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Entry
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- *601023 - VALOSIN-CONTAINING PROTEIN; VCP
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- OMIM
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</form>
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<div class="container hidden-print">
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<div id="mimAlertBanner">
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*601023</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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<ul id="mimFloatingTocMenuItems" class="nav nav-pills nav-stacked mim-floating-toc-padding">
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<li role="presentation">
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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</li>
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#biochemicalFeatures">Biochemical Features</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>
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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>
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<li role="presentation" style="margin-left: 1em">
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<a href="#genotypePhenotypeCorrelations">Genotype/Phenotype Correlations</a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="#animalModel">Animal Model</a>
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</li>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/601023">Table View</a>
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</li>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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</li>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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</li>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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</ul>
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</nav>
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</div>
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</div>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
|
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<span class="panel-title">
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<span class="small">
|
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
|
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</a>
|
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</span>
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</span>
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</div>
|
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000165280;t=ENST00000358901" 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=7415" 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=601023" 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=ENSG00000165280;t=ENST00000358901" 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_001354927,NM_001354928,NM_007126" 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_007126" 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=601023" 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=03013&isoform_id=03013_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/VCP" 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/1263127,2984586,5410290,6005942,6094447,6807907,11095436,11095437,48257098,52745386,83405636,111305821,112818458,119578807,119578808,189065396,209402826,209402842,1238280250,1238280272" 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/P55072" 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=7415" 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=ENSG00000165280;t=ENST00000358901" 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=VCP" 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=VCP" 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+7415" 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/VCP" 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:7415" 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/7415" 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=chr9&hgg_gene=ENST00000681845.1&hgg_start=35056064&hgg_end=35072625&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:12666" 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/vcp" 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=601023[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=601023[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
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<div><a href="https://www.deciphergenomics.org/gene/VCP/overview/clinical-info" class="mim-tip-hint" title="DECIPHER" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'DECIPHER', 'domain': 'DECIPHER'})">DECIPHER</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000165280" 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=VCP" 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=VCP" 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=VCP" 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="#mimLocusSpecificDBsFold" id="mimLocusSpecificDBsToggle" data-toggle="collapse" class="mim-tip-hint mimTriangleToggle" title="A gene-specific database of variation."><span id="mimLocusSpecificDBsToggleTriangle" class="small" style="margin-left: -0.8em;">►</span>Locus Specific DBs</div>
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<div id="mimLocusSpecificDBsFold" class="collapse">
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<div style="margin-left: 0.5em;"><a href="http://www.LOVD.nl/VCP" title="Leiden Muscular Dystrophy pages" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">Leiden Muscular Dystrophy …</a></div><div style="margin-left: 0.5em;"><a href="http://www.molgen.ua.ac.be/ADMutations/" title="Alzheimer Disease & Frontotemporal Dementia Mutation Database" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">Alzheimer Disease & Fr…</a></div>
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</div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=VCP&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/PA37289" 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:12666" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
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<div><a href="https://flybase.org/reports/FBgn0286784.html" class="mim-tip-hint" title="A Database of Drosophila Genes and Genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'FlyBase', 'domain': 'flybase.org'})">FlyBase</a></div>
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<div><a href="https://www.mousephenotype.org/data/genes/MGI:99919" 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/VCP#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:99919" 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/7415/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=7415" 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=WBGene00007352;class=Gene" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">WBGene00007352 </a></div><div style="margin-left: 0.5em;"><a href="https://wormbase.org/db/gene/gene?name=WBGene00008053;class=Gene" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">WBGene00008053 </a></div>
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</div>
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<div><a href="https://zfin.org/ZDB-GENE-030131-5408" 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="mimCellLines">
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellLinesLinksFold" id="mimCellLinesLinksToggle" 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="mimCellLinesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cell Lines</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="mimCellLinesLinksFold" 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://catalog.coriell.org/Search?q=OmimNum:601023" class="definition" title="Coriell Cell Repositories; cell cultures and DNA derived from cell cultures." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'CCR', 'domain': 'ccr.coriell.org'})">Coriell</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:7415" 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=VCP&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> 1187565005<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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601023
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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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VALOSIN-CONTAINING PROTEIN; VCP
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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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CDC48, YEAST, HOMOLOG OF<br />
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p97
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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=VCP" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">VCP</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>
|
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Cytogenetic location: <a href="/geneMap/9/160?start=-3&limit=10&highlight=160">9p13.3</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr9:35056064-35072625&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'})">9:35,056,064-35,072,625</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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9p13.3
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Charcot-Marie-Tooth disease, type 2Y
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Frontotemporal dementia and/or amyotrophic lateral sclerosis 6
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<a href="/entry/613954"> 613954 </a>
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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Inclusion body myopathy with early-onset Paget disease and frontotemporal dementia 1
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<a href="/entry/167320"> 167320 </a>
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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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/601023" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
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<li><a href="/graph/radial/601023" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
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<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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<span class="mim-font">
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
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<strong>TEXT</strong>
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<strong>Description</strong>
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<p>The VCP gene encodes valosin-containing protein, a ubiquitously expressed multifunctional protein that is a member of the AAA+ (ATPase associated with various activities) protein family. It has been implicated in multiple cellular functions ranging from organelle biogenesis to ubiquitin-dependent protein degradation (summary by <a href="#48" class="mim-tip-reference" title="Weihl, C. C., Pestronk, A., Kimonis, V. E. <strong>Valosin-containing protein disease: Inclusion body myopathy with Paget's disease of the bone and fronto-temporal dementia.</strong> Neuromusc. Disord. 19: 308-315, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19380227/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19380227</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19380227[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.nmd.2009.01.009" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19380227">Weihl et al., 2009</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19380227" 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>Cloning and Expression</strong>
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<p>Clathrin is a structural protein found in coated pits and vesicles, organelles which are important in membrane trafficking functions such as endocytosis and Golgi sorting. A 100-kD protein, designated valosin-containing protein or VCP by early investigators, is a structural protein complexed with clathrin (see <a href="/entry/118960">118960</a>). VCP is the homolog of yeast cdc48p, and is a member of a family that includes putative ATP-binding proteins involved in vesicle transport and fusion, 26S proteasome function, and assembly of peroxisomes (<a href="#34" class="mim-tip-reference" title="Pleasure, I. T., Black, M. M., Keen, J. H. <strong>Valosin-containing protein, VCP, is a ubiquitous clathrin-binding protein.</strong> Nature 365: 459-462, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8413590/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8413590</a>] [<a href="https://doi.org/10.1038/365459a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8413590">Pleasure et al., 1993</a>). VCP was cloned from the pig (<a href="#25" class="mim-tip-reference" title="Koller, K. J., Brownstein, M. J. <strong>Use of a cDNA clone to identify a supposed precursor protein containing valosin.</strong> Nature 325: 542-545, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3468358/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3468358</a>] [<a href="https://doi.org/10.1038/325542a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3468358">Koller and Brownstein, 1987</a>) and mouse (<a href="#12" class="mim-tip-reference" title="Egerton, M., Ashe, O. R., Chen, D., Druker, B. J., Burgess, W. H., Samelson, L. E. <strong>VCP, the mammalian homolog of cdc48, is tyrosine phosphorylated in response to T cell antigen receptor activation.</strong> EMBO J. 11: 3533-3540, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1382975/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1382975</a>] [<a href="https://doi.org/10.1002/j.1460-2075.1992.tb05436.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1382975">Egerton et al., 1992</a>). <a href="#11" class="mim-tip-reference" title="Druck, T., Gu, Y., Prabhala. G., Cannizzaro, L. A., Park, S.-H., Huebner, K., Keen, J. H. <strong>Chromosome localization of human genes for clathrin adaptor polypeptides AP2-beta and AP50 and the clathrin-binding protein, VCP.</strong> Genomics 30: 94-97, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8595912/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8595912</a>] [<a href="https://doi.org/10.1006/geno.1995.0016" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8595912">Druck et al. (1995)</a> cloned a portion of the human cDNA. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8413590+8595912+1382975+3468358" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#6" class="mim-tip-reference" title="Cloutier, P., Lavallee-Adam, M., Faubert, D., Blanchette, M., Coulombe, B. <strong>A newly uncovered group of distantly related lysine methyltransferases preferentially interact with molecular chaperones to regulate their activity.</strong> PLoS Genet. 9: e1003210, 2013. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23349634/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23349634</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23349634[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1371/journal.pgen.1003210" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23349634">Cloutier et al. (2013)</a> stated that the deduced 806-amino acid VCP protein contains an N-terminal domain, followed by a linker region, an ATPase domain, a second linker region, a second ATPase domain, and a C-terminal domain. The N-terminal domain consists of a double-psi-barrel superfold and 4-stranded beta barrel, and each ATPase domain consists of Walker A and B motifs and a 4-alpha-helix bundle. VCP is extensively modified by phosphorylation and acetylation, as well as by lysine methylation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23349634" 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>Biochemical Features</strong>
