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<title>
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Entry
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- *611332 - DNAJ/HSP40 HOMOLOG, SUBFAMILY B, MEMBER 6; DNAJB6
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- OMIM
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</nav>
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<input type="hidden" id="mimSearchIndex" name="index" value="entry" />
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<input type="hidden" id="mimSearchStart" name="start" value="1" />
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<input type="hidden" id="mimSearchLimit" name="limit" value="10" />
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<input type="hidden" id="mimSearchSort" name="sort" value="score desc, prefix_sort desc" />
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<input type="search" id="mimEntrySearch" name="search" class="form-control" value="" placeholder="Search OMIM..." maxlength="5000" autocomplete="off" autocorrect="off" autocapitalize="none" spellcheck="false" autofocus />
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Advanced Search
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<li style="margin-left: 0.5em;">
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<a href="/search/advanced/entry"> OMIM </a>
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<li style="margin-left: 0.5em;">
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<a href="/search/advanced/clinicalSynopsis"> Clinical Synopses </a>
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<li style="margin-left: 0.5em;">
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<a href="/search/advanced/geneMap"> Gene Map </a>
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<a href="/history"> Search History </a>
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</form>
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<p />
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*611332</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="#geneFunction">Gene Function</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="#molecularGenetics">Molecular Genetics</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#animalModel">Animal Model</a>
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<li 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/611332">Table View</a>
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</li>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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</li>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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</li>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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</ul>
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</nav>
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<div 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=ENSG00000105993;t=ENST00000262177" 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=10049" 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=611332" 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=ENSG00000105993;t=ENST00000262177" 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_001363676,NM_005494,NM_058246,XM_005249515,XM_005249516,XM_006715823,XM_011515704,XM_047419695,XM_047419696,XM_047419697,XM_047419698" 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_058246" 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=611332" 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=07107&isoform_id=07107_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/DNAJB6" 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/3402485,4885495,5441950,6648623,6681592,6681594,12052934,12652849,12803263,17388799,19855067,41471289,41471290,41473761,49065422,51094673,51094674,62089304,62898934,71297298,119624975,119624976,156181166,158257338,158259511,194375261,194387090,194387542,194388658,530387208,530387210,578813845,767946620,1393169778,2217365115,2217365117,2217365119,2217365121,2462611775,2462611777,2462611779,2462611781,2462611783,2462611785,2462611787" 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/O75190" 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=10049" 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=ENSG00000105993;t=ENST00000262177" 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=DNAJB6" 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=DNAJB6" 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+10049" 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/DNAJB6" 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:10049" 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/10049" 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=chr7&hgg_gene=ENST00000262177.9&hgg_start=157337004&hgg_end=157417439&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:14888" 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:14888" 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=611332[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=611332[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000105993" 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=DNAJB6" 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=DNAJB6" 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=DNAJB6" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=DNAJB6&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/PA27418" 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:14888" 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/FBgn0034091.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:1344381" 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/DNAJB6#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:1344381" 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/10049/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=10049" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="https://wormbase.org/db/gene/gene?name=WBGene00001042;class=Gene" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name'{'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">Wormbase Gene</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-040426-1122" 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=DNAJB6&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>ICD10CM:</strong> G71.031<br />
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">ICD+</a>
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</div>
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<div>
|
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<span class="h3">
|
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<span class="mim-font mim-tip-hint" title="Gene description">
|
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<span class="text-danger"><strong>*</strong></span>
|
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611332
|
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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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DNAJ/HSP40 HOMOLOG, SUBFAMILY B, MEMBER 6; DNAJB6
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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>
|
|
</span>
|
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</p>
|
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</div>
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
MRJ<br />
|
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DJ4
|
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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>
|
|
<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=DNAJB6" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">DNAJB6</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>
|
|
<span class="mim-text-font">
|
|
<strong>
|
|
<em>
|
|
Cytogenetic location: <a href="/geneMap/7/862?start=-3&limit=10&highlight=862">7q36.3</a>
|
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|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr7:157337004-157417439&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'})">7:157,337,004-157,417,439</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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|
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|
|
</span>
|
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</p>
|
|
</div>
|
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|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
<div>
|
|
<a id="geneMap" class="mim-anchor"></a>
|
|
<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
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<thead>
|
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<tr class="active">
|
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<th>
|
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Location
|
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</th>
|
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<th>
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Phenotype
|
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</th>
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<th>
|
|
Phenotype <br /> MIM number
|
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</th>
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Muscular dystrophy, limb-girdle, autosomal dominant 1
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PheneGene Graphics <span class="caret"></span>
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<li><a href="/graph/radial/611332" 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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<p>DNAJB6 belongs to the evolutionarily conserved DNAJ/HSP40 family of proteins, which regulate molecular chaperone activity by stimulating ATPase activity. DNAJ proteins may have up to 3 distinct domains: a conserved 70-amino acid J domain, usually at the N terminus; a glycine/phenylalanine (G/F)-rich region; and a cysteine-rich domain (<a href="#7" class="mim-tip-reference" title="Ohtsuka, K., Hata, M. <strong>Mammalian HSP40/DNAJ homologs: cloning of novel cDNAs and a proposal for their classification and nomenclature.</strong> Cell Stress Chaperones 5: 98-112, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11147971/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11147971</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11147971[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/10.1379/1466-1268(2000)005<0098:mhdhco>2.0.co;2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11147971">Ohtsuka and Hata, 2000</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11147971" 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 searching for DNAJ-like proteins, <a href="#11" class="mim-tip-reference" title="Seki, N., Hattori, A., Hayashi, A., Kozuma, S., Miyajima, N., Saito, T. <strong>Cloning, tissue expression, and chromosomal assignment of human MRJ gene for a member of the DNAJ protein family.</strong> J. Hum. Genet. 44: 185-189, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10319584/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10319584</a>] [<a href="https://doi.org/10.1007/s100380050139" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10319584">Seki et al. (1999)</a> identified and subsequently cloned DNAJB6, which they called MRJ, from a human fetal brain cDNA library. The deduced 241-amino acid protein has a calculated molecular mass of 37 kD. DNAJB6 contains an N-terminal J domain followed by a glycine-rich region, but does not contain a cysteine-rich region. The protein shares 94% sequence identity with the mouse homolog. RT-PCR analysis detected ubiquitous expression of DNAJB6. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10319584" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By searching EST databases for J domain-containing proteins, <a href="#7" class="mim-tip-reference" title="Ohtsuka, K., Hata, M. <strong>Mammalian HSP40/DNAJ homologs: cloning of novel cDNAs and a proposal for their classification and nomenclature.</strong> Cell Stress Chaperones 5: 98-112, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11147971/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11147971</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11147971[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/10.1379/1466-1268(2000)005<0098:mhdhco>2.0.co;2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11147971">Ohtsuka and Hata (2000)</a> identified 10 mouse and human DNAJ homologs, including mouse DnajB6. The predicted type II transmembrane protein contains 242 amino acids. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11147971" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By Northern blot analysis, <a href="#2" class="mim-tip-reference" title="Chuang, J.-Z., Zhou, H., Zhu, M., Li, S.-H., Li, X.-J., Sung, C.-H. <strong>Characterization of a brain-enriched chaperone, MRJ, that inhibits huntingtin aggregation and toxicity independently.</strong> J. Biol. Chem. 277: 19831-19838, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11896048/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11896048</a>] [<a href="https://doi.org/10.1074/jbc.M109613200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11896048">Chuang et al. (2002)</a> found that the expression of human DNAJB6 was highest in brain and much weaker in all other tissues examined. Within brain, expression was highest in hippocampus and thalamus, and lower in amygdala, substantia nigra, corpus callosum, and caudate nucleus. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11896048" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#10" class="mim-tip-reference" title="Sarparanta, J., Jonson, P. H., Golzio, C., Sandell, S., Luque, H., Screen, M., McDonald, K., Stajich, J. M., Mahjneh, I., Vihola, A., Raheem, O., Penttila, S., and 9 others. <strong>Mutations affecting the cytoplasmic functions of the co-chaperone DNAJB6 cause limb-girdle muscular dystrophy.</strong> Nature Genet. 44: 450-455, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22366786/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22366786</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22366786[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/ng.1103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22366786">Sarparanta et al. (2012)</a> found expression of the DNAJB6 gene at Z discs in human skeletal muscle. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22366786" 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>DNAJB6 is expressed as 2 isoforms with distinct cellular localizations: DNAJB6a (326 residues) localizes to the nucleus, whereas DNAJB6b (242 residues) localizes to both the nucleus and the cytoplasm. <a href="#1" class="mim-tip-reference" title="Bengoechea, R., Pittman, S. K., Tuck, E. P., True, H. L., Weihl, C. C. <strong>Myofibrillar disruption and RNA-binding protein aggregation in a mouse model of limb-girdle muscular dystrophy 1D.