000254992, RCV000627789
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<div class="mim-changed mim-change"><p>In a brother and sister who were diagnosed with dilated cardiomyopathy (CMD1HH; 613881) at ages 25 years and 34 years, respectively, Norton et al. (2011) identified heterozygosity for a c.367C-T transition (c.367C-T, NM_004281.3) in exon 2 of the BAG3 gene, resulting in an arg123-to-ter (R123X) substitution. The mutation was present in their father, who had undergone a heart transplant for an unknown type of cardiomyopathy at 40 years of age, and was also present in an asymptomatic sister, but was not found in 2,644 control chromosomes. The brother had undergone heart transplant at 26 years of age, but his affected sister had only mild left ventricular dysfunction. </p></div>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>.0005 CARDIOMYOPATHY, DILATED, 1HH</strong>
|
|
</span>
|
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</h4>
|
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</div>
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<div>
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<span class="mim-text-font">
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|
|
BAG3, 1-BP DEL, 652C
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<br />
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|
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SNP: rs1589630173,
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ClinVar: RCV000023351
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</span>
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<div class="mim-changed mim-change"><p>In a man who was diagnosed with dilated cardiomyopathy (CMD1HH; 613881) at 47 years of age and died at age 54 years, Norton et al. (2011) identified heterozygosity for a 1-bp deletion (c.652delC, NM_004281.3) in exon 3 of the BAG3 gene, resulting in a frameshift predicted to cause a premature termination codon. The mutation was not found in 2,644 control chromosomes. </p></div>
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|
</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0006 CARDIOMYOPATHY, DILATED, 1HH</strong>
|
|
</span>
|
|
</h4>
|
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</div>
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<div>
|
|
<span class="mim-text-font">
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|
|
BAG3, ARG477HIS
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|
|
<br />
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|
|
SNP: rs387906876,
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|
|
ClinVar: RCV000023352, RCV001065815, RCV004700271
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<div class="mim-changed mim-change"><p>In a man who was diagnosed with dilated cardiomyopathy (CMD1HH; 613881) at 50 years of age and underwent heart transplant within a year, Norton et al. (2011) identified heterozygosity for a c.1430G-A transition (c.1430G-A, NM_004281.3) in exon 4 of the BAG3 gene, resulting in an arg477-to-his (R477H) substitution. The mutation was not found in 2,644 control chromosomes. The proband's affected father was deceased, but the mutation was detected in his paternal uncle, who was diagnosed with CMD at 47 years of age and underwent heart transplant at age 57 years. </p></div>
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|
</span>
|
|
</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 CARDIOMYOPATHY, DILATED, 1HH</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
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|
|
BAG3, ARG218TRP
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|
|
|
<br />
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|
|
SNP: rs397514506,
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|
|
|
gnomAD: rs397514506,
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|
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|
|
|
ClinVar: RCV000032660, RCV000171829, RCV000617935, RCV000648836, RCV003144117
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<div class="mim-changed mim-change"><p>In a 76-year-old Japanese man who developed dilated cardiomyopathy at age 73 years (CMD1HH; 613881), Arimura et al. (2011) identified heterozygosity for a c.652C-T transition (c.652C-T, NM_004281.3) in exon 3 of the BAG3 gene, resulting in an arg218-to-trp (R218W) substitution at a highly conserved residue. The patient had 3 affected sisters, 2 of whom had died suddenly; neither of their deceased parents was known to be affected. DNA was not analyzed from any of these family members. Transfection studies in neonatal rat cardiomyocytes (NRCs) demonstrated that wildtype BAG3 had a striated pattern of assembly and colocalized with the Z-disc markers alpha-actinin (see 102575) and desmin (125660), whereas the R218W mutant did not show a striated pattern, and Z-disc assembly as represented by localization of alpha-actinin and desmin was impaired. TUNEL assay in NRCs and quantification of apoptosis in H9c2 cells both indicated that the R218W mutant increased susceptibility to stress-induced apoptosis compared to wildtype. </p></div>
|
|
</span>
|
|
</div>
|
|
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<div>
|
|
<br />
|
|
</div>
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|
|
</div>
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<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0008 CARDIOMYOPATHY, DILATED, 1HH</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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|
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|
|
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|
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<div>
|
|
<span class="mim-text-font">
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|
|
|
BAG3, LEU462PRO
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|
|
|
<br />
|
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|
|
SNP: rs397514507,