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<p><strong><em>Cryoelectron Microscopy</em></strong></p><p>
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<a href="#4" class="mim-tip-reference" title="Banerjee, S., Bartesaghi, A., Merk, A., Rao, P., Bulfer, S. L., Yan, Y., Green, N., Mroczkowski, B., Neitz, R. J., Wipf, P., Falconieri, V., Deshaies, R. J., Milne, J. L. S., Huryn, D., Arkin, M., Subramaniam, S. <strong>2.3 angstrom resolution cryo-EM structure of human p97 and mechanism of allosteric inhibition.</strong> Science 351: 871-875, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26822609/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26822609</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26822609[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.aad7974" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26822609">Banerjee et al. (2016)</a> reported cryoelectron microscopy structures for ADP-bound, full-length, hexameric wildtype p97 in the presence and absence of an allosteric inhibitor at resolutions of 2.3 and 2.4 angstroms, respectively. <a href="#4" class="mim-tip-reference" title="Banerjee, S., Bartesaghi, A., Merk, A., Rao, P., Bulfer, S. L., Yan, Y., Green, N., Mroczkowski, B., Neitz, R. J., Wipf, P., Falconieri, V., Deshaies, R. J., Milne, J. L. S., Huryn, D., Arkin, M., Subramaniam, S. <strong>2.3 angstrom resolution cryo-EM structure of human p97 and mechanism of allosteric inhibition.</strong> Science 351: 871-875, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26822609/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26822609</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26822609[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.aad7974" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26822609">Banerjee et al. (2016)</a> also reported cryoelectron microscopy structures (at resolutions of approximately 3.3, 3.2, and 3.3 angstroms, respectively) for 3 distinct, coexisting functional states of p97 with occupancies of 0, 1, or 2 molecules of adenosine 5-prime-O-(3-thiotriphosphate) (ATP-gamma-S) per protomer. A large corkscrew-like change in molecular architecture, coupled with upward displacement of the N-terminal domain, is observed only when ATP-gamma-S is bound to both the D1 and D2 domains of the protomer. These cryoelectron microscopy structures established the sequence of nucleotide-driven structural changes in p97 at atomic resolution. They also enabled elucidation of the binding mode of an allosteric small-molecule inhibitor to p97 and illustrated how inhibitor binding at the interface between the D1 and D2 domains prevents propagation of the conformational changes necessary for p97 function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26822609" 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="#39" class="mim-tip-reference" title="Twomey, E. C., Ji, Z., Wales, T. E., Bodnar, N. O., Ficarro, S. B., Marto, J. A., Engen, J. R., Rapoport, T. A. <strong>Substrate processing by the Cdc48 ATPase complex is initiated by ubiquitin unfolding.</strong> Science 365: eaax1033, 2019. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31249135/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31249135</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31249135[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.aax1033" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31249135">Twomey et al. (2019)</a> reported cryoelectron microscopy structures of the yeast Cdc48 ATPase in complex with Ufd1 (<a href="/entry/601754">601754</a>)/Npl4 (<a href="/entry/606590">606590</a>) and polyubiquitinated substrate. The structures showed that the Cdc48 complex initiates substrate processing by unfolding a ubiquitin molecule. The unfolded ubiquitin molecule binds to Npl4 and projects its N-terminal segment through both hexameric ATPase rings. Pore loops of the second ring form a staircase that acts as a conveyer belt to move the polypeptide through the central pore. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31249135" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#7" class="mim-tip-reference" title="Cooney, I., Han, H., Stewart, M. G., Carson, R. H., Hansen, D. T., Iwasa, J. H., Price, J. C., Hill, C. P., Shen, P. S. <strong>Structure of the Cdc48 segregase in the act of unfolding an authentic substrate.</strong> Science 365: 502-505, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31249134/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31249134</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31249134[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.aax0486" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31249134">Cooney et al. (2019)</a> reported a 3.7-angstrom-resolution structure of Cdc48 in complex with an adaptor protein and a native substrate. Cdc48 engages substrate by adopting a helical configuration of substrate-binding residues that extends through the central pore of both of the ATPase rings. <a href="#7" class="mim-tip-reference" title="Cooney, I., Han, H., Stewart, M. G., Carson, R. H., Hansen, D. T., Iwasa, J. H., Price, J. C., Hill, C. P., Shen, P. S. <strong>Structure of the Cdc48 segregase in the act of unfolding an authentic substrate.</strong> Science 365: 502-505, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31249134/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31249134</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31249134[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.aax0486" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31249134">Cooney et al. (2019)</a> concluded that their findings indicated a unified hand-over-hand mechanism of protein translocation by Cdc48 and other AAA+ ATPases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31249134" 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="#21" class="mim-tip-reference" title="Johnson, J. O., Mandrioli, J., Benatar, M., Abramzon, Y., Van Deerlin, V. M., Trojanowski, J. Q., Gibbs, J. R., Brunetti, M., Gronka, S., Wuu, J., Ding, J., McCluskey, L., and 25 others. <strong>Exome sequencing reveals VCP mutations as a cause of familial ALS.</strong> Neuron 68: 857-864, 2010. Note: Erratum: Neuron 69: 397 only, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21145000/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21145000</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21145000[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.neuron.2010.11.036" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21145000">Johnson et al. (2010)</a> noted that the VCP gene contains 17 exons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21145000" 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="#11" class="mim-tip-reference" title="Druck, T., Gu, Y., Prabhala. G., Cannizzaro, L. A., Park, S.-H., Huebner, K., Keen, J. H. <strong>Chromosome localization of human genes for clathrin adaptor polypeptides AP2-beta and AP50 and the clathrin-binding protein, VCP.</strong> Genomics 30: 94-97, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8595912/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8595912</a>] [<a href="https://doi.org/10.1006/geno.1995.0016" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8595912">Druck et al. (1995)</a> used a partial human VCP cDNA to probe a panel of somatic cell hybrid DNAs and mapped the VCP gene to chromosome 9pter-q34. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8595912" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By database analysis, <a href="#18" class="mim-tip-reference" title="Hoyle, J., Tan, K. H., Fisher, E. M. C. <strong>Mapping the valosin-containing protein (VCP) gene on human chromosome 9 and mouse chromosome 4, and a likely pseudogene on the mouse X chromosome.</strong> Mammalian Genome 8: 778-780, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9321476/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9321476</a>] [<a href="https://doi.org/10.1007/s003359900566" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9321476">Hoyle et al. (1997)</a> identified a human expressed sequence tag (EST) that shares 80% identity with the mouse 3-prime untranslated region. They designed primers to this EST and amplified and sequenced a 127-bp product from total human DNA. This product detected 1 fragment only in a HindIII digest of total human DNA, indicating there is only 1 VCP sequence in the human genome. Using the 127-bp sequence to screen a human PAC library, followed by FISH analysis, they mapped the VCP gene to chromosome 9p13-p12. They mapped the mouse Vcp gene to mouse chromosome 4 and found a probable pseudogene on the mouse X chromosome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9321476" 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 VCP gene maps to chromosome 9p13.3 (<a href="#21" class="mim-tip-reference" title="Johnson, J. O., Mandrioli, J., Benatar, M., Abramzon, Y., Van Deerlin, V. M., Trojanowski, J. Q., Gibbs, J. R., Brunetti, M., Gronka, S., Wuu, J., Ding, J., McCluskey, L., and 25 others. <strong>Exome sequencing reveals VCP mutations as a cause of familial ALS.</strong> Neuron 68: 857-864, 2010. Note: Erratum: Neuron 69: 397 only, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21145000/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21145000</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21145000[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.neuron.2010.11.036" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21145000">Johnson et al., 2010</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21145000" 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="#52" class="mim-tip-reference" title="Ye, Y., Meyer, H. H., Rapoport, T. A. <strong>The AAA ATPase Cdc48/p97 and its partners transport proteins from the ER into the cytosol.</strong> Nature 414: 652-656, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11740563/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11740563</a>] [<a href="https://doi.org/10.1038/414652a" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11740563">Ye et al. (2001)</a> demonstrated that VCP (CDC48 in yeast and p97 in mammals) is required for the export of endoplasmic reticulum (ER) into the cytosol. Whereas CDC48/p97 was known to function in a complex with the cofactor p47 in membrane fusion, <a href="#52" class="mim-tip-reference" title="Ye, Y., Meyer, H. H., Rapoport, T. A. <strong>The AAA ATPase Cdc48/p97 and its partners transport proteins from the ER into the cytosol.</strong> Nature 414: 652-656, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11740563/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11740563</a>] [<a href="https://doi.org/10.1038/414652a" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11740563">Ye et al. (2001)</a> demonstrated that its role in ER protein export requires the interacting partners UFD1 (<a href="/entry/601754">601754</a>) and NPL4 (<a href="/entry/606590">606590</a>). The AAA ATPase interacts with substrates at the ER membrane and is needed to release them as polyubiquitinated species into the cytosol. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11740563" 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="#55" class="mim-tip-reference" title="Zhang, S.-H., Liu, J., Kobayashi, R., Tonks, N. K. <strong>Identification of the cell cycle regulator VCP (p97/CDC48) as a substrate of the band 4.1-related protein-tyrosine phosphatase PTPH1.</strong> J. Biol. Chem. 274: 17806-17812, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10364224/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10364224</a>] [<a href="https://doi.org/10.1074/jbc.274.25.17806" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10364224">Zhang et al. (1999)</a> created a substrate-trapping mutant of PTPH1 (<a href="/entry/176877">176877</a>) that interacted primarily with VCP in vitro but not in cells. A double mutant of PTPH1 had a marked reduction in phosphotyrosine content, specifically trapped VCP in vivo, and recognized the C-terminal tyrosines of VCP. Immunoblot analysis showed that wildtype PTPH1 specifically dephosphorylated VCP. <a href="#55" class="mim-tip-reference" title="Zhang, S.-H., Liu, J., Kobayashi, R., Tonks, N. K. <strong>Identification of the cell cycle regulator VCP (p97/CDC48) as a substrate of the band 4.1-related protein-tyrosine phosphatase PTPH1.</strong> J. Biol. Chem. 274: 17806-17812, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10364224/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10364224</a>] [<a href="https://doi.org/10.1074/jbc.274.25.17806" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10364224">Zhang et al. (1999)</a> concluded that PTPH1 exerts its effects on cell growth through dephosphorylation of VCP and that tyrosine phosphorylation is an important regulator of VCP function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10364224" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>By yeast 2-hybrid screening, immunoprecipitation analysis and pull-down assays, <a href="#32" class="mim-tip-reference" title="Nagahama, M., Suzuki, M., Hamada, Y., Hatsuzawa, K., Tani, K., Yamamoto, A., Tagaya, M. <strong>SVIP is a novel VCP/p97-interacting protein whose expression causes cell vacuolation.</strong> Molec. Biol. Cell 14: 262-273, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12529442/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12529442</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12529442[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1091/mbc.02-07-0115" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12529442">Nagahama et al. (2003)</a> showed that Svip (<a href="/entry/620965">620965</a>) interacted specifically with Vcp, with the interaction mediated by the coiled-coil regions of Svip and the ND1 domain of Vcp. Vcp formed a complex with p47 (NSFL1C; <a href="/entry/606610">606610</a>) and Ufd1, but the Svip-Vcp complex was distinct, and formation of the 2 Vcp complexes was mutually exclusive. Expression of rat Svip induced formation of large ER-derived vacuoles in HeLa cells, and formation of large vacuoles did not appear to be due to lack of Vcp availability in Vcp-mediated pathways. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12529442" 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="#45" class="mim-tip-reference" title="Watts, G. D. J., Wymer, J., Kovach, M. J., Mehta, S. G., Mumm, S., Darvish, D., Pestronk, A., Whyte, M. P., Kimonis, V. E. <strong>Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia is caused by mutant valosin-containing protein.</strong> Nature Genet. 36: 377-381, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15034582/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15034582</a>] [<a href="https://doi.org/10.1038/ng1332" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15034582">Watts et al. (2004)</a> summarized that VCP has been associated with several essential cell protein pathways including cell cycle, homotypic membrane fusion, nuclear envelope reconstruction, postmitotic Golgi reassembly, DNA damage response, suppressor of apoptosis, and ubiquitin-dependent protein degradation. <a href="#17" class="mim-tip-reference" title="Higashiyama, H., Hirose, F., Yamaguchi, M., Inoue, Y. H., Fujikake, N., Matsukage, A., Kakizuka, A. <strong>Identification of ter94, Drosophila VCP, as a modulator of polyglutamine-induced neurodegeneration.