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Entry
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- *608014 - HEAT-SHOCK 22-KD PROTEIN 8; HSPB8
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- OMIM
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<a href="/search/advanced/entry"> OMIM </a>
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<a href="/search/advanced/clinicalSynopsis"> Clinical Synopses </a>
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<a href="/search/advanced/geneMap"> Gene Map </a>
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<p>
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<span class="h4">*608014</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<li role="presentation">
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneStructure">Gene Structure</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#genotypePhenotypeCorrelations">Genotype/Phenotype Correlations</a>
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</li>
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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/608014">Table View</a>
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</li>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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</li>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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</ul>
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</nav>
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</div>
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</div>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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</span>
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</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=ENSG00000152137;t=ENST00000281938" 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=26353" 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=608014" 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=ENSG00000152137;t=ENST00000281938" 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_014365" 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_014365" 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=608014" 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=06420&isoform_id=06420_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/HSPB8" 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/5901655,6457338,7644380,7657146,10441905,12053367,12803675,13431576,30582591,49065332,119618550,189065564,2545932126,2545932128" 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/Q9UJY1" 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=26353" 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=ENSG00000152137;t=ENST00000281938" 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=HSPB8" 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=HSPB8" 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+26353" 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/HSPB8" 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:26353" 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/26353" 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=chr12&hgg_gene=ENST00000281938.7&hgg_start=119178931&hgg_end=119194746&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/genes/HGNC:30171" 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://medlineplus.gov/genetics/gene/hspb8" class="mim-tip-hint" title="Consumer-friendly information about the effects of genetic variation on human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MedlinePlus Genetics', 'domain': 'medlineplus.gov'})">MedlinePlus Genetics</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=608014[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=608014[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/ENSG00000152137" 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=HSPB8" 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=HSPB8" 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=HSPB8" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="http://www.molgen.ua.ac.be/CMTMutations/" class="mim-tip-hint" title="A gene-specific database of variation." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">Locus Specific DBs</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=HSPB8&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/PA134900173" 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:30171" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
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<div><a href="https://www.mousephenotype.org/data/genes/MGI:2135756" 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/HSPB8#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:2135756" 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/26353/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=26353" 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=WBGene00002023;class=Gene" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name'{'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">Wormbase Gene</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-030131-2480" 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=HSPB8&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
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<span class="text-danger"><strong>*</strong></span>
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608014
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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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HEAT-SHOCK 22-KD PROTEIN 8; HSPB8
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
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HSP22<br />
|
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PROTEIN KINASE H11; H11<br />
|
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E2-INDUCED GENE 1; E2IG1<br />
|
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HEAT-SHOCK 27-KD PROTEIN 8
|
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=HSPB8" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">HSPB8</a></em></strong>
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</span>
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</p>
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</div>
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<div>
|
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<a id="cytogeneticLocation" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
|
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<strong>
|
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<em>
|
|
Cytogenetic location: <a href="/geneMap/12/858?start=-3&limit=10&highlight=858">12q24.23</a>
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|
|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr12:119178931-119194746&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'})">12:119,178,931-119,194,746</a> </span>
|
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</em>
|
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</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
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</p>
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</div>
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<div>
|
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<br />
|
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</div>
|
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<div>
|
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<a id="geneMap" class="mim-anchor"></a>
|
|
<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
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<strong>Gene-Phenotype Relationships</strong>
|
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</span>
|
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</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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<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=608673,621078,158590" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
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</a>
|
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</span>
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Inheritance
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<a href="/geneMap/12/858?start=-3&limit=10&highlight=858">
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12q24.23
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Charcot-Marie-Tooth disease, axonal, type 2L
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<a href="/entry/608673"> 608673 </a>
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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Myopathy, myofibrillar, 13, with rimmed vacuoles
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<span class="mim-font">
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<a href="/entry/621078"> 621078 </a>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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Neuronopathy, distal hereditary motor, autosomal dominant 2
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<span class="mim-font">
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<a href="/entry/158590"> 158590 </a>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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PheneGene Graphics <span class="caret"></span>
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</button>
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<ul class="dropdown-menu" style="width: 17em;">
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<li><a href="/graph/linear/608014" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
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<li><a href="/graph/radial/608014" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
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<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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<span class="mim-font">
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
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<strong>TEXT</strong>
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<strong>Description</strong>
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<div class="mim-changed mim-change"><p>The HSPB8 gene encodes a molecular chaperone that is a component of the chaperone-assisted selective autophagy (CASA) complex, which is is involved in the recognition and removal of misfolded and aggregated cellular proteins through ubiquitination and autophagic degradation. HSPB8 works in conjunction with BAG3 (<a href="/entry/603883">603883</a>), STUB1 (<a href="/entry/607207">607207</a>), and HSPA1A (HSP72; <a href="/entry/140550">140550</a>) in the CASA complex. In muscle, CASA promotes the turnover of structural components damaged by mechanical stress, and in neurons, CASA functions in the removal of misfolded substrates implicated in neurodegenerative diseases (summary by <a href="#18" class="mim-tip-reference" title="Tedesco, B., Vendredy, L., Adriaenssens, E., Cozzi, M., Asselbergh, B., Crippa, V., Cristofani, R., Rusmini, P., Ferrari, V., Casarotto, E., Chierichetti, M., Mina, F., and 15 others. <strong>HSPB8 frameshift mutant aggregates weaken chaperone-assisted selective autophagy in neuromyopathies.</strong> Autophagy 19: 2217-2239, 2023.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/36854646/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">36854646</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=36854646[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/10.1080/15548627.2023.2179780" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="36854646">Tedesco et al., 2023</a>, <a href="#20" class="mim-tip-reference" title="Yang, G., Lv, X., Yang, M., Feng, Y., Wang, G., Yan, C., Lin, P. <strong>Expanding the spectrum of HSPB8-related myopathy: a novel mutation causing atypical pediatric-onset axial and limb-girdle involvement with autophagy abnormalities and molecular dynamics studies.</strong> J. Hum. Genet. 70: 159-165, 2025.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/39548192/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">39548192</a>] [<a href="https://doi.org/10.1038/s10038-024-01305-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="39548192">Yang et al., 2025</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=39548192+36854646" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p></div>
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<strong>Cloning and Expression</strong>
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<p>To identify genes that are regulated by or associated with estrogen action, <a href="#5" class="mim-tip-reference" title="Charpentier, A. H., Bednarek, A. K., Daniel, R. L., Hawkins, K. A., Laflin, K. J., Gaddis, S., MacLeod, M. C., Aldaz, C. M. <strong>Effects of estrogen on global gene expression: identification of novel targets of estrogen action.</strong> Cancer Res. 60: 5977-5983, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11085516/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11085516</a>]" pmid="11085516">Charpentier et al. (2000)</a> performed serial analysis of gene expression (SAGE) on estrogen-responsive breast cancer cells after exposure to estrogen. Using transcript-specific PCR primers for novel sequences that increased more than 10-fold upon treatment with 17-beta estradiol (E2), they cloned 5 cDNAs, designated E2-induced genes (E2IG) 1-5, from a human placenta cDNA library. The E2IG1 cDNA encodes a deduced 196-amino acid protein that contains a central portion homologous to a highly conserved HSP-alpha crystallin domain common to all HSP20 family members. It shows 54% sequence homology to HSP27 (<a href="/entry/602195">602195</a>), suggesting that it is a member of the small HSP family. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11085516" 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 an EST database for sequences containing the alpha-crystallin domain characteristic of small heat-shock proteins, followed by PCR of a placenta cDNA library, <a href="#13" class="mim-tip-reference" title="Kappe, G., Verschuure, P., Philipsen, R. L. A., Staalduinen, A. A., Van de Boogaart, P., Boelens, W. C., De Jong, W. W. <strong>Characterization of two novel human small heat shock proteins: protein kinase-related HspB8 and testis-specific HspB9.</strong> Biochim. Biophys. Acta 1520: 1-6, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11470154/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11470154</a>] [<a href="https://doi.org/10.1016/s0167-4781(01)00237-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11470154">Kappe et al. (2001)</a> cloned HSPB8. Northern blot analysis detected broad expression of a 2.2-kb transcript, with highest abundance in skeletal muscle, heart, and placenta. Expression of HSPB8 was intermediate in several other tissues, but it was not detected in blood. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11470154" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="geneStructure" class="mim-anchor"></a>