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|
|
|
|
|
ClinVar: RCV000032661, RCV000437344
|
|
|
|
|
|
</span>
|
|
</div>
|
|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
<div class="mim-changed mim-change"><p>In a 41-year-old Japanese woman who developed dilated cardiomyopathy at age 34 years (CMD1HH; 613881), Arimura et al. (2011) identified heterozygosity for a c.1385T-C transition (c.1385T-C, NM_004281.3) in exon 4 of the BAG3 gene, resulting in a leu462-to-pro (L462P) substitution at a highly conserved residue. The mutation was also detected in the proband's 27-year-old sister, who did not have overt CMD but showed slight systolic dysfunction, with regional hypokinesia in the posterior ventricular wall. However, the mutation was not found in their unaffected father or brother or in 400 Japanese controls. Their affected mother had died suddenly at age 52 years. Electrocardiographic analysis of the 2 affected individuals showed no primary conduction defect, serum creatine kinase levels were not elevated, and neither showed signs of skeletal myopathy or neuropathy. Transfection studies in neonatal rat cardiomyocytes demonstrated that wildtype BAG3 had a striated pattern of assembly and colocalized with the Z-disc markers alpha-actinin (see 102575) and desmin (125660), whereas the L462P mutant did not show a striated pattern, and Z-disc assembly as represented by localization of alpha-actinin and desmin was impaired. TUNEL assay in NRCs and quantification of apoptosis in H9c2 cells both indicated that the L462P mutant increased susceptibility to stress-induced apoptosis compared to wildtype. </p></div>
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|
</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0009 VARIANT OF UNKNOWN SIGNIFICANCE</strong>
|
|
</span>
|
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</h4>
|
|
</div>
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<div>
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<span class="mim-text-font">
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BAG3, ARG258TRP
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<br />
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|
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SNP: rs117671123,
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gnomAD: rs117671123,
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ClinVar: RCV000032662, RCV000037897, RCV000490529, RCV000590218, RCV000618102, RCV001081302, RCV001107316, RCV003486548
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</span>
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>This variant is classified as a variant of unknown significance because its contribution to cardiac or muscle disease has not been confirmed.</p>
|
|
|
|
<div class="mim-changed mim-change"><p>Lee et al. (2012) identified a heterozygous c.772C-T transition (c.772C-T, NM_004281.3) in the BAG3 gene, resulting in an arg258-to-trp (R258W) substitution at a highly conserved residue in a Chinese father and daughter with prolonged QT interval. The variant was found in 2 of 286 control chromosomes (allele frequency of 0.007). Functional studies were not performed. The variant was identified by study of the daughter, who had myofibrillar myopathy (MFM6; 612954) caused by a de novo heterozygous known pathogenic mutation in the BAG3 gene (P209L; 603883.0001). The father had no abnormal neuromuscular findings, and his prolonged QT interval was asymptomatic. It was unclear whether the R258W variant contributed to the phenotype in either individual. </p></div>
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|
</span>
|
|
</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 MYOPATHY, MYOFIBRILLAR, 6</strong>
|
|
</span>
|
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</h4>
|
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</div>
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<div>
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<span class="mim-text-font">
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BAG3, PRO209GLN
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<br />
|
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SNP: rs121918312,
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ClinVar: RCV000144684, RCV001849971
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</span>
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<div class="mim-changed mim-change"><p>In a man with adult-onset myofibrillar myopathy-6 (MFM6; 612954), Semmler et al. (2014) identified a de novo heterozygous c.626C-A transversion (c.626C-A, NM_004281.3) in exon 3 of the BAG3 gene, resulting in a pro209-to-gln (P209Q) substitution. The mutation was not found in the 1000 Genomes Project or Exome Sequencing Project databases or in either unaffected parent. Functional studies of the variant were not performed, but a different mutation at this codon (P209L; 603883.0001) has been found in multiple patients with MFM6. The patient developed distal lower limb weakness at age 34 years, which progressed to proximal muscle weakness affecting the upper and lower limbs. Muscle biopsy showed vacuoles, core-like lesions, and some necrotic fibers; ultrastructural examination showed tubulofilamentous accumulations, Z-disc streaming, and the accumulation of granulofilamentous material. He also had an axonal sensorimotor polyneuropathy manifest as decreased vibration sense and ataxic gait, but sural nerve biopsy did not show giant axons. He did not have cardiac or respiratory muscle involvement, indicating a relatively mild phenotype. </p></div>
|
|
</span>
|
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</div>
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<div>
|
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<br />
|
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</div>
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</div>
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<div>