</strong> Hum. Molec. Genet. 24: 6588-6602, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26362252/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26362252</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26362252[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddv363" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26362252">Bengoechea et al. (2015)</a> found expression of both isoforms in human and mouse skeletal muscle. In mouse muscle, Dnajb6a showed nuclear localization and Dnajb6b was incorporated into the sarcomere. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26362252" 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="#2" class="mim-tip-reference" title="Chuang, J.-Z., Zhou, H., Zhu, M., Li, S.-H., Li, X.-J., Sung, C.-H. <strong>Characterization of a brain-enriched chaperone, MRJ, that inhibits huntingtin aggregation and toxicity independently.</strong> J. Biol. Chem. 277: 19831-19838, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11896048/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11896048</a>] [<a href="https://doi.org/10.1074/jbc.M109613200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11896048">Chuang et al. (2002)</a> demonstrated that full-length DNAJB6 stimulated ATP hydrolysis by HSP70 (see HSPA1A, <a href="/entry/140550">140550</a>) in a time- and concentration-dependent manner. Both an N-terminal fragment (amino acids 1-109) and a C-terminal fragment (amino acids 108-241) enhanced the ATPase activity of HSP70. Human embryonic kidney 293 cells transfected with mutant huntingtin (HTT; <a href="/entry/613004">613004</a>) N terminus exhibited puncta or aggregates of mutant huntingtin distributed throughout the cytoplasm and nucleus. Coexpression of DNAJB6 delayed aggregate formation and significantly reduced caspase-3 (CASP3; <a href="/entry/600636">600636</a>) activation induced by mutant huntingtin. DNAJB6 also inhibited CASP3 activity augmented by the apoptotic reagent staurosporine. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11896048" 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 PCR analysis of a human/rodent monochromosomal hybrid cell panel and a radiation hybrid panel, <a href="#11" class="mim-tip-reference" title="Seki, N., Hattori, A., Hayashi, A., Kozuma, S., Miyajima, N., Saito, T. <strong>Cloning, tissue expression, and chromosomal assignment of human MRJ gene for a member of the DNAJ protein family.</strong> J. Hum. Genet. 44: 185-189, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10319584/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10319584</a>] [<a href="https://doi.org/10.1007/s100380050139" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10319584">Seki et al. (1999)</a> mapped the DNAJB6 gene to chromosome 11q25. However, <a href="#4" class="mim-tip-reference" title="Gross, M. B. <strong>Personal Communication.</strong> Baltimore, Md. 11/29/2011."None>Gross (2011)</a> mapped the DNAJB6 gene to chromosome 7q36.3 based on alignment of the DNAJB6 sequence (GenBank <a href="https://www.ncbi.nlm.nih.gov/search/all/?term=BC002446" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'GENBANK\', \'domain\': \'ncbi.nlm.nih.gov\'})">BC002446</a>) with the genomic sequence (GRCh37). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10319584" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In affected members of a Caucasian family with autosomal dominant limb-girdle muscular dystrophy (LGMDD1; <a href="/entry/603511">603511</a>), earlier designated LGMD1E, <a href="#6" class="mim-tip-reference" title="Harms, M. B., Sommerville, R. B., Allred, P., Bell, S., Ma, D., Cooper, P., Lopate, G., Pestronk, A., Weihl, C. C., Baloh, R. H. <strong>Exome sequencing reveals DNAJB6 mutations in dominantly-inherited myopathy.</strong> Ann. Neurol. 71: 407-416, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22334415/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22334415</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22334415[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.22683" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22334415">Harms et al. (2012)</a> identified a heterozygous mutation in the DNAJB6 gene (F93L; <a href="#0001">611332.0001</a>). The mutation was identified by whole-genome exome capture followed by next-generation sequencing. Sequencing of the DNAJB6 gene in 13 additional probands with a similar disorder revealed a second mutation (P96R; <a href="#0002">611332.0002</a>) in affected members of an African American family with an autosomal dominant myopathy. Both families had adult-onset of slowly progressive muscle weakness resulting in loss of ambulation after about 20 years, although 1 family had greater involvement of the proximal muscles and the other had greater involvement of the distal muscles. Neither family had cardiac or pulmonary involvement. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22334415" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#10" class="mim-tip-reference" title="Sarparanta, J., Jonson, P. H., Golzio, C., Sandell, S., Luque, H., Screen, M., McDonald, K., Stajich, J. M., Mahjneh, I., Vihola, A., Raheem, O., Penttila, S., and 9 others. <strong>Mutations affecting the cytoplasmic functions of the co-chaperone DNAJB6 cause limb-girdle muscular dystrophy.</strong> Nature Genet. 44: 450-455, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22366786/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22366786</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22366786[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/ng.1103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22366786">Sarparanta et al. (2012)</a> identified 4 different heterozygous mutations in the DNAJB6 gene (<a href="#0001">611332.0001</a>, <a href="#0003">611332.0003</a>-<a href="#0005">611332.0005</a>) in affected members of 9 families with LGMD1E. Five of the families were of Finnish origin (<a href="#9" class="mim-tip-reference" title="Sandell, S., Huovinen, S., Sarparanta, J., Luque, H., Raheem, O., Haapasalo, H., Hackman, P., Udd, B. <strong>The enigma of 7q36 linked autosomal dominant limb girdle muscular dystrophy.</strong> J. Neurol. Neurosurg. Psychiat. 81: 834-839, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20682716/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20682716</a>] [<a href="https://doi.org/10.1136/jnnp.2009.192351" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20682716">Sandell et al., 2010</a> and <a href="#5" class="mim-tip-reference" title="Hackman, P., Sandell, S., Sarparanta, J., Luque, H., Huovinen, S., Palmio, J., Paetau, A., Kalimo, H., Mahjneh, I., Udd, B. <strong>Four new Finnish families with LGMD1D; refinement of the clinical phenotype and the linked 7q36 locus.</strong> Neuromusc. Disord. 21: 338-344, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21376592/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21376592</a>] [<a href="https://doi.org/10.1016/j.nmd.2011.02.008" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21376592">Hackman et al., 2011</a>) and carried the same mutation (<a href="#0003">611332.0003</a>). Two additional families had previously been reported by Speer et al. (<a href="#13" class="mim-tip-reference" title="Speer, M. C., Gilchrist, J. M., Chutkow, J. G., McMichael, R., Westbrook, C. A., Stajich, J. M., Jorgenson, E. M., Gaskell, P. C., Rosi, B. L., Ramesar, R., Vance, J. M., Yamaoka, L. H., Roses, A. D., Pericak-Vance, M. A. <strong>Evidence for locus heterogeneity in autosomal dominant limb-girdle muscular dystrophy.</strong> Am. J. Hum. Genet. 57: 1371-1376, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8533766/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8533766</a>]" pmid="8533766">1995</a>, <a href="#14" class="mim-tip-reference" title="Speer, M. C., Vance, J. M., Grubber, J. M., Graham, F. L., Stajich, J. M., Viles, K. D., Rogala, A., McMichael, R., Chutkow, J., Goldsmith, C., Tim, R. W., Pericak-Vance, M. A. <strong>Identification of a new autosomal dominant limb-girdle muscular dystrophy locus on chromosome 7.</strong> Am. J. Hum. Genet. 64: 556-562, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9973293/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9973293</a>] [<a href="https://doi.org/10.1086/302252" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9973293">1999</a>). Electron microscopy of patient muscle showed Z disc myofibrillar disintegration and autophagic rimmed vacuoles. DNAJB6 was detected in protein accumulations together with its known ligands MLF1 (<a href="/entry/601402">601402</a>) and HSPA8 (<a href="/entry/600816">600816</a>). However, DNAJB6 appeared more in the periphery of the protein accumulations, in contrast to more pronounced colocalization seen in myotilinopathies. Three of the mutations resulted in a phe93-to-leu (F93L) substitution at a highly conserved residue. In vitro functional expression studies showed that the mutations increased the half-life of DNAJB6, extended this effect to the wildtype protein, and reduced the protective antiaggregation effect of DNAJB6. The mutations showed a dominant toxic effect mediated specifically by the cytoplasmic isoform of DNAJB6. The compromised antiaggregation function may lead to impaired protein quality control and accumulation of other proteins. DNAJB6 was found to interact with members of the chaperone-assisted selective autophagy (CASA) complex, including a myofibrillar myopathy (MFM6; <a href="/entry/612954">612954</a>)-related protein BAG3 (<a href="/entry/603883">603883</a>). The findings indicated that LGMD1E is mediated by defective chaperone function, resulting in insufficient maintenance of sarcomeric structures or defective clearance of misfolded sarcomeric proteins. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9973293+21376592+8533766+20682716+22366786" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#15" class="mim-tip-reference" title="Stein, K. C., Bengoechea, R., Harms, M. B., Weihl, C. C., True, H. L. <strong>Myopathy-causing mutations in an HSP40 chaperone disrupt processing of specific client conformers.</strong> J. Biol. Chem. 289: 21120-21130, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24920671/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24920671</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24920671[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1074/jbc.M114.572461" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24920671">Stein et al. (2014)</a> noted that all known LGMD1E mutations localized in the conserved G/F domain of DNAJB6. Using yeast-human chimeric proteins, they found that these DNAJB6 mutants were variably deficient in resolving prion protein aggregates in yeast, with strongest effect shown by the F89I mutation (<a href="#0005">611332.0005</a>) or deletion of the entire G/F domain. TDP43 (TARDBP; <a href="/entry/605078">605078</a>) has a domain similar to that found in yeast prion proteins; in addition, TDP43 aggregates into stress granules during heat shock and accumulates in LGMD1E patient muscle. <a href="#15" class="mim-tip-reference" title="Stein, K. C., Bengoechea, R., Harms, M. B., Weihl, C. C., True, H. L. <strong>Myopathy-causing mutations in an HSP40 chaperone disrupt processing of specific client conformers.</strong> J. Biol. Chem. 289: 21120-21130, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24920671/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24920671</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24920671[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1074/jbc.M114.572461" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24920671">Stein et al. (2014)</a> showed that HeLa cells expressing TDP43 formed nuclear stress bodies during heat shock, and that wildtype, but not G/F mutant, DNAJB6 resolved these stress bodies following recovery from heat shock. LGMD1E patient fibroblasts with the F93L substitution (see <a href="#0001">611332.0001</a>) also showed delayed dissolution of TDP43 nuclear stress bodies following recovery from heat shock. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24920671" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In affected members of a large family with LGMD1E, <a href="#8" class="mim-tip-reference" title="Ruggieri, A., Brancati, F., Zanotti, S., Maggi, L., Pasanisi, M. B., Saredi, S., Terracciano, C., Antozzi, C., D'Alpice, M. R., Sangiuolo, F., Novelli, G., Marshall, C. R., Scherer, S. W., Morandi, L., Federici, L., Massa, R., Mora, M., Minassian, B. A. <strong>Complete loss of the DNAJB6 G/F domain and novel missense mutations cause distal-onset DNAJB6 myopathy.</strong> Acta Neuropath. Commun. 3: 44, 2015. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26205529/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26205529</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26205529[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/s40478-015-0224-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26205529">Ruggieri et al. (2015)</a> identified a heterozygous missense mutation in the DNAJB6 gene (F100V; <a href="#0006">611332.0006</a>). The mutation, which was found by a combination of linkage analysis and exome sequencing, segregated with the disorder in the family. Direct Sanger sequencing of the DNAJB6 gene in 63 patients with sporadic occurrence of a similar disorder identified 4 with de novo heterozygous mutations (<a href="#0003">611332.0003</a>; <a href="#0007">611332.0007</a>-<a href="#0009">611332.0009</a>), thus accounting for 6.4% of the cohort. All the mutations affected the conserved G/F domain, although direct functional studies were not performed. There was some evidence for a genotype/phenotype correlation: proximal G/F mutations were associated with proximal myopathy, whereas distal G/F mutations were associated with distal-onset myopathy. The mutations were predicted to affect the G/F-J interaction in different ways. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26205529" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By exome sequencing in a Hungarian family with a late-onset, mild, and slowly progressive form of LGMDD1, <a href="#16" class="mim-tip-reference" title="Zima, J., Eaton, A., Pal, E., Till, A., Ito, Y. A., Warman-Chardon, J., Hartley, T., Cagnone, G., Melegh, B. I., Boycott, K. M., Melegh, B., Hadzsiev, K. <strong>Intrafamilial variability of limb-girdle muscular dystrophy, LGMD1D type.</strong> Europ. J. Med. Genet. 