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<title>
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Entry
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- *602195 - HEAT-SHOCK 27-KD PROTEIN 1; HSPB1
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- OMIM
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<input type="hidden" id="mimSearchIndex" name="index" value="entry" />
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<input type="hidden" id="mimSearchStart" name="start" value="1" />
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<input type="search" id="mimEntrySearch" name="search" class="form-control" value="" placeholder="Search OMIM..." maxlength="5000" autocomplete="off" autocorrect="off" autocapitalize="none" spellcheck="false" autofocus />
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Advanced Search
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<li style="margin-left: 0.5em;">
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<a href="/search/advanced/entry"> OMIM </a>
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</li>
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<li style="margin-left: 0.5em;">
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<a href="/search/advanced/clinicalSynopsis"> Clinical Synopses </a>
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<li style="margin-left: 0.5em;">
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<a href="/search/advanced/geneMap"> Gene Map </a>
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</form>
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<p />
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<div class="row">
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*602195</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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</li>
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<li role="presentation">
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></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>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#animalModel">Animal Model</a>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/602195">Table View</a>
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</li>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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</li>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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</li>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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</ul>
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</nav>
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</div>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000106211;t=ENST00000248553" 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=3315" 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=602195" 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=ENSG00000106211;t=ENST00000248553" 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_001540" 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_001540" 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=602195" 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=09076&isoform_id=09076_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/HSPB1" 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/32478,35182,241307,662841,1913885,4504517,11036357,12653477,15126735,15215349,15928913,19855073,47115165,49168466,49522676,54696638,86278454,119592209,189053213,194384578,209402784,578877746,2049831263,2049831265,2049831267,2049831269" 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/P04792" 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=3315" 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=ENSG00000106211;t=ENST00000248553" 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=HSPB1" 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=HSPB1" 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+3315" 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/HSPB1" 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:3315" 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/3315" class="mim-tip-hint" title="Gene-specific map, sequence, expression, structure, function, citation, and homology data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Gene', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Gene</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgGene?db=hg38&hgg_chrom=chr7&hgg_gene=ENST00000248553.7&hgg_start=76302673&hgg_end=76304292&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:5246" 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/hspb1" 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=602195[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=602195[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/ENSG00000106211" 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=HSPB1" 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=HSPB1" 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=HSPB1" 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=HSPB1&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/PA29511" 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:5246" 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:96240" 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/HSPB1#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:96240" 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/3315/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=3315" 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="mim#WormbaseGeneFold" id="mimWormbaseGeneToggle" data-toggle="collapse" class="mim-tip-hint mimTriangleToggle" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes."><span id="mimWormbaseGeneToggleTriangle" class="small" style="margin-left: -0.8em;">►</span>Wormbase Gene</div>
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<div id="mimWormbaseGeneFold" class="collapse">
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<div style="margin-left: 0.5em;"><a href="https://wormbase.org/db/gene/gene?name=WBGene00002011;class=Gene" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">WBGene00002011 </a></div><div style="margin-left: 0.5em;"><a href="https://wormbase.org/db/gene/gene?name=WBGene00011906;class=Gene" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">WBGene00011906 </a></div>
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</div>
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<div><a href="https://zfin.org/ZDB-GENE-030326-4" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:3315" class="mim-tip-hint" title="Kyoto Encyclopedia of Genes and Genomes; diagrams of signaling pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'KEGG', 'domain': 'genome.jp'})">KEGG</a></div>
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<div><a href="https://reactome.org/content/query?q=HSPB1&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>SNOMEDCT:</strong> 719510006<br />
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">ICD+</a>
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
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<span class="text-danger"><strong>*</strong></span>
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602195
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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 27-KD PROTEIN 1; HSPB1
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
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HEAT-SHOCK PROTEIN 27; HSP27
|
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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">
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<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=HSPB1" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">HSPB1</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/7/355?start=-3&limit=10&highlight=355">7q11.23</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr7:76302673-76304292&dgv=pack&knownGene=pack&omimGene=pack" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">7:76,302,673-76,304,292</a> </span>
|
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</em>
|
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</strong>
|
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<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
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</p>
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</div>
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<div>
|
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<br />
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</div>
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<div>
|
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<a id="geneMap" class="mim-anchor"></a>
|
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<div style="margin-bottom: 10px;">
|
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<span class="h4 mim-font">
|
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<strong>Gene-Phenotype Relationships</strong>
|
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</span>
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</div>
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Phenotype <br /> MIM number
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Charcot-Marie-Tooth disease, axonal, type 2F
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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Neuronopathy, distal hereditary motor, autosomal dominant 3
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</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/602195" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
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<li><a href="/graph/radial/602195" 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-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>Cloning and Expression</strong>