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<h4 href="#mimGeneStructureFold" id="mimGeneStructureToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<span id="mimGeneStructureToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<span class="mim-font">
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<strong>Gene Structure</strong>
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<p><a href="#13" class="mim-tip-reference" title="Kappe, G., Verschuure, P., Philipsen, R. L. A., Staalduinen, A. A., Van de Boogaart, P., Boelens, W. C., De Jong, W. W. <strong>Characterization of two novel human small heat shock proteins: protein kinase-related HspB8 and testis-specific HspB9.</strong> Biochim. Biophys. Acta 1520: 1-6, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11470154/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11470154</a>] [<a href="https://doi.org/10.1016/s0167-4781(01)00237-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11470154">Kappe et al. (2001)</a> determined that the HSPB8 gene contains at least 3 exons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11470154" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="mapping" class="mim-anchor"></a>
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<h4 href="#mimMappingFold" id="mimMappingToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<span id="mimMappingToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<strong>Mapping</strong>
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</h4>
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<p>By sequence analysis, <a href="#5" class="mim-tip-reference" title="Charpentier, A. H., Bednarek, A. K., Daniel, R. L., Hawkins, K. A., Laflin, K. J., Gaddis, S., MacLeod, M. C., Aldaz, C. M. <strong>Effects of estrogen on global gene expression: identification of novel targets of estrogen action.</strong> Cancer Res. 60: 5977-5983, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11085516/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11085516</a>]" pmid="11085516">Charpentier et al. (2000)</a> mapped the E2IG1 gene to chromosome 12 between markers D12S366 and D12S340. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11085516" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="geneFunction" class="mim-anchor"></a>
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<h4 href="#mimGeneFunctionFold" id="mimGeneFunctionToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<strong>Gene Function</strong>
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<p><a href="#4" class="mim-tip-reference" title="Carra, S., Sivilotti, M., Chavez Zobel, A. T., Lambert, H., Landry, J. <strong>HspB8, a small heat shock protein mutated in human neuromuscular disorders, has in vivo chaperone activity in cultured cells.</strong> Hum. Molec. Genet. 14: 1659-1669, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15879436/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15879436</a>] [<a href="https://doi.org/10.1093/hmg/ddi174" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15879436">Carra et al. (2005)</a> investigated the capacity of HSPB8 to prevent protein aggregation in cells using Htt (<a href="/entry/613004">613004</a>) protein containing 43 glutamine residues (Htt43Q) as a model. In control conditions, Htt43Q accumulated in perinuclear inclusions composed of SDS-insoluble aggregates. In most cells, cotransfection with HSPB8 blocked inclusion formation. Biochemical analyses indicated that HSPB8 inhibited the accumulation of insoluble Htt43Q as efficiently as HSP40 (DNAJB1; <a href="/entry/604572">604572</a>), which was taken as a positive control. Htt43Q then accumulated in the SDS-soluble fraction, provided that protein degradation was blocked by proteasome and autophagy inhibitors. In contrast, HSPB1 (<a href="/entry/602195">602195</a>) and alpha-B-crystallin (CRYAB; <a href="/entry/123590">123590</a>) had no effect. Analyses of HSPB1/HSPB8 chimeric proteins indicated that the C-terminal domain of HSPB8 contains the specific sequence necessary for chaperone activity. The K141N mutation (<a href="#0001">608014.0001</a>) significantly reduced the chaperone activity of the protein. <a href="#4" class="mim-tip-reference" title="Carra, S., Sivilotti, M., Chavez Zobel, A. T., Lambert, H., Landry, J. <strong>HspB8, a small heat shock protein mutated in human neuromuscular disorders, has in vivo chaperone activity in cultured cells.</strong> Hum. Molec. Genet. 14: 1659-1669, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15879436/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15879436</a>] [<a href="https://doi.org/10.1093/hmg/ddi174" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15879436">Carra et al. (2005)</a> hypothesized that a decrease in HSPB8 chaperone activity may contribute to the development of some neuropathies. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15879436" 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="Abdel-Nour, M., Carneiro, L. A. M., Downey, J., Tsalikis, J., Outlioua, A., Prescott, D., Da Costa, L. S., Hovingh, E. S., Farahvash, A., Gaudet, R. G., Molinaro, R., van Dalen, R., and 11 others. <strong>The heme-regulated inhibitor is a cytosolic sensor of protein misfolding that controls innate immune signaling.</strong> Science 365: eaaw4144, 2019. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31273097/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31273097</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31273097[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.aaw4144" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31273097">Abdel-Nour et al. (2019)</a> found that the EIF2-alpha (<a href="/entry/603907">603907</a>) kinase heme-regulated inhibitor (HRI; <a href="/entry/613635">613635</a>) controls NOD1 (<a href="/entry/605980">605980</a>) signalosome folding and activation through a process requiring eIF2-alpha, the transcription factor ATF4 (<a href="/entry/604064">604064</a>), and the heat-shock protein HSPB8. The HRI/eIF2-alpha signaling axis was also essential for signaling downstream of the innate immune mediators NOD2 (<a href="/entry/605956">605956</a>), MAVS (<a href="/entry/609676">609676</a>), and TRIF (<a href="/entry/607601">607601</a>) but dispensable for pathways dependent on MyD88 (<a href="/entry/602170">602170</a>) or STING (<a href="/entry/612374">612374</a>). Moreover, filament-forming alpha-synuclein (<a href="/entry/163890">163890</a>) activated HRI-dependent responses, which suggested that the HRI pathway may restrict toxic oligomer formation. <a href="#1" class="mim-tip-reference" title="Abdel-Nour, M., Carneiro, L. A. M., Downey, J., Tsalikis, J., Outlioua, A., Prescott, D., Da Costa, L. S., Hovingh, E. S., Farahvash, A., Gaudet, R. G., Molinaro, R., van Dalen, R., and 11 others. <strong>The heme-regulated inhibitor is a cytosolic sensor of protein misfolding that controls innate immune signaling.</strong> Science 365: eaaw4144, 2019. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31273097/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31273097</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31273097[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.aaw4144" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31273097">Abdel-Nour et al. (2019)</a> proposed that HRI, eIF2-alpha, and HSPB8 define a novel cytosolic unfolded protein response (cUPR) essential for optimal innate immune signaling by large molecular platforms, functionally homologous to the PERK (EIF2AK3; <a href="/entry/604032">604032</a>)/eIF2-alpha/HSPA5 (<a href="/entry/138120">138120</a>) axis of the endoplasmic reticulum (ER) unfolded protein response. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31273097" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Reviews</em></strong></p><p>
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<a href="#3" class="mim-tip-reference" title="Benndorf, R., Welsh, M. J. <strong>Shocking degeneration.</strong> Nature Genet. 36: 547-548, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15167925/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15167925</a>] [<a href="https://doi.org/10.1038/ng0604-547" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15167925">Benndorf and Welsh (2004)</a> reviewed the role of heat-shock proteins in neuromuscular function, as indicated by the association of mutations in 2 of these genes, HSP22 and HSP27, with human neuromuscular disorders. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15167925" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><strong><em>Distal Hereditary Motor Neuronopathy Type IIA</em></strong>
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<div class="mim-changed mim-change"><p>In affected members of 4 families with autosomal dominant distal hereditary motor neuronopathy type IIA (dHMN2A; <a href="/entry/158590">158590</a>), <a href="#12" class="mim-tip-reference" title="Irobi, J., Van Impe, K., Seeman, P., Jordanova, A., Dierick, I,., Verpoorten, N., Michalik, A., De Vriendt, E., Jacobs, A., Van Gerwen, V., Vennekens, K., Mazanec, R., and 11 others. <strong>Hot-spot residue in small heat-shock protein 22 causes distal motor neuropathy.</strong> Nature Genet. 36: 597-601, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15122253/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15122253</a>] [<a href="https://doi.org/10.1038/ng1328" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15122253">Irobi et al. (2004)</a> identified heterozygous missense mutations in the same codon of the HSPB8 gene (K141N, <a href="#0001">608014.0001</a> and K141E, <a href="#0002">608014.0002</a>). The K141N substitution resulted from a c.423G-C transversion. Expression studies of the mutant proteins in COS cells showed an increased interaction between HSPB8 and HSPB1, leading to the formation of intracellular aggregates. Of note, <a href="#17" class="mim-tip-reference" title="Tang, B., Zhao, G., Luo, W., Xia, K., Cai, F., Pan, Q., Zhang, R., Zhang, F., Liu, X., Chen, B., Zhang, C., Shen, L., Jiang, H., Long, Z., Dai, H. <strong>Small heat-shock protein 22 mutated in autosomal dominant Charcot-Marie-Tooth disease type 2L.</strong> Hum. Genet. 116: 222-224, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15565283/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15565283</a>] [<a href="https://doi.org/10.1007/s00439-004-1218-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15565283">Tang et al. (2005)</a> identified a K141N mutation resulting from a c.423G-T transversion (<a href="#0003">608014.0003</a>) in affected members of a Chinese family with Charcot-Marie-Tooth disease type 2L (<a href="/entry/608673">608673</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15565283+15122253" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p></div>
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<div class="mim-changed mim-change"><p>In a woman and her 2 children (family 1) with HMND2 and later onset of myofibrillar myopathy, <a href="#8" class="mim-tip-reference" title="Ghaoui, R., Palmio, J., Brewer, J., Lek, M., Needham, M., Evila, A., Hackman, P., Jonson, P.-H., Penttila, S., Vihola, A., Huovinen, S., Lindfors, M., and 9 others. <strong>Mutations in HSPB8 causing a new phenotype of distal myopathy and motor neuropathy.</strong> Neurology 86: 391-398, 2016. Note: Erratum: Neurology 86: 1077, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26718575/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26718575</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26718575[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/10.1212/WNL.0000000000002324" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26718575">Ghaoui et al. (2016)</a> identified a heterozygous missense mutation in the HSPB8 gene (K141E; <a href="#0002">608014.0002</a>). The mutation, which was found by next-generation sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Segregation studies indicated that the mutation occurred de novo in the mother. In vitro studies showed that the mutant K141E protein lost its ability to prevent abnormal protein aggregation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26718575" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p></div>
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<div class="mim-changed mim-change"><p><a href="#10" class="mim-tip-reference" title="Irobi, J., Almeida-Souza, L., Asselbergh, B., De Winter, V., Goethals, S., Dierick, I., Krishnan, J., Timmermans, J.-P., Robberecht, W., De Jonghe, P., Van Den Bosch, L., Janssens, S., Timmerman, V. <strong>Mutant HSPB8 causes motor neuron-specific neurite degeneration.</strong> Hum. Molec. Genet. 19: 3254-3265, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20538880/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20538880</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20538880[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/ddq234" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20538880">Irobi et al. (2010)</a> compared the effect of mutant HSPB8 in primary neuronal and glial cell cultures of rat and mouse cells. In rat motor neurons, expression of both HSPB8 K141N (<a href="#0001">608014.0001</a>) and K141E (<a href="#0002">608014.0002</a>) mutations resulted in neurite degeneration, as manifested by a reduction in number of neurites per cell, as well as in a reduction in average length of the neurites. Expression of the K141E, and to a lesser extent the K141N, mutation also induced spheroids in the neurites. There were no signs of apoptosis in motor neurons, showing that mutant HSPB8 resulted in neurite degeneration without inducing neuronal death. While overt in rat motor neurons, these phenotypes were only very mildly present in embryonic mouse sensory neurons and completely absent in embryonic mouse cortical neurons and glial cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20538880" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p></div>
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<div class="mim-changed mim-change"><p><a href="#11" class="mim-tip-reference" title="Irobi, J., Holmgren, A., De Winter, V., Asselbergh, B., Gettemans, J., Adriaensen, D., Ceuterick-de Groote, C., Van Coster, R., De Jonghe, P., Timmerman, V. <strong>Mutant HSPB8 causes protein aggregates and a reduced mitochondrial membrane potential in dermal fibroblasts from distal hereditary motor neuropathy patients.</strong> Neuromusc. Disord. 22: 699-711, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22595202/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22595202</a>] [<a href="https://doi.org/10.1016/j.nmd.2012.04.005" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22595202">Irobi et al. (2012)</a> found that cultured fibroblasts derived from 2 patients with the K141N mutation (<a href="#0001">608014.0001</a>) showed transient HSPB8-positive intracellular protein aggregates. Early passages had small aggregates, whereas later passages had fewer and larger aggregates that decreased over time due to activation of the ubiquitin proteosomal removal process. Mitochondrial membrane potential was reduced in early passage mutant fibroblasts, although mitochondrial morphology was normal, and the mitochondrial potential was restored with time. There was no significant evidence of apoptosis. Electron microscopy showed decreased numbers of myelinated and unmyelinated sensory axons with mild axonal abnormalities. The authors noted the drawbacks in using nonneuronal cells to study neuropathologic disease mechanisms, and suggested that studies of motor neurons or reprogrammed iPS cell-derived motor neurons would be more informative for studying this disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22595202" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p></div>