63: 103655, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31034989/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31034989</a>] [<a href="https://doi.org/10.1016/j.ejmg.2019.04.012" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31034989">Zima et al. (2020)</a> identified a heterozygous missense mutation in the DNAJB6 gene (F91V; <a href="#0010">611332.0010</a>). The authors noted that previous mutations involving the phe91 residue (<a href="#0007">611332.0007</a> and <a href="#0008">611332.0008</a>) were associated with a more severe form of the disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31034989" 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 zebrafish, <a href="#10" class="mim-tip-reference" title="Sarparanta, J., Jonson, P. H., Golzio, C., Sandell, S., Luque, H., Screen, M., McDonald, K., Stajich, J. M., Mahjneh, I., Vihola, A., Raheem, O., Penttila, S., and 9 others. <strong>Mutations affecting the cytoplasmic functions of the co-chaperone DNAJB6 cause limb-girdle muscular dystrophy.</strong> Nature Genet. 44: 450-455, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22366786/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22366786</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22366786[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/ng.1103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22366786">Sarparanta et al. (2012)</a> found expression of the Dnajb6 gene as early as the embryonic 5-somite stage. Injection of 2-cell embryos with a splice-blocking morpholino resulted in a reproducible muscle fiber detachment phenotype. Detachment of slow fibers from their insertion sites at the vertical myoseptum was evident as early as 2 days after fertilization, suggesting adhesion failure with mechanical load. These data indicated that loss of Dnajb6 leads to defects in muscle integrity. Injection of the human mutants F93L (see, e.g., <a href="#0001">611332.0001</a>) or F89I (<a href="#0005">611332.0005</a>) also caused the muscular phenotype, and coinjection with wildtype Dnajb6 showed enhanced severity of the phenotype, consistent with a dominant-negative effect. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22366786" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#1" class="mim-tip-reference" title="Bengoechea, R., Pittman, S. K., Tuck, E. P., True, H. L., Weihl, C. C. <strong>Myofibrillar disruption and RNA-binding protein aggregation in a mouse model of limb-girdle muscular dystrophy 1D.</strong> Hum. Molec. Genet. 24: 6588-6602, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26362252/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26362252</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26362252[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddv363" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26362252">Bengoechea et al. (2015)</a> found that transgenic mice expressing the LGMD1E-associated DNAJB6 F93L mutation (<a href="#0001">611332.0001</a>) in the Dnajb6b isoform had early lethality due to profound muscle weakness, whereas mice with the mutation in the Dnajb6a isoform were unaffected after 1 year. Muscle biopsy of affected mice showed localization of mutant Dnajb6b in the Z-disc, myofibrillar disorganization, desmin and keratin inclusions, and abnormal sarcoplasmic protein aggregations of RNA-binding proteins. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26362252" 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">rs387907046 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387907046;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=rs387907046" 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=rs387907046" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In affected members of a Caucasian family with autosomal dominant limb-girdle muscular dystrophy type 1E (LGMDD1; <a href="/entry/603511">603511</a>), <a href="#6" class="mim-tip-reference" title="Harms, M. B., Sommerville, R. B., Allred, P., Bell, S., Ma, D., Cooper, P., Lopate, G., Pestronk, A., Weihl, C. C., Baloh, R. H. <strong>Exome sequencing reveals DNAJB6 mutations in dominantly-inherited myopathy.</strong> Ann. Neurol. 71: 407-416, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22334415/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22334415</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22334415[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.22683" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22334415">Harms et al. (2012)</a> identified a heterozygous 277T-C transition in the DNAJB6 gene, resulting in a phe93-to-leu (F93L) substitution in a highly conserved residue within the G/F domain. The mutation was not found in over 3,000 controls. Five affected individuals had onset of limb-girdle weakness beginning in the fourth decade. The disorder was manifest as difficulty in climbing stairs or getting up from the floor. In 2 patients, the quadriceps muscles were less affected than the hamstrings. None had cardiac, pulmonary, or bulbar involvement. The disorder was slowly progressive, but a wheelchair was required after about 20 years. Skeletal muscle biopsy from 3 patients showed a chronic myopathy with rimmed vacuoles, variation in fiber size, and internal nuclei. Immunostaining showed TDP43 (<a href="/entry/605078">605078</a>)- and DNAJB6-positive accumulation in multiple fibers; some inclusions were around and within the vacuoles. Serum creatine kinase was increased, and EMG showed clear myopathic changes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22334415" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#10" class="mim-tip-reference" title="Sarparanta, J., Jonson, P. H., Golzio, C., Sandell, S., Luque, H., Screen, M., McDonald, K., Stajich, J. M., Mahjneh, I., Vihola, A., Raheem, O., Penttila, S., and 9 others. <strong>Mutations affecting the cytoplasmic functions of the co-chaperone DNAJB6 cause limb-girdle muscular dystrophy.</strong> Nature Genet. 44: 450-455, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22366786/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22366786</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22366786[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/ng.1103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22366786">Sarparanta et al. (2012)</a> identified a heterozygous 277T-C transition in 4 affected individuals from an Italian family with LGMDD1. The F93L substitution can also be caused by a 279C-G transversion (<a href="#0003">611332.0003</a>) and a 279C-A transversion (<a href="#0004">611332.0004</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22366786" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In affected members of an African American family with limb-girdle muscular dystrophy type 1E (LGMDD1; <a href="/entry/603511">603511</a>), <a href="#6" class="mim-tip-reference" title="Harms, M. B., Sommerville, R. B., Allred, P., Bell, S., Ma, D., Cooper, P., Lopate, G., Pestronk, A., Weihl, C. C., Baloh, R. H. <strong>Exome sequencing reveals DNAJB6 mutations in dominantly-inherited myopathy.</strong> Ann. Neurol. 71: 407-416, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22334415/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22334415</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22334415[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.22683" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22334415">Harms et al. (2012)</a> identified a heterozygous 287C-G transversion in the DNAJB6 gene, resulting in a pro96-to-arg (P96R) substitution at a highly conserved residue in the G/F domain. The mutation was not found in over 3,000 controls. Three affected individuals from an African American family had a distal-predominant myopathy with onset between ages 18 and 35 years. Weakness began in the lower limbs, often manifest as tripping, but progressed to include the hands and proximal legs with loss of ambulation after about 20 to 40 years. There was no cardiac or pulmonary involvement. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22334415" 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 16 affected members from 5 Finnish families with limb-girdle muscular dystrophy type 1E (LGMDD1; <a href="/entry/603511">603511</a>), previously reported by <a href="#9" class="mim-tip-reference" title="Sandell, S., Huovinen, S., Sarparanta, J., Luque, H., Raheem, O., Haapasalo, H., Hackman, P., Udd, B. <strong>The enigma of 7q36 linked autosomal dominant limb girdle muscular dystrophy.</strong> J. Neurol. Neurosurg. Psychiat. 81: 834-839, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20682716/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20682716</a>] [<a href="https://doi.org/10.1136/jnnp.2009.192351" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20682716">Sandell et al. (2010)</a> and <a href="#5" class="mim-tip-reference" title="Hackman, P., Sandell, S., Sarparanta, J., Luque, H., Huovinen, S., Palmio, J., Paetau, A., Kalimo, H., Mahjneh, I., Udd, B. <strong>Four new Finnish families with LGMD1D; refinement of the clinical phenotype and the linked 7q36 locus.</strong> Neuromusc. Disord. 21: 338-344, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21376592/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21376592</a>] [<a href="https://doi.org/10.1016/j.nmd.2011.02.008" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21376592">Hackman et al. (2011)</a>, <a href="#10" class="mim-tip-reference" title="Sarparanta, J., Jonson, P. H., Golzio, C., Sandell, S., Luque, H., Screen, M., McDonald, K., Stajich, J. M., Mahjneh, I., Vihola, A., Raheem, O., Penttila, S., and 9 others. <strong>Mutations affecting the cytoplasmic functions of the co-chaperone DNAJB6 cause limb-girdle muscular dystrophy.</strong> Nature Genet. 44: 450-455, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22366786/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22366786</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22366786[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/ng.1103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22366786">Sarparanta et al. (2012)</a> identified a heterozygous 279C-G transversion in exon 5 of the DNAJB6 gene, resulting in a phe93-to-leu (F93L) substitution at a highly conserved residue in the G/F domain. The mutation was not found in 202 Finnish, 104 Italian, or 215 U.S. control individuals. The F93L substitution can also be caused by a 277T-C transition (<a href="#0001">611332.0001</a>) and a 279C-A transversion (<a href="#0004">611332.0004</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=21376592+20682716+22366786" 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 57-year-old man (patient 3s) with sporadic occurrence of LGMD1E and onset at age 45, <a href="#8" class="mim-tip-reference" title="Ruggieri, A., Brancati, F., Zanotti, S., Maggi, L., Pasanisi, M. B., Saredi, S., Terracciano, C., Antozzi, C., D'Alpice, M. R., Sangiuolo, F., Novelli, G., Marshall, C. R., Scherer, S. W., Morandi, L., Federici, L., Massa, R., Mora, M., Minassian, B. A. <strong>Complete loss of the DNAJB6 G/F domain and novel missense mutations cause distal-onset DNAJB6 myopathy.</strong> Acta Neuropath. Commun. 3: 44, 2015. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26205529/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26205529</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26205529[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/s40478-015-0224-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26205529">Ruggieri et al. (2015)</a> identified a de novo heterozygous c.279C-G transversion (c.279C-G, NC_000007.14) in the DNAJB6 gene. The mutation was found by Sanger sequencing. He had proximal and distal muscle weakness affecting only the lower limbs and remained ambulatory. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26205529" 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 8 affected individuals of an Italian family with limb-girdle muscular dystrophy type 1E (LGMDD1; <a href="/entry/603511">603511</a>), <a href="#10" class="mim-tip-reference" title="Sarparanta, J., Jonson, P. H., Golzio, C., Sandell, S., Luque, H., Screen, M., McDonald, K., Stajich, J. M., Mahjneh, I., Vihola, A., Raheem, O., Penttila, S., and 9 others. <strong>Mutations affecting the cytoplasmic functions of the co-chaperone DNAJB6 cause limb-girdle muscular dystrophy.</strong> Nature Genet. 44: 450-455, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22366786/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22366786</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22366786[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/ng.1103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22366786">Sarparanta et al. (2012)</a> identified a heterozygous 279C-A transversion in exon 5 of the DNAJB6 gene, resulting in a phe93-to-leu (F93L) substitution at a highly conserved residue in the G/F domain. The F93L substitution can also be caused by a 277T-C transition (<a href="#0001">611332.0001</a>) and a 279C-G transversion (<a href="#0003">611332.0003</a>). The mutation was not found in 202 Finnish, 104 Italian, or 215 U.S. control individuals. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22366786" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In affected members of 2 families from the U.S. with limb-girdle muscular dystrophy type 1E (LGMDD1; <a href="/entry/603511">603511</a>), originally reported by Speer et al. (<a href="#13" class="mim-tip-reference" title="Speer, M. C., Gilchrist, J. M., Chutkow, J. G., McMichael, R., Westbrook, C. A., Stajich, J. M., Jorgenson, E. M., Gaskell, P. C., Rosi, B. L., Ramesar, R., Vance, J. M., Yamaoka, L. H., Roses, A. D., Pericak-Vance, M. A. <strong>Evidence for locus heterogeneity in autosomal dominant limb-girdle muscular dystrophy.</strong> Am. J. Hum. Genet. 57: 1371-1376, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8533766/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8533766</a>]" pmid="8533766">1995</a>, <a href="#14" class="mim-tip-reference" title="Speer, M. C., Vance, J. M., Grubber, J. M., Graham, F. L., Stajich, J. M., Viles, K. D., Rogala, A., McMichael, R., Chutkow, J., Goldsmith, C., Tim, R. W., Pericak-Vance, M. A. <strong>Identification of a new autosomal dominant limb-girdle muscular dystrophy locus on chromosome 7.</strong> Am. J. Hum. Genet. 64: 556-562, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9973293/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9973293</a>] [<a href="https://doi.org/10.1086/302252" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9973293">1999</a>), <a href="#10" class="mim-tip-reference" title="Sarparanta, J., Jonson, P. H., Golzio, C., Sandell, S., Luque, H., Screen, M., McDonald, K., Stajich, J. M., Mahjneh, I., Vihola, A., Raheem, O., Penttila, S., and 9 others. <strong>Mutations affecting the cytoplasmic functions of the co-chaperone DNAJB6 cause limb-girdle muscular dystrophy.</strong> Nature Genet. 