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<p>The heat-shock proteins (HSPs) belong to a larger group of polypeptides, the stress proteins, that are induced in various combinations in response to environmental challenges and developmental transitions. Synthesis of the small (27-kD) HSP has been shown to be correlated with the acquisition of thermotolerance. <a href="#9" class="mim-tip-reference" title="Hickey, E., Brandon, S. E., Sadis, S., Smale, G., Weber, L. A. <strong>Molecular cloning of sequences encoding the human heat-shock proteins and their expression during hyperthermia.</strong> Gene 43: 147-154, 1986.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3019832/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3019832</a>] [<a href="https://doi.org/10.1016/0378-1119(86)90018-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3019832">Hickey et al. (1986)</a> cloned a HeLa cell cDNA encoding HSP27. By screening a human genomic library with this HSP27 cDNA, <a href="#8" class="mim-tip-reference" title="Hickey, E., Brandon, S. E., Potter, R., Stein, G., Stein, J., Weber, L. A. <strong>Sequence and organization of genes encoding the human 27 kDa heat shock protein.</strong> Nucleic Acids Res. 14: 4127-4145, 1986. Note: Erratum: Nucleic Acids Res. 14: 8230 only, 1986.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3714473/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3714473</a>] [<a href="https://doi.org/10.1093/nar/14.10.4127" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3714473">Hickey et al. (1986)</a> isolated the HSP27 genomic sequence. The deduced 199-amino acid HSP27 protein shows sequence similarity to mammalian alpha-crystallins (e.g., <a href="/entry/123580">123580</a>). Approximately 20% of its residues are susceptible to phosphorylation. The HSP27 gene produced a 2.2-kb transcript in an in vitro transcription assay. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=3714473+3019832" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#3" class="mim-tip-reference" title="Carper, S. W., Rocheleau, T. A., Storm, F. K. <strong>cDNA sequence of a human heat shock protein HSP27.</strong> Nucleic Acids Res. 18: 6457 only, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2243808/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2243808</a>] [<a href="https://doi.org/10.1093/nar/18.21.6457" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2243808">Carper et al. (1990)</a> cloned an HSP27 cDNA derived from heat-shocked human A549 lung carcinoma cells. The cDNA encodes a deduced 205-amino acid protein whose first 193 amino acids are identical to those of the predicted HSP27 protein reported by <a href="#8" class="mim-tip-reference" title="Hickey, E., Brandon, S. E., Potter, R., Stein, G., Stein, J., Weber, L. A. <strong>Sequence and organization of genes encoding the human 27 kDa heat shock protein.</strong> Nucleic Acids Res. 14: 4127-4145, 1986. Note: Erratum: Nucleic Acids Res. 14: 8230 only, 1986.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3714473/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3714473</a>] [<a href="https://doi.org/10.1093/nar/14.10.4127" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3714473">Hickey et al. (1986)</a>. <a href="#3" class="mim-tip-reference" title="Carper, S. W., Rocheleau, T. A., Storm, F. K. <strong>cDNA sequence of a human heat shock protein HSP27.</strong> Nucleic Acids Res. 18: 6457 only, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2243808/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2243808</a>] [<a href="https://doi.org/10.1093/nar/18.21.6457" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2243808">Carper et al. (1990)</a> suggested that the C-terminal differences of these deduced HSP27 proteins may be a result of a DNA sequencing artifact. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=3714473+2243808" 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>PSEUDOGENES</em></strong></p><p>
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<a href="#8" class="mim-tip-reference" title="Hickey, E., Brandon, S. E., Potter, R., Stein, G., Stein, J., Weber, L. A. <strong>Sequence and organization of genes encoding the human 27 kDa heat shock protein.</strong> Nucleic Acids Res. 14: 4127-4145, 1986. Note: Erratum: Nucleic Acids Res. 14: 8230 only, 1986.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3714473/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3714473</a>] [<a href="https://doi.org/10.1093/nar/14.10.4127" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3714473">Hickey et al. (1986)</a> identified a processed HSP27 pseudogene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3714473" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>Gene Structure</strong>
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<p><a href="#9" class="mim-tip-reference" title="Hickey, E., Brandon, S. E., Sadis, S., Smale, G., Weber, L. A. <strong>Molecular cloning of sequences encoding the human heat-shock proteins and their expression during hyperthermia.</strong> Gene 43: 147-154, 1986.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3019832/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3019832</a>] [<a href="https://doi.org/10.1016/0378-1119(86)90018-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3019832">Hickey et al. (1986)</a> determined that the HSP27 gene has 3 exons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3019832" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>Mapping</strong>
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<p><a href="#11" class="mim-tip-reference" title="Hunt, C. R., Goswami, P. C., Kozak, C. A. <strong>Assignment of the mouse Hsp25 and Hsp105 genes to the distal region of chromosome 5 by linkage analysis.</strong> Genomics 45: 462-463, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9344682/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9344682</a>] [<a href="https://doi.org/10.1006/geno.1997.4973" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9344682">Hunt et al. (1997)</a> mapped the mouse Hsp25 gene to chromosome 5 in a region homologous to 7q in the human. They also mapped the mouse Hsp105 gene to chromosome 5 but suggested that the human homolog is probably on 13q, not chromosome 7. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9344682" 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="#16" class="mim-tip-reference" title="Stock, A. D., Spallone, P. A., Dennis, T. R., Netski, D., Morris, C. A., Mervis, C. B., Hobart, H. H. <strong>Heat shock protein 27 gene: chromosomal and molecular location and relationship to Williams syndrome.</strong> Am. J. Med. Genet. 120A: 320-325, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12838549/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12838549</a>] [<a href="https://doi.org/10.1002/ajmg.a.20055" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12838549">Stock et al. (2003)</a> used FISH to map the HSP27 gene to 7q11.23. This band also contains the site of the deletion associated with Williams syndrome (<a href="/entry/194050">194050</a>). <a href="#16" class="mim-tip-reference" title="Stock, A. D., Spallone, P. A., Dennis, T. R., Netski, D., Morris, C. A., Mervis, C. B., Hobart, H. H. <strong>Heat shock protein 27 gene: chromosomal and molecular location and relationship to Williams syndrome.</strong> Am. J. Med. Genet. 120A: 320-325, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12838549/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12838549</a>] [<a href="https://doi.org/10.1002/ajmg.a.20055" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12838549">Stock et al. (2003)</a> used 2-color FISH on previously G-banded and photographed metaphase chromosomes from Williams syndrome cell lines and peripheral blood. In 6 Williams syndrome patients with longer deletions that extended telomeric to the classic Williams syndrome deletion region, they found that HSP27 was telomeric to several markers and was deleted in 3. They discussed the possible role of HSP27 in the cognitive features of Williams syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12838549" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#14" class="mim-tip-reference" title="New, L., Jiang, Y., Zhao, M., Liu, K., Zhu, W., Flood, L. J., Kato, Y., Parry, G. C. N., Han, J. <strong>PRAK, a novel protein kinase regulated by the p38 MAP kinase.</strong> EMBO J. 17: 3372-3384, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9628874/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9628874</a>] [<a href="https://doi.org/10.1093/emboj/17.12.3372" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9628874">New et al. (1998)</a> demonstrated that MAPKAPK5 (<a href="/entry/606723">606723</a>) is a major stress-activated kinase that can phosphorylate HSP27 in vitro. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9628874" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using a cellular model of Huntington disease (<a href="/entry/143100">143100</a>), <a href="#18" class="mim-tip-reference" title="Wyttenbach, A., Sauvageot, O., Carmichael, J., Diaz-Latoud, C., Arrigo, A.-P., Rubinsztein, D. C. <strong>Heat shock protein 27 prevents cellular polyglutamine toxicity and suppresses the increase of reactive oxygen species caused by huntingtin.</strong> Hum. Molec. Genet. 11: 1137-1151, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11978772/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11978772</a>] [<a href="https://doi.org/10.1093/hmg/11.9.1137" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11978772">Wyttenbach et al. (2002)</a> identified HSP27 as a suppressor of polyglutamine (polyQ)-mediated cell death. In contrast to HSP40 (see <a href="/entry/604572">604572</a>) and HSP70 (see <a href="/entry/140550">140550</a>) chaperones, HSP27 suppressed polyQ death without suppressing polyQ aggregation. While polyQ-induced cell death was reduced by inhibiting cytochrome c release from mitochondria, protection by HSP27 was regulated by its phosphorylation status and was independent of its ability to bind to cytochrome c. However, mutant huntingtin (HTT; <a href="/entry/613004">613004</a>) caused increased levels of reactive oxygen species (ROS) in neuronal and nonneuronal cells. ROS contributed to cell death because both N-acetyl-L-cysteine and glutathione in its reduced form suppressed polyQ-mediated cell death. HSP27 decreased ROS in cells expressing mutant huntingtin, suggesting that this chaperone may protect cells against oxidative stress. The authors proposed that a polyQ mutation may induce ROS that directly contribute to cell death, and that HSP27 may be an antagonist of this process. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11978772" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>The alpha-crystallin subunits alpha-A (<a href="/entry/123580">123580</a>) and alpha-B (<a href="/entry/123590">123590</a>) each can form an oligomer by itself or with the other. <a href="#7" class="mim-tip-reference" title="Fu, L., Liang, J. J.-N. <strong>Detection of protein-protein interactions among lens crystallins in a mammalian two-hybrid system assay.</strong> J. Biol. Chem. 277: 4255-4260, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11700327/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11700327</a>] [<a href="https://doi.org/10.1074/jbc.M110027200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11700327">Fu and Liang (2002)</a> used a 2-hybrid system to study heterogeneous interactions among lens crystallins of different classes. They found interactions between alpha-A- (or alpha-B-) and beta-B2- (<a href="/entry/123620">123620</a>) or gamma-C-(<a href="/entry/123680">123680</a>) crystallins, but the intensity of interaction was one-third that of alpha-A-alpha-B interactions. HSP27 showed similar interaction properties with alpha-B-crystallin. Experiments with N- and C-terminal domain-truncated mutants demonstrated that both N- and C-terminal domains were important in alpha-A-crystallin self-interaction, but that only the C-terminal domain was important in alpha-B-crystallin self-interaction. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11700327" 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>When fed a diet supplemented with cholesterol, Apoe (<a href="/entry/107741">107741</a>) -/- mice develop inflammatory atherosclerosis. <a href="#15" class="mim-tip-reference" title="Rayner, K., Chen, Y.-X., McNulty, M., Simard, T., Zhao, X., Wells, D. J., de Belleroche, J., O'Brien, E. R. <strong>Extracellular release of the atheroprotective heat shock protein 27 is mediated by estrogen and competitively inhibits acLDL binding to scavenger receptor-A.</strong> Circ. Res. 103: 133-141, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18566345/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18566345</a>] [<a href="https://doi.org/10.1161/CIRCRESAHA.108.172155" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18566345">Rayner et al. (2008)</a> found that overexpression of human HSP27 reduced atherosclerotic lesions in aortic arches excised from Apoe -/- female mice by 35% compared with Apoe -/- controls. HSP27 overexpression had no effect on atherosclerotic lesions in Apoe -/- male mice. However, there was an inverse correlation between serum HSP27 level and atherosclerotic lesion area in both male and female Apoe -/- mice. HSP27 was secreted from cultured human macrophages in response to estrogen and acetylated low density lipoprotein (acLDL). Extracellular HSP27 bound the scavenger receptor SRA (MSR1; <a href="/entry/153622">153622</a>) on murine macrophages and prevented acLDL uptake. Extracellular HSP27 also decreased acLDL-induced release of the proinflammatory cytokine Il1b (<a href="/entry/147720">147720</a>) and increased the release of the antiinflammatory cytokine Il10 (<a href="/entry/124092">124092</a>) by mouse macrophages. Overexpression of HSP27 in Apoe -/- mouse macrophages reduced their adherence and migration in vitro. <a href="#15" class="mim-tip-reference" title="Rayner, K., Chen, Y.-X., McNulty, M., Simard, T., Zhao, X., Wells, D. J., de Belleroche, J., O'Brien, E. R. <strong>Extracellular release of the atheroprotective heat shock protein 27 is mediated by estrogen and competitively inhibits acLDL binding to scavenger receptor-A.</strong> Circ. Res. 103: 133-141, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18566345/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18566345</a>] [<a href="https://doi.org/10.1161/CIRCRESAHA.108.172155" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18566345">Rayner et al. (2008)</a> concluded that HSP27 is atheroprotective, possibly by competing for uptake of atherogenic lipids by macrophages or by attenuating inflammation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18566345" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#5" class="mim-tip-reference" title="de Thonel, A., Vandekerckhove, J., Lanneau, D., Selvakumar, S., Courtois, G., Hazoume, A., Brunet, M., Maurel, S., Hammann, A., Ribeil, J. A., Zermati, Y., Gabet, A. S., Boyes, J., Solary, E., Hermine, O., Garrido, C. <strong>HSP27 controls GATA-1 protein level during erythroid cell differentiation.</strong> Blood 116: 85-96, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20410505/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20410505</a>] [<a href="https://doi.org/10.1182/blood-2009-09-241778" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20410505">De Thonel et al. (2010)</a> stated that HSP27 is a ubiquitin-binding protein involved in proteasomal degradation of certain proteins under stress conditions. They found that HSP27 was involved in proteasome-mediated degradation of GATA1 (<a href="/entry/305371">305371</a>), a transcription factor that directs erythroblast proliferation, but not differentiation. Knockdown of HSP27 or overexpression of GATA1 inhibited differentiation of primary cultured human erythroid cells and the K562 erythroleukemia cell line. HSP27-mediated GATA1 degradation was reduced by proteasome inhibitors and required prior acetylation of GATA1 and serine phosphorylation of HSP27 via the p38 MAP kinase (MAPK14; <a href="/entry/600289">600289</a>) pathway. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20410505" 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>Axonal Charcot-Marie-Tooth Disease Type 2F</em></strong></p><p>
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In affected members of 2 families with axonal Charcot-Marie-Tooth disease type 2F (CMT2F; <a href="/entry/606595">606595</a>) and in affected members of 4 families with distal hereditary motor neuropathy (HMN2B; <a href="/entry/608634">608634</a>), <a href="#6" class="mim-tip-reference" title="Evgrafov, O. V., Mersiyanova, I., Irobi, J., Van Den Bosch, L., Dierick, I., Leung, C. L., Schagina, O., Verpoorten, N., Van Impe, K., Fedotov, V., Dadali, E., Auer-Grumbach, M., and 14 others. <strong>Mutant small heat-shock protein 27 causes axonal Charcot-Marie-Tooth disease and distal hereditary motor neuropathy.</strong> Nature Genet. 36: 602-606, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15122254/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15122254</a>] [<a href="https://doi.org/10.1038/ng1354" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15122254">Evgrafov et al. (2004)</a> identified heterozygous mutations in the HSPB1 gene (<a href="#0001">602195.0001</a>-<a href="#0004">602195.0004</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15122254" 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>Distal Hereditary Motor Neuronopathy 3, Autosomal Dominant</em></strong></p><p>
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<a href="#10" class="mim-tip-reference" title="Houlden, H., Laura, M., Wavrant-De Vrieze, F., Blake, J., Wood, N., Reilly, M. M. <strong>Mutations in the HSP27 (HSPB1) gene cause dominant, recessive, and sporadic distal HMN/CMT type 2.</strong> Neurology 71: 1660-1668, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18832141/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18832141</a>] [<a href="https://doi.org/10.1212/01.wnl.0000319696.14225.67" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18832141">Houlden et al. (2008)</a> identified 4 different heterozygous mutations in the HSPB1 gene (see, e.g., <a href="#0001">602195.0001</a>; <a href="#0007">602195.0007</a>) in affected members of 4 of 25 families with autosomal dominant distal hereditary motor neuronopathy-3 (HMND3; <a href="/entry/608634">608634</a>). An additional patient with autosomal recessive inheritance was found to have a homozygous mutation (<a href="#0008">602195.0008</a>). All patients had a predominant motor neuropathy without clinical sensory abnormalities. No HSPB1 mutations were found in 90 families with CMT2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18832141" 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>Variant Function</em></strong></p><p>
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<a href="#2" 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 (<a href="/entry/608014">608014</a>) 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><a href="#4" class="mim-tip-reference" title="d'Ydewalle, C., Krishnan, J., Chiheb, D. M., Van Damme, P., Irobi, J., Kozikowski, A. P., Vanden Berghe, P., Timmerman, V., Robberecht, W., Van Den Bosch, L. <strong>HDAC6 inhibitors reverse axonal loss in a mouse model of mutant HSPB1-induced Charcot-Marie-Tooth disease.</strong> Nature Med. 17: 968-974, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21785432/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21785432</a>] [<a href="https://doi.org/10.1038/nm.2396" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21785432">D'Ydewalle et al. (2011)</a> demonstrated that transgenic mice expressing the S135F (<a href="#0001">602195.0001</a>) or P182L (<a href="#0004">602195.0004</a>) Hspb1 mutations developed clinical and pathologic features of axonal CMT or distal HMN. Mutant mice developed progressive motor impairment, decreased muscle strength, and clawed hindpaws, features that were more apparent in P182L mice, as P182L is associated with the dHMN phenotype. S135F mutants showed sensory abnormalities, whereas P182L mutant mice did not. Sensory loss in the S135F mutants was associated with decreased sensory amplitudes on electrophysiologic studies and impaired mitochondrial axonal transport in dorsal root ganglion cells. Both mouse mutants showed distal axonal loss on nerve biopsy, and both had a decrease in acetylated alpha-tubulin (TUBA1A; <a href="/entry/602529">602529</a>) in peripheral nerves. Treatment of S135F mutant mice with an HDAC6 (<a href="/entry/300272">300272</a>) inhibitor resulted in restoration of axonal transport and partial reversal of the CMT phenotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21785432" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=602195[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">rs28939680 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs28939680;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=rs28939680" 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=rs28939680" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In affected members of a Russian family with Charcot-Marie-Tooth disease type 2F (CMT2F; <a href="/entry/606595">606595</a>) previously reported by <a href="#12" class="mim-tip-reference" title="Ismailov, S. M., Fedotov, V. P., Dadali, E. L., Polyakov, A. V., Van Broeckhoven, C., Ivanov, V. I., De Jonghe, P., Timmerman, V., Evgrafov, O. V. <strong>A new locus for autosomal dominant Charcot-Marie-Tooth disease type 2 (CMT2F) maps to chromosome 7q11-q21.</strong> Europ. J. Hum. Genet. 9: 646-650, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11528513/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11528513</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200686" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11528513">Ismailov et al. (2001)</a>, <a href="#6" class="mim-tip-reference" title="Evgrafov, O. V., Mersiyanova, I., Irobi, J., Van Den Bosch, L., Dierick, I., Leung, C. L., Schagina, O., Verpoorten, N., Van Impe, K., Fedotov, V., Dadali, E., Auer-Grumbach, M., and 14 others. <strong>Mutant small heat-shock protein 27 causes axonal Charcot-Marie-Tooth disease and distal hereditary motor neuropathy.</strong> Nature Genet. 36: 602-606, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15122254/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15122254</a>] [<a href="https://doi.org/10.1038/ng1354" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15122254">Evgrafov et al. (2004)</a> identified a heterozygous c.404C-T transition in exon 2 of the HSPB1 gene, resulting in a ser135-to-phe (S135F) substitution. In affected members of an unrelated family from the United Kingdom with autosomal dominant distal hereditary motor neuronopathy 3 (HMND3; <a href="/entry/608634">608634</a>), the authors identified the same mutation in heterozygosity. The S135F mutation occurs in a highly conserved alpha-crystallin domain of the protein. In vitro expression of the mutant protein resulted in reduced viability of neuronal cells and impaired neurofilament assembly. <a href="#6" class="mim-tip-reference" title="Evgrafov, O. V., Mersiyanova, I., Irobi, J., Van Den Bosch, L., Dierick, I., Leung, C. L., Schagina, O., Verpoorten, N., Van Impe, K., Fedotov, V., Dadali, E., Auer-Grumbach, M., and 14 others. <strong>Mutant small heat-shock protein 27 causes axonal Charcot-Marie-Tooth disease and distal hereditary motor neuropathy.