</strong> Cell Death Differ. 9: 264-273, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11859409/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11859409</a>] [<a href="https://doi.org/10.1038/sj.cdd.4400955" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11859409">Higashiyama et al. (2002)</a> identified a fruit fly VCP loss-of-function mutant as a dominant suppressor of expanded polyglutamine-induced neuronal degeneration. The suppressive effects of the loss-of-function mutant did not seem to result from inhibition of polyglutamine aggregate formation but rather from the degree of loss of VCP function. This suggested that a gene dosage response for VCP expression is essential to its function in expanded polyglutamine-induced neuronal degeneration. In support of this idea, transgenic fruit flies in which VCP levels were elevated experienced severe apoptotic cell death, whereas homozygous VCP loss-of-function mutants were embryonic lethal. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11859409+15034582" 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="#53" class="mim-tip-reference" title="Ye, Y., Shibata, Y., Yun, C., Ron, D., Rapoport, T. A. <strong>A membrane protein complex mediates retro-translocation from the ER lumen into the cytosol.</strong> Nature 429: 841-847, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15215856/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15215856</a>] [<a href="https://doi.org/10.1038/nature02656" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15215856">Ye et al. (2004)</a> found that VIMP (<a href="/entry/607918">607918</a>) recruits the p97 ATPase (VCP) and its cofactor, the UFD1/NPL4 complex, to the ER for retrotranslocation of misfolded proteins into the cytosol. They noted that all pathways of retrotranslocation appear to require the function of the p97 ATPase complex, which may provide the general driving force for the movement of proteins into the cytosol. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15215856" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>Using a library of endoribonuclease-prepared short interfering RNAs (esiRNAs), <a href="#24" class="mim-tip-reference" title="Kittler, R., Putz, G., Pelletier, L., Poser, I., Heninger, A.-K., Drechsel, D., Fischer, S., Konstantinova, I., Habermann, B., Grabner, H., Yaspo, M.-L., Himmelbauer, H., Korn, B., Neugebauer, K., Pisabarro, M. T., Buchholz, F. <strong>An endoribonuclease-prepared siRNA screen in human cells identifies genes essential for cell division.</strong> Nature 432: 1036-1040, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15616564/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15616564</a>] [<a href="https://doi.org/10.1038/nature03159" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15616564">Kittler et al. (2004)</a> identified 37 genes required for cell division, one of which was VCP. These 37 genes included several splicing factors for which knockdown generates mitotic spindle defects. In addition, a putative nuclear-export terminator was found to speed up cell proliferation and mitotic progression after knockdown. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15616564" 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="#41" class="mim-tip-reference" title="Uchiyama, K., Totsukawa, G., Puhka, M., Kaneko, Y., Jokitalo, E., Dreveny, I., Beuron, F., Zhang, X., Freemont, P., Kondo, H. <strong>p37 is a p97 adaptor required for Golgi and ER biogenesis in interphase and at the end of mitosis.</strong> Dev. Cell 11: 803-816, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17141156/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17141156</a>] [<a href="https://doi.org/10.1016/j.devcel.2006.10.016" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17141156">Uchiyama et al. (2006)</a> found that rodent p37 (<a href="/entry/610686">610686</a>) formed a complex with p97 in cytosol and localized to Golgi and ER. Small interfering RNA experiments in HeLa cells revealed that p37 was required for Golgi and ER biogenesis. Injection of anti-p37 antibodies into HeLa cells at different stages of the cell cycle showed that p37 was involved in Golgi and ER maintenance during interphase and in their reassembly at the end of mitosis. In an in vitro Golgi reassembly assay, the p97/p37 complex showed membrane fusion activity that required p115 (<a href="/entry/603344">603344</a>)-GM130 (GOLGA2; <a href="/entry/602580">602580</a>) tethering and SNARE GS15 (BET1L; <a href="/entry/615417">615417</a>). VCIP135 (VCPIP1) was also required, but its deubiquitinating activity was unnecessary for p97/p37-mediated activities. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17141156" 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="#35" class="mim-tip-reference" title="Ramadan, K., Bruderer, R., Spiga, F. M., Popp, O., Baur, T., Gotta, M., Meyer, H. H. <strong>Cdc48/p97 promotes reformation of the nucleus by extracting the kinase Aurora B from chromatin.</strong> Nature 450: 1258-1262, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18097415/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18097415</a>] [<a href="https://doi.org/10.1038/nature06388" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18097415">Ramadan et al. (2007)</a> showed that p97 stimulates nucleus reformation by inactivating the chromatin-associated kinase Aurora B (<a href="/entry/604970">604970</a>). During mitosis, Aurora B inhibits nucleus reformation by preventing chromosome decondensation and formation of the nuclear envelope membrane. During exit from mitosis, p97 binds to Aurora B after its ubiquitylation and extracts it from chromatin. This leads to inactivation of Aurora B on chromatin, thus allowing chromatin decondensation and nuclear envelope formation. <a href="#35" class="mim-tip-reference" title="Ramadan, K., Bruderer, R., Spiga, F. M., Popp, O., Baur, T., Gotta, M., Meyer, H. H. <strong>Cdc48/p97 promotes reformation of the nucleus by extracting the kinase Aurora B from chromatin.</strong> Nature 450: 1258-1262, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18097415/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18097415</a>] [<a href="https://doi.org/10.1038/nature06388" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18097415">Ramadan et al. (2007)</a> concluded that their data revealed an essential pathway that regulates reformation of the nucleus after mitosis and defined ubiquitin-dependent protein extraction as a common mechanism of Cdc48/p97 activity also during nucleus formation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18097415" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>Using a chromatin immunoprecipitation assay, <a href="#54" class="mim-tip-reference" title="Zhang, B., Tomita, Y., Qiu, Y., He, J., Morii, E., Noguchi, S., Aozasa, K. <strong>E74-like factor 2 regulates vasolin-containing protein expression.</strong> Biochem. Biophys. Res. Commun. 356: 536-541, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17368566/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17368566</a>] [<a href="https://doi.org/10.1016/j.bbrc.2007.02.160" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17368566">Zhang et al. (2007)</a> showed that ELF2 (<a href="/entry/619798">619798</a>) bound specifically to the 5-prime-flanking sequence of the VCP gene in MCF7 human breast cancer cells. Knockdown of ELF2 in MCF7 cells reduced VCP expression and cell viability. Immunohistochemical analysis revealed that ELF2 expression correlated with VCP expression and proliferative activity of cells in breast cancer specimens. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17368566" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>By immunoprecipitation analysis, <a href="#3" class="mim-tip-reference" title="Ballar, P., Zhong, Y., Nagahama, M., Tagaya, M., Shen, Y., Fang, S. <strong>Identification of SVIP as an endogenous inhibitor of endoplasmic reticulum-associated degradation.</strong> J. Biol. Chem. 282: 33908-33914, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17872946/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17872946</a>] [<a href="https://doi.org/10.1074/jbc.M704446200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17872946">Ballar et al. (2007)</a> showed that SVIP formed a trimeric complex with VCP and derlin-1 (DERL1; <a href="/entry/608813">608813</a>). VCP and derlin-1 are also common interacting partners of GP78 (AMFR; <a href="/entry/603243">603243</a>), but formation of the 2 complexes was mutually exclusive. By interacting with VCP and derlin-1, SVIP inhibited interaction of GP78 with CD3-delta (CD3D; <a href="/entry/186790">186790</a>), VCP, and derlin-1, resulting in inhibition of CD3-delta ubiquitination and subsequent loading to VCP for retrotranslocation. The results suggested that SVIP is an endogenous inhibitor of ER-associated degradation (ERAD) that acts by regulating assembly of the GP78/VCP/derlin-1 complex. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17872946" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>Using human cell lines, <a href="#31" class="mim-tip-reference" title="Mueller, B., Klemm, E. J., Spooner, E., Claessen, J. H., Ploegh, H. L. <strong>SEL1L nucleates a protein complex required for dislocation of misfolded glycoproteins.</strong> Proc. Nat. Acad. Sci. 105: 12325-12330, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18711132/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18711132</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18711132[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0805371105" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18711132">Mueller et al. (2008)</a> identified several components of a protein complex required for retrotranslocation or dislocation of misfolded proteins from the ER lumen to the cytosol for proteasome-dependent degradation. These included SEL1L (<a href="/entry/602329">602329</a>), HRD1 (SYVN1; <a href="/entry/608046">608046</a>), derlin-2 (DERL2; <a href="/entry/610304">610304</a>), the ATPase p97, PDI (P4HB; <a href="/entry/176790">176790</a>), BIP (HSPA5; <a href="/entry/138120">138120</a>), calnexin (CANX; <a href="/entry/114217">114217</a>), AUP1 (<a href="/entry/602434">602434</a>), UBXD8 (FAF2), UBC6E (UBE2J1; <a href="/entry/616175">616175</a>), and OS9 (<a href="/entry/609677">609677</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18711132" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>By affinity purification, SDS-PAGE, and mass spectrometry, <a href="#6" class="mim-tip-reference" title="Cloutier, P., Lavallee-Adam, M., Faubert, D., Blanchette, M., Coulombe, B. <strong>A newly uncovered group of distantly related lysine methyltransferases preferentially interact with molecular chaperones to regulate their activity.</strong> PLoS Genet. 9: e1003210, 2013. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23349634/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23349634</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23349634[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1371/journal.pgen.1003210" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23349634">Cloutier et al. (2013)</a> found that METTL21D (<a href="/entry/615260">615260</a>) expressed in HEK293 cells interacted with endogenous VCP, ASPSCR1 (<a href="/entry/606236">606236</a>), and UBXN6 (<a href="/entry/611946">611946</a>). In vitro methylation assays showed that recombinant METTL21D methylated VCP, which was abrogated by mutation of lys315 in ATPase domain 1 of VCP. Methylation reduced the activity of VCP ATPase domain 1, but it had no effect on the activity of VCP ATPase domain 2. METTL21D did not methylate ASPSRC1 or UBXN6, but the presence of ASPSRC1, but not UBXN6, enhanced METTL21D-dependent VCP methylation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23349634" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In immunoprecipitation studies, <a href="#5" class="mim-tip-reference" title="Clemen, C. S., Tangavelou, K., Strucksberg, K.-H., Just, S., Gaertner, L., Regus-Leidig, H., Stumpf, M., Reimann, J., Coras, R., Morgan, R. O., Fernandez, M.-P., Hofmann, A., Muller, S., Schoser, B., Hanisch, F.-G., Rottbauer, W., Blumcke, I., von Horsten, S., Eichinger, L., Schroder, R. <strong>Strumpellin is a novel valosin-containing protein binding partner linking hereditary spastic paraplegia to protein aggregation diseases.</strong> Brain 133: 2920-2941, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20833645/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20833645</a>] [<a href="https://doi.org/10.1093/brain/awq222" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20833645">Clemen et al. (2010)</a> identified strumpellin (KIAA0196; <a href="/entry/601657">601657</a>) as a binding partner with VCP. Strumpellin was detected in pathologic protein aggregates in muscle tissue derived from patients with IBMPFD1 (<a href="/entry/167320">167320</a>) as well as in various myofibrillar myopathies and in cortical neurons of a mouse model of Huntington disease (HD; <a href="/entry/143100">143100</a>). These findings suggested that strumpellin, like VCP, may have a role in various protein aggregate diseases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20833645" 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="#27" class="mim-tip-reference" title="Maric, M., Maculins, T., De Piccoli, G., Labib, K. <strong>Cdc48 and a ubiquitin ligase drive disassembly of the CMG helicase at the end of DNA replication.</strong> Science 346: 1253596, 2014. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25342810/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25342810</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25342810[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1253596" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25342810">Maric et al. (2014)</a> showed that the CMG helicase, composed of Cdc45 (<a href="/entry/603465">603465</a>)/Mcm (see MCM7, <a href="/entry/600592">600592</a>)/GINS (see <a href="/entry/610608">610608</a>), is ubiquitylated during the final stages of chromosome replication in S. cerevisiae, specifically on its Mcm7 subunit. The yeast F-box protein Dia2 is essential in vivo for ubiquitylation of CMG, and the SCF(Dia2) ubiquitin ligase (see <a href="/entry/603134">603134</a>) is also required to ubiquitylate CMG in vitro on its Mcm7 subunit in extracts of S-phase yeast cells. <a href="#27" class="mim-tip-reference" title="Maric, M., Maculins, T., De Piccoli, G., Labib, K. <strong>Cdc48 and a ubiquitin ligase drive disassembly of the CMG helicase at the end of DNA replication.</strong> Science 346: 1253596, 2014. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25342810/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25342810</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25342810[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1253596" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25342810">Maric et al. (2014)</a> concluded that their data identified 2 key features of helicase disassembly in budding yeast. First, there is an essential role for the F-box protein Dia2, which drives ubiquitylation of the CMG helicase on its Mcm7 subunit. Second, the Cdc48 segregase is required to break ubiquitylated CMG into its component parts. Once separated from GINS and Cdc45, the Mcm2-7 hexamer is less stable, so that all of the subunits of the CMG helicase are lost from the newly replicated DNA. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25342810" 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="#30" class="mim-tip-reference" title="Moreno, S. P., Bailey, R., Campion, N., Herron, S., Gambus, A. <strong>Polyubiquitylation drives replisome disassembly at the termination of DNA replication.</strong> Science 346: 477-481, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25342805/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25342805</a>] [<a href="https://doi.org/10.1126/science.1253585" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25342805">Moreno et al. (2014)</a> presented evidence consistent with the idea that polyubiquitylation of a replisome component, MCM7, leads to its disassembly at the converging terminating forks due to the action of the p97/VCP/CDC48 protein remodeler. Using Xenopus laevis egg extract, the authors showed that blocking polyubiquitylation results in the prolonged association of the active helicase with replicating chromatin. The MCM7 subunit was the only component of the active helicase found to be polyubiquitylated during replication termination. The observed polyubiquitylation was followed by disassembly of the active helicase dependent on p97/VCP. <a href="#30" class="mim-tip-reference" title="Moreno, S. P., Bailey, R., Campion, N., Herron, S., Gambus, A. <strong>Polyubiquitylation drives replisome disassembly at the termination of DNA replication.</strong> Science 346: 477-481, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25342805/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25342805</a>] [<a href="https://doi.org/10.1126/science.1253585" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25342805">Moreno et al. (2014)</a> concluded that their data provided insight into the mechanism of replisome disassembly during eukaryotic DNA replication termination. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25342805" 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="#33" class="mim-tip-reference" title="Olmos, Y., Hodgson, L., Mantell, J., Verkade, P., Carlton, J. G. <strong>ESCRT-III controls nuclear envelope reformation.</strong> Nature 522: 236-239, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26040713/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26040713</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26040713[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature14503" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26040713">Olmos et al. (2015)</a> demonstrated that the endosomal sorting complex required for transport-III (ESCRT-III) machinery localizes to sites of annular fusion in the forming nuclear envelope in human cells, and is necessary for proper postmitotic nucleocytoplasmic compartmentalization. The ESCRT-III component CHMP2A (<a href="/entry/610893">610893</a>) is directed to the forming nuclear envelope through binding to CHMP4B (<a href="/entry/610897">610897</a>), and provides an activity essential for nuclear envelope reformation. Localization also requires the p97 complex (see <a href="/entry/601023">601023</a>) member UFD1. <a href="#33" class="mim-tip-reference" title="Olmos, Y., Hodgson, L., Mantell, J., Verkade, P., Carlton, J. G. <strong>ESCRT-III controls nuclear envelope reformation.</strong> Nature 522: 236-239, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26040713/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26040713</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26040713[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature14503" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26040713">Olmos et al. (2015)</a> concluded that their results described a novel role for the ESCRT machinery in cell division and demonstrated a conservation of the machineries involved in topologically equivalent mitotic membrane remodeling events. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26040713" 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="#43" class="mim-tip-reference" title="van Haaften-Visser, D. Y., Harakalova, M., Mocholi, E., van Montfrans, J. M., Elkadri, A., Rieter, E., Fiedler, K., van Hasselt, P. M., Triffaux, E. M. M., van Haelst, M. M., Nijman, I. J., Kloosterman, W. P., Nieuwenhuis, E. E. S., Muise, A. M., Cuppen, E., Houwen, R. H. J., Coffer, P. J. <strong>Ankyrin repeat and zinc-finger domain-containing 1 mutations are associated with infantile-onset inflammatory bowel disease.</strong> J. Biol. Chem. 292: 7904-7920, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28302725/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28302725</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28302725[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1074/jbc.M116.772038" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28302725">Van Haaften-Visser et al. (2017)</a> found that human VCP interacted with ANKZF1 (<a href="/entry/617541">617541</a>) in the cytoplasm of U2OS osteosarcoma cells and that the complex translocated toward mitochondria following H2O2-induced oxidative stress. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28302725" 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="#51" class="mim-tip-reference" title="Yasuda, S., Tsuchiya, H., Kaiho, A., Guo, Q., Ikeuchi, K., Endo, A., Arai, N., Ohtake, F., Murata, S., Inada, T., Baumeister, W., Fernandez-Busnadiego, R., Tanaka, K., Saeki, Y. <strong>Stress- and ubiquitylation-dependent phase separation of the proteasome.</strong> Nature 578: 296-300, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32025036/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32025036</a>] [<a href="https://doi.org/10.1038/s41586-020-1982-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32025036">Yasuda et al. (2020)</a> demonstrated that proteasome-containing nuclear foci form under acute hyperosmotic stress. These foci are transient structures that contain ubiquitylated proteins, VCP, and multiple proteasome-interacting proteins, which collectively constitute a proteolytic center. The major substrates for degradation by these foci were ribosomal proteins that failed to properly assemble. Notably, the proteasome foci exhibited properties of liquid droplets. RAD23B (<a href="/entry/600062">600062</a>), a substrate-shuttling factor for the proteasome, and ubiquitylated proteins were necessary for formation of proteasome foci. In mechanistic terms, a liquid-liquid phase separation was triggered by multivalent interactions of 2 ubiquitin-associated domains of RAD23B and ubiquitin chains consisting of 4 or more ubiquitin molecules. <a href="#51" class="mim-tip-reference" title="Yasuda, S., Tsuchiya, H., Kaiho, A., Guo, Q., Ikeuchi, K., Endo, A., Arai, N., Ohtake, F., Murata, S., Inada, T., Baumeister, W., Fernandez-Busnadiego, R., Tanaka, K., Saeki, Y. <strong>Stress- and ubiquitylation-dependent phase separation of the proteasome.</strong> Nature 578: 296-300, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32025036/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32025036</a>] [<a href="https://doi.org/10.1038/s41586-020-1982-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32025036">Yasuda et al. (2020)</a> concluded that their results suggested that ubiquitin chain-dependent phase separation induces the formation of a nuclear proteolytic compartment that promotes proteasomal degradation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32025036" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In in vitro studies, <a href="#9" class="mim-tip-reference" title="Darwich, N. F., Phan, J. M., Kim, B., Suh, E., Papatriantafyllou, J. D., Changolkar, L., Nguyen, A. T., O'Rourke, C. M., He, Z., Porta, S., Gibbons, G. S., Luk, K. C., and 10 others. <strong>Autosomal dominant VCP hypomorph mutation impairs disaggregation of PHF-tau.</strong> Science 370: eaay8826, 2020. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33004675/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33004675</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=33004675[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.aay8826" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33004675">Darwich et al. (2020)</a> found that VCP normally acts as a disaggregase for polyubiquitinated phosphorylated pathologic tau fibrils derived from brains of patients with Alzheimer disease (see, e.g., AD, <a href="/entry/104300">104300</a>). This function was ATP- and polyubiquitin-dependent. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33004675" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>By immunoprecipitation and mass spectrometry analyses in HEK293 cells, <a href="#13" class="mim-tip-reference" title="Fielden, J., Wiseman, K., Torrecilla, I., Li, S., Hume, S., Chiang, S. C., Ruggiano, A., Narayan Singh, A., Freire, R., Hassanieh, S., Domingo, E., Vendrell, I., Fischer, R., Kessler, B. M., Maughan, T. S., El-Khamisy, S. F., Ramadan, K. <strong>TEX264 coordinates p97- and SPRTN-mediated resolution of topoisomerase 1-DNA adducts.</strong> Nature Commun. 11: 1274, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32152270/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32152270</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=32152270[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/s41467-020-15000-w" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32152270">Fielden et al. (2020)</a> identified p97 as an interacting partner of TOP1 (<a href="/entry/126420">126420</a>), a protein that regulates DNA topology to ensure efficient DNA replication and transcription. By interacting with TOP1, p97 functioned as a modulator of TOP1 cleavage complex (TOP1cc) repair, as p97 ATPase activity was needed to counteract TOP1cc accumulation in human cells. The authors identified TEX264 (<a href="/entry/620608">620608</a>) as a p97 cofactor. TEX264 simultaneously interacted with p97 and TOP1 to form a complex to bridge recruitment of p97 specifically to TOP1cc. TEX264 knockout caused substantial TOP1cc accumulation, which led to significantly delayed DNA damage repair. This phenotype was similar to that of TDP1 (<a href="/entry/607198">607198</a>) depletion, as TEX264 was epistatic with TDP1 and interacted with TDP1 to promote TOP1cc repair. TEX264 function in TOP1cc repair was mediated by sumoylation. TOP1 was sumoylated, and TEX264, which contains 2 putative SUMO-interacting motifs (SIMs) in its GyrI-like domain, bound to sumoylated TOP1 for its recruitment to TOP1cc. In addition, SPRTN (<a href="/entry/616086">616086</a>), a metalloprotease that proteolytically cleaves TOP1, contributed to TOP1cc repair. TEX264 associated with SPRTN at the nuclear periphery and acted at replication forks. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32152270" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="mim-changed mim-change"><p>By yeast 2-hybrid screen of a human testis cDNA library, <a href="#26" class="mim-tip-reference" title="Korner, M., Meyer, S. R., Marincola, G., Kern, M. J., Grimm, C., Schuelein-Voelk, C., Fischer, U., Hofmann, K., Buchberger, A. <strong>The FAM104 proteins VCF1/2 promote the nuclear localization of p97/VCP.</strong> eLife 12: e92409, 2023.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/37713320/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">37713320</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=37713320[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.7554/eLife.92409" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="37713320">Korner et al. (2023)</a> demonstrated that various isoforms of both VCF1 (<a href="/entry/621109">621109</a>) and VCF2 (<a href="/entry/301141">301141</a>) interacted with p97. Mutation analysis showed that the interaction was mediated by the N domain of p97 and the C-terminal alpha helices of VCF1 and VCF2. VCF1 and VCF2 associated with specific p97 complexes in cells, including p97-UFD1-NPL4 and p97-UBXN2B, but not with all p97 complexes. Ectopic expression of VCF1 or VCF2 increased nuclear p97 levels in HeLa cells, suggesting that VCF proteins target p97 to the nucleus. Moreover, ectopic expression of VCF1 isoforms 1 and 2 induced chromatin binding of p97 in HEK293T cells. In contrast, VCF1/VCF2 double-knockout reduced nuclear p97 levels in HeLa cells, indicating that VCF1 and VCF2 modulate the nucleocytoplasmic distribution of p97. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=37713320" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p></div>
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<div class="mim-changed mim-change"><p>Using pull-down analyses in transfected U2OS cells, <a href="#29" class="mim-tip-reference" title="Mirsanaye, A. S., Hoffmann, S., Weisser, M., Mund, A., Lopez Mendez, B., Typas, D., van den Boom, J., Benedict, B., Hendriks, I. A., Nielsen, M. L., Meyer, H., Duxin, J. P., Montoya, G., Mailand, N. <strong>VCF1 is a p97/VCP cofactor promoting recognition of ubiquitylated p97-UFD1-NPL4 substrates.</strong> Nature Commun. 15: 2459, 2024.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/38503733/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">38503733</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=38503733[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/s41467-024-46760-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="38503733">Mirsanaye et al. (2024)</a> identified VCF1 as a p97-interacting protein. The interaction was direct, tight, and mediated by the p97 N domain and by a distinct motif in the VCF1 C terminus. VCF1 formed joint complexes on p97 hexamers with other p97 cofactors, including UFD1-NPL4. By forming a complex with p97-UFD1-NPL4, VCF1 stimulated p97-UFD1-NPL4 recruitment to ubiquitylated substrates to facilitate their degradation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=38503733" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p></div>
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<p><strong><em>Inclusion Body Myopathy with Paget Disease of Bone and Frontotemporal Dementia</em></strong></p><p>