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<p><strong><em>Axonal Charcot-Marie-Tooth Disease Type 2L</em></strong>
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<div class="mim-changed mim-change"><p>In affected members of a Chinese family with axonal Charcot-Marie-Tooth disease type 2L (CMT2L; <a href="/entry/608673">608673</a>), <a href="#17" class="mim-tip-reference" title="Tang, B., Zhao, G., Luo, W., Xia, K., Cai, F., Pan, Q., Zhang, R., Zhang, F., Liu, X., Chen, B., Zhang, C., Shen, L., Jiang, H., Long, Z., Dai, H. <strong>Small heat-shock protein 22 mutated in autosomal dominant Charcot-Marie-Tooth disease type 2L.</strong> Hum. Genet. 116: 222-224, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15565283/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15565283</a>] [<a href="https://doi.org/10.1007/s00439-004-1218-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15565283">Tang et al. (2005)</a> identified a heterozygous K141N missense mutation in the HSPB8 gene (<a href="#0003">608014.0003</a>), resulting from a c.423G-T transversion. No functional studies were performed. Of note, <a href="#12" class="mim-tip-reference" title="Irobi, J., Van Impe, K., Seeman, P., Jordanova, A., Dierick, I,., Verpoorten, N., Michalik, A., De Vriendt, E., Jacobs, A., Van Gerwen, V., Vennekens, K., Mazanec, R., and 11 others. <strong>Hot-spot residue in small heat-shock protein 22 causes distal motor neuropathy.</strong> Nature Genet. 36: 597-601, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15122253/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15122253</a>] [<a href="https://doi.org/10.1038/ng1328" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15122253">Irobi et al. (2004)</a> identified a K141N mutation resulting from a c.423G-C transversion (<a href="#0001">608014.0001</a>) in affected members of 2 families with autosomal dominant distal hereditary motor neuronopathy-2 (HMND2; <a href="/entry/158590">158590</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15565283+15122253" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p></div>
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<div class="mim-changed mim-change"><p>In a 27-year-old Korean man, born of unrelated parents, with CMT2L, <a href="#14" class="mim-tip-reference" title="Nakhro, K., Park, J.-M., Kim, Y. J., Yoon, B. R., Yoo, J. H., Koo, H., Choi, B.-O., Chung, K. W. <strong>A novel Lys141Thr mutation in small heat shock protein 22 (HSPB8) gene in Charcot-Marie-Tooth disease type 2L.</strong> Neuromusc. Disord. 23: 656-663, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23796487/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23796487</a>] [<a href="https://doi.org/10.1016/j.nmd.2013.05.009" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23796487">Nakhro et al. (2013)</a> identified a de novo heterozygous K141T mutation in the HSPB8 gene (<a href="#0009">608014.0009</a>). The mutation, which was found by exome sequencing, was not present in public databases. Functional studies of the variant were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23796487" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p></div>
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<div class="mim-changed mim-change"><p><strong><em>Myofibrillar Myopathy-13 With Rimmed Vacuoles</em></strong>
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<div class="mim-changed mim-change"><p>In 2 affected members of a French Caucasian family (family 2) with myofibrillar myopathy-13 with rimmed vacuoles (MFM13; <a href="/entry/621078">621078</a>), <a href="#8" class="mim-tip-reference" title="Ghaoui, R., Palmio, J., Brewer, J., Lek, M., Needham, M., Evila, A., Hackman, P., Jonson, P.-H., Penttila, S., Vihola, A., Huovinen, S., Lindfors, M., and 9 others. <strong>Mutations in HSPB8 causing a new phenotype of distal myopathy and motor neuropathy.</strong> Neurology 86: 391-398, 2016. Note: Erratum: Neurology 86: 1077, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26718575/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26718575</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26718575[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/10.1212/WNL.0000000000002324" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26718575">Ghaoui et al. (2016)</a> identified a heterozygous frameshift mutation in the last exon of the HSPB8 gene (<a href="#0004">608014.0004</a>), predicted to result in a frameshift and extension of the protein by 18 amino acids (Pro173SerfsTer43). The mutation, which was found by next-generation sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The proband also carried a heterozygous missense variant (K238E) in the SQSTM1 gene (<a href="/entry/601530">601530</a>), but his affected cousin did not carry that variant. Functional studies of the variants were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26718575" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p></div>
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<div class="mim-changed mim-change"><p>In 3 members of a French family with MFM13, <a href="#2" class="mim-tip-reference" title="Al-Tahan, S., Weiss, L., Yu, H., Tang, S., Saporta, M., Vihola, A., Mozaffar, T., Udd, B., Kimonis, V. <strong>New family with HSPB8-associated autosomal dominant rimmed vacuolar myopathy.</strong> Neurol. Genet. 5: e349, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31403083/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31403083</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31403083[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/10.1212/NXG.0000000000000349" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31403083">Al-Tahan et al. (2019)</a> identified a heterozygous frameshift mutation in the HSPB8 gene (<a href="#0004">608014.0004</a>), the same mutation reported by <a href="#8" class="mim-tip-reference" title="Ghaoui, R., Palmio, J., Brewer, J., Lek, M., Needham, M., Evila, A., Hackman, P., Jonson, P.-H., Penttila, S., Vihola, A., Huovinen, S., Lindfors, M., and 9 others. <strong>Mutations in HSPB8 causing a new phenotype of distal myopathy and motor neuropathy.</strong> Neurology 86: 391-398, 2016. Note: Erratum: Neurology 86: 1077, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26718575/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26718575</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26718575[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/10.1212/WNL.0000000000002324" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26718575">Ghaoui et al. (2016)</a>. The mutation, which was found by whole-genome sequencing, was not present in gnomAD. Western blot analysis of patient fibroblasts showed a 50% reduction of the HSPB8 protein. There was increased expression of autophagosomal markers LC3B (<a href="/entry/609604">609604</a>) and SQSTM1. Patient fibroblasts had excessive amounts of HSPB8 protein aggregates in response to heat shock compared to controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=26718575+31403083" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p></div>
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<div class="mim-changed mim-change"><p>In 6 patients from 3 unrelated families with MFM13, <a href="#7" class="mim-tip-reference" title="Echaniz-Laguna, A., Lornage, X., Lannes, B., Schneider, R., Bierry, G., Dondaine, N., Boland, A., Deleuze, J.-F., Bohm, J., Thompson, J., Laporte, J., Biancalana, V. <strong>HSPB8 haploinsufficiency causes dominant adult-onset axial and distal myopathy.</strong> Acta Neuropath. 134: 163-165, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28501893/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28501893</a>] [<a href="https://doi.org/10.1007/s00401-017-1724-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28501893">Echaniz-Laguna et al. (2017)</a> identified a heterozygous frameshift mutation in the HSPB8 gene (<a href="#0005">608014.0005</a>) and extension of the protein by 17 amino acids (Gln170GlyfsTer45). The mutation, which was found by exome sequencing or targeted sequencing and confirmed by Sanger sequencing, segregated with the disorder in families A and B; the patient in family C was a sporadic case. The mutation was not present in gnomAD. Western blot analysis of cells from 1 patient showed that HSPB8 protein levels were reduced by 60%. Neither an elongated nor a truncated HSPB8 protein was identified using an antibody to the N-terminal region, suggesting to the authors that the mutation induces nonsense-mediated mRNA decay or protein degradation and may result in HSPB8 haploinsufficiency. The patients presented with adult-onset axial and distal myopathy without evidence of a neuropathy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28501893" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p></div>
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<div class="mim-changed mim-change"><p>In a 23-year-old man with MFM13 manifest as proximal limb-girdle muscle weakness, <a href="#15" class="mim-tip-reference" title="Nicolau, S., Liewluck, T., Elliott, J. L., Engel, A. G., Milone, M. <strong>A novel heterozygous mutation in the C-terminal region of HSPB8 leads to limb-girdle rimmed vacuolar myopathy.</strong> Neuromusc. Disord. 30: 236-240, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32165108/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32165108</a>] [<a href="https://doi.org/10.1016/j.nmd.2020.02.005" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32165108">Nicolau et al. (2020)</a> identified a de novo heterozygous frameshift mutation in the C-terminal region of the HSPB8 gene (Thr194SerfsTer23; <a href="#0006">608014.0006</a>) that resulted in extension of the protein. The mutation, which was found by whole-exome sequencing, was not present in gnomAD. Functional studies of the variant were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32165108" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p></div>
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<div class="mim-changed mim-change"><p>In 6 affected members of a multigenerational Japanese family with MFM13, <a href="#9" class="mim-tip-reference" title="Inoue-Shibui, A., Niihori, T., Kobayashi, M., Suzuki, N., Izumi, R., Warita, H., Hara, K., Shirota, M., Funayama, R., Nakayama, K., Nishino, I., Aoki, M., Aoki, Y. <strong>A novel deletion in the C-terminal region of HSPB8 in a family with rimmed vacuolar myopathy.</strong> J. Hum. Genet. 66: 965-972, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33744911/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33744911</a>] [<a href="https://doi.org/10.1038/s10038-021-00916-y" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33744911">Inoue-Shibui et al. (2021)</a> identified a heterozygous frameshift mutation in the C terminus of the HSPB8 gene (<a href="#0007">608014.0007</a>), predicted to result in a frameshift and elongation of the protein (Thr176TrpfsTer38). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies of the variant were not performed, but these authors suggested that the mutant transcript would escape nonsense-mediated mRNA decay. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33744911" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p></div>
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<div class="mim-changed mim-change"><p>In an 18-year-old Chinese girl with MFM13, <a href="#20" class="mim-tip-reference" title="Yang, G., Lv, X., Yang, M., Feng, Y., Wang, G., Yan, C., Lin, P. <strong>Expanding the spectrum of HSPB8-related myopathy: a novel mutation causing atypical pediatric-onset axial and limb-girdle involvement with autophagy abnormalities and molecular dynamics studies.</strong> J. Hum. Genet. 70: 159-165, 2025.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/39548192/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">39548192</a>] [<a href="https://doi.org/10.1038/s10038-024-01305-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="39548192">Yang et al. (2025)</a> identified a de novo heterozygous frameshift mutation in the C terminus of the HSPB8 gene (<a href="#0008">608014.0008</a>), resulting in a frameshift and extension of the protein by 49 amino acids (Glu192AspfsTer55). The mutation, which was found by whole-exome sequencing, was not present in the gnomAD database. Direct functional studies of the variant were not performed, but patient muscle biopsy showed accumulation of autophagy molecules. The authors concluded that the mutant transcript likely evaded nonsense-mediated mRNA decay, and suggested that it may result in a toxic gain of function, likely leading to dysregulation of autophagy. The patient had onset of axial and limb-girdle myopathy at 6 years of age. She did not have sensory involvement. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=39548192" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p></div>
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<div class="mim-changed mim-change"><p><a href="#18" class="mim-tip-reference" title="Tedesco, B., Vendredy, L., Adriaenssens, E., Cozzi, M., Asselbergh, B., Crippa, V., Cristofani, R., Rusmini, P., Ferrari, V., Casarotto, E., Chierichetti, M., Mina, F., and 15 others. <strong>HSPB8 frameshift mutant aggregates weaken chaperone-assisted selective autophagy in neuromyopathies.</strong> Autophagy 19: 2217-2239, 2023.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/36854646/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">36854646</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=36854646[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/10.1080/15548627.2023.2179780" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="36854646">Tedesco et al. (2023)</a> found that different mutations affecting the C terminus of HSPB8 associated with MFM13 resulted in an identical carboxy-terminal extension of the protein and that the added amino acid sequence is prone to aggregation. Detailed in vitro studies of 3 HSPB8 C-terminal frameshift mutations, P173SfsX43 (<a href="#0004">608014.0004</a>), T194SfsX23 (<a href="#0006">608014.0006</a>), and Q170GfsX45 (<a href="#0005">608014.0005</a>), in HeLa cells, human myoblasts, murine NSC34 neuroblastoma cells, and HEK293 cells showed that the mutant proteins interacted with other CASA subunits (wildtype HSPB8, BAG3, HSPA1A, and STUB1) and formed highly insoluble cytoplasmic aggregate structures that contained ubiquitinated CASA substrates, suggesting disruption of HSPB8 autophagy chaperone function. The abnormal aggregates were associated with 2 autophagy receptors SQSTM1/p62 and TAX1BP1 (<a href="/entry/605326">605326</a>). Human myoblasts expressing the frameshift mutations showed impaired differentiation and disorganization of the sarcomere structure. The overall findings were consistent a toxic gain-of-function effect of these mutations, ultimately resulting in a general failure of proteostasis affecting muscle cells. The authors noted that haploinsufficiency had previously been suggested as the pathomechanism of C-terminal mutations, but that their findings confirmed a dominant toxic gain-of-function effect. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=36854646" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p></div>