44: 450-455, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22366786/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22366786</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22366786[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/ng.1103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22366786">Sarparanta et al. (2012)</a> identified a heterozygous c.265T-A transversion (which they referred to as c.267T-A) in the DNAJB6 gene, resulting in a phe89-to-ile (F89I) substitution at a highly conserved residue in the G/F domain. The mutation was not found in 202 Finnish, 104 Italian, or 215 U.S. control individuals. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8533766+9973293+22366786" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In affected members of an American family with LGMD1E, <a href="#3" class="mim-tip-reference" title="Couthouis, J., Raphael, A. R., Siskind, C., Findlay, A. R., Buenrostro, J. D., Greenleaf, W. J., Vogel, H., Day, J. W., Flanigan, K. M., Gitler, A. D. <strong>Exome sequencing identifies a DNAJB6 mutation in a family with dominantly-inherited limb-girdle muscular dystrophy.</strong> Neuromusc. Disord. 24: 431-435, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24594375/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24594375</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24594375[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.2014.01.014" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24594375">Couthouis et al. (2014)</a> identified a heterozygous c.265T-A transversion in the DNAJB6 gene, resulting in a phe89-to-ile (F89I) substitution. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder. It was filtered against the dbSNP (build 137), 1000 Genomes Project, and Exome Sequencing project databases. <a href="#3" class="mim-tip-reference" title="Couthouis, J., Raphael, A. R., Siskind, C., Findlay, A. R., Buenrostro, J. D., Greenleaf, W. J., Vogel, H., Day, J. W., Flanigan, K. M., Gitler, A. D. <strong>Exome sequencing identifies a DNAJB6 mutation in a family with dominantly-inherited limb-girdle muscular dystrophy.</strong> Neuromusc. Disord. 24: 431-435, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24594375/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24594375</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24594375[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.2014.01.014" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24594375">Couthouis et al. (2014)</a> stated that the mutation was the same as that identified by <a href="#10" class="mim-tip-reference" title="Sarparanta, J., Jonson, P. H., Golzio, C., Sandell, S., Luque, H., Screen, M., McDonald, K., Stajich, J. M., Mahjneh, I., Vihola, A., Raheem, O., Penttila, S., and 9 others. <strong>Mutations affecting the cytoplasmic functions of the co-chaperone DNAJB6 cause limb-girdle muscular dystrophy.</strong> Nature Genet. 44: 450-455, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22366786/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22366786</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22366786[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/ng.1103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22366786">Sarparanta et al. (2012)</a>. Haplotype analysis determined that the mutation arose independently in the families reported by <a href="#3" class="mim-tip-reference" title="Couthouis, J., Raphael, A. R., Siskind, C., Findlay, A. R., Buenrostro, J. D., Greenleaf, W. J., Vogel, H., Day, J. W., Flanigan, K. M., Gitler, A. D. <strong>Exome sequencing identifies a DNAJB6 mutation in a family with dominantly-inherited limb-girdle muscular dystrophy.</strong> Neuromusc. Disord. 24: 431-435, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24594375/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24594375</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24594375[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.2014.01.014" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24594375">Couthouis et al. (2014)</a> and <a href="#10" class="mim-tip-reference" title="Sarparanta, J., Jonson, P. H., Golzio, C., Sandell, S., Luque, H., Screen, M., McDonald, K., Stajich, J. M., Mahjneh, I., Vihola, A., Raheem, O., Penttila, S., and 9 others. <strong>Mutations affecting the cytoplasmic functions of the co-chaperone DNAJB6 cause limb-girdle muscular dystrophy.</strong> Nature Genet. 44: 450-455, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22366786/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22366786</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22366786[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/ng.1103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22366786">Sarparanta et al. (2012)</a>, suggesting that it may be a mutation hotspot. Functional studies of the variant were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=24594375+22366786" 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">rs869320700 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs869320700;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=rs869320700" 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=rs869320700" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In affected members of a large Italian family with limb-girdle muscular dystrophy type 1E (LGMDD1; <a href="/entry/603511">603511</a>), originally reported by <a href="#12" class="mim-tip-reference" title="Servidei, S., Capon, F., Spinazzola, A., Mirabella, M., Semprini, S., de Rosa, G., Gennarelli, M., Sangiuolo, F., Ricci, E., Mohrenweiser, H. W., Dallapiccola, B., Tonali, P., Novelli, G. <strong>A distinctive autosomal dominant vacuolar neuromyopathy linked to 19p13.</strong> Neurology 53: 830-837, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10489050/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10489050</a>] [<a href="https://doi.org/10.1212/wnl.53.4.830" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10489050">Servidei et al. (1999)</a>, <a href="#8" class="mim-tip-reference" title="Ruggieri, A., Brancati, F., Zanotti, S., Maggi, L., Pasanisi, M. B., Saredi, S., Terracciano, C., Antozzi, C., D'Alpice, M. R., Sangiuolo, F., Novelli, G., Marshall, C. R., Scherer, S. W., Morandi, L., Federici, L., Massa, R., Mora, M., Minassian, B. A. <strong>Complete loss of the DNAJB6 G/F domain and novel missense mutations cause distal-onset DNAJB6 myopathy.</strong> Acta Neuropath. Commun. 3: 44, 2015. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26205529/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26205529</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26205529[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/s40478-015-0224-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26205529">Ruggieri et al. (2015)</a> identified a heterozygous c.298T-G transversion in the DNAJ6 gene, resulting in a phe100-to-val (F100V) substitution at a highly conserved residue in the G/F domain. The mutation, which was found using a combination of linkage analysis and exome sequencing, segregated with the disorder in the family and was not found in the dbSNP (build 142), 1000 Genomes Project, Exome Sequencing Project, or ExAC databases. One 30-year-old clinically unaffected family member also carried the mutation. The distribution of muscle weakness in affected family members tended to be more distal than proximal. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10489050+26205529" 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 a 39-year-old woman (patient 1s) with sporadic limb-girdle muscular dystrophy type 1E (LGMDD1; <a href="/entry/603511">603511</a>), <a href="#8" class="mim-tip-reference" title="Ruggieri, A., Brancati, F., Zanotti, S., Maggi, L., Pasanisi, M. B., Saredi, S., Terracciano, C., Antozzi, C., D'Alpice, M. R., Sangiuolo, F., Novelli, G., Marshall, C. R., Scherer, S. W., Morandi, L., Federici, L., Massa, R., Mora, M., Minassian, B. A. <strong>Complete loss of the DNAJB6 G/F domain and novel missense mutations cause distal-onset DNAJB6 myopathy.</strong> Acta Neuropath. Commun. 3: 44, 2015. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26205529/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26205529</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26205529[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/s40478-015-0224-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26205529">Ruggieri et al. (2015)</a> identified a de novo heterozygous c.271T-A transversion (c.271T-A, NC_000007.14) in the DNAJ6 gene, resulting in a phe91-to-ile (F91I) substitution at highly conserved residue in the G/F domain. Functional studies of the variant were not performed. The patient had onset at age 16 years and severe involvement of the proximal and distal muscles of the upper and lower limbs resulting in loss of ambulation at age 30. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26205529" 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> rs759982570 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs759982570;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/rs759982570?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=rs759982570" 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=rs759982570" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a 59-year-old woman (patient 2s) with sporadic limb-girdle muscular dystrophy type 1E (LGMDD1; <a href="/entry/603511">603511</a>), <a href="#8" class="mim-tip-reference" title="Ruggieri, A., Brancati, F., Zanotti, S., Maggi, L., Pasanisi, M. B., Saredi, S., Terracciano, C., Antozzi, C., D'Alpice, M. R., Sangiuolo, F., Novelli, G., Marshall, C. R., Scherer, S. W., Morandi, L., Federici, L., Massa, R., Mora, M., Minassian, B. A. <strong>Complete loss of the DNAJB6 G/F domain and novel missense mutations cause distal-onset DNAJB6 myopathy.</strong> Acta Neuropath. Commun. 3: 44, 2015. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26205529/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26205529</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26205529[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/s40478-015-0224-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26205529">Ruggieri et al. (2015)</a> identified a de novo heterozygous c.273C-G transversion (c.273C-G, NC_000007.14) in the DNAJ6 gene, resulting in a phe91-to-leu (F91L) substitution at a highly conserved residue in the G/F domain. Functional studies of the variant were not performed. The patient had a severe form of the disorder, with onset at age 11 years, proximal and distal involvement of the upper and lower limbs, loss of ambulation at age 40, dysphagia, dysarthria, and late-onset respiratory difficulties. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26205529" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0009 MUSCULAR DYSTROPHY, LIMB-GIRDLE, AUTOSOMAL DOMINANT 1</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs869320702 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs869320702;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=rs869320702" 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=rs869320702" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a 39-year-old woman (patient 4s) with sporadic limb-girdle muscular dystrophy type 1E (LGMDD1; <a href="/entry/603511">603511</a>), <a href="#8" class="mim-tip-reference" title="Ruggieri, A., Brancati, F., Zanotti, S., Maggi, L., Pasanisi, M. B., Saredi, S., Terracciano, C., Antozzi, C., D'Alpice, M. R., Sangiuolo, F., Novelli, G., Marshall, C. R., Scherer, S. W., Morandi, L., Federici, L., Massa, R., Mora, M., Minassian, B. A. <strong>Complete loss of the DNAJB6 G/F domain and novel missense mutations cause distal-onset DNAJB6 myopathy.</strong> Acta Neuropath. Commun. 3: 44, 2015. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26205529/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26205529</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26205529[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/s40478-015-0224-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26205529">Ruggieri et al. (2015)</a> identified a de novo heterozygous G-to-A transition (c.346+5G-A) in a consensus splice site sequence of the DNAJ6 gene. Analysis of patient cells showed that the mutation resulted in the skipping of exon 5 and absence of the entire G/F domain. Additional functional studies of the variant were not performed. The patient had a severe phenotype, with onset at age 6 years, proximal and distal involvement of the upper and lower limbs, and loss of ambulation at age 37. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26205529" 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">rs869320701 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs869320701;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=rs869320701" 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=rs869320701" 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=RCV000591783 OR RCV000845572" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000591783, RCV000845572" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000591783...</a>
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<p>By exome sequencing in a Hungarian family with a late-onset, mild, and slowly progressive form of autosomal dominant limb-girdle muscular dystrophy-1 (LGMDD1; <a href="/entry/603511">603511</a>), <a href="#16" class="mim-tip-reference" title="Zima, J., Eaton, A., Pal, E., Till, A., Ito, Y. A., Warman-Chardon, J., Hartley, T., Cagnone, G., Melegh, B. I., Boycott, K. M., Melegh, B., Hadzsiev, K. <strong>Intrafamilial variability of limb-girdle muscular dystrophy, LGMD1D type.</strong> Europ. J. Med. Genet. 63: 103655, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31034989/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31034989</a>] [<a href="https://doi.org/10.1016/j.ejmg.2019.04.012" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31034989">Zima et al. (2020)</a> identified a heterozygous c.271T-G transversion (c.271T-G, NM_005494.2) in the DNAJ6 gene, resulting in a phe91-to-val (F91V) substitution at a highly conserved residue. The family had a milder course than that reported in patients with LGMDD1 with variants at the same residue (<a href="#0007">611332.0007</a>; <a href="#0008">611332.0008</a>). Symptoms in the Hungarian family were first reported in the third and fourth decade of life in 2 males, and 1 female in the family was asymptomatic in her early 60s with only mild features on muscle biopsy and MRI. The authors raised the question of whether this could be a disease with sex-influenced expression. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31034989" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>REFERENCES</strong>
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Bengoechea, R., Pittman, S. K., Tuck, E. P., True, H. L., Weihl, C. C.