|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0011 CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2JJ</strong>
|
|
</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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BAG3, PRO209SER
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<br />
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ClinVar: RCV005065323
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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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<div class="mim-changed mim-change"><p>In 9 affected individuals from 2 large multigenerational families with axonal Charcot-Marie-Tooth disease type 2JJ (CMT2JJ; 621095), Shy et al. (2018) identified a heterozygous c.625C-T transition in exon 3 of the BAG3 gene, resulting in a pro209-to-ser (P209S) substitution at a conserved residue in 1 of the 2 Ile-Pro-Val (IPV) motifs that mediates binding to HSPB8 (608014). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. The patients had no clinical evidence of a myopathy; neither muscle biopsy nor sural nerve biopsy were performed. </p><p>In a mother and daughter from a nonconsanguineous Chinese family with CMT2JJ, Fu et al. (2020) identified a heterozygous P209S mutation (c.625C-T, NM_004281) in the BAG3 gene. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The variant was not found in the ExAC or gnomAD databases. Functional studies of the variant and studies of patient cells were not performed. </p></div>
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</span>
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</div>
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<div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0012 MYOPATHY, MYOFIBRILLAR, 6</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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BAG3, PRO470SER
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<br />
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SNP: rs756020699,
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gnomAD: rs756020699,
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ClinVar: RCV001046418, RCV003339442
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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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<div class="mim-changed mim-change"><p>In a Japanese man and his mother with adult-onset myofibrillar myopathy-6 (MFM6; 612954) and an axonal sensorimotor peripheral neuropathy consistent with Charcot-Marie-Tooth disease, Hamaguchi et al. (2020) identified a heterozygous c.1408C-T transition (c.1408C-T, NM_004281.3) in the BAG3 gene, resulting in a pro470-to-ser (P470S) substitution. The mutation was found by sequencing a MFM-targeted gene panel and confirmed by Sanger sequencing. No other family members were sequenced. Functional studies of the variant were not performed. </p></div>
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</span>
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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>.0013 NEURONOPATHY, DISTAL HEREDITARY MOTOR, AUTOSOMAL DOMINANT 15 (1 family)</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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BAG3, 4-BP INS, 1513GGAC
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<br />
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ClinVar: RCV005065324
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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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<div class="mim-changed mim-change"><p>In 8 affected members of a Spanish family with autosomal dominant distal hereditary motor neuronopathy-15 (HMND15; 621094), de Fuenmayor-Fernandez de la Hoz et al. (2024) identified a heterozygous 4-bp insertion (c.1513_1514insGGAC, NM_004281.3) in the BAG3 gene, predicted to result in a frameshift and premature termination (Val505GlyfsTer6) that would eliminate the LEAD sequence, a functional caspase recognition and cleavage site. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The variant was not present in public databases, including gnomAD. Western blot analysis of muscle tissue from 2 patients showed presence of a truncated BAG3 protein. </p></div>
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</span>
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>REFERENCES</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<ol>
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<li>
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<p class="mim-text-font">
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<strong>BAG3 pro209 mutants associated with myopathy and neuropathy relocate chaperones of the CASA-complex to aggresomes.</strong>
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Sci. Rep. 10: 8755, 2020.
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[PubMed: 32472079]
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<p class="mim-text-font">
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Arimura, T., Ishikawa, T., Nunoda, S., Kawai, S., Kimura, A.
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<strong>Dilated cardiomyopathy-associated BAG3 mutations impair Z-disc assembly and enhance sensitivity to apoptosis in cardiomyocytes.</strong>
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Hum. Mutat. 32: 1481-1491, 2011.
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<p class="mim-text-font">
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de Fuenmayor-Fernandez de la Hoz, C. P., Lupo, V., Bermejo-Guerrero, L., Martin-Jimenez, P., Hernandez-Lain, A., Olive, M., Gallardo, E., Esteban-Perez, J., Espinos, C., Dominguez-Gonzalez, C.
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<strong>Distal hereditary motor neuronopathy as a new phenotype associated with variants in BAG3.</strong>
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J. Neurol. 271: 986-994, 2024.