</strong> Nature Genet. 36: 602-606, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15122254/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15122254</a>] [<a href="https://doi.org/10.1038/ng1354" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15122254">Evgrafov et al. (2004)</a> suggested that these deficits may be responsible for premature axonal degeneration, which underlies both CMT and dHMN. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15122254+11528513" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#10" class="mim-tip-reference" title="Houlden, H., Laura, M., Wavrant-De Vrieze, F., Blake, J., Wood, N., Reilly, M. M. <strong>Mutations in the HSP27 (HSPB1) gene cause dominant, recessive, and sporadic distal HMN/CMT type 2.</strong> Neurology 71: 1660-1668, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18832141/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18832141</a>] [<a href="https://doi.org/10.1212/01.wnl.0000319696.14225.67" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18832141">Houlden et al. (2008)</a> identified a heterozygous S135F mutation in affected members of a large family with HMND3. The mean age at onset was 21 years, and sensory abnormalities were not present. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18832141" 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>Variant Function</em></strong></p><p>
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In cultured mouse motor neurons, <a href="#19" class="mim-tip-reference" title="Zhai, J., Lin, H., Julien, J.-P., Schlaepfer, W. W. <strong>Disruption of neurofilament network with aggregation of light neurofilament protein: a common pathway leading to motor neuron degeneration due to Charcot-Marie-Tooth disease-linked mutations in NFL and HSPB1.</strong> Hum. Molec. Genet. 16: 3103-3116, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17881652/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17881652</a>] [<a href="https://doi.org/10.1093/hmg/ddm272" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17881652">Zhai et al. (2007)</a> showed that expression of S135F-mutant HSPB1 led to progressive degeneration of motor neurons with disruption of the neurofilament network and aggregation of NEFL (<a href="/entry/162280">162280</a>) protein. The 2 proteins were found to associate together, and the S135F mutant had a dominant effect. Similarly, expression of NEFL mutants (e.g., <a href="/entry/162280#0003">162280.0003</a>) also led to disruption of the neurofilament network and aggregation of NEFL, and wildtype HSPB1 induced reversal of NEFL aggregates. <a href="#19" class="mim-tip-reference" title="Zhai, J., Lin, H., Julien, J.-P., Schlaepfer, W. W. <strong>Disruption of neurofilament network with aggregation of light neurofilament protein: a common pathway leading to motor neuron degeneration due to Charcot-Marie-Tooth disease-linked mutations in NFL and HSPB1.</strong> Hum. Molec. Genet. 16: 3103-3116, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17881652/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17881652</a>] [<a href="https://doi.org/10.1093/hmg/ddm272" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17881652">Zhai et al. (2007)</a> suggested that disruption of the neurofilament network with aggregation of NEFL is a common triggering event of motor neuron degeneration in CMT2E (<a href="/entry/607684">607684</a>) and CMT2F. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17881652" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs29001571 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs29001571;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs29001571?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs29001571" 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=rs29001571" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In affected members of a Belgian family with autosomal dominant distal hereditary motor neuronopathy 3 (HMND3; <a href="/entry/608634">608634</a>), <a href="#6" class="mim-tip-reference" title="Evgrafov, O. V., Mersiyanova, I., Irobi, J., Van Den Bosch, L., Dierick, I., Leung, C. L., Schagina, O., Verpoorten, N., Van Impe, K., Fedotov, V., Dadali, E., Auer-Grumbach, M., and 14 others. <strong>Mutant small heat-shock protein 27 causes axonal Charcot-Marie-Tooth disease and distal hereditary motor neuropathy.</strong> Nature Genet. 36: 602-606, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15122254/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15122254</a>] [<a href="https://doi.org/10.1038/ng1354" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15122254">Evgrafov et al. (2004)</a> identified a heterozygous c.379C-T transition in exon 2 of the HSPB1 gene, resulting in an arg127-to-trp (R127W) substitution. The mutation occurs in a highly conserved alpha-crystallin domain of the protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15122254" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In affected members of 4 Chinese Han families with late-onset Charcot-Marie-Tooth disease type 2F (CMT2F; <a href="/entry/606595">606595</a>), <a href="#17" class="mim-tip-reference" title="Tang, B., Liu, X., Zhao, G., Luo, W., Xia, K., Pan, Q., Cai, F., Hu, Z., Zhang, C., Chen, B., Zhang, F., Shen, L., Zhang, R., Jiang, H. <strong>Mutation analysis of the small heat shock protein 27 gene in Chinese patients with Charcot-Marie-Tooth disease.</strong> Arch. Neurol. 62: 1201-1207, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16087758/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16087758</a>] [<a href="https://doi.org/10.1001/archneur.62.8.1201" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16087758">Tang et al. (2005)</a> identified heterozygosity for the R127W substitution. Haplotype analysis indicated a founder effect. Three mutation carriers from different families, ranging in age from 23 to 37 years, were asymptomatic, possibly reflecting age-dependent penetrance. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16087758" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs28937568 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs28937568;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=rs28937568" 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=rs28937568" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In affected members of a Croatian family with autosomal dominant distal hereditary motor neuronopathy-3 (HMND3; <a href="/entry/608634">608634</a>), <a href="#6" class="mim-tip-reference" title="Evgrafov, O. V., Mersiyanova, I., Irobi, J., Van Den Bosch, L., Dierick, I., Leung, C. L., Schagina, O., Verpoorten, N., Van Impe, K., Fedotov, V., Dadali, E., Auer-Grumbach, M., and 14 others. <strong>Mutant small heat-shock protein 27 causes axonal Charcot-Marie-Tooth disease and distal hereditary motor neuropathy.</strong> Nature Genet. 36: 602-606, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15122254/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15122254</a>] [<a href="https://doi.org/10.1038/ng1354" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15122254">Evgrafov et al. (2004)</a> identified a heterozygous c.452C-T transition in exon 2 of the HSPB1 gene, resulting in a thr151-to-ile (T151I) substitution. The mutation occurs in a highly conserved alpha-crystallin domain of the protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15122254" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs28937569 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs28937569;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=rs28937569" 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=rs28937569" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In affected members of an Austrian family with autosomal dominant distal hereditary motor neuropathy-3 (HMND3; <a href="/entry/608634">608634</a>), <a href="#6" class="mim-tip-reference" title="Evgrafov, O. V., Mersiyanova, I., Irobi, J., Van Den Bosch, L., Dierick, I., Leung, C. L., Schagina, O., Verpoorten, N., Van Impe, K., Fedotov, V., Dadali, E., Auer-Grumbach, M., and 14 others. <strong>Mutant small heat-shock protein 27 causes axonal Charcot-Marie-Tooth disease and distal hereditary motor neuropathy.</strong> Nature Genet. 36: 602-606, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15122254/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15122254</a>] [<a href="https://doi.org/10.1038/ng1354" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15122254">Evgrafov et al. (2004)</a> identified a heterozygous c.545C-T transition in exon 3 of the HSPB1 gene, resulting in a pro182-to-leu (P182L) substitution. The mutation occurs in the variable C-terminal tail of the protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15122254" 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>Variant Function</em></strong></p><p>
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By in vitro functional expression studies, <a href="#1" class="mim-tip-reference" title="Ackerley, S., James, P. A., Kalli, A., French, S., Davies, K. E., Talbot, K. <strong>A mutation in the small heat-shock protein HSPB1 leading to distal hereditary motor neuronopathy disrupts neurofilament assembly and the axonal transport of specific cellular cargoes.</strong> Hum. Molec. Genet. 15: 347-354, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16368711/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16368711</a>] [<a href="https://doi.org/10.1093/hmg/ddi452" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16368711">Ackerley et al. (2006)</a> showed that in mouse primary cortical cells the P182L-mutant protein formed aggregates and failed to be transported down neuronal processes unlike the wildtype protein. Coexpression of the mutant and wildtype protein resulted in sequestration of the wildtype protein into mutant aggregates. Mutant HSPB1 also disrupted the formation of intracellular neurofilaments and disrupted the transport of specific cellular cargoes, such as the p150 dynactin (DCTN1; <a href="/entry/601143">601143</a>), but not mitochondria. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16368711" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0005 CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2F</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs28939681 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs28939681;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs28939681?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs28939681" 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=rs28939681" 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=RCV000007910" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007910" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007910</a>