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<strong>Myofibrillar disruption and RNA-binding protein aggregation in a mouse model of limb-girdle muscular dystrophy 1D.</strong>
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Hum. Molec. Genet. 24: 6588-6602, 2015.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26362252/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26362252</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26362252[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=26362252" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/ddv363" target="_blank">Full Text</a>]
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Chuang, J.-Z., Zhou, H., Zhu, M., Li, S.-H., Li, X.-J., Sung, C.-H.
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<strong>Characterization of a brain-enriched chaperone, MRJ, that inhibits huntingtin aggregation and toxicity independently.</strong>
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J. Biol. Chem. 277: 19831-19838, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11896048/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11896048</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11896048" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1074/jbc.M109613200" target="_blank">Full Text</a>]
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Couthouis, J., Raphael, A. R., Siskind, C., Findlay, A. R., Buenrostro, J. D., Greenleaf, W. J., Vogel, H., Day, J. W., Flanigan, K. M., Gitler, A. D.
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<strong>Exome sequencing identifies a DNAJB6 mutation in a family with dominantly-inherited limb-girdle muscular dystrophy.</strong>
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Neuromusc. Disord. 24: 431-435, 2014.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24594375/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24594375</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24594375[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=24594375" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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<strong>Personal Communication.</strong>
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Baltimore, Md. 11/29/2011.
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Hackman, P., Sandell, S., Sarparanta, J., Luque, H., Huovinen, S., Palmio, J., Paetau, A., Kalimo, H., Mahjneh, I., Udd, B.
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<strong>Four new Finnish families with LGMD1D; refinement of the clinical phenotype and the linked 7q36 locus.</strong>
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Neuromusc. Disord. 21: 338-344, 2011.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21376592/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21376592</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21376592" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Harms, M. B., Sommerville, R. B., Allred, P., Bell, S., Ma, D., Cooper, P., Lopate, G., Pestronk, A., Weihl, C. C., Baloh, R. H.
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<strong>Exome sequencing reveals DNAJB6 mutations in dominantly-inherited myopathy.</strong>
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Ann. Neurol. 71: 407-416, 2012.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22334415/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22334415</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22334415[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=22334415" 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/ana.22683" target="_blank">Full Text</a>]
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Ohtsuka, K., Hata, M.
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<strong>Mammalian HSP40/DNAJ homologs: cloning of novel cDNAs and a proposal for their classification and nomenclature.</strong>
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Cell Stress Chaperones 5: 98-112, 2000.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11147971/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11147971</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11147971[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=11147971" 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/10.1379/1466-1268(2000)005<0098:mhdhco>2.0.co;2" target="_blank">Full Text</a>]
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<a id="8" class="mim-anchor"></a>
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<a id="Ruggieri2015" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Ruggieri, A., Brancati, F., Zanotti, S., Maggi, L., Pasanisi, M. B., Saredi, S., Terracciano, C., Antozzi, C., D'Alpice, M. R., Sangiuolo, F., Novelli, G., Marshall, C. R., Scherer, S. W., Morandi, L., Federici, L., Massa, R., Mora, M., Minassian, B. A.
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<strong>Complete loss of the DNAJB6 G/F domain and novel missense mutations cause distal-onset DNAJB6 myopathy.</strong>
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Acta Neuropath. Commun. 3: 44, 2015. Note: Electronic Article.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26205529/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26205529</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26205529[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=26205529" 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/10.1186/s40478-015-0224-0" target="_blank">Full Text</a>]
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<a id="9" class="mim-anchor"></a>
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<a id="Sandell2010" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Sandell, S., Huovinen, S., Sarparanta, J., Luque, H., Raheem, O., Haapasalo, H., Hackman, P., Udd, B.
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<strong>The enigma of 7q36 linked autosomal dominant limb girdle muscular dystrophy.</strong>
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J. Neurol. Neurosurg. Psychiat. 81: 834-839, 2010.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20682716/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20682716</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20682716" 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/10.1136/jnnp.2009.192351" target="_blank">Full Text</a>]
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<a id="Sarparanta2012" class="mim-anchor"></a>
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<div class="">
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Sarparanta, J., Jonson, P. H., Golzio, C., Sandell, S., Luque, H., Screen, M., McDonald, K., Stajich, J. M., Mahjneh, I., Vihola, A., Raheem, O., Penttila, S., and 9 others.
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<strong>Mutations affecting the cytoplasmic functions of the co-chaperone DNAJB6 cause limb-girdle muscular dystrophy.</strong>
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Nature Genet. 44: 450-455, 2012.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22366786/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22366786</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22366786[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=22366786" 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/ng.1103" target="_blank">Full Text</a>]
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Seki, N., Hattori, A., Hayashi, A., Kozuma, S., Miyajima, N., Saito, T.
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<strong>Cloning, tissue expression, and chromosomal assignment of human MRJ gene for a member of the DNAJ protein family.</strong>
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J. Hum. Genet. 44: 185-189, 1999.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10319584/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10319584</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10319584" 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/s100380050139" target="_blank">Full Text</a>]
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<a id="Servidei1999" class="mim-anchor"></a>
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<div class="">
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Servidei, S., Capon, F., Spinazzola, A., Mirabella, M., Semprini, S., de Rosa, G., Gennarelli, M., Sangiuolo, F., Ricci, E., Mohrenweiser, H. W., Dallapiccola, B., Tonali, P., Novelli, G.
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<strong>A distinctive autosomal dominant vacuolar neuromyopathy linked to 19p13.</strong>
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Neurology 53: 830-837, 1999.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10489050/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10489050</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10489050" 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/10.1212/wnl.53.4.830" target="_blank">Full Text</a>]
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<a id="13" class="mim-anchor"></a>
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<a id="Speer1995" class="mim-anchor"></a>
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Speer, M. C., Gilchrist, J. M., Chutkow, J. G., McMichael, R., Westbrook, C. A., Stajich, J. M., Jorgenson, E. M., Gaskell, P. C., Rosi, B. L., Ramesar, R., Vance, J. M., Yamaoka, L. H., Roses, A. D., Pericak-Vance, M. A.
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<strong>Evidence for locus heterogeneity in autosomal dominant limb-girdle muscular dystrophy.</strong>
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Am. J. Hum. Genet. 57: 1371-1376, 1995.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8533766/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8533766</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8533766" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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<a id="14" class="mim-anchor"></a>
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<a id="Speer1999" class="mim-anchor"></a>
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<div class="">
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Speer, M. C., Vance, J. M., Grubber, J. M., Graham, F. L., Stajich, J. M., Viles, K. D., Rogala, A., McMichael, R., Chutkow, J., Goldsmith, C., Tim, R. W., Pericak-Vance, M. A.
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<strong>Identification of a new autosomal dominant limb-girdle muscular dystrophy locus on chromosome 7.</strong>
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Am. J. Hum. Genet. 64: 556-562, 1999.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9973293/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9973293</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9973293" 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/10.1086/302252" target="_blank">Full Text</a>]
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<a id="Stein2014" class="mim-anchor"></a>
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Stein, K. C., Bengoechea, R., Harms, M. B., Weihl, C. C., True, H. L.
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<strong>Myopathy-causing mutations in an HSP40 chaperone disrupt processing of specific client conformers.</strong>
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J. Biol. Chem. 289: 21120-21130, 2014.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24920671/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24920671</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24920671[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=24920671" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1074/jbc.M114.572461" target="_blank">Full Text</a>]
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<a id="16" class="mim-anchor"></a>
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<a id="Zima2020" class="mim-anchor"></a>
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Zima, J., Eaton, A., Pal, E., Till, A., Ito, Y. A., Warman-Chardon, J., Hartley, T., Cagnone, G., Melegh, B. I., Boycott, K. M., Melegh, B., Hadzsiev, K.