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<div class="mim-changed mim-change"><p>Dominantly inherited HSPB8 mutations affecting the conserved lysine-141 residue (K141) are found in patients with motor neuropathy (HMND2; <a href="/entry/158590">158590</a>) or sensorimotor neuropathy (CMT2L; <a href="/entry/608673">608673</a>), whereas dominant or de novo frameshift mutations at the HSPB8 C terminus, resulting in elongated proteins, are predominantly associated with myofibrillar myopathy-13 with rimmed vacuoles (MFM13; <a href="/entry/621078">621078</a>) (<a href="#18" class="mim-tip-reference" title="Tedesco, B., Vendredy, L., Adriaenssens, E., Cozzi, M., Asselbergh, B., Crippa, V., Cristofani, R., Rusmini, P., Ferrari, V., Casarotto, E., Chierichetti, M., Mina, F., and 15 others. <strong>HSPB8 frameshift mutant aggregates weaken chaperone-assisted selective autophagy in neuromyopathies.</strong> Autophagy 19: 2217-2239, 2023.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/36854646/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">36854646</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=36854646[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/10.1080/15548627.2023.2179780" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="36854646">Tedesco et al., 2023</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=36854646" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p></div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=608014[MIM]" class="btn btn-default mim-tip-hint" role="button" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs104894345 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894345;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=rs104894345" 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=rs104894345" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<div class="mim-changed mim-change"><p>In affected members of a Belgian family with autosomal dominant distal hereditary motor neuronopathy-2 (HMND2; <a href="/entry/158590">158590</a>), previously reported by <a href="#19" class="mim-tip-reference" title="Timmerman, V., Raeymaekers, P., Nelis, E., De Jonghe, P., Muylle, L., Ceuterick, C., Martin, J.-J., Van Broeckhoven, C. <strong>Linkage analysis of distal hereditary motor neuropathy type II (distal HMN II) in a single pedigree.</strong> J. Neurol. Sci. 109: 41-48, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1517763/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1517763</a>] [<a href="https://doi.org/10.1016/0022-510x(92)90091-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1517763">Timmerman et al. (1992)</a>, and in affected members of a large Czech family with HMND2, <a href="#12" class="mim-tip-reference" title="Irobi, J., Van Impe, K., Seeman, P., Jordanova, A., Dierick, I,., Verpoorten, N., Michalik, A., De Vriendt, E., Jacobs, A., Van Gerwen, V., Vennekens, K., Mazanec, R., and 11 others. <strong>Hot-spot residue in small heat-shock protein 22 causes distal motor neuropathy.</strong> Nature Genet. 36: 597-601, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15122253/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15122253</a>] [<a href="https://doi.org/10.1038/ng1328" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15122253">Irobi et al. (2004)</a> identified a heterozygous c.423G-C transversion in exon 2 of the HSPB8 gene, resulting in a lys141-to-asn (K141N) substitution. The mutation cosegregated with the disease in both families. The K141N mutation affects a highly conserved residue in the central alpha-crystallin domain of the protein. Normally, HSPB8 interacts with HSPB1 (<a href="/entry/602195">602195</a>). Expression studies of the K141N mutant protein in COS cells showed an increased interaction between HSPB8 and HSPB1, leading to the formation of intracellular aggregates. Of note, <a href="#17" class="mim-tip-reference" title="Tang, B., Zhao, G., Luo, W., Xia, K., Cai, F., Pan, Q., Zhang, R., Zhang, F., Liu, X., Chen, B., Zhang, C., Shen, L., Jiang, H., Long, Z., Dai, H. <strong>Small heat-shock protein 22 mutated in autosomal dominant Charcot-Marie-Tooth disease type 2L.</strong> Hum. Genet. 116: 222-224, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15565283/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15565283</a>] [<a href="https://doi.org/10.1007/s00439-004-1218-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15565283">Tang et al. (2005)</a> identified a K141N mutation resulting from a c.423G-T transversion (<a href="#0003">608014.0003</a>) in affected members of a Chinese family with Charcot-Marie-Tooth disease type 2L (CMT2L; <a href="/entry/608673">608673</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1517763+15565283+15122253" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p></div>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs104894351 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894351;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=rs104894351" 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=rs104894351" 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=RCV000002736 OR RCV001216811 OR RCV001532719" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000002736, RCV001216811, RCV001532719" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000002736...</a>
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<div class="mim-changed mim-change"><p>In affected members of an English family and a Bulgarian family with autosomal dominant distal hereditary motor neuronopathy-2 (HMND2; <a href="/entry/158590">158590</a>), <a href="#12" class="mim-tip-reference" title="Irobi, J., Van Impe, K., Seeman, P., Jordanova, A., Dierick, I,., Verpoorten, N., Michalik, A., De Vriendt, E., Jacobs, A., Van Gerwen, V., Vennekens, K., Mazanec, R., and 11 others. <strong>Hot-spot residue in small heat-shock protein 22 causes distal motor neuropathy.</strong> Nature Genet. 36: 597-601, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15122253/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15122253</a>] [<a href="https://doi.org/10.1038/ng1328" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15122253">Irobi et al. (2004)</a> identified a heterozygous c.421A-G transition in exon 2 of the HSPB8 gene, resulting in a lys141-to-glu (K141E) substitution. The mutation cosegregated with the disease in both families. The K141E mutation affects a highly conserved residue in the central alpha-crystallin domain of the protein. Normally, HSPB8 interacts with HSPB1 (<a href="/entry/602195">602195</a>). Expression studies of the mutant K141E protein in COS cells showed an increased interaction between HSPB8 and HSPB1, leading to the formation of intracellular aggregates. A different mutation in the same codon was identified in 2 other families with HMND2 (<a href="#0001">608014.0001</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15122253" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p></div>
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<div class="mim-changed mim-change"><p>In a woman and her 2 children (family 1) with HMND2 and later onset of myofibrillar myopathy, <a href="#8" class="mim-tip-reference" title="Ghaoui, R., Palmio, J., Brewer, J., Lek, M., Needham, M., Evila, A., Hackman, P., Jonson, P.-H., Penttila, S., Vihola, A., Huovinen, S., Lindfors, M., and 9 others. <strong>Mutations in HSPB8 causing a new phenotype of distal myopathy and motor neuropathy.</strong> Neurology 86: 391-398, 2016. Note: Erratum: Neurology 86: 1077, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26718575/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26718575</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26718575[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/10.1212/WNL.0000000000002324" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26718575">Ghaoui et al. (2016)</a> identified a heterozygous c.421A-G transition (c.421A-G, NM_014365) in the HSPB8 gene, resulting in a lys141-to-glu (K141E) substitution. The mutation, which was found by next-generation sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Segregation studies indicated that the mutation occurred de novo in the mother. In vitro studies showed that the mutant K141E protein lost its ability to prevent abnormal protein aggregation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26718575" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p></div>
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<div class="mim-changed mim-change"><p>In a mother and her trizygotic triplets with young adult onset of a hereditary motor neuropathy and myofibrillar myopathy, <a href="#6" class="mim-tip-reference" title="Cortese, A., Laura, M., Casali, C., Nishino, I., Hayashi, Y. K., Magri, S., Taroni, F., Stuani, C., Saveri, P., Moggio, M., Ripolone, M., Prelle, A., Pisciotta, C., Sagnelli, A., Pichiecchio, A., Reilly, M. M., Buratti, E., Pareyson, D. <strong>Altered TDP-43-dependent splicing in HSPB8-related distal hereditary motor neuropathy and myofibrillar myopathy.</strong> Europ. J. Neurol. 25: 154-163, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29029362/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29029362</a>] [<a href="https://doi.org/10.1111/ene.13478" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29029362">Cortese et al. (2018)</a> identified a heterozygous K141E mutation in the HSPB8 gene. Studies of muscle biopsy from 1 patient showed decreased mRNA levels of TDP43 (<a href="/entry/605078">605078</a>), which was associated with abnormal splicing of TDP43 substrates. Of note, the mother and 1 of the triplets also carried a heterozygous missense variant of unknown significance (H248R) in the BAG3 gene (<a href="/entry/603883">603883</a>). The findings confirmed that mutant HSPB8 can cause a combined neuromuscular disorder exhibiting both motor neuropathy and myofibrillar myopathy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29029362" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p></div>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs104894345 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894345;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=rs104894345" 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=rs104894345" 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=RCV000002737 OR RCV000192250 OR RCV002472922" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000002737, RCV000192250, RCV002472922" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000002737...</a>
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<div class="mim-changed mim-change"><p>In affected members of a large Chinese family with axonal Charcot-Marie-Tooth disease type 2L (CMT2L; <a href="/entry/608673">608673</a>) in which <a href="#16" class="mim-tip-reference" title="Tang, B., Luo, W., Xia, K., Xiao, J., Jiang, H., Shen, L., Tang, J., Zhao, G., Cai, F., Pan, Q., Dai, H., Yang, Q., Xia, J., Evgrafov, O. V. <strong>A new locus for autosomal dominant Charcot-Marie-Tooth disease type 2 (CMT2L) maps to chromosome 12q24.</strong> Hum. Genet. 114: 527-533, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15021985/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15021985</a>] [<a href="https://doi.org/10.1007/s00439-004-1102-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15021985">Tang et al. (2004)</a> assigned the underlying locus to 12q24, <a href="#17" class="mim-tip-reference" title="Tang, B., Zhao, G., Luo, W., Xia, K., Cai, F., Pan, Q., Zhang, R., Zhang, F., Liu, X., Chen, B., Zhang, C., Shen, L., Jiang, H., Long, Z., Dai, H. <strong>Small heat-shock protein 22 mutated in autosomal dominant Charcot-Marie-Tooth disease type 2L.</strong> Hum. Genet. 116: 222-224, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15565283/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15565283</a>] [<a href="https://doi.org/10.1007/s00439-004-1218-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15565283">Tang et al. (2005)</a> identified a c.423G-T transversion in exon 2 of the HSPB8 gene, resulting in a lys141-to-asn (K141N) substitution. Functional studies were not performed. Of note, <a href="#12" class="mim-tip-reference" title="Irobi, J., Van Impe, K., Seeman, P., Jordanova, A., Dierick, I,., Verpoorten, N., Michalik, A., De Vriendt, E., Jacobs, A., Van Gerwen, V., Vennekens, K., Mazanec, R., and 11 others. <strong>Hot-spot residue in small heat-shock protein 22 causes distal motor neuropathy.</strong> Nature Genet. 36: 597-601, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15122253/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15122253</a>] [<a href="https://doi.org/10.1038/ng1328" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15122253">Irobi et al. (2004)</a> identified a K141N mutation resulting from a c.423G-C transversion (<a href="#0001">608014.0001</a>) in affected members of 2 families with autosomal dominant distal hereditary motor neuronopathy-2 (HMND2; <a href="/entry/158590">158590</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15021985+15565283+15122253" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p></div>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1954727159 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1954727159;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=rs1954727159" 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=rs1954727159" 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=RCV001267528 OR RCV005055454" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001267528, RCV005055454" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001267528...</a>