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<p>In affected members of a Belgian family with Charcot-Marie-Tooth disease type 2F (CMT2F; <a href="/entry/606595">606595</a>), <a href="#6" class="mim-tip-reference" title="Evgrafov, O. V., Mersiyanova, I., Irobi, J., Van Den Bosch, L., Dierick, I., Leung, C. L., Schagina, O., Verpoorten, N., Van Impe, K., Fedotov, V., Dadali, E., Auer-Grumbach, M., and 14 others. <strong>Mutant small heat-shock protein 27 causes axonal Charcot-Marie-Tooth disease and distal hereditary motor neuropathy.</strong> Nature Genet. 36: 602-606, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15122254/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15122254</a>] [<a href="https://doi.org/10.1038/ng1354" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15122254">Evgrafov et al. (2004)</a> identified a heterozygous c.406C-T transition in exon 2 of the HSPB1 gene, resulting in an arg136-to-trp (R136W) substitution. The mutation occurs in a highly conserved alpha-crystallin domain of the protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15122254" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0006 NEURONOPATHY, DISTAL HEREDITARY MOTOR, AUTOSOMAL DOMINANT 3</strong>
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HSPB1, PRO182SER
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs104894020 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894020;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=rs104894020" 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=rs104894020" 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=RCV000007911 OR RCV000809907" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007911, RCV000809907" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007911...</a>
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<span class="mim-text-font">
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<p>In a Japanese patient with autosomal dominant distal hereditary motor neuronopathy-3 (HMND3; <a href="/entry/608634">608634</a>), <a href="#13" class="mim-tip-reference" title="Kijima, K., Numakura, C., Goto, T., Takahashi, T., Otagiri, T., Umetsu, K., Hayasaka, K. <strong>Small heat shock protein 27 mutation in a Japanese patient with distal hereditary motor neuropathy.</strong> J. Hum. Genet. 50: 473-476, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16155736/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16155736</a>] [<a href="https://doi.org/10.1007/s10038-005-0280-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16155736">Kijima et al. (2005)</a> identified heterozygosity for a c.544C-T transition in exon 3 of the HSBP1 gene, resulting in a pro182-to-ser (P182S) substitution. The mutation was not detected in his parents or older brother or in 100 control chromosomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16155736" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0007 NEURONOPATHY, DISTAL HEREDITARY MOTOR, AUTOSOMAL DOMINANT 3</strong>
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HSPB1, ARG140GLY
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121909112 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121909112;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=rs121909112" 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=rs121909112" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000007912 OR RCV000688660 OR RCV001174175 OR RCV001508210 OR RCV001794438 OR RCV002326670 OR RCV005042012" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007912, RCV000688660, RCV001174175, RCV001508210, RCV001794438, RCV002326670, RCV005042012" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007912...</a>
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</span>
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<span class="mim-text-font">
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<p>In affected individuals from an Indian family with autosomal dominant distal hereditary motor neuronopathy-3 (HMND3; <a href="/entry/608634">608634</a>), <a href="#10" class="mim-tip-reference" title="Houlden, H., Laura, M., Wavrant-De Vrieze, F., Blake, J., Wood, N., Reilly, M. M. <strong>Mutations in the HSP27 (HSPB1) gene cause dominant, recessive, and sporadic distal HMN/CMT type 2.</strong> Neurology 71: 1660-1668, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18832141/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18832141</a>] [<a href="https://doi.org/10.1212/01.wnl.0000319696.14225.67" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18832141">Houlden et al. (2008)</a> identified a heterozygous c.418C-G transversion in exon 2 of the HSPB1 gene, resulting in an arg140-to-gly (R140G) substitution in the alpha-crystallin domain. The mean age of onset in this family was 29 years, and both father and son had distal motor neuropathy without sensory abnormalities. Two additional Indian patients with sporadic HMN2B were also found to carry the R140G mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18832141" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0008 NEURONOPATHY, DISTAL HEREDITARY MOTOR, TYPE IIB, AUTOSOMAL RECESSIVE</strong>
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HSPB1, LEU99MET
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121909113 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121909113;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=rs121909113" 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=rs121909113" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000007913" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007913" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007913</a>
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<p>In a Pakistani patient, born of consanguineous parents, with distal HMN2B (<a href="/entry/608634">608634</a>), <a href="#10" class="mim-tip-reference" title="Houlden, H., Laura, M., Wavrant-De Vrieze, F., Blake, J., Wood, N., Reilly, M. M. <strong>Mutations in the HSP27 (HSPB1) gene cause dominant, recessive, and sporadic distal HMN/CMT type 2.</strong> Neurology 71: 1660-1668, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18832141/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18832141</a>] [<a href="https://doi.org/10.1212/01.wnl.0000319696.14225.67" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18832141">Houlden et al. (2008)</a> identified a homozygous 295C-A transversion in exon 1 of the HSPB1 gene, resulting in a leu99-to-met (L99M) substitution in the alpha-crystallin domain. He had onset at age 37 years of difficulty walking, and had distal muscle weakness and atrophy without sensory involvement. The patient's unaffected mother and sister were heterozygous for the mutation, suggesting that it may act in a dose-dependent fashion. This was the first report of autosomal recessive inheritance of HSPB1 mutations. The mutation occurred in a conserved residue and was not found in 220 controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18832141" 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="references"class="mim-anchor"></a>
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<h4 href="#mimReferencesFold" id="mimReferencesToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<span id="mimReferencesToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<strong>REFERENCES</strong>
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<a id="Ackerley2006" class="mim-anchor"></a>
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Ackerley, S., James, P. A., Kalli, A., French, S., Davies, K. E., Talbot, K.
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<strong>A mutation in the small heat-shock protein HSPB1 leading to distal hereditary motor neuronopathy disrupts neurofilament assembly and the axonal transport of specific cellular cargoes.</strong>
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Hum. Molec. Genet. 15: 347-354, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16368711/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16368711</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16368711" 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/ddi452" target="_blank">Full Text</a>]
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<a id="Benndorf2004" class="mim-anchor"></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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<a id="Carper1990" class="mim-anchor"></a>
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Carper, S. W., Rocheleau, T. A., Storm, F. K.
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<strong>cDNA sequence of a human heat shock protein HSP27.</strong>
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Nucleic Acids Res. 18: 6457 only, 1990.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2243808/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2243808</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2243808" 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/nar/18.21.6457" target="_blank">Full Text</a>]
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<a id="d'Ydewalle2011" class="mim-anchor"></a>
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d'Ydewalle, C., Krishnan, J., Chiheb, D. M., Van Damme, P., Irobi, J., Kozikowski, A. P., Vanden Berghe, P., Timmerman, V., Robberecht, W., Van Den Bosch, L.
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<strong>HDAC6 inhibitors reverse axonal loss in a mouse model of mutant HSPB1-induced Charcot-Marie-Tooth disease.</strong>
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Nature Med. 17: 968-974, 2011.
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[<a href="https://doi.org/10.1038/nm.2396" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1182/blood-2009-09-241778" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/0378-1119(86)90018-1" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1212/01.wnl.0000319696.14225.67" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1006/geno.1997.4973" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/sj.ejhg.5200686" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/s10038-005-0280-6" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/emboj/17.12.3372" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18566345/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18566345</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18566345" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1161/CIRCRESAHA.108.172155" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ajmg.a.20055" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1001/archneur.62.8.1201" target="_blank">Full Text</a>]
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<strong>Heat shock protein 27 prevents cellular polyglutamine toxicity and suppresses the increase of reactive oxygen species caused by huntingtin.</strong>
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[<a href="https://doi.org/10.1093/hmg/11.9.1137" target="_blank">Full Text</a>]
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Zhai, J., Lin, H., Julien, J.-P., Schlaepfer, W. W.