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<strong>Intrafamilial variability of limb-girdle muscular dystrophy, LGMD1D type.</strong>
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Europ. J. Med. Genet. 63: 103655, 2020.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31034989/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31034989</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31034989" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.ejmg.2019.04.012" target="_blank">Full Text</a>]
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Sonja A. Rasmussen - updated : 08/09/2022
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<div class="row collapse" id="mimCollapseContributors">
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Patricia A. Hartz - updated : 07/05/2017<br>Cassandra L. Kniffin - updated : 5/2/2016<br>Cassandra L. Kniffin - updated : 4/7/2016<br>Cassandra L. Kniffin - updated : 4/21/2014<br>Cassandra L. Kniffin - updated : 5/8/2012<br>Cassandra L. Kniffin - updated : 4/2/2012<br>Matthew B. Gross - updated : 11/29/2011
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Creation Date:
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Patricia A. Hartz : 8/16/2007
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carol : 08/09/2022
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<span class="mim-text-font">
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carol : 09/27/2018<br>carol : 09/26/2018<br>carol : 07/05/2017<br>carol : 03/27/2017<br>carol : 05/03/2016<br>ckniffin : 5/2/2016<br>alopez : 4/13/2016<br>ckniffin : 4/7/2016<br>carol : 4/23/2014<br>mcolton : 4/22/2014<br>ckniffin : 4/21/2014<br>carol : 5/8/2012<br>ckniffin : 5/8/2012<br>carol : 4/4/2012<br>ckniffin : 4/2/2012<br>mgross : 11/29/2011<br>wwang : 9/15/2009<br>carol : 8/16/2007<br>carol : 8/16/2007<br>carol : 8/16/2007<br>carol : 8/16/2007
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<span class="mim-font">
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<strong>*</strong> 611332
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<h3>
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<span class="mim-font">
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DNAJ/HSP40 HOMOLOG, SUBFAMILY B, MEMBER 6; DNAJB6
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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<span class="mim-font">
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MRJ<br />
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DJ4
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<strong><em>HGNC Approved Gene Symbol: DNAJB6</em></strong>
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<strong>ICD10CM:</strong> G71.031;
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<strong>
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<em>
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Cytogenetic location: 7q36.3
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Genomic coordinates <span class="small">(GRCh38)</span> : 7:157,337,004-157,417,439 </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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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</h4>
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<div>
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
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<td rowspan="1">
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<span class="mim-font">
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7q36.3
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</span>
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</td>
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<td>
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<span class="mim-font">
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Muscular dystrophy, limb-girdle, autosomal dominant 1
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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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603511
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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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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
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</span>
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</h4>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Description</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>DNAJB6 belongs to the evolutionarily conserved DNAJ/HSP40 family of proteins, which regulate molecular chaperone activity by stimulating ATPase activity. DNAJ proteins may have up to 3 distinct domains: a conserved 70-amino acid J domain, usually at the N terminus; a glycine/phenylalanine (G/F)-rich region; and a cysteine-rich domain (Ohtsuka and Hata, 2000). </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>By database searching for DNAJ-like proteins, Seki et al. (1999) identified and subsequently cloned DNAJB6, which they called MRJ, from a human fetal brain cDNA library. The deduced 241-amino acid protein has a calculated molecular mass of 37 kD. DNAJB6 contains an N-terminal J domain followed by a glycine-rich region, but does not contain a cysteine-rich region. The protein shares 94% sequence identity with the mouse homolog. RT-PCR analysis detected ubiquitous expression of DNAJB6. </p><p>By searching EST databases for J domain-containing proteins, Ohtsuka and Hata (2000) identified 10 mouse and human DNAJ homologs, including mouse DnajB6. The predicted type II transmembrane protein contains 242 amino acids. </p><p>By Northern blot analysis, Chuang et al. (2002) found that the expression of human DNAJB6 was highest in brain and much weaker in all other tissues examined. Within brain, expression was highest in hippocampus and thalamus, and lower in amygdala, substantia nigra, corpus callosum, and caudate nucleus. </p><p>Sarparanta et al. (2012) found expression of the DNAJB6 gene at Z discs in human skeletal muscle. </p><p>DNAJB6 is expressed as 2 isoforms with distinct cellular localizations: DNAJB6a (326 residues) localizes to the nucleus, whereas DNAJB6b (242 residues) localizes to both the nucleus and the cytoplasm. Bengoechea et al. (2015) found expression of both isoforms in human and mouse skeletal muscle. In mouse muscle, Dnajb6a showed nuclear localization and Dnajb6b was incorporated into the sarcomere. </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>Chuang et al. (2002) demonstrated that full-length DNAJB6 stimulated ATP hydrolysis by HSP70 (see HSPA1A, 140550) in a time- and concentration-dependent manner. Both an N-terminal fragment (amino acids 1-109) and a C-terminal fragment (amino acids 108-241) enhanced the ATPase activity of HSP70. Human embryonic kidney 293 cells transfected with mutant huntingtin (HTT; 613004) N terminus exhibited puncta or aggregates of mutant huntingtin distributed throughout the cytoplasm and nucleus. Coexpression of DNAJB6 delayed aggregate formation and significantly reduced caspase-3 (CASP3; 600636) activation induced by mutant huntingtin. DNAJB6 also inhibited CASP3 activity augmented by the apoptotic reagent staurosporine. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Mapping</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>By PCR analysis of a human/rodent monochromosomal hybrid cell panel and a radiation hybrid panel, Seki et al. (1999) mapped the DNAJB6 gene to chromosome 11q25. However, Gross (2011) mapped the DNAJB6 gene to chromosome 7q36.3 based on alignment of the DNAJB6 sequence (GenBank BC002446) with the genomic sequence (GRCh37). </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>In affected members of a Caucasian family with autosomal dominant limb-girdle muscular dystrophy (LGMDD1; 603511), earlier designated LGMD1E, Harms et al. (2012) identified a heterozygous mutation in the DNAJB6 gene (F93L; 611332.0001). The mutation was identified by whole-genome exome capture followed by next-generation sequencing. Sequencing of the DNAJB6 gene in 13 additional probands with a similar disorder revealed a second mutation (P96R; 611332.0002) in affected members of an African American family with an autosomal dominant myopathy. Both families had adult-onset of slowly progressive muscle weakness resulting in loss of ambulation after about 20 years, although 1 family had greater involvement of the proximal muscles and the other had greater involvement of the distal muscles. Neither family had cardiac or pulmonary involvement. </p><p>Sarparanta et al. (2012) identified 4 different heterozygous mutations in the DNAJB6 gene (611332.0001, 611332.0003-611332.0005) in affected members of 9 families with LGMD1E. Five of the families were of Finnish origin (Sandell et al., 2010 and Hackman et al., 2011) and carried the same mutation (611332.0003). Two additional families had previously been reported by Speer et al. (1995, 1999). Electron microscopy of patient muscle showed Z disc myofibrillar disintegration and autophagic rimmed vacuoles. DNAJB6 was detected in protein accumulations together with its known ligands MLF1 (601402) and HSPA8 (600816). However, DNAJB6 appeared more in the periphery of the protein accumulations, in contrast to more pronounced colocalization seen in myotilinopathies. Three of the mutations resulted in a phe93-to-leu (F93L) substitution at a highly conserved residue. In vitro functional expression studies showed that the mutations increased the half-life of DNAJB6, extended this effect to the wildtype protein, and reduced the protective antiaggregation effect of DNAJB6. The mutations showed a dominant toxic effect mediated specifically by the cytoplasmic isoform of DNAJB6. The compromised antiaggregation function may lead to impaired protein quality control and accumulation of other proteins. DNAJB6 was found to interact with members of the chaperone-assisted selective autophagy (CASA) complex, including a myofibrillar myopathy (MFM6; 612954)-related protein BAG3 (603883). The findings indicated that LGMD1E is mediated by defective chaperone function, resulting in insufficient maintenance of sarcomeric structures or defective clearance of misfolded sarcomeric proteins. </p><p>Stein et al. (2014) noted that all known LGMD1E mutations localized in the conserved G/F domain of DNAJB6. Using yeast-human chimeric proteins, they found that these DNAJB6 mutants were variably deficient in resolving prion protein aggregates in yeast, with strongest effect shown by the F89I mutation (611332.0005) or deletion of the entire G/F domain. TDP43 (TARDBP; 605078) has a domain similar to that found in yeast prion proteins; in addition, TDP43 aggregates into stress granules during heat shock and accumulates in LGMD1E patient muscle. Stein et al. (2014) showed that HeLa cells expressing TDP43 formed nuclear stress bodies during heat shock, and that wildtype, but not G/F mutant, DNAJB6 resolved these stress bodies following recovery from heat shock. LGMD1E patient fibroblasts with the F93L substitution (see 611332.0001) also showed delayed dissolution of TDP43 nuclear stress bodies following recovery from heat shock. </p><p>In affected members of a large family with LGMD1E, Ruggieri et al. (2015) identified a heterozygous missense mutation in the DNAJB6 gene (F100V; 611332.0006). The mutation, which was found by a combination of linkage analysis and exome sequencing, segregated with the disorder in the family. Direct Sanger sequencing of the DNAJB6 gene in 63 patients with sporadic occurrence of a similar disorder identified 4 with de novo heterozygous mutations (611332.0003; 611332.0007-611332.0009), thus accounting for 6.4% of the cohort. All the mutations affected the conserved G/F domain, although direct functional studies were not performed. There was some evidence for a genotype/phenotype correlation: proximal G/F mutations were associated with proximal myopathy, whereas distal G/F mutations were associated with distal-onset myopathy. The mutations were predicted to affect the G/F-J interaction in different ways. </p><p>By exome sequencing in a Hungarian family with a late-onset, mild, and slowly progressive form of LGMDD1, Zima et al. (2020) identified a heterozygous missense mutation in the DNAJB6 gene (F91V; 611332.0010). The authors noted that previous mutations involving the phe91 residue (611332.0007 and 611332.0008) were associated with a more severe form of the disease. </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">
|
|
<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">
|
|
<p>In zebrafish, Sarparanta et al. (2012) found expression of the Dnajb6 gene as early as the embryonic 5-somite stage. Injection of 2-cell embryos with a splice-blocking morpholino resulted in a reproducible muscle fiber detachment phenotype. Detachment of slow fibers from their insertion sites at the vertical myoseptum was evident as early as 2 days after fertilization, suggesting adhesion failure with mechanical load. These data indicated that loss of Dnajb6 leads to defects in muscle integrity. Injection of the human mutants F93L (see, e.g., 611332.0001) or F89I (611332.0005) also caused the muscular phenotype, and coinjection with wildtype Dnajb6 showed enhanced severity of the phenotype, consistent with a dominant-negative effect. </p><p>Bengoechea et al. (2015) found that transgenic mice expressing the LGMD1E-associated DNAJB6 F93L mutation (611332.0001) in the Dnajb6b isoform had early lethality due to profound muscle weakness, whereas mice with the mutation in the Dnajb6a isoform were unaffected after 1 year. Muscle biopsy of affected mice showed localization of mutant Dnajb6b in the Z-disc, myofibrillar disorganization, desmin and keratin inclusions, and abnormal sarcoplasmic protein aggregations of RNA-binding proteins. </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>
|
|
<span class="mim-font">
|
|
<strong>ALLELIC VARIANTS</strong>
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</span>
|
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<strong>10 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 MUSCULAR DYSTROPHY, LIMB-GIRDLE, AUTOSOMAL DOMINANT 1</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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DNAJB6, PHE93LEU, 277T-C
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<br />
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SNP: rs387907046,
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ClinVar: RCV000023891