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<div class="mim-changed mim-change"><p>In 2 affected members of a French Caucasian family (family 2) with myofibrillar myopathy-13 with rimmed vacuoles (MFM13; <a href="/entry/621078">621078</a>), <a href="#8" class="mim-tip-reference" title="Ghaoui, R., Palmio, J., Brewer, J., Lek, M., Needham, M., Evila, A., Hackman, P., Jonson, P.-H., Penttila, S., Vihola, A., Huovinen, S., Lindfors, M., and 9 others. <strong>Mutations in HSPB8 causing a new phenotype of distal myopathy and motor neuropathy.</strong> Neurology 86: 391-398, 2016. Note: Erratum: Neurology 86: 1077, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26718575/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26718575</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26718575[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/10.1212/WNL.0000000000002324" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26718575">Ghaoui et al. (2016)</a> identified a heterozygous 1-bp insertion (c.515insC, NM_014365) in the last exon of the HSPB8 gene, predicted to result in a frameshift and extension of the protein by 18 amino acids (Pro173SerfsTer43). The mutation, which was found by next-generation sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The proband also carried a heterozygous missense variant (K238E) in the SQSTM1 gene (<a href="/entry/601530">601530</a>), but his affected cousin did not carry that variant. Functional studies of the variants were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26718575" 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 3 members of a French family with MFM13, <a href="#2" class="mim-tip-reference" title="Al-Tahan, S., Weiss, L., Yu, H., Tang, S., Saporta, M., Vihola, A., Mozaffar, T., Udd, B., Kimonis, V. <strong>New family with HSPB8-associated autosomal dominant rimmed vacuolar myopathy.</strong> Neurol. Genet. 5: e349, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31403083/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31403083</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31403083[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/10.1212/NXG.0000000000000349" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31403083">Al-Tahan et al. (2019)</a> identified a heterozygous 1-bp duplication (c.515dupC), predicted to result in a frameshift and elongation of the HSPB8 protein (Pro173SerfsTer43), the same mutation reported by <a href="#8" class="mim-tip-reference" title="Ghaoui, R., Palmio, J., Brewer, J., Lek, M., Needham, M., Evila, A., Hackman, P., Jonson, P.-H., Penttila, S., Vihola, A., Huovinen, S., Lindfors, M., and 9 others. <strong>Mutations in HSPB8 causing a new phenotype of distal myopathy and motor neuropathy.</strong> Neurology 86: 391-398, 2016. Note: Erratum: Neurology 86: 1077, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26718575/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26718575</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26718575[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/10.1212/WNL.0000000000002324" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26718575">Ghaoui et al. (2016)</a>. The mutation, which was found by whole-genome sequencing, was not present in gnomAD. Western blot analysis of patient fibroblasts showed a 50% reduction of the HSPB8 protein. There was increased expression of autophagosomal markers LC3B and SQSTM1. Patient fibroblasts had excessive amounts of HSPB8 protein aggregates in response to heat shock compared to controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=26718575+31403083" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p></div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV002290198 OR RCV004587340 OR RCV005055397" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV002290198, RCV004587340, RCV005055397" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV002290198...</a>
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<div class="mim-changed mim-change"><p>In 6 patients from 3 unrelated families with myofibrillar myopathy-13 with rimmed vacuoles (MFM13; <a href="/entry/621078">621078</a>), <a href="#7" class="mim-tip-reference" title="Echaniz-Laguna, A., Lornage, X., Lannes, B., Schneider, R., Bierry, G., Dondaine, N., Boland, A., Deleuze, J.-F., Bohm, J., Thompson, J., Laporte, J., Biancalana, V. <strong>HSPB8 haploinsufficiency causes dominant adult-onset axial and distal myopathy.</strong> Acta Neuropath. 134: 163-165, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28501893/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28501893</a>] [<a href="https://doi.org/10.1007/s00401-017-1724-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28501893">Echaniz-Laguna et al. (2017)</a> identified a heterozygous 2-bp deletion (c.508_509delCA, NM_014365.2) in the HSPB8 gene, predicted to result in a frameshift and extension of the protein by 17 amino acids (Gln170GlyfsTer45). The mutation, which was found by exome sequencing or targeted sequencing and confirmed by Sanger sequencing, segregated with the disorder in families A and B; the patient in family C was a sporadic case. The mutation was not present in gnomAD. Western blot analysis of cells from 1 patient showed that the HSPB8 protein levels were reduced by 60%. Neither an elongated nor a truncated HSPB8 protein was identified using an antibody to the N-terminal region, suggesting to the authors that the mutation induces nonsense-mediated mRNA decay or protein degradation and may result in HSPB8 haploinsufficiency. The patients presented with adult-onset axial and distal myopathy without evidence of a neuropathy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28501893" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p></div>
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<strong><div class="mim-changed mim-change">.0006 MYOPATHY, MYOFIBRILLAR, 13, WITH RIMMED VACUOLES</div></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">rs1954727878 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1954727878;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=rs1954727878" 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=rs1954727878" 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=RCV001249293 OR RCV005055453" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001249293, RCV005055453" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001249293...</a>
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<div class="mim-changed mim-change"><p>In a 23-year-old man with myofibrillar myopathy-13 with rimmed vacuoles (MFM13; <a href="/entry/621078">621078</a>), <a href="#15" class="mim-tip-reference" title="Nicolau, S., Liewluck, T., Elliott, J. L., Engel, A. G., Milone, M. <strong>A novel heterozygous mutation in the C-terminal region of HSPB8 leads to limb-girdle rimmed vacuolar myopathy.</strong> Neuromusc. Disord. 30: 236-240, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32165108/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32165108</a>] [<a href="https://doi.org/10.1016/j.nmd.2020.02.005" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32165108">Nicolau et al. (2020)</a> identified a de novo heterozygous 4-bp duplication (c.577_580dupGTCA, NM_014365) in the C-terminal region of the HSPB8 gene, predicted to result in a frameshift and elongation of the protein (Thr194SerfsTer23). The mutation, which was found by whole-exome sequencing, was not present in gnomAD. Functional studies of the variant were not performed. The phenotype was manifest as proximal limb-girdle muscle weakness. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32165108" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p></div>
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<strong><div class="mim-changed mim-change">.0007 MYOPATHY, MYOFIBRILLAR, 13, WITH RIMMED VACUOLES</div></strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV005055413" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV005055413" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV005055413</a>
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<div class="mim-changed mim-change"><p>In 6 affected members of a multigenerational Japanese family with myofibrillar myopathy-13 with rimmed vacuoles (MFM13; <a href="/entry/621078">621078</a>), <a href="#9" class="mim-tip-reference" title="Inoue-Shibui, A., Niihori, T., Kobayashi, M., Suzuki, N., Izumi, R., Warita, H., Hara, K., Shirota, M., Funayama, R., Nakayama, K., Nishino, I., Aoki, M., Aoki, Y. <strong>A novel deletion in the C-terminal region of HSPB8 in a family with rimmed vacuolar myopathy.</strong> J. Hum. Genet. 66: 965-972, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33744911/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33744911</a>] [<a href="https://doi.org/10.1038/s10038-021-00916-y" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33744911">Inoue-Shibui et al. (2021)</a> identified a heterozygous 5-bp deletion (c.525_529del, NM_014365.3) in the HSPB8 gene, predicted to result in a frameshift and elongation of the protein (Thr176TrpfsTer38). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies of the variant were not performed, but these authors suggested that the mutant transcript would escape nonsense-mediated mRNA decay. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33744911" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p></div>
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<strong><div class="mim-changed mim-change">.0008 MYOPATHY, MYOFIBRILLAR, 13, WITH RIMMED VACUOLES</div></strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV005055415" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV005055415" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV005055415</a>
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<div class="mim-changed mim-change"><p>In an 18-year-old Chinese girl with myofibrillar myopathy-13 with rimmed vacuoles (MFM13; <a href="/entry/621078">621078</a>), <a href="#20" class="mim-tip-reference" title="Yang, G., Lv, X., Yang, M., Feng, Y., Wang, G., Yan, C., Lin, P. <strong>Expanding the spectrum of HSPB8-related myopathy: a novel mutation causing atypical pediatric-onset axial and limb-girdle involvement with autophagy abnormalities and molecular dynamics studies.</strong> J. Hum. Genet. 70: 159-165, 2025.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/39548192/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">39548192</a>] [<a href="https://doi.org/10.1038/s10038-024-01305-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="39548192">Yang et al. (2025)</a> identified a de novo heterozygous del/ins mutation (c.576_579delinsCAG, NM_014365) in the HSPB8 gene, resulting in a frameshift and extension of the protein by 49 amino acids (Glu192AspfsTer55). The mutation, which was found by whole-exome sequencing, was not present in the gnomAD database. Direct functional studies of the variant were not performed, but patient muscle biopsy showed accumulation of autophagy molecules. The authors concluded that the mutant transcript likely evaded nonsense-mediated mRNA decay, and suggested that it may result in a toxic gain of function, likely leading to dysregulation of autophagy. The patient had onset of axial and limb-girdle myopathy at 6 years of age. She did not have sensory involvement. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=39548192" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p></div>
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<strong><div class="mim-changed mim-change">.0009 CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2L</div></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">rs1565929090 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1565929090;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=rs1565929090" 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=rs1565929090" 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=RCV000789966 OR RCV005055445" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000789966, RCV005055445" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000789966...</a>
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<div class="mim-changed mim-change"><p>In a 27-year-old Korean man, born of unrelated parents, with axonal Charcot-Marie-Tooth disease type 2L (CMT2L; <a href="/entry/608673">608673</a>), <a href="#14" class="mim-tip-reference" title="Nakhro, K., Park, J.-M., Kim, Y. J., Yoon, B. R., Yoo, J. H., Koo, H., Choi, B.-O., Chung, K. W. <strong>A novel Lys141Thr mutation in small heat shock protein 22 (HSPB8) gene in Charcot-Marie-Tooth disease type 2L.</strong> Neuromusc. Disord. 23: 656-663, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23796487/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23796487</a>] [<a href="https://doi.org/10.1016/j.nmd.2013.05.009" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23796487">Nakhro et al. (2013)</a> identified a de novo heterozygous c.422A-C transversion in the HSPB8 gene, resulting in a lys141-to-thr (K141T) substitution at a conserved residue in the alpha-crystallin domain. The mutation, which was found by exome sequencing, was not present in public databases. Functional studies of the variant were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23796487" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p></div>
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<a id="Abdel-Nour2019" class="mim-anchor"></a>
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Abdel-Nour, M., Carneiro, L. A. M., Downey, J., Tsalikis, J., Outlioua, A., Prescott, D., Da Costa, L. S., Hovingh, E. S., Farahvash, A., Gaudet, R. G., Molinaro, R., van Dalen, R., and 11 others.
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<strong>The heme-regulated inhibitor is a cytosolic sensor of protein misfolding that controls innate immune signaling.</strong>
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Science 365: eaaw4144, 2019. Note: Electronic Article.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31273097/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31273097</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31273097[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=31273097" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1126/science.aaw4144" target="_blank">Full Text</a>]
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Al-Tahan, S., Weiss, L., Yu, H., Tang, S., Saporta, M., Vihola, A., Mozaffar, T., Udd, B., Kimonis, V.
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<strong>New family with HSPB8-associated autosomal dominant rimmed vacuolar myopathy.</strong>
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Neurol. Genet. 5: e349, 2019.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31403083/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31403083</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31403083[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=31403083" 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/NXG.0000000000000349" target="_blank">Full Text</a>]
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Benndorf, R., Welsh, M. J.
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<strong>Shocking degeneration.</strong>
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Nature Genet. 36: 547-548, 2004.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15167925/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15167925</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15167925" 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/ng0604-547" target="_blank">Full Text</a>]
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Carra, S., Sivilotti, M., Chavez Zobel, A. T., Lambert, H., Landry, J.
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<strong>HspB8, a small heat shock protein mutated in human neuromuscular disorders, has in vivo chaperone activity in cultured cells.</strong>
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Hum. Molec. Genet. 14: 1659-1669, 2005.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15879436/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15879436</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15879436" 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/ddi174" target="_blank">Full Text</a>]
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Charpentier, A. H., Bednarek, A. K., Daniel, R. L., Hawkins, K. A., Laflin, K. J., Gaddis, S., MacLeod, M. C., Aldaz, C. M.