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<a href="#45" class="mim-tip-reference" title="Watts, G. D. J., Wymer, J., Kovach, M. J., Mehta, S. G., Mumm, S., Darvish, D., Pestronk, A., Whyte, M. P., Kimonis, V. E. <strong>Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia is caused by mutant valosin-containing protein.</strong> Nature Genet. 36: 377-381, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15034582/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15034582</a>] [<a href="https://doi.org/10.1038/ng1332" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15034582">Watts et al. (2004)</a> identified missense mutations in VCP as the cause of inclusion body myopathy with Paget disease of bone and frontotemporal dementia (IBMPFD; <a href="/entry/167320">167320</a>). Ten of 13 families with this disorder had an amino acid change at arginine-155, either to histidine, proline, or cysteine. Arginine-155 of VCP was conserved in homologs through all species examined except in 2 C. elegans homologs, which had glutamine at that position. Arginine-191 was invariant in all species examined, and arginine-95 was substituted by histidine in only 2 species. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15034582" 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="#45" class="mim-tip-reference" title="Watts, G. D. J., Wymer, J., Kovach, M. J., Mehta, S. G., Mumm, S., Darvish, D., Pestronk, A., Whyte, M. P., Kimonis, V. E. <strong>Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia is caused by mutant valosin-containing protein.</strong> Nature Genet. 36: 377-381, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15034582/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15034582</a>] [<a href="https://doi.org/10.1038/ng1332" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15034582">Watts et al. (2004)</a> suggested that since patients with IBMPFD are viable with relatively late onset of disease, the mutations identified do not disrupt the cell cycle or apoptosis pathways. They proposed that mutations in VCP cause Paget disease of bone by compromising ubiquitin binding and target similar cellular pathways or proteins. They suggested that the progressive neuronal degeneration has to do with protein quality control and ubiquitin protein degradation pathways. <a href="#45" class="mim-tip-reference" title="Watts, G. D. J., Wymer, J., Kovach, M. J., Mehta, S. G., Mumm, S., Darvish, D., Pestronk, A., Whyte, M. P., Kimonis, V. E. <strong>Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia is caused by mutant valosin-containing protein.</strong> Nature Genet. 36: 377-381, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15034582/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15034582</a>] [<a href="https://doi.org/10.1038/ng1332" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15034582">Watts et al. (2004)</a> concluded that because IBMPFD is a dominant progressive syndrome, the mutations they identified are probably relatively subtle, and aging, oxidative stress, and endoplasmic reticulum stress probably define a threshold at which the IBMPFD phenotype becomes manifest. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15034582" 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 vitro functional expression studies by <a href="#46" class="mim-tip-reference" title="Weihl, C. C., Dalal, S., Pestronk, A., Hanson, P. I. <strong>Inclusion body myopathy-associated mutations in p97/VCP impair endoplasmic reticulum-associated degradation.</strong> Hum. Molec. Genet. 15: 189-199, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16321991/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16321991</a>] [<a href="https://doi.org/10.1093/hmg/ddi426" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16321991">Weihl et al. (2006)</a> showed that cells transfected with the mutant R155H (<a href="#0001">601023.0001</a>) and R95G (<a href="#0004">601023.0004</a>) proteins developed a prominent increase in diffuse and aggregated ubiquitin conjugates and showed impaired function of ERAD, as well as a distorted ER structure. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16321991" 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 human cells with IBMPFD-associated mutations, <a href="#22" class="mim-tip-reference" title="Ju, J.-S., Miller, S. E., Hanson, P. I., Weihl, C. C. <strong>Impaired protein aggregate handling and clearance underlie the pathogenesis of p97/VCP-associated disease.</strong> J. Biol. Chem. 283: 30289-30299, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18715868/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18715868</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18715868[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1074/jbc.M805517200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18715868">Ju et al. (2008)</a> found that treatment with a proteasome inhibitor resulted in increased cell death and an increase in perinuclear ubiquitinated proteins, but no clear aggresomes, compared to wildtype. Expression of an aggregate protein in mutant cells did not result in proper formation of inclusion bodies or aggresomes. A similar lack of inclusion body formation was observed in mutant mouse muscle fibers in vivo. Further studies showed that mutant VCP trapped aggregated proteins but failed to release them to aggresomes or inclusion bodies. This was reversed upon coexpression with HDAC6 (<a href="/entry/300272">300272</a>), a VCP-binding protein that facilitates formation of aggresomes. <a href="#22" class="mim-tip-reference" title="Ju, J.-S., Miller, S. E., Hanson, P. I., Weihl, C. C. <strong>Impaired protein aggregate handling and clearance underlie the pathogenesis of p97/VCP-associated disease.</strong> J. Biol. Chem. 283: 30289-30299, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18715868/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18715868</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18715868[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1074/jbc.M805517200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18715868">Ju et al. (2008)</a> concluded that mutations in the VCP gene impaired the proper clearance of aggregated proteins. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18715868" 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>Frontotemporal Dementia and/or Amyotrophic Lateral Sclerosis 5</em></strong></p><p>
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Using exome sequencing, <a href="#21" class="mim-tip-reference" title="Johnson, J. O., Mandrioli, J., Benatar, M., Abramzon, Y., Van Deerlin, V. M., Trojanowski, J. Q., Gibbs, J. R., Brunetti, M., Gronka, S., Wuu, J., Ding, J., McCluskey, L., and 25 others. <strong>Exome sequencing reveals VCP mutations as a cause of familial ALS.</strong> Neuron 68: 857-864, 2010. Note: Erratum: Neuron 69: 397 only, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21145000/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21145000</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21145000[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.neuron.2010.11.036" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21145000">Johnson et al. (2010)</a> identified a heterozygous mutation in the VCP gene (R191Q; <a href="#0006">601023.0006</a>) in 4 affected members of an Italian family with frontotemporal dementia and/or amyotrophic lateral sclerosis-6 (FTDALS6; <a href="/entry/613954">613954</a>). Screening of the VCP gene in 210 familial ALS cases and 78 autopsy-proven ALS cases identified 3 additional pathogenic VCP mutations (<a href="#0001">601023.0001</a>, <a href="/entry/601012#0008">601012.0008</a>, and <a href="#0009">601023.0009</a>) in 4 patients. The findings expanded the phenotype associated with VCP mutations to include classic ALS. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21145000" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 3 unrelated adult Dutch patients with the behavioral variant of FTD without signs of myopathy or motor neuron disease (<a href="/entry/613954">613954</a>), <a href="#50" class="mim-tip-reference" title="Wong, T. H., Pottier, C., Hondius, D. C., Meeter, L. H. H., van Rooij, J. G. J., Melhem, S., The Netherlands Brain bank, van Minkelen, R., van Duijn, C. M., Rozemuller, A. J. M., Seelaar, H., Rademakers, R., van Swieten, J. C. <strong>Three VCP mutations in patients with frontotemporal dementia.</strong> J. Alzheimers Dis. 65: 1139-1146, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30103325/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30103325</a>] [<a href="https://doi.org/10.3233/JAD-180301" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30103325">Wong et al. (2018)</a> identified heterozygous missense mutations in the VCP gene (R159S, <a href="#0013">601023.0013</a>, T262S, and M158V). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, were not present in the gnomAD database. Functional studies of the variants were not performed. Postmortem examination of 2 patients (patients 2 and 3) showed prominent frontal atrophy with neuronal loss and gliosis, as well as neuronal intranuclear inclusions (NII), short dystrophic neurites (DN), and positive immunostaining for TDP43 and p62 (SQSTM1; <a href="/entry/601530">601530</a>). A few hyperphosphorylated tau (MAPT; <a href="/entry/157140">157140</a>) deposits without amyloid plaques were observed in 1 patient, and several amyloid plaques were observed in the other patient. Rare NII showed VCP-positive immunostaining. The pathologic findings were consistent with FTLD-TDP subtype D, although the severity and distribution of the pathologic findings varied somewhat between the 2 patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30103325" 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 4 adult patients from 2 unrelated families with the behavioral variant of FTD without signs of myopathy, bone disease, or motor neuron disease, <a href="#9" class="mim-tip-reference" title="Darwich, N. F., Phan, J. M., Kim, B., Suh, E., Papatriantafyllou, J. D., Changolkar, L., Nguyen, A. T., O'Rourke, C. M., He, Z., Porta, S., Gibbons, G. S., Luk, K. C., and 10 others. <strong>Autosomal dominant VCP hypomorph mutation impairs disaggregation of PHF-tau.</strong> Science 370: eaay8826, 2020. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33004675/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33004675</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=33004675[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.aay8826" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33004675">Darwich et al. (2020)</a> identified the same heterozygous missense mutation in (D395G; <a href="#0014">601023.0014</a>). The substitution occurred at a conserved residue in the lid subdomain of the D1 ATPase domain. The mutation, which was found by targeted, whole-exome, or whole-genome sequencing, segregated with the disorder in both families. It was not present in the gnomAD database. Neuropathologic examination of 1 patient showed frontal atrophy, neuronal vacuolization, and abundant phosphorylated tau (MAPT; <a href="/entry/157140">157140</a>) aggregates identical to neurofibrillary tangles (NFT) observed in patients with Alzheimer disease (see, e.g., AD, <a href="/entry/104300">104300</a>). MAPT mutations were absent in both families. The distribution of the vacuoles and NFTs were inversely related: vacuoles were more prominent in the occipital cortex, which showed minimal neurodegeneration, whereas NFTs were more prominent in frontal regions and other areas that showed cerebral atrophy, neuronal loss, and reactive gliosis. TDP43 (<a href="/entry/605078">605078</a>), beta-amyloid (APP; <a href="/entry/104760">104760</a>), SNCA (<a href="/entry/163890">163890</a>), and prion protein (PRNP; <a href="/entry/176640">176640</a>) aggregates were not observed. The pathologic tau distribution was confirmed by brain imaging studies. In vitro functional expression studies showed that the D395G mutation resulted in decreased ATPase activity with a 30% reduction in maximum enzyme velocity compared to controls, which was consistent with a hypomorphic mutation. Additional in vitro studies showed that VCP normally acts as a disaggregase for polyubiquitinated phosphorylated pathologic tau fibrils derived from brains of patients with Alzheimer disease. Cells with the D395G mutation had increased intracellular tau aggregates, suggesting that this specific mutation impairs the turnover of pathologic tau aggregates, resulting in neurodegeneration. Transgenic mice expressing this mutation showed similar pathologic tau accumulation when seeded with AD-derived tau (see ANIMAL MODEL). <a href="#9" class="mim-tip-reference" title="Darwich, N. F., Phan, J. M., Kim, B., Suh, E., Papatriantafyllou, J. D., Changolkar, L., Nguyen, A. T., O'Rourke, C. M., He, Z., Porta, S., Gibbons, G. S., Luk, K. C., and 10 others. <strong>Autosomal dominant VCP hypomorph mutation impairs disaggregation of PHF-tau.</strong> Science 370: eaay8826, 2020. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33004675/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33004675</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=33004675[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.aay8826" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33004675">Darwich et al. (2020)</a> emphasized the distinct pathogenetic mechanism associated with this mutation, and named this disease 'vacuolar tauopathy' (VT). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33004675" 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="#40" class="mim-tip-reference" title="Tyzack, G. E., Luisier, R., Taha, D. M., Neeves, J., Modic, M., Mitchell, J. S., Meyer, I., Greensmith, L., Newcombe, J., Ule, J., Luscombe, N. M., Patani, R. <strong>Widespread FUS mislocalization is a molecular hallmark of amyotrophic lateral sclerosis.</strong> Brain 142: 2572-2580, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31368485/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31368485</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31368485[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/brain/awz217" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31368485">Tyzack et al. (2019)</a> examined motor neurons derived from 2 human induced pluripotent stem cell (iPSC) lines with different heterozygous VCP mutations (R155C, <a href="#0002">601023.0002</a> and R191Q, <a href="#0006">601023.0006</a>) and identified a decrease in the nuclear to cytoplasmic localization of the FUS (<a href="/entry/137070">137070</a>) protein during motor neuron differentiation compared to controls. <a href="#40" class="mim-tip-reference" title="Tyzack, G. E., Luisier, R., Taha, D. M., Neeves, J., Modic, M., Mitchell, J. S., Meyer, I., Greensmith, L., Newcombe, J., Ule, J., Luscombe, N. M., Patani, R. <strong>Widespread FUS mislocalization is a molecular hallmark of amyotrophic lateral sclerosis.</strong> Brain 142: 2572-2580, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31368485/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31368485</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31368485[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/brain/awz217" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31368485">Tyzack et al. (2019)</a> also identified a reduction in the nuclear to cytoplasmic localization of the FUS protein in motor neurons from the ventral spinal cord of transgenic mice with a heterozygous mutation in the VCP gene (A232E; <a href="#0003">601023.0003</a>). This reduction was not seen in mice with a SOD1 (<a href="/entry/147450">147450</a>) G93A mutation, where FUS remained in the nucleus. <a href="#40" class="mim-tip-reference" title="Tyzack, G. E., Luisier, R., Taha, D. M., Neeves, J., Modic, M., Mitchell, J. S., Meyer, I., Greensmith, L., Newcombe, J., Ule, J., Luscombe, N. M., Patani, R. <strong>Widespread FUS mislocalization is a molecular hallmark of amyotrophic lateral sclerosis.</strong> Brain 142: 2572-2580, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31368485/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31368485</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31368485[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/brain/awz217" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31368485">Tyzack et al. (2019)</a> next identified evidence for nuclear to cytoplasmic FUS mislocalization in postmortem spinal cord tissue from individuals with sporadic ALS compared to controls. After identifying RNA binding targets of the FUS protein, <a href="#40" class="mim-tip-reference" title="Tyzack, G. E., Luisier, R., Taha, D. M., Neeves, J., Modic, M., Mitchell, J. S., Meyer, I., Greensmith, L., Newcombe, J., Ule, J., Luscombe, N. M., Patani, R. <strong>Widespread FUS mislocalization is a molecular hallmark of amyotrophic lateral sclerosis.</strong> Brain 142: 2572-2580, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31368485/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31368485</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31368485[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/brain/awz217" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31368485">Tyzack et al. (2019)</a> found that the FUS protein bound extensively to an aberrantly retained intron 9 within the SFPQ (<a href="/entry/605199">605199</a>) transcript. This aberrant SFPQ transcript was increased in the human iPSC cell lines with the heterozygous VCP mutations compared to controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31368485" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#15" class="mim-tip-reference" title="Harley, J., Hagemann, C., Serio, A., Patani, R. <strong>FUS is lost from nuclei and gained in neurites of motor neurons in a human stem cell model of VCP-related ALS. (Letter)</strong> Brain 143: e103, 2020. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33253377/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33253377</a>] [<a href="https://doi.org/10.1093/brain/awaa339" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33253377">Harley et al. (2020)</a> identified a decreased nuclear to cytoplasmic ratio of FUS in highly enriched spinal motor neurons that were derived from human iPSC cell lines with heterozygous VCP mutations. This mislocalization of FUS extended to the neuronal processes. <a href="#15" class="mim-tip-reference" title="Harley, J., Hagemann, C., Serio, A., Patani, R. <strong>FUS is lost from nuclei and gained in neurites of motor neurons in a human stem cell model of VCP-related ALS. (Letter)</strong> Brain 143: e103, 2020. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33253377/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33253377</a>] [<a href="https://doi.org/10.1093/brain/awaa339" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33253377">Harley et al. (2020)</a> hypothesized that the nuclear loss of the FUS protein may impair its role in pre-mRNA splicing and play a role in neurodegeneration. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33253377" 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>Charcot-Marie-Tooth Disease Type 2Y</em></strong></p><p>