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<strong>Disruption of neurofilament network with aggregation of light neurofilament protein: a common pathway leading to motor neuron degeneration due to Charcot-Marie-Tooth disease-linked mutations in NFL and HSPB1.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17881652/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17881652</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17881652" 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/ddm272" target="_blank">Full Text</a>]
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<span class="mim-text-font">
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Cassandra L. Kniffin - updated : 12/15/2011
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Patricia A. Hartz - updated : 6/15/2011<br>Cassandra L. Kniffin - updated : 10/30/2009<br>Cassandra L. Kniffin - updated : 9/2/2009<br>Patricia A. Hartz - updated : 4/15/2009<br>Cassandra L. Kniffin - updated : 4/6/2009<br>Victor A. McKusick - updated : 12/16/2005<br>Cassandra L. Kniffin - updated : 11/4/2005<br>Victor A. McKusick - updated : 6/14/2004<br>Jane Kelly - updated : 3/5/2004<br>Victor A. McKusick - updated : 8/5/2003<br>George E. Tiller - updated : 12/17/2002<br>Dawn Watkins-Chow - updated : 2/26/2002<br>Patti M. Sherman - updated : 5/11/1999<br>Barbara J. Biery - updated : 4/21/1999
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<a id="creationDate" class="mim-anchor"></a>
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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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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Victor A. McKusick : 12/16/1997
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</span>
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 11/27/2023
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alopez : 10/17/2023<br>carol : 12/12/2022<br>carol : 12/16/2011<br>ckniffin : 12/15/2011<br>mgross : 8/30/2011<br>terry : 6/15/2011<br>wwang : 11/5/2009<br>ckniffin : 10/30/2009<br>wwang : 9/15/2009<br>wwang : 9/10/2009<br>ckniffin : 9/2/2009<br>mgross : 4/15/2009<br>mgross : 4/15/2009<br>wwang : 4/15/2009<br>ckniffin : 4/6/2009<br>ckniffin : 3/16/2007<br>carol : 12/29/2005<br>wwang : 12/28/2005<br>terry : 12/16/2005<br>wwang : 11/15/2005<br>wwang : 11/14/2005<br>ckniffin : 11/4/2005<br>ckniffin : 4/4/2005<br>tkritzer : 6/29/2004<br>terry : 6/14/2004<br>alopez : 5/28/2004<br>tkritzer : 5/4/2004<br>ckniffin : 5/3/2004<br>alopez : 3/5/2004<br>alopez : 3/5/2004<br>alopez : 3/5/2004<br>tkritzer : 8/6/2003<br>tkritzer : 8/5/2003<br>tkritzer : 8/5/2003<br>cwells : 12/17/2002<br>mgross : 2/26/2002<br>alopez : 4/14/2000<br>mgross : 5/27/1999<br>psherman : 5/11/1999<br>psherman : 4/21/1999<br>psherman : 4/21/1999<br>terry : 7/24/1998<br>mark : 12/16/1997<br>mark : 12/16/1997
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<span class="mim-font">
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<strong>*</strong> 602195
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<h3>
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HEAT-SHOCK 27-KD PROTEIN 1; HSPB1
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<br />
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<em>Alternative titles; symbols</em>
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HEAT-SHOCK PROTEIN 27; HSP27
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: HSPB1</em></strong>
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<strong>SNOMEDCT:</strong> 719510006;
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<strong>
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<em>
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Cytogenetic location: 7q11.23
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Genomic coordinates <span class="small">(GRCh38)</span> : 7:76,302,673-76,304,292 </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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<strong>Gene-Phenotype Relationships</strong>
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Location
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Phenotype
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Phenotype <br /> MIM number
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Inheritance
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Phenotype <br /> mapping key
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<span class="mim-font">
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7q11.23
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<span class="mim-font">
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Charcot-Marie-Tooth disease, axonal, type 2F
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<td>
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<span class="mim-font">
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606595
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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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Neuronopathy, distal hereditary motor, autosomal dominant 3
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<span class="mim-font">
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608634
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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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</table>
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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>Cloning and Expression</strong>
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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 heat-shock proteins (HSPs) belong to a larger group of polypeptides, the stress proteins, that are induced in various combinations in response to environmental challenges and developmental transitions. Synthesis of the small (27-kD) HSP has been shown to be correlated with the acquisition of thermotolerance. Hickey et al. (1986) cloned a HeLa cell cDNA encoding HSP27. By screening a human genomic library with this HSP27 cDNA, Hickey et al. (1986) isolated the HSP27 genomic sequence. The deduced 199-amino acid HSP27 protein shows sequence similarity to mammalian alpha-crystallins (e.g., 123580). Approximately 20% of its residues are susceptible to phosphorylation. The HSP27 gene produced a 2.2-kb transcript in an in vitro transcription assay. </p><p>Carper et al. (1990) cloned an HSP27 cDNA derived from heat-shocked human A549 lung carcinoma cells. The cDNA encodes a deduced 205-amino acid protein whose first 193 amino acids are identical to those of the predicted HSP27 protein reported by Hickey et al. (1986). Carper et al. (1990) suggested that the C-terminal differences of these deduced HSP27 proteins may be a result of a DNA sequencing artifact. </p><p><strong><em>PSEUDOGENES</em></strong></p><p>
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Hickey et al. (1986) identified a processed HSP27 pseudogene. </p>
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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>Hickey et al. (1986) determined that the HSP27 gene has 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>Hunt et al. (1997) mapped the mouse Hsp25 gene to chromosome 5 in a region homologous to 7q in the human. They also mapped the mouse Hsp105 gene to chromosome 5 but suggested that the human homolog is probably on 13q, not chromosome 7. </p><p>Stock et al. (2003) used FISH to map the HSP27 gene to 7q11.23. This band also contains the site of the deletion associated with Williams syndrome (194050). Stock et al. (2003) used 2-color FISH on previously G-banded and photographed metaphase chromosomes from Williams syndrome cell lines and peripheral blood. In 6 Williams syndrome patients with longer deletions that extended telomeric to the classic Williams syndrome deletion region, they found that HSP27 was telomeric to several markers and was deleted in 3. They discussed the possible role of HSP27 in the cognitive features of Williams syndrome. </p>
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</span>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene 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>New et al. (1998) demonstrated that MAPKAPK5 (606723) is a major stress-activated kinase that can phosphorylate HSP27 in vitro. </p><p>Using a cellular model of Huntington disease (143100), Wyttenbach et al. (2002) identified HSP27 as a suppressor of polyglutamine (polyQ)-mediated cell death. In contrast to HSP40 (see 604572) and HSP70 (see 140550) chaperones, HSP27 suppressed polyQ death without suppressing polyQ aggregation. While polyQ-induced cell death was reduced by inhibiting cytochrome c release from mitochondria, protection by HSP27 was regulated by its phosphorylation status and was independent of its ability to bind to cytochrome c. However, mutant huntingtin (HTT; 613004) caused increased levels of reactive oxygen species (ROS) in neuronal and nonneuronal cells. ROS contributed to cell death because both N-acetyl-L-cysteine and glutathione in its reduced form suppressed polyQ-mediated cell death. HSP27 decreased ROS in cells expressing mutant huntingtin, suggesting that this chaperone may protect cells against oxidative stress. The authors proposed that a polyQ mutation may induce ROS that directly contribute to cell death, and that HSP27 may be an antagonist of this process. </p><p>The alpha-crystallin subunits alpha-A (123580) and alpha-B (123590) each can form an oligomer by itself or with the other. Fu and Liang (2002) used a 2-hybrid system to study heterogeneous interactions among lens crystallins of different classes. They found interactions between alpha-A- (or alpha-B-) and beta-B2- (123620) or gamma-C-(123680) crystallins, but the intensity of interaction was one-third that of alpha-A-alpha-B interactions. HSP27 showed similar interaction properties with alpha-B-crystallin. Experiments with N- and C-terminal domain-truncated mutants demonstrated that both N- and C-terminal domains were important in alpha-A-crystallin self-interaction, but that only the C-terminal domain was important in alpha-B-crystallin self-interaction. </p><p>When fed a diet supplemented with cholesterol, Apoe (107741) -/- mice develop inflammatory atherosclerosis. Rayner et al. (2008) found that overexpression of human HSP27 reduced atherosclerotic lesions in aortic arches excised from Apoe -/- female mice by 35% compared with Apoe -/- controls. HSP27 overexpression had no effect on atherosclerotic lesions in Apoe -/- male mice. However, there was an inverse correlation between serum HSP27 level and atherosclerotic lesion area in both male and female Apoe -/- mice. HSP27 was secreted from cultured human macrophages in response to estrogen and acetylated low density lipoprotein (acLDL). Extracellular HSP27 bound the scavenger receptor SRA (MSR1; 153622) on murine macrophages and prevented acLDL uptake. Extracellular HSP27 also decreased acLDL-induced release of the proinflammatory cytokine Il1b (147720) and increased the release of the antiinflammatory cytokine Il10 (124092) by mouse macrophages. Overexpression of HSP27 in Apoe -/- mouse macrophages reduced their adherence and migration in vitro. Rayner et al. (2008) concluded that HSP27 is atheroprotective, possibly by competing for uptake of atherogenic lipids by macrophages or by attenuating inflammation. </p><p>De Thonel et al. (2010) stated that HSP27 is a ubiquitin-binding protein involved in proteasomal degradation of certain proteins under stress conditions. They found that HSP27 was involved in proteasome-mediated degradation of GATA1 (305371), a transcription factor that directs erythroblast proliferation, but not differentiation. Knockdown of HSP27 or overexpression of GATA1 inhibited differentiation of primary cultured human erythroid cells and the K562 erythroleukemia cell line. HSP27-mediated GATA1 degradation was reduced by proteasome inhibitors and required prior acetylation of GATA1 and serine phosphorylation of HSP27 via the p38 MAP kinase (MAPK14; 600289) pathway. </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>Axonal Charcot-Marie-Tooth Disease Type 2F</em></strong></p><p>
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In affected members of 2 families with axonal Charcot-Marie-Tooth disease type 2F (CMT2F; 606595) and in affected members of 4 families with distal hereditary motor neuropathy (HMN2B; 608634), Evgrafov et al. (2004) identified heterozygous mutations in the HSPB1 gene (602195.0001-602195.0004). </p><p><strong><em>Distal Hereditary Motor Neuronopathy 3, Autosomal Dominant</em></strong></p><p>