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In affected members of a Caucasian family with autosomal dominant limb-girdle muscular dystrophy type 1E (LGMDD1; 603511), Harms et al. (2012) identified a heterozygous 277T-C transition in the DNAJB6 gene, resulting in a phe93-to-leu (F93L) substitution in a highly conserved residue within the G/F domain. The mutation was not found in over 3,000 controls. Five affected individuals had onset of limb-girdle weakness beginning in the fourth decade. The disorder was manifest as difficulty in climbing stairs or getting up from the floor. In 2 patients, the quadriceps muscles were less affected than the hamstrings. None had cardiac, pulmonary, or bulbar involvement. The disorder was slowly progressive, but a wheelchair was required after about 20 years. Skeletal muscle biopsy from 3 patients showed a chronic myopathy with rimmed vacuoles, variation in fiber size, and internal nuclei. Immunostaining showed TDP43 (605078)- and DNAJB6-positive accumulation in multiple fibers; some inclusions were around and within the vacuoles. Serum creatine kinase was increased, and EMG showed clear myopathic changes. </p><p>Sarparanta et al. (2012) identified a heterozygous 277T-C transition in 4 affected individuals from an Italian family with LGMDD1. The F93L substitution can also be caused by a 279C-G transversion (611332.0003) and a 279C-A transversion (611332.0004). </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>.0002 MUSCULAR DYSTROPHY, LIMB-GIRDLE, AUTOSOMAL DOMINANT 1</strong>
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</span>
|
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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DNAJB6, PRO96ARG
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<br />
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SNP: rs387907047,
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ClinVar: RCV000023892, RCV000594360
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</span>
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</div>
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<div>
|
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<span class="mim-text-font">
|
|
<p>In affected members of an African American family with limb-girdle muscular dystrophy type 1E (LGMDD1; 603511), Harms et al. (2012) identified a heterozygous 287C-G transversion in the DNAJB6 gene, resulting in a pro96-to-arg (P96R) substitution at a highly conserved residue in the G/F domain. The mutation was not found in over 3,000 controls. Three affected individuals from an African American family had a distal-predominant myopathy with onset between ages 18 and 35 years. Weakness began in the lower limbs, often manifest as tripping, but progressed to include the hands and proximal legs with loss of ambulation after about 20 to 40 years. There was no cardiac or pulmonary involvement. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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<strong>.0003 MUSCULAR DYSTROPHY, LIMB-GIRDLE, AUTOSOMAL DOMINANT 1</strong>
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</span>
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</h4>
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</div>
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<div>
|
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<span class="mim-text-font">
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DNAJB6, PHE93LEU, 279C-G
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<br />
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SNP: rs149278319,
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gnomAD: rs149278319,
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ClinVar: RCV000024240, RCV000498905
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</span>
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In 16 affected members from 5 Finnish families with limb-girdle muscular dystrophy type 1E (LGMDD1; 603511), previously reported by Sandell et al. (2010) and Hackman et al. (2011), Sarparanta et al. (2012) identified a heterozygous 279C-G transversion in exon 5 of the DNAJB6 gene, resulting in a phe93-to-leu (F93L) substitution at a highly conserved residue in the G/F domain. The mutation was not found in 202 Finnish, 104 Italian, or 215 U.S. control individuals. The F93L substitution can also be caused by a 277T-C transition (611332.0001) and a 279C-A transversion (611332.0004). </p><p>In a 57-year-old man (patient 3s) with sporadic occurrence of LGMD1E and onset at age 45, Ruggieri et al. (2015) identified a de novo heterozygous c.279C-G transversion (c.279C-G, NC_000007.14) in the DNAJB6 gene. The mutation was found by Sanger sequencing. He had proximal and distal muscle weakness affecting only the lower limbs and remained ambulatory. </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>.0004 MUSCULAR DYSTROPHY, LIMB-GIRDLE, AUTOSOMAL DOMINANT 1</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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DNAJB6, PHE93LEU, 279C-A
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<br />
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SNP: rs149278319,
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gnomAD: rs149278319,
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ClinVar: RCV000024241, RCV000414366
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In 8 affected individuals of an Italian family with limb-girdle muscular dystrophy type 1E (LGMDD1; 603511), Sarparanta et al. (2012) identified a heterozygous 279C-A transversion in exon 5 of the DNAJB6 gene, resulting in a phe93-to-leu (F93L) substitution at a highly conserved residue in the G/F domain. The F93L substitution can also be caused by a 277T-C transition (611332.0001) and a 279C-G transversion (611332.0003). The mutation was not found in 202 Finnish, 104 Italian, or 215 U.S. control individuals. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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<strong>.0005 MUSCULAR DYSTROPHY, LIMB-GIRDLE, AUTOSOMAL DOMINANT 1</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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DNAJB6, PHE89ILE
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<br />
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SNP: rs387907150,
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gnomAD: rs387907150,
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ClinVar: RCV000024242, RCV000724639
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</span>
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</div>
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<div>
|
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<span class="mim-text-font">
|
|
<p>In affected members of 2 families from the U.S. with limb-girdle muscular dystrophy type 1E (LGMDD1; 603511), originally reported by Speer et al. (1995, 1999), Sarparanta et al. (2012) identified a heterozygous c.265T-A transversion (which they referred to as c.267T-A) in the DNAJB6 gene, resulting in a phe89-to-ile (F89I) substitution at a highly conserved residue in the G/F domain. The mutation was not found in 202 Finnish, 104 Italian, or 215 U.S. control individuals. </p><p>In affected members of an American family with LGMD1E, Couthouis et al. (2014) identified a heterozygous c.265T-A transversion in the DNAJB6 gene, resulting in a phe89-to-ile (F89I) substitution. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder. It was filtered against the dbSNP (build 137), 1000 Genomes Project, and Exome Sequencing project databases. Couthouis et al. (2014) stated that the mutation was the same as that identified by Sarparanta et al. (2012). Haplotype analysis determined that the mutation arose independently in the families reported by Couthouis et al. (2014) and Sarparanta et al. (2012), suggesting that it may be a mutation hotspot. Functional studies of the variant were not performed. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0006 MUSCULAR DYSTROPHY, LIMB-GIRDLE, AUTOSOMAL DOMINANT 1</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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DNAJ6, PHE100VAL
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<br />
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SNP: rs869320700,
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ClinVar: RCV000210839
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In affected members of a large Italian family with limb-girdle muscular dystrophy type 1E (LGMDD1; 603511), originally reported by Servidei et al. (1999), Ruggieri et al. (2015) identified a heterozygous c.298T-G transversion in the DNAJ6 gene, resulting in a phe100-to-val (F100V) substitution at a highly conserved residue in the G/F domain. The mutation, which was found using a combination of linkage analysis and exome sequencing, segregated with the disorder in the family and was not found in the dbSNP (build 142), 1000 Genomes Project, Exome Sequencing Project, or ExAC databases. One 30-year-old clinically unaffected family member also carried the mutation. The distribution of muscle weakness in affected family members tended to be more distal than proximal. </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>.0007 MUSCULAR DYSTROPHY, LIMB-GIRDLE, AUTOSOMAL DOMINANT 1</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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DNAJ6, PHE91ILE
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<br />
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SNP: rs869320701,
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ClinVar: RCV000210825
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a 39-year-old woman (patient 1s) with sporadic limb-girdle muscular dystrophy type 1E (LGMDD1; 603511), Ruggieri et al. (2015) identified a de novo heterozygous c.271T-A transversion (c.271T-A, NC_000007.14) in the DNAJ6 gene, resulting in a phe91-to-ile (F91I) substitution at highly conserved residue in the G/F domain. Functional studies of the variant were not performed. The patient had onset at age 16 years and severe involvement of the proximal and distal muscles of the upper and lower limbs resulting in loss of ambulation at age 30. </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>.0008 MUSCULAR DYSTROPHY, LIMB-GIRDLE, AUTOSOMAL DOMINANT 1</strong>
|
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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DNAJ6, PHE91LEU
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<br />
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SNP: rs759982570,
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gnomAD: rs759982570,
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ClinVar: RCV000210832, RCV000726936, RCV001814119
|
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
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<p>In a 59-year-old woman (patient 2s) with sporadic limb-girdle muscular dystrophy type 1E (LGMDD1; 603511), Ruggieri et al. (2015) identified a de novo heterozygous c.273C-G transversion (c.273C-G, NC_000007.14) in the DNAJ6 gene, resulting in a phe91-to-leu (F91L) substitution at a highly conserved residue in the G/F domain. Functional studies of the variant were not performed. The patient had a severe form of the disorder, with onset at age 11 years, proximal and distal involvement of the upper and lower limbs, loss of ambulation at age 40, dysphagia, dysarthria, and late-onset respiratory difficulties. </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>.0009 MUSCULAR DYSTROPHY, LIMB-GIRDLE, AUTOSOMAL DOMINANT 1</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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DNAJ6, IVS5DS, G-A, +5
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<br />
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SNP: rs869320702,
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ClinVar: RCV000210843
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In a 39-year-old woman (patient 4s) with sporadic limb-girdle muscular dystrophy type 1E (LGMDD1; 603511), Ruggieri et al. (2015) identified a de novo heterozygous G-to-A transition (c.346+5G-A) in a consensus splice site sequence of the DNAJ6 gene. Analysis of patient cells showed that the mutation resulted in the skipping of exon 5 and absence of the entire G/F domain. Additional functional studies of the variant were not performed. The patient had a severe phenotype, with onset at age 6 years, proximal and distal involvement of the upper and lower limbs, and loss of ambulation at age 37. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>.0010 MUSCULAR DYSTROPHY, LIMB-GIRDLE, AUTOSOMAL DOMINANT 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
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<span class="mim-text-font">
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DNAJ6, PHE91VAL
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<br />
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|
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SNP: rs869320701,
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|
|
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|
|
ClinVar: RCV000591783, RCV000845572
|
|
|
|
|
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</span>
|
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>By exome sequencing in a Hungarian family with a late-onset, mild, and slowly progressive form of autosomal dominant limb-girdle muscular dystrophy-1 (LGMDD1; 603511), Zima et al. (2020) identified a heterozygous c.271T-G transversion (c.271T-G, NM_005494.2) in the DNAJ6 gene, resulting in a phe91-to-val (F91V) substitution at a highly conserved residue. The family had a milder course than that reported in patients with LGMDD1 with variants at the same residue (611332.0007; 611332.0008). Symptoms in the Hungarian family were first reported in the third and fourth decade of life in 2 males, and 1 female in the family was asymptomatic in her early 60s with only mild features on muscle biopsy and MRI. The authors raised the question of whether this could be a disease with sex-influenced expression. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>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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Bengoechea, R., Pittman, S. K., Tuck, E. P., True, H. L., Weihl, C. C.
|
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<strong>Myofibrillar disruption and RNA-binding protein aggregation in a mouse model of limb-girdle muscular dystrophy 1D.</strong>
|
|
Hum. Molec. Genet. 24: 6588-6602, 2015.