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In 5 affected members of a family with autosomal dominant axonal Charcot-Marie-Tooth disease type 2Y (CMT2Y; <a href="/entry/616687">616687</a>), <a href="#14" class="mim-tip-reference" title="Gonzalez, M. A., Feely, S. M., Speziani, F., Strickland, A. V., Danzi, M., Bacon, C., Lee, Y., Chou, T.-F., Blanton, S. H., Weihl, C. C., Zuchner, S., Shy, M. E. <strong>A novel mutation in VCP causes Charcot-Marie-Tooth type 2 disease.</strong> Brain 137: 2897-2902, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25125609/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25125609</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25125609[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/brain/awu224" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25125609">Gonzalez et al. (2014)</a> identified a heterozygous missense mutation in the VCP gene (E185K; <a href="#0010">601023.0010</a>). The mutation, which was found by whole-exome sequencing, segregated with the disorder in the family. In vitro functional expression studies showed that the variant impaired autophagic function of VCP, leading to the accumulation of immature autophagosomes. ATPase function of the variant was normal. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25125609" 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>Functional Effects of VCP Mutations</em></strong></p><p>
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<a href="#6" class="mim-tip-reference" title="Cloutier, P., Lavallee-Adam, M., Faubert, D., Blanchette, M., Coulombe, B. <strong>A newly uncovered group of distantly related lysine methyltransferases preferentially interact with molecular chaperones to regulate their activity.</strong> PLoS Genet. 9: e1003210, 2013. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23349634/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23349634</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23349634[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1371/journal.pgen.1003210" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23349634">Cloutier et al. (2013)</a> found that the R155H (<a href="#0001">601023.0001</a>), R159H (<a href="#0007">601023.0007</a>), and R191Q (<a href="#0006">601023.0006</a>) mutations in VCP did not alter in vitro methylation of VCP by METTL21D. However, ASPSRC1 did not enhance methylation of VCP containing these mutations, as it did with wildtype VCP. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23349634" 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="#28" class="mim-tip-reference" title="Mehta, S. G., Khare, M., Ramani, R., Watts, G. D. J., Simon, M., Osann, K. E., Donkervoort, S., Dec, E., Nalbandian, A., Platt, J., Pasquali, M., Wang, A., Mozaffar, T., Smith, C. D., Kimonis, V. E. <strong>Genotype-phenotype studies of VCP-associated inclusion body myopathy with Paget disease of bone and/or frontotemporal dementia.</strong> Clin. Genet. 83: 422-431, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22909335/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22909335</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22909335[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1111/cge.12000" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22909335">Mehta et al. (2013)</a> analyzed clinical and biochemical markers from a database of 190 individuals from 27 families harboring 10 missense mutations in the VCP gene. Among these, 145 mutation carriers were symptomatic and 45 were presymptomatic. The most common clinical feature (in 91% of patients) was onset of myopathic weakness at a mean age of 43 years. Paget disease of the bone was found in 52% of patients at a mean age of 41 years. Frontotemporal dementia occurred in 30% of patients at a mean age of 55 years. Significant genotype-phenotype correlations were difficult to establish because of small numbers. However, patients with the R155C mutation (<a href="#0002">601023.0002</a>) had a more severe phenotype with an earlier onset of myopathy and Paget disease, as well as decreased survival, compared to those with the R155H mutation (<a href="#0001">601023.0001</a>). A diagnosis of ALS was found in at least 13 (8.9%) individuals from the 27 families, including 10 patients with the R155H mutation, and 5 (3%) patients were diagnosed with Parkinson disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22909335" 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="#2" class="mim-tip-reference" title="Al-Obeidi, E., Al-Tahan, S., Surampalli, A., Goyal, N., Wang, A. K., Hermann, A., Omizo, M., Smith, C., Mozaffar, T., Kimonis, V. <strong>Genotype-phenotype study in patients with valosin-containing protein mutations associated with multisystem proteinopathy.</strong> Clin. Genet. 93: 119-125, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28692196/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28692196</a>] [<a href="https://doi.org/10.1111/cge.13095" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28692196">Al-Obeidi et al. (2018)</a> studied 231 individuals from 36 families carrying 15 different heterozygous VCP mutations. Of these individuals, 187 were clinically symptomatic and 44 were presymptomatic carriers. The cohort of patients were of various ethnicities, including European, Brazilian, Hispanic/Apache, and an African-American. Most (90%) of symptomatic patients presented with myopathy at a mean age of 43 years (range, 20-70 years). Paget disease of bone was identified in 42% of patients with a mean age at onset of 41 years (range, 23-65 years), and dementia was diagnosed in 29.4% of patients at a mean age of 55.9 years (range, 30-80 years). When possible to ascertain, the dementia included sociobehavioral and language changes, as well as loss of executive function. Sixteen (8.6%) of patients were diagnosed with ALS associated with upper and lower motor neuron degeneration. Some patients were diagnosed with Parkinson disease (3.8%) or Alzheimer disease (2.1%). Although VCP mutations are associated with a triad of symptoms, only 10% of patients had all 3 features of myopathy, bone disease, and dementia. After stratification by mutation type, there were no apparent genotype/phenotype correlations, although the R159C mutation was associated with a slightly later age at onset of myopathy (57 years) compared to other mutations. Functional studies of the variants were not performed. The authors emphasized the enormous phenotypic heterogeneity both between and within families. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28692196" 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="#37" class="mim-tip-reference" title="Schiava, M., Ikenaga, C., Villar-Quiles, R. N., Caballero-Avila, M., Topf, A., Nishino, I., Kimonis, V., Udd, B., Schoser, B., Zanoteli, E., Souza, P. V. S., Tasca, G., and 49 others. <strong>Genotype-phenotype correlations in valosin-containing protein disease: a retrospective muticentre study.</strong> J. Neurol. Neurosurg. Psychiat. 27July, 2022. Note: Advance Electronic Publication.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35896379/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35896379</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=35896379[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1136/jnnp-2022-328921" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="35896379">Schiava et al. (2022)</a> reported clinical and genetic data on 234 symptomatic patients (70% male) from 194 families from 24 countries with mutations in the VCP gene. Only 7 patients (2.9%) had the classic triad of myopathy, bone disease, and dementia. Muscle weakness affecting both proximal or distal muscles of the lower and/or upper limbs was the first symptom in 90.7% of patients and was present in all but 1 patient at last assessment. Paget disease of bone occurred in 28.2%, dysautonomia in 21.2%, lower motor neuron signs in 21.2%, and frontotemporal dementia in 14.3%. Of 57 identified variants, 4 (R155H, <a href="#0001">601023.0001</a>; R155C, <a href="#0002">601023.0002</a>; R159H, <a href="#0007">601023.0007</a>; and R93C) accounted for 54.7% of the patients. Exons 5 and 3 represented hotspots. All but one of the mutations were missense. No mutations were exclusively associated with specific mutations, but R155C, which occurred more frequently in females, showed a more severe phenotype with an earlier onset. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=35896379" 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="#47" class="mim-tip-reference" title="Weihl, C. C., Miller, S. E., Hanson, P. I., Pestronk, A. <strong>Transgenic expression of inclusion body myopathy associated mutant p97/VCP causes weakness and ubiquitinated protein inclusions in mice.</strong> Hum. Molec. Genet. 16: 919-928, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17329348/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17329348</a>] [<a href="https://doi.org/10.1093/hmg/ddm037" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17329348">Weihl et al. (2007)</a> found that transgenic mice overexpressing the R155H mutation became progressively weaker in a dose-dependent manner starting at 6 months of age. There was abnormal muscle pathology, with coarse internal architecture, vacuolation, and disorganized membrane morphology with reduced caveolin-3 (CAV3; <a href="/entry/601253">601253</a>) expression at the sarcolemma. Even before animals displayed measurable weakness, there was an increase in ubiquitin-containing protein inclusions and high molecular weight ubiquitinated proteins. These findings suggested a dysregulation in protein degradation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17329348" 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="#8" class="mim-tip-reference" title="Custer, S. K., Neumann, M., Lu, H., Wright, A. C., Taylor, J. P. <strong>Transgenic mice expressing mutant forms VCP/p97 recapitulate the full spectrum of IBMPFD including degeneration in muscle, brain and bone.</strong> Hum. Molec. Genet. 19: 1741-1755, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20147319/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20147319</a>] [<a href="https://doi.org/10.1093/hmg/ddq050" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20147319">Custer et al. (2010)</a> developed and characterized transgenic mice with ubiquitous expression of wildtype and disease-causing versions of human VCP/p97. Mice expressing VCP/p97 harboring the mutations R155H (<a href="#0001">601023.0001</a>) or A232E (<a href="#0003">601023.0003</a>) exhibited progressive muscle weakness, and developed inclusion body myopathy including rimmed vacuoles and TDP43 (<a href="/entry/605078">605078</a>) pathology. The brain showed widespread TDP43 pathology, and the skeleton exhibited severe osteopenia accompanied by focal lytic and sclerotic lesions in vertebrae and femur. In vitro studies indicated that mutant VCP caused inappropriate activation of the NF-kappa-B (see <a href="/entry/164011">164011</a>) signaling cascade, which could contribute to the mechanism of pathogenesis in multiple tissues including muscle, bone, and brain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20147319" 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="#9" class="mim-tip-reference" title="Darwich, N. F., Phan, J. M., Kim, B., Suh, E., Papatriantafyllou, J. D., Changolkar, L., Nguyen, A. T., O'Rourke, C. M., He, Z., Porta, S., Gibbons, G. S., Luk, K. C., and 10 others. <strong>Autosomal dominant VCP hypomorph mutation impairs disaggregation of PHF-tau.</strong> Science 370: eaay8826, 2020. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33004675/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33004675</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=33004675[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.aay8826" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33004675">Darwich et al. (2020)</a> found that transgenic mice expressing the VCP D395G (<a href="#0014">601023.0014</a>) mutation did not spontaneously develop a neurodegenerative phenotype and their brains did not show abnormal tau (MAPT; <a href="/entry/157140">157140</a>) accumulation. However, when stimulated with pathologic tau derived from patients with Alzheimer disease (see, e.g., AD; <a href="/entry/104300">104300</a>), transgenic mice had accumulation of pathologic tau aggregates in several brain regions. The findings suggested that neurons with this VCP mutation have increased susceptibility to pathologic tau aggregation under certain circumstances, resulting in downstream neurodegeneration. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33004675" 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 mass spectroscopy analysis, <a href="#49" class="mim-tip-reference" title="Weiss, L., Jung, K.-M., Nalbandian, A., Llewellyn, K., Yu, H., Ta, L., Chang, I., Migliore, M., Squire, E., Ahmed, F., Piomelli, D., Kimonis, V. <strong>Ceramide contributes to pathogenesis and may be targeted for therapy in VCP inclusion body myopathy.</strong> Hum. Molec. Genet. 29: 3945-3953, 2020. Note: Erratum: Hum. Molec. Genet. 33: 1020 only, 2024.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33410456/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33410456</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=33410456[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddaa248" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33410456">Weiss et al. (2020)</a> showed that ceramide levels were elevated in primary myoblasts from both mice homozygous for the Vcp R155H mutation and patients with VCP disease. Treatment with exogenous ceramide stimulated autophagy, a key feature of VCP disease pathology, in myoblasts from mice homozygous for the Vcp R155H mutation. Inhibition of ceramide biosynthesis mitigated VCP-associated autophagy and TDP43 pathology in patient myoblasts derived from induced pluripotent stem cells (iPSCs). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33410456" 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 purified recombinant proteins, <a href="#20" class="mim-tip-reference" title="Johnson, A. E., Orr, B. O., Fetter, R. D., Moughamian, A. J., Primeaux, L. A., Geier, E. G., Yokoyama, J. S., Miller, B. L., Davis, G. W. <strong>SVIP is a molecular determinant of lysosomal dynamic stability, neurodegeneration and lifespan.</strong> Nature Commun. 12: 513, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33479240/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33479240</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=33479240[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/s41467-020-20796-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33479240">Johnson et al. (2021)</a> showed that Drosophila Svip bound Vcp. Svip localized to lysosome tubules distributed throughout the cytosol. By binding Vcp, Svip recruited Vcp to tubular lysosomes in Drosophila. Knockout analysis revealed that Svip-dependent Vcp recruitment was essential to stabilize lysosomal structure and function in Drosophila. Synthetic recruitment of Vcp to lysosomes in Svip-knockout Drosophila was sufficient to enhance stability of a dynamic lysosomal network. Further analysis demonstrated that Svip functioned in muscle, affecting organismal motility and lifespan of Drosophila. Svip-knockout Drosophila displayed age-related muscle defects, and ultrastructural visualization showed muscle wasting in Svip-knockout Drosophila that could be rescued by muscle Svip expression. Using a biochemical screen, the authors identified a disease-causing pro134-to-leu (P134L) mutation in Vcp that impaired Svip binding and the lysosomal network in muscle in Drosophila. The Vcp P134L mutant protein aggregated in an age-dependent manner and caused muscle degeneration, mirroring many of the phenotypes in Svip-knockout Drosophila. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33479240" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In 7 of 13 families with autosomal dominant inclusion body myopathy with early-onset Paget disease and frontotemporal dementia (IBMPFD1; <a href="/entry/167320">167320</a>), <a href="#45" class="mim-tip-reference" title="Watts, G. D. J., Wymer, J., Kovach, M. J., Mehta, S. G., Mumm, S., Darvish, D., Pestronk, A., Whyte, M. P., Kimonis, V. E. <strong>Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia is caused by mutant valosin-containing protein.</strong> Nature Genet. 36: 377-381, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15034582/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15034582</a>] [<a href="https://doi.org/10.1038/ng1332" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15034582">Watts et al. (2004)</a> identified a G-to-A transition at nucleotide 464 of the VCP gene, resulting in an arg155-to-his substitution (R155H). This mutation appears to have arisen independently on several haplotype backgrounds. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15034582" 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="#44" class="mim-tip-reference" title="Viassolo, V., Previtali, S. C., Schiatti, E., Magnani, G., Minetti, C., Zara, F., Grasso, M., Dagna-Bricarelli, F., Di Maria, E. <strong>Inclusion body myopathy, Paget's disease of the bone and frontotemporal dementia: recurrence of the VCP R155H mutation in an Italian family and implications for genetic counselling.</strong> Clin. Genet. 74: 54-60, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18341608/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18341608</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2008.00984.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18341608">Viassolo et al. (2008)</a> identified heterozygosity for the R155H mutation in 3 affected members of an Italian family with IBMPFD. All 3 had progressive inclusion body myopathy and rapidly progressive severe dementia, but only 1 developed Paget disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18341608" 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 vitro functional expression studies by <a href="#46" class="mim-tip-reference" title="Weihl, C. C., Dalal, S., Pestronk, A., Hanson, P. I. <strong>Inclusion body myopathy-associated mutations in p97/VCP impair endoplasmic reticulum-associated degradation.</strong> Hum. Molec. Genet. 15: 189-199, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16321991/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16321991</a>] [<a href="https://doi.org/10.1093/hmg/ddi426" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16321991">Weihl et al. (2006)</a> showed that R155H-mutant protein properly assembled into a hexameric structure and showed normal ATPase activity. Cell transfected with the mutant protein showed a prominent increase in diffuse and aggregated ubiquitin conjugates and impaired function of endoplasmic reticulum-associated degradation (ERAD), as well as a distorted ER structure. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16321991" 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="#21" class="mim-tip-reference" title="Johnson, J. O., Mandrioli, J., Benatar, M., Abramzon, Y., Van Deerlin, V. M., Trojanowski, J. Q., Gibbs, J. R., Brunetti, M., Gronka, S., Wuu, J., Ding, J., McCluskey, L., and 25 others. <strong>Exome sequencing reveals VCP mutations as a cause of familial ALS.</strong> Neuron 68: 857-864, 2010. Note: Erratum: Neuron 69: 397 only, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21145000/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21145000</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21145000[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.neuron.2010.11.036" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21145000">Johnson et al. (2010)</a> identified heterozygosity for the R155H mutation, which they stated resulted from an 853G-A transition in exon 5, in a member of the family reported by <a href="#45" class="mim-tip-reference" title="Watts, G. D. J., Wymer, J., Kovach, M. J., Mehta, S. G., Mumm, S., Darvish, D., Pestronk, A., Whyte, M. P., Kimonis, V. E. <strong>Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia is caused by mutant valosin-containing protein.</strong> Nature Genet. 36: 377-381, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15034582/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15034582</a>] [<a href="https://doi.org/10.1038/ng1332" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15034582">Watts et al. (2004)</a>. However, the family member reported by <a href="#21" class="mim-tip-reference" title="Johnson, J. O., Mandrioli, J., Benatar, M., Abramzon, Y., Van Deerlin, V. M., Trojanowski, J. Q., Gibbs, J. R., Brunetti, M., Gronka, S., Wuu, J., Ding, J., McCluskey, L., and 25 others. <strong>Exome sequencing reveals VCP mutations as a cause of familial ALS.</strong> Neuron 68: 857-864, 2010. Note: Erratum: Neuron 69: 397 only, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21145000/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21145000</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21145000[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.neuron.2010.11.036" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21145000">Johnson et al. (2010)</a> had classic ALS (FTDALS6; <a href="/entry/613954">613954</a>) without evidence of Paget disease, myopathy, or frontotemporal dementia. Postmortem examination of this patient showed loss of brainstem and spinal cord motor neurons with Bunina bodies in surviving neurons, TDP43 (TARDBP; <a href="/entry/605078">605078</a>)-positive immunostaining, and mild pallor of the lateral descending corticospinal tracts, all features consistent with diagnosis of ALS. The findings expanded the phenotype associated with VCP mutations, even within a single family. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15034582+21145000" 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">rs121909330 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121909330;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=rs121909330" 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=rs121909330" 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=RCV000008990 OR RCV000372207 OR RCV000685660 OR RCV001095424" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000008990, RCV000372207, RCV000685660, RCV001095424" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000008990...</a>
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<p>In 2 of 13 families with autosomal dominant inclusion body myopathy with early-onset Paget disease and frontotemporal dementia (IBMPFD1; <a href="/entry/167320">167320</a>), <a href="#45" class="mim-tip-reference" title="Watts, G. D. J., Wymer, J., Kovach, M. J., Mehta, S. G., Mumm, S., Darvish, D., Pestronk, A., Whyte, M. P., Kimonis, V. E. <strong>Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia is caused by mutant valosin-containing protein.</strong> Nature Genet. 36: 377-381, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15034582/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15034582</a>] [<a href="https://doi.org/10.1038/ng1332" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15034582">Watts et al. (2004)</a> identified a C-to-T transition at nucleotide 463 of the VCP gene, resulting in an arg155-to-cys substitution (R155C). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15034582" 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="#23" class="mim-tip-reference" title="Kim, E.-J., Park, Y.-E., Kim, D.-S., Ahn, B.-Y., Kim, H.-S., Chang, Y. H., Kim, S.-J,, Kim, H.-J., Lee, H.-W., Seeley, W. W., Kim, S. <strong>Inclusion body myopathy with Paget disease of bone and frontotemporal dementia linked to VCP p.Arg155Cys in a Korean family.</strong> Arch. Neurol. 68: 787-796, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21320982/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21320982</a>] [<a href="https://doi.org/10.1001/archneurol.2010.376" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21320982">Kim et al. (2011)</a> identified a heterozygous R155C mutation in 3 Korean sibs with IBMPFD. The proband developed progressive dementia presenting as fluent aphasia and language difficulties with onset at age 47. She never developed myopathy, but did develop asymptomatic Paget disease with increased serum alkaline phosphatase and lytic bone lesions on imaging. Her brother developed slowly progressive proximal muscle weakness at age 50, followed by frontotemporal dementia characterized initially by comprehension defects at age 54. He never had Paget disease, although serum alkaline phosphatase was increased. A second brother developed muscle weakness at age 47, followed by Paget disease at age 53, and dementia at age 61. Brain MRI in all patients showed asymmetric atrophy in the anterior inferior and lateral temporal lobes and inferior parietal lobule with ventricular dilatation on the affected side (2 on the left, 1 on the right). Two had glucose hypometabolism in the lateral temporal and inferior parietal areas, with less involvement of the anterior temporal and frontal lobes compared to those with typical semantic dementia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21320982" 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>.0003 INCLUSION BODY MYOPATHY WITH EARLY-ONSET PAGET DISEASE AND FRONTOTEMPORAL DEMENTIA 1</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121909331 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121909331;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=rs121909331" 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=rs121909331" 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=RCV000008991 OR RCV001172005" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000008991, RCV001172005" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000008991...</a>
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<p>In 1 of 13 families with autosomal dominant inclusion body myopathy with early-onset Paget disease and frontotemporal dementia (IBMPFD1; <a href="/entry/167320">167320</a>), <a href="#45" class="mim-tip-reference" title="Watts, G. D. J., Wymer, J., Kovach, M. J., Mehta, S. G., Mumm, S., Darvish, D., Pestronk, A., Whyte, M. P., Kimonis, V. E. <strong>Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia is caused by mutant valosin-containing protein.</strong> Nature Genet. 36: 377-381, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15034582/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15034582</a>] [<a href="https://doi.org/10.1038/ng1332" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15034582">Watts et al. (2004)</a> identified a C-to-A transversion at nucleotide 695 of the VCP gene, resulting in an ala-to-glu change at codon 232 (A232E). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15034582" 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>.0004 INCLUSION BODY MYOPATHY WITH EARLY-ONSET PAGET DISEASE AND FRONTOTEMPORAL DEMENTIA 1</strong>
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VCP, ARG95GLY
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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> rs121909332 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121909332;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/rs121909332?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=rs121909332" 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=rs121909332" 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=RCV000008992" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000008992" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000008992</a>
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<p>In 1 of 13 families with autosomal dominant inclusion body myopathy with early-onset Paget disease and frontotemporal dementia (IBMPFD1; <a href="/entry/167320">167320</a>), <a href="#45" class="mim-tip-reference" title="Watts, G. D. J., Wymer, J., Kovach, M. J., Mehta, S. G., Mumm, S., Darvish, D., Pestronk, A., Whyte, M. P., Kimonis, V. E. <strong>Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia is caused by mutant valosin-containing protein.</strong> Nature Genet. 36: 377-381, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15034582/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15034582</a>] [<a href="https://doi.org/10.1038/ng1332" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15034582">Watts et al. (2004)</a> identified a C-to-G transversion at nucleotide 283 of the VCP gene, resulting in an arg-to-gly substitution at codon 95 (R95G). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15034582" 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 vitro functional expression studies by <a href="#46" class="mim-tip-reference" title="Weihl, C. C., Dalal, S., Pestronk, A., Hanson, P. I. <strong>Inclusion body myopathy-associated mutations in p97/VCP impair endoplasmic reticulum-associated degradation.</strong> Hum. Molec. Genet. 15: 189-199, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16321991/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16321991</a>] [<a href="https://doi.org/10.1093/hmg/ddi426" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16321991">Weihl et al. (2006)</a> showed that cells transfected with R95G-mutant protein developed a prominent increased in diffuse and aggregated ubiquitin conjugates and impaired function of endoplasmic reticulum-associated degradation (ERAD), as well as a distorted ER structure. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16321991" 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 INCLUSION BODY MYOPATHY WITH EARLY-ONSET PAGET DISEASE AND FRONTOTEMPORAL DEMENTIA 1</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121909329 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121909329;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=rs121909329" 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=rs121909329" 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=RCV000008993 OR RCV001387337 OR RCV003137504" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000008993, RCV001387337, RCV003137504" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000008993...</a>