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Houlden et al. (2008) identified 4 different heterozygous mutations in the HSPB1 gene (see, e.g., 602195.0001; 602195.0007) in affected members of 4 of 25 families with autosomal dominant distal hereditary motor neuronopathy-3 (HMND3; 608634). An additional patient with autosomal recessive inheritance was found to have a homozygous mutation (602195.0008). All patients had a predominant motor neuropathy without clinical sensory abnormalities. No HSPB1 mutations were found in 90 families with CMT2. </p><p><strong><em>Variant Function</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 (608014) 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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<h4>
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<span class="mim-font">
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<strong>Animal Model</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>D'Ydewalle et al. (2011) demonstrated that transgenic mice expressing the S135F (602195.0001) or P182L (602195.0004) Hspb1 mutations developed clinical and pathologic features of axonal CMT or distal HMN. Mutant mice developed progressive motor impairment, decreased muscle strength, and clawed hindpaws, features that were more apparent in P182L mice, as P182L is associated with the dHMN phenotype. S135F mutants showed sensory abnormalities, whereas P182L mutant mice did not. Sensory loss in the S135F mutants was associated with decreased sensory amplitudes on electrophysiologic studies and impaired mitochondrial axonal transport in dorsal root ganglion cells. Both mouse mutants showed distal axonal loss on nerve biopsy, and both had a decrease in acetylated alpha-tubulin (TUBA1A; 602529) in peripheral nerves. Treatment of S135F mutant mice with an HDAC6 (300272) inhibitor resulted in restoration of axonal transport and partial reversal of the CMT phenotype. </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>ALLELIC VARIANTS</strong>
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</span>
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<strong>8 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 CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2F</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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NEURONOPATHY, DISTAL HEREDITARY MOTOR, AUTOSOMAL DOMINANT 3, INCLUDED
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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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HSPB1, SER135PHE
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<br />
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SNP: rs28939680,
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ClinVar: RCV000007904, RCV000007905, RCV000789332, RCV003482225
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In affected members of a Russian family with Charcot-Marie-Tooth disease type 2F (CMT2F; 606595) previously reported by Ismailov et al. (2001), Evgrafov et al. (2004) identified a heterozygous c.404C-T transition in exon 2 of the HSPB1 gene, resulting in a ser135-to-phe (S135F) substitution. In affected members of an unrelated family from the United Kingdom with autosomal dominant distal hereditary motor neuronopathy 3 (HMND3; 608634), the authors identified the same mutation in heterozygosity. The S135F mutation occurs in a highly conserved alpha-crystallin domain of the protein. In vitro expression of the mutant protein resulted in reduced viability of neuronal cells and impaired neurofilament assembly. Evgrafov et al. (2004) suggested that these deficits may be responsible for premature axonal degeneration, which underlies both CMT and dHMN. </p><p>Houlden et al. (2008) identified a heterozygous S135F mutation in affected members of a large family with HMND3. The mean age at onset was 21 years, and sensory abnormalities were not present. </p><p><strong><em>Variant Function</em></strong></p><p>
|
|
In cultured mouse motor neurons, Zhai et al. (2007) showed that expression of S135F-mutant HSPB1 led to progressive degeneration of motor neurons with disruption of the neurofilament network and aggregation of NEFL (162280) protein. The 2 proteins were found to associate together, and the S135F mutant had a dominant effect. Similarly, expression of NEFL mutants (e.g., 162280.0003) also led to disruption of the neurofilament network and aggregation of NEFL, and wildtype HSPB1 induced reversal of NEFL aggregates. Zhai et al. (2007) suggested that disruption of the neurofilament network with aggregation of NEFL is a common triggering event of motor neuron degeneration in CMT2E (607684) and CMT2F. </p>
|
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
|
|
<h4>
|
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<span class="mim-font">
|
|
<strong>.0002 NEURONOPATHY, DISTAL HEREDITARY MOTOR, AUTOSOMAL DOMINANT 3</strong>
|
|
</span>
|
|
</h4>
|
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</div>
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<div>
|
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<span class="mim-text-font">
|
|
CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2F, INCLUDED
|
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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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HSPB1, ARG127TRP
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|
|
<br />
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|
|
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SNP: rs29001571,
|
|
|
|
|
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gnomAD: rs29001571,
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|
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ClinVar: RCV000007906, RCV000007907, RCV000489743, RCV002354152
|
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|
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|
|
</span>
|
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In affected members of a Belgian family with autosomal dominant distal hereditary motor neuronopathy 3 (HMND3; 608634), Evgrafov et al. (2004) identified a heterozygous c.379C-T transition in exon 2 of the HSPB1 gene, resulting in an arg127-to-trp (R127W) substitution. The mutation occurs in a highly conserved alpha-crystallin domain of the protein. </p><p>In affected members of 4 Chinese Han families with late-onset Charcot-Marie-Tooth disease type 2F (CMT2F; 606595), Tang et al. (2005) identified heterozygosity for the R127W substitution. Haplotype analysis indicated a founder effect. Three mutation carriers from different families, ranging in age from 23 to 37 years, were asymptomatic, possibly reflecting age-dependent penetrance. </p>
|
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0003 NEURONOPATHY, DISTAL HEREDITARY MOTOR, AUTOSOMAL DOMINANT 3</strong>
|
|
</span>
|
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</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
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HSPB1, THR151ILE
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|
<br />
|
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|
|
SNP: rs28937568,
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|
|
ClinVar: RCV000007908, RCV000809687, RCV001174177, RCV001815164
|
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</span>
|
|
</div>
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|
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<div>
|
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<span class="mim-text-font">
|
|
<p>In affected members of a Croatian family with autosomal dominant distal hereditary motor neuronopathy-3 (HMND3; 608634), Evgrafov et al. (2004) identified a heterozygous c.452C-T transition in exon 2 of the HSPB1 gene, resulting in a thr151-to-ile (T151I) substitution. The mutation occurs in a highly conserved alpha-crystallin domain of the protein. </p>
|
|
</span>
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|
</div>
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<div>
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|
<br />
|
|
</div>
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|
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</div>
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<div>
|
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|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0004 NEURONOPATHY, DISTAL HEREDITARY MOTOR, AUTOSOMAL DOMINANT 3</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
HSPB1, PRO182LEU
|
|
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|
|
<br />
|
|
|
|
SNP: rs28937569,
|
|
|
|
|
|
|
|
ClinVar: RCV000007909, RCV005089204
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members of an Austrian family with autosomal dominant distal hereditary motor neuropathy-3 (HMND3; 608634), Evgrafov et al. (2004) identified a heterozygous c.545C-T transition in exon 3 of the HSPB1 gene, resulting in a pro182-to-leu (P182L) substitution. The mutation occurs in the variable C-terminal tail of the protein. </p><p><strong><em>Variant Function</em></strong></p><p>
|
|
By in vitro functional expression studies, Ackerley et al. (2006) showed that in mouse primary cortical cells the P182L-mutant protein formed aggregates and failed to be transported down neuronal processes unlike the wildtype protein. Coexpression of the mutant and wildtype protein resulted in sequestration of the wildtype protein into mutant aggregates. Mutant HSPB1 also disrupted the formation of intracellular neurofilaments and disrupted the transport of specific cellular cargoes, such as the p150 dynactin (DCTN1; 601143), but not mitochondria. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0005 CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2F</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
HSPB1, ARG136TRP
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs28939681,
|
|
|
|
|
|
gnomAD: rs28939681,
|
|
|
|
|
|
ClinVar: RCV000007910
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members of a Belgian family with Charcot-Marie-Tooth disease type 2F (CMT2F; 606595), Evgrafov et al. (2004) identified a heterozygous c.406C-T transition in exon 2 of the HSPB1 gene, resulting in an arg136-to-trp (R136W) substitution. The mutation occurs in a highly conserved alpha-crystallin domain of the protein. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0006 NEURONOPATHY, DISTAL HEREDITARY MOTOR, AUTOSOMAL DOMINANT 3</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
HSPB1, PRO182SER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs104894020,
|
|
|
|
|
|
|
|
ClinVar: RCV000007911, RCV000809907
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a Japanese patient with autosomal dominant distal hereditary motor neuronopathy-3 (HMND3; 608634), Kijima et al. (2005) identified heterozygosity for a c.544C-T transition in exon 3 of the HSBP1 gene, resulting in a pro182-to-ser (P182S) substitution. The mutation was not detected in his parents or older brother or in 100 control chromosomes. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 NEURONOPATHY, DISTAL HEREDITARY MOTOR, AUTOSOMAL DOMINANT 3</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
HSPB1, ARG140GLY
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121909112,
|
|
|
|
|
|
|
|
ClinVar: RCV000007912, RCV000688660, RCV001174175, RCV001508210, RCV001794438, RCV002326670, RCV005042012
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected individuals from an Indian family with autosomal dominant distal hereditary motor neuronopathy-3 (HMND3; 608634), Houlden et al. (2008) identified a heterozygous c.418C-G transversion in exon 2 of the HSPB1 gene, resulting in an arg140-to-gly (R140G) substitution in the alpha-crystallin domain. The mean age of onset in this family was 29 years, and both father and son had distal motor neuropathy without sensory abnormalities. Two additional Indian patients with sporadic HMN2B were also found to carry the R140G mutation. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0008 NEURONOPATHY, DISTAL HEREDITARY MOTOR, TYPE IIB, AUTOSOMAL RECESSIVE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
HSPB1, LEU99MET
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121909113,
|
|
|
|
|
|
|
|
ClinVar: RCV000007913
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a Pakistani patient, born of consanguineous parents, with distal HMN2B (608634), Houlden et al. (2008) identified a homozygous 295C-A transversion in exon 1 of the HSPB1 gene, resulting in a leu99-to-met (L99M) substitution in the alpha-crystallin domain. He had onset at age 37 years of difficulty walking, and had distal muscle weakness and atrophy without sensory involvement. The patient's unaffected mother and sister were heterozygous for the mutation, suggesting that it may act in a dose-dependent fashion. This was the first report of autosomal recessive inheritance of HSPB1 mutations. The mutation occurred in a conserved residue and was not found in 220 controls. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</div>
|
|
|
|
<div>
|
|
<ol>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Ackerley, S., James, P. A., Kalli, A., French, S., Davies, K. E., Talbot, K.