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<strong>Effects of estrogen on global gene expression: identification of novel targets of estrogen action.</strong>
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Cancer Res. 60: 5977-5983, 2000.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11085516/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11085516</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11085516" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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<div class="mim-changed mim-change">
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<p class="mim-text-font">
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Cortese, A., Laura, M., Casali, C., Nishino, I., Hayashi, Y. K., Magri, S., Taroni, F., Stuani, C., Saveri, P., Moggio, M., Ripolone, M., Prelle, A., Pisciotta, C., Sagnelli, A., Pichiecchio, A., Reilly, M. M., Buratti, E., Pareyson, D.
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<strong>Altered TDP-43-dependent splicing in HSPB8-related distal hereditary motor neuropathy and myofibrillar myopathy.</strong>
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[<a href="https://doi.org/10.1111/ene.13478" target="_blank">Full Text</a>]
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<div class="mim-changed mim-change">
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<p class="mim-text-font">
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Echaniz-Laguna, A., Lornage, X., Lannes, B., Schneider, R., Bierry, G., Dondaine, N., Boland, A., Deleuze, J.-F., Bohm, J., Thompson, J., Laporte, J., Biancalana, V.
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<strong>HSPB8 haploinsufficiency causes dominant adult-onset axial and distal myopathy.</strong>
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Acta Neuropath. 134: 163-165, 2017.
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[<a href="https://doi.org/10.1007/s00401-017-1724-8" target="_blank">Full Text</a>]
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<div class="mim-changed mim-change">
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Ghaoui, R., Palmio, J., Brewer, J., Lek, M., Needham, M., Evila, A., Hackman, P., Jonson, P.-H., Penttila, S., Vihola, A., Huovinen, S., Lindfors, M., and 9 others.
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<strong>Mutations in HSPB8 causing a new phenotype of distal myopathy and motor neuropathy.</strong>
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Neurology 86: 391-398, 2016. Note: Erratum: Neurology 86: 1077, 2016.
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[<a href="https://doi.org/10.1212/WNL.0000000000002324" target="_blank">Full Text</a>]
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Inoue-Shibui, A., Niihori, T., Kobayashi, M., Suzuki, N., Izumi, R., Warita, H., Hara, K., Shirota, M., Funayama, R., Nakayama, K., Nishino, I., Aoki, M., Aoki, Y.
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<strong>A novel deletion in the C-terminal region of HSPB8 in a family with rimmed vacuolar myopathy.</strong>
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J. Hum. Genet. 66: 965-972, 2021.
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[<a href="https://doi.org/10.1038/s10038-021-00916-y" target="_blank">Full Text</a>]
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Irobi, J., Almeida-Souza, L., Asselbergh, B., De Winter, V., Goethals, S., Dierick, I., Krishnan, J., Timmermans, J.-P., Robberecht, W., De Jonghe, P., Van Den Bosch, L., Janssens, S., Timmerman, V.
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<strong>Mutant HSPB8 causes motor neuron-specific neurite degeneration.</strong>
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Hum. Molec. Genet. 19: 3254-3265, 2010.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20538880/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20538880</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20538880[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=20538880" 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/ddq234" target="_blank">Full Text</a>]
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Irobi, J., Holmgren, A., De Winter, V., Asselbergh, B., Gettemans, J., Adriaensen, D., Ceuterick-de Groote, C., Van Coster, R., De Jonghe, P., Timmerman, V.
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<strong>Mutant HSPB8 causes protein aggregates and a reduced mitochondrial membrane potential in dermal fibroblasts from distal hereditary motor neuropathy patients.</strong>
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[<a href="https://doi.org/10.1016/j.nmd.2012.04.005" target="_blank">Full Text</a>]
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Irobi, J., Van Impe, K., Seeman, P., Jordanova, A., Dierick, I,., Verpoorten, N., Michalik, A., De Vriendt, E., Jacobs, A., Van Gerwen, V., Vennekens, K., Mazanec, R., and 11 others.
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[<a href="https://doi.org/10.1038/ng1328" target="_blank">Full Text</a>]
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<strong>Characterization of two novel human small heat shock proteins: protein kinase-related HspB8 and testis-specific HspB9.</strong>
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[<a href="https://doi.org/10.1016/s0167-4781(01)00237-8" target="_blank">Full Text</a>]
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<strong>A novel Lys141Thr mutation in small heat shock protein 22 (HSPB8) gene in Charcot-Marie-Tooth disease type 2L.</strong>
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[<a href="https://doi.org/10.1016/j.nmd.2013.05.009" target="_blank">Full Text</a>]
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Nicolau, S., Liewluck, T., Elliott, J. L., Engel, A. G., Milone, M.
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<strong>A novel heterozygous mutation in the C-terminal region of HSPB8 leads to limb-girdle rimmed vacuolar myopathy.</strong>
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[<a href="https://doi.org/10.1016/j.nmd.2020.02.005" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15021985/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15021985</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15021985" 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/s00439-004-1102-1" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/s00439-004-1218-3" target="_blank">Full Text</a>]
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Tedesco, B., Vendredy, L., Adriaenssens, E., Cozzi, M., Asselbergh, B., Crippa, V., Cristofani, R., Rusmini, P., Ferrari, V., Casarotto, E., Chierichetti, M., Mina, F., and 15 others.
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[<a href="https://doi.org/10.1016/0022-510x(92)90091-x" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/s10038-024-01305-x" target="_blank">Full Text</a>]
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Cassandra L. Kniffin - updated : 02/03/2025
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Ada Hamosh - updated : 04/08/2020<br>George E. Tiller - updated : 09/17/2013<br>George E. Tiller - updated : 6/16/2008<br>Victor A. McKusick - updated : 4/15/2005<br>Victor A. McKusick - updated : 6/14/2004<br>Cassandra L. Kniffin - updated : 5/3/2004<br>Patricia A. Hartz - updated : 12/16/2003
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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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Carol A. Bocchini : 8/6/2003
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alopez : 02/07/2025
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alopez : 02/07/2025<br>alopez : 02/06/2025<br>ckniffin : 02/03/2025<br>carol : 04/26/2024<br>alopez : 10/16/2023<br>alopez : 04/08/2020<br>alopez : 09/17/2013<br>ckniffin : 1/24/2013<br>wwang : 9/15/2009<br>wwang : 6/19/2008<br>terry : 6/16/2008<br>ckniffin : 3/16/2007<br>tkritzer : 4/18/2005<br>terry : 4/15/2005<br>tkritzer : 6/29/2004<br>terry : 6/14/2004<br>alopez : 5/28/2004<br>tkritzer : 5/5/2004<br>tkritzer : 5/4/2004<br>ckniffin : 5/3/2004<br>mgross : 12/17/2003<br>mgross : 12/16/2003<br>tkritzer : 8/7/2003<br>tkritzer : 8/7/2003<br>carol : 8/6/2003
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<span class="mim-font">
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<strong>*</strong> 608014
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<div>
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<h3>
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<span class="mim-font">
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HEAT-SHOCK 22-KD PROTEIN 8; HSPB8
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</h3>
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</div>
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<br />
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</p>
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<h4>
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<span class="mim-font">
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HSP22<br />
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PROTEIN KINASE H11; H11<br />
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E2-INDUCED GENE 1; E2IG1<br />
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HEAT-SHOCK 27-KD PROTEIN 8
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</span>
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</h4>
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: HSPB8</em></strong>
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</span>
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<strong>
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<em>
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Cytogenetic location: 12q24.23
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Genomic coordinates <span class="small">(GRCh38)</span> : 12:119,178,931-119,194,746 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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</span>
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</p>
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<span class="mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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<div>
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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Location
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</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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Inheritance
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</th>
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Phenotype <br /> mapping key
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<td rowspan="3">
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<span class="mim-font">
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12q24.23
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<span class="mim-font">
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Charcot-Marie-Tooth disease, axonal, type 2L
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<span class="mim-font">
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608673
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<span class="mim-font">
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Autosomal dominant
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<span class="mim-font">
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3
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<span class="mim-font">
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Myopathy, myofibrillar, 13, with rimmed vacuoles
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<span class="mim-font">
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621078
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<span class="mim-font">
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Autosomal dominant
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<td>
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<span class="mim-font">
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3
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<tr>
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<td>
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<span class="mim-font">
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Neuronopathy, distal hereditary motor, autosomal dominant 2
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<td>
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<span class="mim-font">
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158590
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</td>
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<span class="mim-font">
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Autosomal dominant
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</td>
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<td>
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<span class="mim-font">
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3
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</table>
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<div>
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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
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</span>
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</h4>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Description</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>The HSPB8 gene encodes a molecular chaperone that is a component of the chaperone-assisted selective autophagy (CASA) complex, which is is involved in the recognition and removal of misfolded and aggregated cellular proteins through ubiquitination and autophagic degradation. HSPB8 works in conjunction with BAG3 (603883), STUB1 (607207), and HSPA1A (HSP72; 140550) in the CASA complex. In muscle, CASA promotes the turnover of structural components damaged by mechanical stress, and in neurons, CASA functions in the removal of misfolded substrates implicated in neurodegenerative diseases (summary by Tedesco et al., 2023, Yang et al., 2025). </p>
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</span>
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<div>
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<br />
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<div>
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<h4>
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<span class="mim-font">