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<p class="mim-text-font">
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Fu, J., Ma, M., Song, J., Pang, M., Li, G., Zhang, J.
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<strong>BAG3 p.Pro209Ser mutation identified in a Chinese family with Charcot-Marie-Tooth disease.</strong>
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J. Neurol. 267: 1080-1085, 2020.
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[PubMed: 31853710]
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[Full Text: https://doi.org/10.1007/s00415-019-09680-8]
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<p class="mim-text-font">
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Gross, M. B.
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<strong>Personal Communication.</strong>
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Baltimore, Md. 4/24/2015.
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Hamaguchi, M., Kokubun, N., Inoue, M., Komagamine, T., Aoki, R., Nishino, I., Hirata, K.
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<strong>A family with adult-onset myofibrillar myopathy with BAG3 mutation (P470S) presenting with axonal polyneuropathy.</strong>
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Neuromusc. Disord. 30: 727-731, 2020.
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[PubMed: 32859500]
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[Full Text: https://doi.org/10.1016/j.nmd.2020.07.012]
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Homma, S., Iwasaki, M., Shelton, G. D., Engvall, E., Reed, J. C., Takayama, S.
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<strong>BAG3 deficiency results in fulminant myopathy and early lethality.</strong>
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Am. J. Path. 169: 761-773, 2006.
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[PubMed: 16936253]
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[Full Text: https://doi.org/10.2353/ajpath.2006.060250]
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Jaffer, F., Murphy, S. M., Scoto, M., Healy, E., Rossor, A. M., Brandner, S., Phadke, R., Selcen, D., Jungbluth, H., Muntoni, F., Reilly, M. M.
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<strong>BAG3 mutations: another cause of giant axonal neuropathy.</strong>
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J. Peripher. Nerv. Syst. 17: 210-216, 2012.
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[Full Text: https://doi.org/10.1111/j.1529-8027.2012.00409.x]
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<p class="mim-text-font">
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Jiang, Y., Woronicz, J. D., Liu, W., Goeddel, D. V.
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<strong>Prevention of constitutive TNF receptor 1 signaling by silencer of death domains.</strong>
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Science 283: 543-546, 1999. Note: Erratum: Science 283: 1852 only, 1999.
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[PubMed: 9915703]
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[Full Text: https://doi.org/10.1126/science.283.5401.543]
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</p>
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<p class="mim-text-font">
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Kim, S. J., Nam, S. H., Kanwal, S., Nam, D. E., Yoo, D. H., Chae, J.-H., Suh, Y.-L., Chung, K. W., Choi, B.-O.
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<strong>BAG3 mutation in a patient with atypical phenotypes of myofibrillar myopathy and Charcot-Marie-Tooth disease.</strong>
|
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Genes Genomics 40: 1269-1277, 2018.
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[PubMed: 30145633]
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[Full Text: https://doi.org/10.1007/s13258-018-0721-1]
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<p class="mim-text-font">
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Lee, H. C., Cherk, S. W., Chan, S. K., Wong, S., Tong, T. W., Ho, W. S., Chan, A. Y., Lee, K. C., Mak, C. M.
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<strong>BAG3-related myofibrillar myopathy in a Chinese family.</strong>
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Clin. Genet. 81: 394-398, 2012.
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[PubMed: 21361913]
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[Full Text: https://doi.org/10.1111/j.1399-0004.2011.01659.x]
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<p class="mim-text-font">
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Liao, Q., Ozawa, F., Friess, H., Zimmermann, A., Takayama, S., Reed, J. C., Kleeff, J., Buchler, M. W.
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<strong>The anti-apoptotic protein BAG-3 is overexpressed in pancreatic cancer and induced by heat stress in pancreatic cancer cell lines.</strong>
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FEBS Lett. 503: 151-157, 2001.
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<p class="mim-text-font">
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Malatesta, L., Arya, K., Gokden, M., Stefans, V., Veerapandiyan, A.
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<strong>BAG3 myopathy presenting with prominent neuropathic phenotype and no cardiac or respiratory involvement: a case report and literature review.</strong>
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J. Clin. Neuromusc. Dis. 21: 230-239, 2020.
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<p class="mim-text-font">
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Norton, N., Li, D., Rieder, M. J., Siegfried, J. D., Rampersaud, E., Zuchner, S., Mangos, S., Gonzalez-Quintana, J., Wang, L., McGee, S., Reiser, J., Martin, E., Nickerson, D. A., Hershberger, R. E.