|
|
<strong>A mutation in the small heat-shock protein HSPB1 leading to distal hereditary motor neuronopathy disrupts neurofilament assembly and the axonal transport of specific cellular cargoes.</strong>
|
|
Hum. Molec. Genet. 15: 347-354, 2006.
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|
|
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|
|
[PubMed: 16368711]
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|
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[Full Text: https://doi.org/10.1093/hmg/ddi452]
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|
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</p>
|
|
</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Benndorf, R., Welsh, M. J.
|
|
<strong>Shocking degeneration.</strong>
|
|
Nature Genet. 36: 547-548, 2004.
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[PubMed: 15167925]
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[Full Text: https://doi.org/10.1038/ng0604-547]
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</p>
|
|
</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Carper, S. W., Rocheleau, T. A., Storm, F. K.
|
|
<strong>cDNA sequence of a human heat shock protein HSP27.</strong>
|
|
Nucleic Acids Res. 18: 6457 only, 1990.
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|
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[PubMed: 2243808]
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|
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[Full Text: https://doi.org/10.1093/nar/18.21.6457]
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</p>
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</li>
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<li>
|
|
<p class="mim-text-font">
|
|
d'Ydewalle, C., Krishnan, J., Chiheb, D. M., Van Damme, P., Irobi, J., Kozikowski, A. P., Vanden Berghe, P., Timmerman, V., Robberecht, W., Van Den Bosch, L.
|
|
<strong>HDAC6 inhibitors reverse axonal loss in a mouse model of mutant HSPB1-induced Charcot-Marie-Tooth disease.</strong>
|
|
Nature Med. 17: 968-974, 2011.
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[PubMed: 21785432]
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[Full Text: https://doi.org/10.1038/nm.2396]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
de Thonel, A., Vandekerckhove, J., Lanneau, D., Selvakumar, S., Courtois, G., Hazoume, A., Brunet, M., Maurel, S., Hammann, A., Ribeil, J. A., Zermati, Y., Gabet, A. S., Boyes, J., Solary, E., Hermine, O., Garrido, C.
|
|
<strong>HSP27 controls GATA-1 protein level during erythroid cell differentiation.</strong>
|
|
Blood 116: 85-96, 2010.
|
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|
|
|
[PubMed: 20410505]
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|
[Full Text: https://doi.org/10.1182/blood-2009-09-241778]
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</p>
|
|
</li>
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<li>
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|
<p class="mim-text-font">
|
|
Evgrafov, O. V., Mersiyanova, I., Irobi, J., Van Den Bosch, L., Dierick, I., Leung, C. L., Schagina, O., Verpoorten, N., Van Impe, K., Fedotov, V., Dadali, E., Auer-Grumbach, M., and 14 others.
|
|
<strong>Mutant small heat-shock protein 27 causes axonal Charcot-Marie-Tooth disease and distal hereditary motor neuropathy.</strong>
|
|
Nature Genet. 36: 602-606, 2004.
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[PubMed: 15122254]
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[Full Text: https://doi.org/10.1038/ng1354]
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|
|
</p>
|
|
</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Fu, L., Liang, J. J.-N.
|
|
<strong>Detection of protein-protein interactions among lens crystallins in a mammalian two-hybrid system assay.</strong>
|
|
J. Biol. Chem. 277: 4255-4260, 2002.
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|
|
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|
|
[PubMed: 11700327]
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|
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|
|
[Full Text: https://doi.org/10.1074/jbc.M110027200]
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|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Hickey, E., Brandon, S. E., Potter, R., Stein, G., Stein, J., Weber, L. A.
|
|
<strong>Sequence and organization of genes encoding the human 27 kDa heat shock protein.</strong>
|
|
Nucleic Acids Res. 14: 4127-4145, 1986. Note: Erratum: Nucleic Acids Res. 14: 8230 only, 1986.
|
|
|
|
|
|
[PubMed: 3714473]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1093/nar/14.10.4127]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Hickey, E., Brandon, S. E., Sadis, S., Smale, G., Weber, L. A.
|
|
<strong>Molecular cloning of sequences encoding the human heat-shock proteins and their expression during hyperthermia.</strong>
|
|
Gene 43: 147-154, 1986.
|
|
|
|
|
|
[PubMed: 3019832]
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|
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|
|
|
[Full Text: https://doi.org/10.1016/0378-1119(86)90018-1]
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|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Houlden, H., Laura, M., Wavrant-De Vrieze, F., Blake, J., Wood, N., Reilly, M. M.
|
|
<strong>Mutations in the HSP27 (HSPB1) gene cause dominant, recessive, and sporadic distal HMN/CMT type 2.</strong>
|
|
Neurology 71: 1660-1668, 2008.
|
|
|
|
|
|
[PubMed: 18832141]
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|
|
|
|
|
[Full Text: https://doi.org/10.1212/01.wnl.0000319696.14225.67]
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|
|
|
|
|
</p>
|
|
</li>
|
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|
|
<li>
|
|
<p class="mim-text-font">
|
|
Hunt, C. R., Goswami, P. C., Kozak, C. A.
|
|
<strong>Assignment of the mouse Hsp25 and Hsp105 genes to the distal region of chromosome 5 by linkage analysis.</strong>
|
|
Genomics 45: 462-463, 1997.
|
|
|
|
|
|
[PubMed: 9344682]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1006/geno.1997.4973]
|
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|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Ismailov, S. M., Fedotov, V. P., Dadali, E. L., Polyakov, A. V., Van Broeckhoven, C., Ivanov, V. I., De Jonghe, P., Timmerman, V., Evgrafov, O. V.
|
|
<strong>A new locus for autosomal dominant Charcot-Marie-Tooth disease type 2 (CMT2F) maps to chromosome 7q11-q21.</strong>
|
|
Europ. J. Hum. Genet. 9: 646-650, 2001.
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Zhai, J., Lin, H., Julien, J.-P., Schlaepfer, W. W.
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<strong>Disruption of neurofilament network with aggregation of light neurofilament protein: a common pathway leading to motor neuron degeneration due to Charcot-Marie-Tooth disease-linked mutations in NFL and HSPB1.</strong>
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Cassandra L. Kniffin - updated : 12/15/2011<br>Patricia A. Hartz - updated : 6/15/2011<br>Cassandra L. Kniffin - updated : 10/30/2009<br>Cassandra L. Kniffin - updated : 9/2/2009<br>Patricia A. Hartz - updated : 4/15/2009<br>Cassandra L. Kniffin - updated : 4/6/2009<br>Victor A. McKusick - updated : 12/16/2005<br>Cassandra L. Kniffin - updated : 11/4/2005<br>Victor A. McKusick - updated : 6/14/2004<br>Jane Kelly - updated : 3/5/2004<br>Victor A. McKusick - updated : 8/5/2003<br>George E. Tiller - updated : 12/17/2002<br>Dawn Watkins-Chow - updated : 2/26/2002<br>Patti M. Sherman - updated : 5/11/1999<br>Barbara J. Biery - updated : 4/21/1999
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Victor A. McKusick : 12/16/1997
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