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<strong>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>To identify genes that are regulated by or associated with estrogen action, Charpentier et al. (2000) performed serial analysis of gene expression (SAGE) on estrogen-responsive breast cancer cells after exposure to estrogen. Using transcript-specific PCR primers for novel sequences that increased more than 10-fold upon treatment with 17-beta estradiol (E2), they cloned 5 cDNAs, designated E2-induced genes (E2IG) 1-5, from a human placenta cDNA library. The E2IG1 cDNA encodes a deduced 196-amino acid protein that contains a central portion homologous to a highly conserved HSP-alpha crystallin domain common to all HSP20 family members. It shows 54% sequence homology to HSP27 (602195), suggesting that it is a member of the small HSP family. </p><p>By searching an EST database for sequences containing the alpha-crystallin domain characteristic of small heat-shock proteins, followed by PCR of a placenta cDNA library, Kappe et al. (2001) cloned HSPB8. Northern blot analysis detected broad expression of a 2.2-kb transcript, with highest abundance in skeletal muscle, heart, and placenta. Expression of HSPB8 was intermediate in several other tissues, but it was not detected in blood. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Structure</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Kappe et al. (2001) determined that the HSPB8 gene contains at least 3 exons. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Mapping</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>By sequence analysis, Charpentier et al. (2000) mapped the E2IG1 gene to chromosome 12 between markers D12S366 and D12S340. </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>Carra et al. (2005) investigated the capacity of HSPB8 to prevent protein aggregation in cells using Htt (613004) protein containing 43 glutamine residues (Htt43Q) as a model. In control conditions, Htt43Q accumulated in perinuclear inclusions composed of SDS-insoluble aggregates. In most cells, cotransfection with HSPB8 blocked inclusion formation. Biochemical analyses indicated that HSPB8 inhibited the accumulation of insoluble Htt43Q as efficiently as HSP40 (DNAJB1; 604572), which was taken as a positive control. Htt43Q then accumulated in the SDS-soluble fraction, provided that protein degradation was blocked by proteasome and autophagy inhibitors. In contrast, HSPB1 (602195) and alpha-B-crystallin (CRYAB; 123590) had no effect. Analyses of HSPB1/HSPB8 chimeric proteins indicated that the C-terminal domain of HSPB8 contains the specific sequence necessary for chaperone activity. The K141N mutation (608014.0001) significantly reduced the chaperone activity of the protein. Carra et al. (2005) hypothesized that a decrease in HSPB8 chaperone activity may contribute to the development of some neuropathies. </p><p>Abdel-Nour et al. (2019) found that the EIF2-alpha (603907) kinase heme-regulated inhibitor (HRI; 613635) controls NOD1 (605980) signalosome folding and activation through a process requiring eIF2-alpha, the transcription factor ATF4 (604064), and the heat-shock protein HSPB8. The HRI/eIF2-alpha signaling axis was also essential for signaling downstream of the innate immune mediators NOD2 (605956), MAVS (609676), and TRIF (607601) but dispensable for pathways dependent on MyD88 (602170) or STING (612374). Moreover, filament-forming alpha-synuclein (163890) activated HRI-dependent responses, which suggested that the HRI pathway may restrict toxic oligomer formation. Abdel-Nour et al. (2019) proposed that HRI, eIF2-alpha, and HSPB8 define a novel cytosolic unfolded protein response (cUPR) essential for optimal innate immune signaling by large molecular platforms, functionally homologous to the PERK (EIF2AK3; 604032)/eIF2-alpha/HSPA5 (138120) axis of the endoplasmic reticulum (ER) unfolded protein response. </p><p><strong><em>Reviews</em></strong></p><p>
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Benndorf and Welsh (2004) reviewed the role of heat-shock proteins in neuromuscular function, as indicated by the association of mutations in 2 of these genes, HSP22 and HSP27, with human neuromuscular disorders. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p><strong><em>Distal Hereditary Motor Neuronopathy Type IIA</em></strong></p><p>
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In affected members of 4 families with autosomal dominant distal hereditary motor neuronopathy type IIA (dHMN2A; 158590), Irobi et al. (2004) identified heterozygous missense mutations in the same codon of the HSPB8 gene (K141N, 608014.0001 and K141E, 608014.0002). The K141N substitution resulted from a c.423G-C transversion. Expression studies of the mutant proteins in COS cells showed an increased interaction between HSPB8 and HSPB1, leading to the formation of intracellular aggregates. Of note, Tang et al. (2005) identified a K141N mutation resulting from a c.423G-T transversion (608014.0003) in affected members of a Chinese family with Charcot-Marie-Tooth disease type 2L (608673). </p><p>In a woman and her 2 children (family 1) with HMND2 and later onset of myofibrillar myopathy, Ghaoui et al. (2016) identified a heterozygous missense mutation in the HSPB8 gene (K141E; 608014.0002). The mutation, which was found by next-generation sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Segregation studies indicated that the mutation occurred de novo in the mother. In vitro studies showed that the mutant K141E protein lost its ability to prevent abnormal protein aggregation. </p><p>Irobi et al. (2010) compared the effect of mutant HSPB8 in primary neuronal and glial cell cultures of rat and mouse cells. In rat motor neurons, expression of both HSPB8 K141N (608014.0001) and K141E (608014.0002) mutations resulted in neurite degeneration, as manifested by a reduction in number of neurites per cell, as well as in a reduction in average length of the neurites. Expression of the K141E, and to a lesser extent the K141N, mutation also induced spheroids in the neurites. There were no signs of apoptosis in motor neurons, showing that mutant HSPB8 resulted in neurite degeneration without inducing neuronal death. While overt in rat motor neurons, these phenotypes were only very mildly present in embryonic mouse sensory neurons and completely absent in embryonic mouse cortical neurons and glial cells. </p><p>Irobi et al. (2012) found that cultured fibroblasts derived from 2 patients with the K141N mutation (608014.0001) showed transient HSPB8-positive intracellular protein aggregates. Early passages had small aggregates, whereas later passages had fewer and larger aggregates that decreased over time due to activation of the ubiquitin proteosomal removal process. Mitochondrial membrane potential was reduced in early passage mutant fibroblasts, although mitochondrial morphology was normal, and the mitochondrial potential was restored with time. There was no significant evidence of apoptosis. Electron microscopy showed decreased numbers of myelinated and unmyelinated sensory axons with mild axonal abnormalities. The authors noted the drawbacks in using nonneuronal cells to study neuropathologic disease mechanisms, and suggested that studies of motor neurons or reprogrammed iPS cell-derived motor neurons would be more informative for studying this disease. </p><p><strong><em>Axonal Charcot-Marie-Tooth Disease Type 2L</em></strong></p><p>
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In affected members of a Chinese family with axonal Charcot-Marie-Tooth disease type 2L (CMT2L; 608673), Tang et al. (2005) identified a heterozygous K141N missense mutation in the HSPB8 gene (608014.0003), resulting from a c.423G-T transversion. No functional studies were performed. Of note, Irobi et al. (2004) identified a K141N mutation resulting from a c.423G-C transversion (608014.0001) in affected members of 2 families with autosomal dominant distal hereditary motor neuronopathy-2 (HMND2; 158590). </p><p>In a 27-year-old Korean man, born of unrelated parents, with CMT2L, Nakhro et al. (2013) identified a de novo heterozygous K141T mutation in the HSPB8 gene (608014.0009). The mutation, which was found by exome sequencing, was not present in public databases. Functional studies of the variant were not performed. </p><p><strong><em>Myofibrillar Myopathy-13 With Rimmed Vacuoles</em></strong></p><p>
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In 2 affected members of a French Caucasian family (family 2) with myofibrillar myopathy-13 with rimmed vacuoles (MFM13; 621078), Ghaoui et al. (2016) identified a heterozygous frameshift mutation in the last exon of the HSPB8 gene (608014.0004), predicted to result in a frameshift and extension of the protein by 18 amino acids (Pro173SerfsTer43). The mutation, which was found by next-generation sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The proband also carried a heterozygous missense variant (K238E) in the SQSTM1 gene (601530), but his affected cousin did not carry that variant. Functional studies of the variants were not performed. </p><p>In 3 members of a French family with MFM13, Al-Tahan et al. (2019) identified a heterozygous frameshift mutation in the HSPB8 gene (608014.0004), the same mutation reported by Ghaoui et al. (2016). The mutation, which was found by whole-genome sequencing, was not present in gnomAD. Western blot analysis of patient fibroblasts showed a 50% reduction of the HSPB8 protein. There was increased expression of autophagosomal markers LC3B (609604) and SQSTM1. Patient fibroblasts had excessive amounts of HSPB8 protein aggregates in response to heat shock compared to controls. </p><p>In 6 patients from 3 unrelated families with MFM13, Echaniz-Laguna et al. (2017) identified a heterozygous frameshift mutation in the HSPB8 gene (608014.0005) and extension of the protein by 17 amino acids (Gln170GlyfsTer45). The mutation, which was found by exome sequencing or targeted sequencing and confirmed by Sanger sequencing, segregated with the disorder in families A and B; the patient in family C was a sporadic case. The mutation was not present in gnomAD. Western blot analysis of cells from 1 patient showed that HSPB8 protein levels were reduced by 60%. Neither an elongated nor a truncated HSPB8 protein was identified using an antibody to the N-terminal region, suggesting to the authors that the mutation induces nonsense-mediated mRNA decay or protein degradation and may result in HSPB8 haploinsufficiency. The patients presented with adult-onset axial and distal myopathy without evidence of a neuropathy. </p><p>In a 23-year-old man with MFM13 manifest as proximal limb-girdle muscle weakness, Nicolau et al. (2020) identified a de novo heterozygous frameshift mutation in the C-terminal region of the HSPB8 gene (Thr194SerfsTer23; 608014.0006) that resulted in extension of the protein. The mutation, which was found by whole-exome sequencing, was not present in gnomAD. Functional studies of the variant were not performed. </p><p>In 6 affected members of a multigenerational Japanese family with MFM13, Inoue-Shibui et al. (2021) identified a heterozygous frameshift mutation in the C terminus of the HSPB8 gene (608014.0007), predicted to result in a frameshift and elongation of the protein (Thr176TrpfsTer38). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies of the variant were not performed, but these authors suggested that the mutant transcript would escape nonsense-mediated mRNA decay. </p><p>In an 18-year-old Chinese girl with MFM13, Yang et al. (2025) identified a de novo heterozygous frameshift mutation in the C terminus of the HSPB8 gene (608014.0008), resulting in a frameshift and extension of the protein by 49 amino acids (Glu192AspfsTer55). The mutation, which was found by whole-exome sequencing, was not present in the gnomAD database. Direct functional studies of the variant were not performed, but patient muscle biopsy showed accumulation of autophagy molecules. The authors concluded that the mutant transcript likely evaded nonsense-mediated mRNA decay, and suggested that it may result in a toxic gain of function, likely leading to dysregulation of autophagy. The patient had onset of axial and limb-girdle myopathy at 6 years of age. She did not have sensory involvement. </p><p>Tedesco et al. (2023) found that different mutations affecting the C terminus of HSPB8 associated with MFM13 resulted in an identical carboxy-terminal extension of the protein and that the added amino acid sequence is prone to aggregation. Detailed in vitro studies of 3 HSPB8 C-terminal frameshift mutations, P173SfsX43 (608014.0004), T194SfsX23 (608014.0006), and Q170GfsX45 (608014.0005), in HeLa cells, human myoblasts, murine NSC34 neuroblastoma cells, and HEK293 cells showed that the mutant proteins interacted with other CASA subunits (wildtype HSPB8, BAG3, HSPA1A, and STUB1) and formed highly insoluble cytoplasmic aggregate structures that contained ubiquitinated CASA substrates, suggesting disruption of HSPB8 autophagy chaperone function. The abnormal aggregates were associated with 2 autophagy receptors SQSTM1/p62 and TAX1BP1 (605326). Human myoblasts expressing the frameshift mutations showed impaired differentiation and disorganization of the sarcomere structure. The overall findings were consistent a toxic gain-of-function effect of these mutations, ultimately resulting in a general failure of proteostasis affecting muscle cells. The authors noted that haploinsufficiency had previously been suggested as the pathomechanism of C-terminal mutations, but that their findings confirmed a dominant toxic gain-of-function effect. </p>
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</span>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Genotype/Phenotype Correlations</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Dominantly inherited HSPB8 mutations affecting the conserved lysine-141 residue (K141) are found in patients with motor neuropathy (HMND2; 158590) or sensorimotor neuropathy (CMT2L; 608673), whereas dominant or de novo frameshift mutations at the HSPB8 C terminus, resulting in elongated proteins, are predominantly associated with myofibrillar myopathy-13 with rimmed vacuoles (MFM13; 621078) (Tedesco et al., 2023). </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>ALLELIC VARIANTS</strong>
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</span>
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<strong>9 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 NEURONOPATHY, DISTAL HEREDITARY MOTOR, AUTOSOMAL DOMINANT 2</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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HSPB8, 423G-C, LYS141ASN
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<br />
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SNP: rs104894345,
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ClinVar: RCV000002735
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<div class="mim-changed mim-change"><p>In affected members of a Belgian family with autosomal dominant distal hereditary motor neuronopathy-2 (HMND2; 158590), previously reported by Timmerman et al. (1992), and in affected members of a large Czech family with HMND2, Irobi et al. (2004) identified a heterozygous c.423G-C transversion in exon 2 of the HSPB8 gene, resulting in a lys141-to-asn (K141N) substitution. The mutation cosegregated with the disease in both families. The K141N mutation affects a highly conserved residue in the central alpha-crystallin domain of the protein. Normally, HSPB8 interacts with HSPB1 (602195). Expression studies of the K141N mutant protein in COS cells showed an increased interaction between HSPB8 and HSPB1, leading to the formation of intracellular aggregates. Of note, Tang et al. (2005) identified a K141N mutation resulting from a c.423G-T transversion (608014.0003) in affected members of a Chinese family with Charcot-Marie-Tooth disease type 2L (CMT2L; 608673). </p></div>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0002 NEURONOPATHY, DISTAL HEREDITARY MOTOR, AUTOSOMAL DOMINANT 2</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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HSPB8, LYS141GLU