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[PubMed: 26362252]
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[Full Text: https://doi.org/10.1093/hmg/ddv363]
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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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Chuang, J.-Z., Zhou, H., Zhu, M., Li, S.-H., Li, X.-J., Sung, C.-H.
|
|
<strong>Characterization of a brain-enriched chaperone, MRJ, that inhibits huntingtin aggregation and toxicity independently.</strong>
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J. Biol. Chem. 277: 19831-19838, 2002.
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[PubMed: 11896048]
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[Full Text: https://doi.org/10.1074/jbc.M109613200]
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</p>
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<li>
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<p class="mim-text-font">
|
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Couthouis, J., Raphael, A. R., Siskind, C., Findlay, A. R., Buenrostro, J. D., Greenleaf, W. J., Vogel, H., Day, J. W., Flanigan, K. M., Gitler, A. D.
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|
<strong>Exome sequencing identifies a DNAJB6 mutation in a family with dominantly-inherited limb-girdle muscular dystrophy.</strong>
|
|
Neuromusc. Disord. 24: 431-435, 2014.
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[PubMed: 24594375]
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[Full Text: https://doi.org/10.1016/j.nmd.2014.01.014]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Gross, M. B.
|
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<strong>Personal Communication.</strong>
|
|
Baltimore, Md. 11/29/2011.
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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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Hackman, P., Sandell, S., Sarparanta, J., Luque, H., Huovinen, S., Palmio, J., Paetau, A., Kalimo, H., Mahjneh, I., Udd, B.
|
|
<strong>Four new Finnish families with LGMD1D; refinement of the clinical phenotype and the linked 7q36 locus.</strong>
|
|
Neuromusc. Disord. 21: 338-344, 2011.
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[PubMed: 21376592]
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[Full Text: https://doi.org/10.1016/j.nmd.2011.02.008]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Harms, M. B., Sommerville, R. B., Allred, P., Bell, S., Ma, D., Cooper, P., Lopate, G., Pestronk, A., Weihl, C. C., Baloh, R. H.
|
|
<strong>Exome sequencing reveals DNAJB6 mutations in dominantly-inherited myopathy.</strong>
|
|
Ann. Neurol. 71: 407-416, 2012.
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[PubMed: 22334415]
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[Full Text: https://doi.org/10.1002/ana.22683]
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</p>
|
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Ohtsuka, K., Hata, M.
|
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<strong>Mammalian HSP40/DNAJ homologs: cloning of novel cDNAs and a proposal for their classification and nomenclature.</strong>
|
|
Cell Stress Chaperones 5: 98-112, 2000.
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[PubMed: 11147971]
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[Full Text: https://doi.org/10.1379/1466-1268(2000)005<0098:mhdhco>2.0.co;2]
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</p>
|
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Ruggieri, A., Brancati, F., Zanotti, S., Maggi, L., Pasanisi, M. B., Saredi, S., Terracciano, C., Antozzi, C., D'Alpice, M. R., Sangiuolo, F., Novelli, G., Marshall, C. R., Scherer, S. W., Morandi, L., Federici, L., Massa, R., Mora, M., Minassian, B. A.
|
|
<strong>Complete loss of the DNAJB6 G/F domain and novel missense mutations cause distal-onset DNAJB6 myopathy.</strong>
|
|
Acta Neuropath. Commun. 3: 44, 2015. Note: Electronic Article.
|
|
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|
|
[PubMed: 26205529]
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|
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[Full Text: https://doi.org/10.1186/s40478-015-0224-0]
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</p>
|
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</li>
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<li>
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<p class="mim-text-font">
|
|
Sandell, S., Huovinen, S., Sarparanta, J., Luque, H., Raheem, O., Haapasalo, H., Hackman, P., Udd, B.
|
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<strong>The enigma of 7q36 linked autosomal dominant limb girdle muscular dystrophy.</strong>
|
|
J. Neurol. Neurosurg. Psychiat. 81: 834-839, 2010.
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|
|
[PubMed: 20682716]
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[Full Text: https://doi.org/10.1136/jnnp.2009.192351]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Sarparanta, J., Jonson, P. H., Golzio, C., Sandell, S., Luque, H., Screen, M., McDonald, K., Stajich, J. M., Mahjneh, I., Vihola, A., Raheem, O., Penttila, S., and 9 others.
|
|
<strong>Mutations affecting the cytoplasmic functions of the co-chaperone DNAJB6 cause limb-girdle muscular dystrophy.</strong>
|
|
Nature Genet. 44: 450-455, 2012.
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|
|
[PubMed: 22366786]
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[Full Text: https://doi.org/10.1038/ng.1103]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Seki, N., Hattori, A., Hayashi, A., Kozuma, S., Miyajima, N., Saito, T.
|
|
<strong>Cloning, tissue expression, and chromosomal assignment of human MRJ gene for a member of the DNAJ protein family.</strong>
|
|
J. Hum. Genet. 44: 185-189, 1999.
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|
[PubMed: 10319584]
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[Full Text: https://doi.org/10.1007/s100380050139]
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</p>
|
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</li>
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<li>
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<p class="mim-text-font">
|
|
Servidei, S., Capon, F., Spinazzola, A., Mirabella, M., Semprini, S., de Rosa, G., Gennarelli, M., Sangiuolo, F., Ricci, E., Mohrenweiser, H. W., Dallapiccola, B., Tonali, P., Novelli, G.
|
|
<strong>A distinctive autosomal dominant vacuolar neuromyopathy linked to 19p13.</strong>
|
|
Neurology 53: 830-837, 1999.
|
|
|
|
|
|
[PubMed: 10489050]
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|
|
[Full Text: https://doi.org/10.1212/wnl.53.4.830]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Speer, M. C., Gilchrist, J. M., Chutkow, J. G., McMichael, R., Westbrook, C. A., Stajich, J. M., Jorgenson, E. M., Gaskell, P. C., Rosi, B. L., Ramesar, R., Vance, J. M., Yamaoka, L. H., Roses, A. D., Pericak-Vance, M. A.
|
|
<strong>Evidence for locus heterogeneity in autosomal dominant limb-girdle muscular dystrophy.</strong>
|
|
Am. J. Hum. Genet. 57: 1371-1376, 1995.
|
|
|
|
|
|
[PubMed: 8533766]
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</p>
|
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</li>
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<li>
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<p class="mim-text-font">
|
|
Speer, M. C., Vance, J. M., Grubber, J. M., Graham, F. L., Stajich, J. M., Viles, K. D., Rogala, A., McMichael, R., Chutkow, J., Goldsmith, C., Tim, R. W., Pericak-Vance, M. A.
|
|
<strong>Identification of a new autosomal dominant limb-girdle muscular dystrophy locus on chromosome 7.</strong>
|
|
Am. J. Hum. Genet. 64: 556-562, 1999.
|
|
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|
|
[PubMed: 9973293]
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|
|
[Full Text: https://doi.org/10.1086/302252]
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</p>
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Stein, K. C., Bengoechea, R., Harms, M. B., Weihl, C. C., True, H. L.
|
|
<strong>Myopathy-causing mutations in an HSP40 chaperone disrupt processing of specific client conformers.</strong>
|
|
J. Biol. Chem. 289: 21120-21130, 2014.
|
|
|
|
|
|
[PubMed: 24920671]
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|
|
[Full Text: https://doi.org/10.1074/jbc.M114.572461]
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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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Zima, J., Eaton, A., Pal, E., Till, A., Ito, Y. A., Warman-Chardon, J., Hartley, T., Cagnone, G., Melegh, B. I., Boycott, K. M., Melegh, B., Hadzsiev, K.
|
|
<strong>Intrafamilial variability of limb-girdle muscular dystrophy, LGMD1D type.</strong>
|
|
Europ. J. Med. Genet. 63: 103655, 2020.
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|
|
[PubMed: 31034989]
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[Full Text: https://doi.org/10.1016/j.ejmg.2019.04.012]
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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>
|
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<div class="row">
|
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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">
|
|
Contributors:
|
|
</span>
|
|
</div>
|
|
<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
|
|
<span class="mim-text-font">
|
|
Sonja A. Rasmussen - updated : 08/09/2022<br>Patricia A. Hartz - updated : 07/05/2017<br>Cassandra L. Kniffin - updated : 5/2/2016<br>Cassandra L. Kniffin - updated : 4/7/2016<br>Cassandra L. Kniffin - updated : 4/21/2014<br>Cassandra L. Kniffin - updated : 5/8/2012<br>Cassandra L. Kniffin - updated : 4/2/2012<br>Matthew B. Gross - updated : 11/29/2011
|
|
</span>
|
|
</div>
|
|
</div>
|
|
</div>
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<div>
|
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<br />
|
|
</div>
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Patricia A. Hartz : 8/16/2007
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carol : 08/09/2022<br>carol : 09/27/2018<br>carol : 09/26/2018<br>carol : 07/05/2017<br>carol : 03/27/2017<br>carol : 05/03/2016<br>ckniffin : 5/2/2016<br>alopez : 4/13/2016<br>ckniffin : 4/7/2016<br>carol : 4/23/2014<br>mcolton : 4/22/2014<br>ckniffin : 4/21/2014<br>carol : 5/8/2012<br>ckniffin : 5/8/2012<br>carol : 4/4/2012<br>ckniffin : 4/2/2012<br>mgross : 11/29/2011<br>wwang : 9/15/2009<br>carol : 8/16/2007<br>carol : 8/16/2007<br>carol : 8/16/2007<br>carol : 8/16/2007
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