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<strong>Genome-wide studies of copy number variation and exome sequencing identify rare variants in BAG3 as a cause of dilated cardiomyopathy.</strong>
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Am. J. Hum. Genet. 88: 273-282, 2011.
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<p class="mim-text-font">
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Odgerel, Z., Sarkozy, A., Lee, H.-S., McKenna, C., Rankin, J., Straub, V., Lochmuller, H., Paola, F., D'Amico, A., Bertini, E., Bushby, K., Goldfarb, L. G.
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<strong>Inheritance patterns and phenotypic features of myofibrillar myopathy associated with a BAG3 mutation.</strong>
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<p class="mim-text-font">
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Pagliuca, M. G., Lerose, R., Cagliano, S., Leone, A.
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<strong>Regulation by heavy metals and temperature of the human BAG-3 gene, a modulator of Hsp70 activity.</strong>
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FEBS Lett. 541: 11-15, 2003.
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<p class="mim-text-font">
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Selcen, D., Muntoni, F., Burton, B. K., Pegoraro, E., Sewry, C., Bite, A. V., Engel, A. G.
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<strong>Mutation in BAG3 causes severe dominant childhood muscular dystrophy.</strong>
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Ann. Neurol. 65: 83-89, 2009.
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[PubMed: 19085932]
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[Full Text: https://doi.org/10.1002/ana.21553]
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</p>
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<li>
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<p class="mim-text-font">
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Semmler, A.-L., Sacconi, S., Bach, J. E., Liebe, C., Burmann, J., Kley, R. A., Ferbert, A., Anderheiden, R., Van den Bergh, P., Martin, J.-J., De Jonghe, P., Neuen-Jacob, E., and 9 others.
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<strong>Unusual multisystemic involvement and a novel BAG3 mutation revealed by NGS screening in a large cohort of myofibrillar myopathies.</strong>
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Orphanet J. Rare Dis. 9: 121, 2014. Note: Electronic Article.
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[PubMed: 25208129]
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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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Shy, M., Rebelo, A. P., Feely, S. M. E., Abreu, L. A., Tao, F., Swenson, A., Bacon, C., Zuchner, S.
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<strong>Mutations in BAG3 cause adult-onset Charcot-Marie-Tooth disease.</strong>
|
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J. Neurol. Neurosurg. Psychiat. 89: 313-315, 2018.
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[PubMed: 28754666]
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[Full Text: https://doi.org/10.1136/jnnp-2017-315929]
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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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Takayama, S., Xie, Z., Reed, J. C.
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<strong>An evolutionarily conserved family of Hsp70/Hsc70 molecular chaperone regulators.</strong>
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[PubMed: 9873016]
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</p>
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</li>
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</ol>
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<div>
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<br />
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</div>
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</div>
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</div>
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<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>
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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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Cassandra L. Kniffin - updated : 02/10/2025<br>Matthew B. Gross - updated : 04/24/2015<br>Cassandra L. Kniffin - updated : 10/14/2014<br>Cassandra L. Kniffin - updated : 6/2/2014<br>Cassandra L. Kniffin - updated : 1/2/2013<br>Marla J. F. O'Neill - updated : 11/20/2012<br>Marla J. F. O'Neill - updated : 4/8/2011<br>Patricia A. Hartz - updated : 8/2/2010<br>Cassandra L. Kniffin - updated : 8/10/2009
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</span>
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</div>
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<span class="text-nowrap mim-text-font">
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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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Rebekah S. Rasooly : 6/7/1999
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Edit History:
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alopez : 02/10/2025<br>ckniffin : 02/10/2025<br>carol : 12/21/2017<br>carol : 12/18/2017<br>mgross : 04/24/2015<br>carol : 10/17/2014<br>mcolton : 10/15/2014<br>ckniffin : 10/14/2014<br>ckniffin : 6/2/2014<br>carol : 1/10/2013<br>ckniffin : 1/2/2013<br>alopez : 11/21/2012<br>terry : 11/20/2012<br>alopez : 11/19/2012<br>carol : 4/8/2011<br>mgross : 8/11/2010<br>terry : 8/2/2010<br>wwang : 8/28/2009<br>ckniffin : 8/10/2009<br>alopez : 6/7/1999
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