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<br />
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SNP: rs104894351,
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ClinVar: RCV000002736, RCV001216811, RCV001532719
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<div class="mim-changed mim-change"><p>In affected members of an English family and a Bulgarian family with autosomal dominant distal hereditary motor neuronopathy-2 (HMND2; 158590), Irobi et al. (2004) identified a heterozygous c.421A-G transition in exon 2 of the HSPB8 gene, resulting in a lys141-to-glu (K141E) substitution. The mutation cosegregated with the disease in both families. The K141E mutation affects a highly conserved residue in the central alpha-crystallin domain of the protein. Normally, HSPB8 interacts with HSPB1 (602195). Expression studies of the mutant K141E protein in COS cells showed an increased interaction between HSPB8 and HSPB1, leading to the formation of intracellular aggregates. A different mutation in the same codon was identified in 2 other families with HMND2 (608014.0001). </p></div>
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<div class="mim-changed mim-change"><p>In a woman and her 2 children (family 1) with HMND2 and later onset of myofibrillar myopathy, Ghaoui et al. (2016) identified a heterozygous c.421A-G transition (c.421A-G, NM_014365) in the HSPB8 gene, resulting in a lys141-to-glu (K141E) substitution. The mutation, which was found by next-generation sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Segregation studies indicated that the mutation occurred de novo in the mother. In vitro studies showed that the mutant K141E protein lost its ability to prevent abnormal protein aggregation. </p></div>
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<div class="mim-changed mim-change"><p>In a mother and her trizygotic triplets with young adult onset of a hereditary motor neuropathy and myofibrillar myopathy, Cortese et al. (2018) identified a heterozygous K141E mutation in the HSPB8 gene. Studies of muscle biopsy from 1 patient showed decreased mRNA levels of TDP43 (605078), which was associated with abnormal splicing of TDP43 substrates. Of note, the mother and 1 of the triplets also carried a heterozygous missense variant of unknown significance (H248R) in the BAG3 gene (603883). The findings confirmed that mutant HSPB8 can cause a combined neuromuscular disorder exhibiting both motor neuropathy and myofibrillar myopathy. </p></div>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0003 CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2L</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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HSPB8, 423G-T, LYS141ASN
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<br />
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SNP: rs104894345,
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ClinVar: RCV000002737, RCV000192250, RCV002472922
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<div class="mim-changed mim-change"><p>In affected members of a large Chinese family with axonal Charcot-Marie-Tooth disease type 2L (CMT2L; 608673) in which Tang et al. (2004) assigned the underlying locus to 12q24, Tang et al. (2005) identified a c.423G-T transversion in exon 2 of the HSPB8 gene, resulting in a lys141-to-asn (K141N) substitution. Functional studies were not performed. Of note, Irobi et al. (2004) identified a K141N mutation resulting from a c.423G-C transversion (608014.0001) in affected members of 2 families with autosomal dominant distal hereditary motor neuronopathy-2 (HMND2; 158590). </p></div>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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|
<strong>.0004 MYOPATHY, MYOFIBRILLAR, 13, WITH RIMMED VACUOLES</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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HSPB8, 1-BP DUP, 515C
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<br />
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SNP: rs1954727159,
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ClinVar: RCV001267528, RCV005055454
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<div class="mim-changed mim-change"><p>In 2 affected members of a French Caucasian family (family 2) with myofibrillar myopathy-13 with rimmed vacuoles (MFM13; 621078), Ghaoui et al. (2016) identified a heterozygous 1-bp insertion (c.515insC, NM_014365) in the last exon of the HSPB8 gene, predicted to result in a frameshift and extension of the protein by 18 amino acids (Pro173SerfsTer43). The mutation, which was found by next-generation sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The proband also carried a heterozygous missense variant (K238E) in the SQSTM1 gene (601530), but his affected cousin did not carry that variant. Functional studies of the variants were not performed. </p><p>In 3 members of a French family with MFM13, Al-Tahan et al. (2019) identified a heterozygous 1-bp duplication (c.515dupC), predicted to result in a frameshift and elongation of the HSPB8 protein (Pro173SerfsTer43), the same mutation reported by Ghaoui et al. (2016). The mutation, which was found by whole-genome sequencing, was not present in gnomAD. Western blot analysis of patient fibroblasts showed a 50% reduction of the HSPB8 protein. There was increased expression of autophagosomal markers LC3B and SQSTM1. Patient fibroblasts had excessive amounts of HSPB8 protein aggregates in response to heat shock compared to controls. </p></div>
|
|
</span>
|
|
</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0005 MYOPATHY, MYOFIBRILLAR, 13, WITH RIMMED VACUOLES</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
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<span class="mim-text-font">
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|
|
HSPB8, 2-BP DEL, 508CA
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|
<br />
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|
|
ClinVar: RCV002290198, RCV004587340, RCV005055397
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|
|
</span>
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|
</div>
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|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<div class="mim-changed mim-change"><p>In 6 patients from 3 unrelated families with myofibrillar myopathy-13 with rimmed vacuoles (MFM13; 621078), Echaniz-Laguna et al. (2017) identified a heterozygous 2-bp deletion (c.508_509delCA, NM_014365.2) in the HSPB8 gene, predicted to result in a frameshift and extension of the protein by 17 amino acids (Gln170GlyfsTer45). The mutation, which was found by exome sequencing or targeted sequencing and confirmed by Sanger sequencing, segregated with the disorder in families A and B; the patient in family C was a sporadic case. The mutation was not present in gnomAD. Western blot analysis of cells from 1 patient showed that the HSPB8 protein levels were reduced by 60%. Neither an elongated nor a truncated HSPB8 protein was identified using an antibody to the N-terminal region, suggesting to the authors that the mutation induces nonsense-mediated mRNA decay or protein degradation and may result in HSPB8 haploinsufficiency. The patients presented with adult-onset axial and distal myopathy without evidence of a neuropathy. </p></div>
|
|
</span>
|
|
</div>
|
|
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|
|
|
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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>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0006 MYOPATHY, MYOFIBRILLAR, 13, WITH RIMMED VACUOLES</strong>
|
|
</span>
|
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</h4>
|
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</div>
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<div>
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|
<span class="mim-text-font">
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|
|
HSPB8, 4-BP DUP, 577GTCA
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<br />
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|
|
SNP: rs1954727878,
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|
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|
|
ClinVar: RCV001249293, RCV005055453
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</span>
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<div class="mim-changed mim-change"><p>In a 23-year-old man with myofibrillar myopathy-13 with rimmed vacuoles (MFM13; 621078), Nicolau et al. (2020) identified a de novo heterozygous 4-bp duplication (c.577_580dupGTCA, NM_014365) in the C-terminal region of the HSPB8 gene, predicted to result in a frameshift and elongation of the protein (Thr194SerfsTer23). The mutation, which was found by whole-exome sequencing, was not present in gnomAD. Functional studies of the variant were not performed. The phenotype was manifest as proximal limb-girdle muscle weakness. </p></div>
|
|
</span>
|
|
</div>
|
|
|
|
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|
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<div>
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<br />
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</div>
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|
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</div>
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|
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|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 MYOPATHY, MYOFIBRILLAR, 13, WITH RIMMED VACUOLES</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
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|
|
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|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
HSPB8, 5-BP DEL, NT525
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|
|
|
<br />
|
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|
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|
|
|
ClinVar: RCV005055413
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|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<div class="mim-changed mim-change"><p>In 6 affected members of a multigenerational Japanese family with myofibrillar myopathy-13 with rimmed vacuoles (MFM13; 621078), Inoue-Shibui et al. (2021) identified a heterozygous 5-bp deletion (c.525_529del, NM_014365.3) in the HSPB8 gene, predicted to result in a frameshift and elongation of the protein (Thr176TrpfsTer38). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies of the variant were not performed, but these authors suggested that the mutant transcript would escape nonsense-mediated mRNA decay. </p></div>
|
|
</span>
|
|
</div>
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|
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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>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0008 MYOPATHY, MYOFIBRILLAR, 13, WITH RIMMED VACUOLES</strong>
|
|
</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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HSPB8, 4-BP DEL/3-BP INS, 576CAG
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<br />
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ClinVar: RCV005055415
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</span>
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</div>
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<div>
|
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<span class="mim-text-font">
|
|
<div class="mim-changed mim-change"><p>In an 18-year-old Chinese girl with myofibrillar myopathy-13 with rimmed vacuoles (MFM13; 621078), Yang et al. (2025) identified a de novo heterozygous del/ins mutation (c.576_579delinsCAG, NM_014365) in the HSPB8 gene, resulting in a frameshift and extension of the protein by 49 amino acids (Glu192AspfsTer55). The mutation, which was found by whole-exome sequencing, was not present in the gnomAD database. Direct functional studies of the variant were not performed, but patient muscle biopsy showed accumulation of autophagy molecules. The authors concluded that the mutant transcript likely evaded nonsense-mediated mRNA decay, and suggested that it may result in a toxic gain of function, likely leading to dysregulation of autophagy. The patient had onset of axial and limb-girdle myopathy at 6 years of age. She did not have sensory involvement. </p></div>
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|
</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0009 CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2L</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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HSPB8, LYS141THR
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<br />
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SNP: rs1565929090,
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ClinVar: RCV000789966, RCV005055445
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<div class="mim-changed mim-change"><p>In a 27-year-old Korean man, born of unrelated parents, with axonal Charcot-Marie-Tooth disease type 2L (CMT2L; 608673), Nakhro et al. (2013) identified a de novo heterozygous c.422A-C transversion in the HSPB8 gene, resulting in a lys141-to-thr (K141T) substitution at a conserved residue in the alpha-crystallin domain. The mutation, which was found by exome sequencing, was not present in public databases. Functional studies of the variant were not performed. </p></div>
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<span class="mim-font">
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Cassandra L. Kniffin - updated : 02/03/2025<br>Ada Hamosh - updated : 04/08/2020<br>George E. Tiller - updated : 09/17/2013<br>George E. Tiller - updated : 6/16/2008<br>Victor A. McKusick - updated : 4/15/2005<br>Victor A. McKusick - updated : 6/14/2004<br>Cassandra L. Kniffin - updated : 5/3/2004<br>Patricia A. Hartz - updated : 12/16/2003
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alopez : 02/07/2025<br>alopez : 02/07/2025<br>alopez : 02/06/2025<br>ckniffin : 02/03/2025<br>carol : 04/26/2024<br>alopez : 10/16/2023<br>alopez : 04/08/2020<br>alopez : 09/17/2013<br>ckniffin : 1/24/2013<br>wwang : 9/15/2009<br>wwang : 6/19/2008<br>terry : 6/16/2008<br>ckniffin : 3/16/2007<br>tkritzer : 4/18/2005<br>terry : 4/15/2005<br>tkritzer : 6/29/2004<br>terry : 6/14/2004<br>alopez : 5/28/2004<br>tkritzer : 5/5/2004<br>tkritzer : 5/4/2004<br>ckniffin : 5/3/2004<br>mgross : 12/17/2003<br>mgross : 12/16/2003<br>tkritzer : 8/7/2003<br>tkritzer : 8/7/2003<br>carol : 8/6/2003
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