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<p>In 1 of 13 families with autosomal dominant inclusion body myopathy with early-onset Paget disease and frontotemporal dementia (IBMPFD1; <a href="/entry/167320">167320</a>), <a href="#45" class="mim-tip-reference" title="Watts, G. D. J., Wymer, J., Kovach, M. J., Mehta, S. G., Mumm, S., Darvish, D., Pestronk, A., Whyte, M. P., Kimonis, V. E. <strong>Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia is caused by mutant valosin-containing protein.</strong> Nature Genet. 36: 377-381, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15034582/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15034582</a>] [<a href="https://doi.org/10.1038/ng1332" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15034582">Watts et al. (2004)</a> identified a G-to-C transversion at nucleotide 464 of the VCP gene, resulting in an arg-to-pro substitution at codon 155 (R155P). This family was originally reported by <a href="#38" class="mim-tip-reference" title="Tucker, W. S., Jr., Hubbard, W. H., Stryker, T. D., Morgan, S. W., Evans, O. B., Freemon, F. R., Theil, G. B. <strong>A new familial disorder of combined lower motor neuron degeneration and skeletal disorganization.</strong> Trans. Assoc. Am. Phys. 95: 126-134, 1982.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7182974/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7182974</a>]" pmid="7182974">Tucker et al. (1982)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7182974+15034582" 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 INCLUSION BODY MYOPATHY WITH EARLY-ONSET PAGET DISEASE AND FRONTOTEMPORAL DEMENTIA 1</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121909334 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121909334;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/rs121909334?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=rs121909334" 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=rs121909334" 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=RCV000008994 OR RCV000023064 OR RCV000516636 OR RCV000555373 OR RCV002496309" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000008994, RCV000023064, RCV000516636, RCV000555373, RCV002496309" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000008994...</a>
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<p>In 1 of 13 families with autosomal dominant inclusion body myopathy with early-onset Paget disease and frontotemporal dementia (IBMPFD1; <a href="/entry/167320">167320</a>), <a href="#45" class="mim-tip-reference" title="Watts, G. D. J., Wymer, J., Kovach, M. J., Mehta, S. G., Mumm, S., Darvish, D., Pestronk, A., Whyte, M. P., Kimonis, V. E. <strong>Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia is caused by mutant valosin-containing protein.</strong> Nature Genet. 36: 377-381, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15034582/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15034582</a>] [<a href="https://doi.org/10.1038/ng1332" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15034582">Watts et al. (2004)</a> identified a G-to-C transversion at nucleotide 572 of the VCP gene, resulting in an arg-to-gln substitution at codon 191 (R191Q). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15034582" 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 exome sequencing, <a href="#21" class="mim-tip-reference" title="Johnson, J. O., Mandrioli, J., Benatar, M., Abramzon, Y., Van Deerlin, V. M., Trojanowski, J. Q., Gibbs, J. R., Brunetti, M., Gronka, S., Wuu, J., Ding, J., McCluskey, L., and 25 others. <strong>Exome sequencing reveals VCP mutations as a cause of familial ALS.</strong> Neuron 68: 857-864, 2010. Note: Erratum: Neuron 69: 397 only, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21145000/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21145000</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21145000[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.neuron.2010.11.036" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21145000">Johnson et al. (2010)</a> identified heterozygosity for the R191Q mutation in the VCP gene, which they stated resulted from a 961G-A transition in exon 5, in 4 affected members of an Italian family with frontotemporal dementia and/or amyotrophic lateral sclerosis-6 (FTDALS6; <a href="/entry/613954">613954</a>). Affected individuals presented in adulthood with limb-onset motor neuron symptoms that rapidly progressed to involve all 4 limbs and the bulbar musculature, consistent with a classical ALS phenotype. All patients had unequivocal upper and lower motor signs, and none had evidence of Paget disease. One patient showed mild frontotemporal dementia. Autopsy material was not available. A parent of the proband had died at age 58 with dementia, parkinsonism, Paget disease, and upper limb weakness, suggesting IBMPFD. The findings indicated an expanded phenotypic spectrum for VCP mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21145000" 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="#36" class="mim-tip-reference" title="Sacconi, S., Camano, P., de Greef, J. C., Lemmers, R. J. L. F., Salviati, L., Boileau, P., Lopez de Munain Arregui, A., van der Maarel, S. M., Desnuelle, C. <strong>Patients with a phenotype consistent with facioscapulohumeral muscular dystrophy display genetic and epigenetic heterogeneity.</strong> J. Med. Genet. 49: 41-46, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21984748/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21984748</a>] [<a href="https://doi.org/10.1136/jmedgenet-2011-100101" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21984748">Sacconi et al. (2012)</a> identified a heterozygous R191Q mutation in 2 unrelated men in their fifties who presented with a phenotype consistent with IBMPFD. One had scapuloperoneal weakness without facial involvement and increased serum creatine kinase. The second patient had facial weakness, shoulder and pelvic girdle weakness, and anterior foreleg weakness. Creatine kinase was increased 4-fold. Muscle biopsies of both patients showed mild dystrophic changes, but no inclusion bodies. EMG showed myopathic patterns. One patient was later found to have a mild dysexecutive syndrome, but neither had evidence of Paget disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21984748" 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 INCLUSION BODY MYOPATHY WITH EARLY-ONSET PAGET DISEASE AND FRONTOTEMPORAL DEMENTIA 1</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121909335 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121909335;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/rs121909335?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=rs121909335" 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=rs121909335" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In 4 affected sibs of an Austrian family with autosomal dominant inclusion body myopathy and Paget disease but without dementia (IBMPFD1; <a href="/entry/167320">167320</a>), <a href="#16" class="mim-tip-reference" title="Haubenberger, D., Bittner, R. E., Rauch-Shorny, S., Zimprich, F., Mannhalter, C., Wagner, L., Mineva, I., Vass, K., Auff, E., Zimprich, A. <strong>Inclusion body myopathy and Paget disease is linked to a novel mutation in the VCP gene.</strong> Neurology 65: 1304-1305, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16247064/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16247064</a>] [<a href="https://doi.org/10.1212/01.wnl.0000180407.15369.92" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16247064">Haubenberger et al. (2005)</a> identified a heterozygous 688G-A transition in exon 5 of the VCP gene, resulting in an arg159-to-his (R159H) substitution. The mutation occurred in a highly conserved region close to the codon 155 hotspot described by <a href="#45" class="mim-tip-reference" title="Watts, G. D. J., Wymer, J., Kovach, M. J., Mehta, S. G., Mumm, S., Darvish, D., Pestronk, A., Whyte, M. P., Kimonis, V. E. <strong>Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia is caused by mutant valosin-containing protein.</strong> Nature Genet. 36: 377-381, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15034582/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15034582</a>] [<a href="https://doi.org/10.1038/ng1332" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15034582">Watts et al. (2004)</a> and was not present in 384 control chromosomes. None of the 4 affected sibs demonstrated frontotemporal dementia even though all were over 60 years of age. <a href="#16" class="mim-tip-reference" title="Haubenberger, D., Bittner, R. E., Rauch-Shorny, S., Zimprich, F., Mannhalter, C., Wagner, L., Mineva, I., Vass, K., Auff, E., Zimprich, A. <strong>Inclusion body myopathy and Paget disease is linked to a novel mutation in the VCP gene.</strong> Neurology 65: 1304-1305, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16247064/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16247064</a>] [<a href="https://doi.org/10.1212/01.wnl.0000180407.15369.92" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16247064">Haubenberger et al. (2005)</a> noted that only approximately 30% of patients with VCP mutations develop dementia, illustrating phenotypic variability. In a follow-up of this family, <a href="#42" class="mim-tip-reference" title="van der Zee, J., Pirici, D., Van Langenhove, T., Engelborghs, S., Vandenberghe, R., Hoffmann, M., Pusswald, G., Van den Broeck, M., Peeters, K., Mattheijssens, M., Martin, J.-J., De Deyn, P. P., Cruts, M., Haubenberger, D., Kumar-Singh, S., Zimprich, A., Van Broeckhoven, C. <strong>Clinical heterogeneity in 3 unrelated families linked to VCP p.Arg159His.</strong> Neurology 73: 626-632, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19704082/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19704082</a>] [<a href="https://doi.org/10.1212/WNL.0b013e3181b389d9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19704082">van der Zee et al. (2009)</a> noted that 1 patient had developed dementia at age 64. <a href="#42" class="mim-tip-reference" title="van der Zee, J., Pirici, D., Van Langenhove, T., Engelborghs, S., Vandenberghe, R., Hoffmann, M., Pusswald, G., Van den Broeck, M., Peeters, K., Mattheijssens, M., Martin, J.-J., De Deyn, P. P., Cruts, M., Haubenberger, D., Kumar-Singh, S., Zimprich, A., Van Broeckhoven, C. <strong>Clinical heterogeneity in 3 unrelated families linked to VCP p.Arg159His.</strong> Neurology 73: 626-632, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19704082/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19704082</a>] [<a href="https://doi.org/10.1212/WNL.0b013e3181b389d9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19704082">Van der Zee et al. (2009)</a> also identified the R159H mutation in affected members of 2 unrelated Belgian families. In 1 family, patients presented with frontotemporal lobar degeneration only, whereas in the other family, patients developed frontotemporal lobar degeneration, Paget disease of the bone, or both without signs of inclusion body myopathy for any of the mutation carriers. Haplotype analysis showed that the 2 families and the Austrian family reported by <a href="#16" class="mim-tip-reference" title="Haubenberger, D., Bittner, R. E., Rauch-Shorny, S., Zimprich, F., Mannhalter, C., Wagner, L., Mineva, I., Vass, K., Auff, E., Zimprich, A. <strong>Inclusion body myopathy and Paget disease is linked to a novel mutation in the VCP gene.</strong> Neurology 65: 1304-1305, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16247064/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16247064</a>] [<a href="https://doi.org/10.1212/01.wnl.0000180407.15369.92" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16247064">Haubenberger et al. (2005)</a> were unrelated. Autopsy data of 3 patients from the 2 Belgian families showed frontotemporal lobar degeneration with numerous ubiquitin-immunoreactive, intranuclear inclusions and dystrophic neurites staining positive for TDP43 (TARDBP; <a href="/entry/605078">605078</a>) protein. <a href="#42" class="mim-tip-reference" title="van der Zee, J., Pirici, D., Van Langenhove, T., Engelborghs, S., Vandenberghe, R., Hoffmann, M., Pusswald, G., Van den Broeck, M., Peeters, K., Mattheijssens, M., Martin, J.-J., De Deyn, P. P., Cruts, M., Haubenberger, D., Kumar-Singh, S., Zimprich, A., Van Broeckhoven, C. <strong>Clinical heterogeneity in 3 unrelated families linked to VCP p.Arg159His.</strong> Neurology 73: 626-632, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19704082/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19704082</a>] [<a href="https://doi.org/10.1212/WNL.0b013e3181b389d9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19704082">Van der Zee et al. (2009)</a> commented on the high degree of clinical heterogeneity and incomplete penetrance of the disorder in different families carrying the same mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15034582+16247064+19704082" 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="De Ridder, W., Azmi, A., Clemen, C. S., Eichinger, L., Hofmann, A., Schroder, R., Johnson, K., Topf, A., Straub, V., De Jonghe, P., Maudsley, S., De Bleecker, J. L., Baets, J. <strong>Multisystem proteinopathy due to a homozygous p.Arg159His VCP mutation.</strong> Neurology 94: e785-e796, 2020. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31848255/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31848255</a>] [<a href="https://doi.org/10.1212/WNL.0000000000008763" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31848255">De Ridder et al. (2020)</a> reported a 36-year-old Belgian man with onset of IBMPFD1 at age 29 years who carried a homozygous R159H mutation in the VCP gene. His 63-year-old father, who carried the mutation in heterozygous state, had a similar myopathic phenotype with later onset at age 58. His 60-year-old mother, who was also heterozygous for the mutation, was clinically unaffected. The proband presented with progressive proximal muscle weakness with possible neurogenic features and high serum creatine kinase; an asymptomatic Paget bone lesion was later identified. Neither patient had dementia. Functional studies of the variant were not performed, but proteomic analysis of skeletal muscle from the proband and his father, as well as from 3 additional patients with VCP-related myopathy, showed changes in upstream regulators involved in myogenesis, muscle regeneration, oxidative stress, endoplasmic reticulum stress, stress granules, and the unfolded protein response. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31848255" 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 FRONTOTEMPORAL DEMENTIA AND/OR AMYOTROPHIC LATERAL SCLEROSIS 6</strong>
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<p>In affected members of a family with frontotemporal dementia and/or amyotrophic lateral sclerosis-6 (FTDALS6; <a href="/entry/613954">613954</a>), <a href="#21" class="mim-tip-reference" title="Johnson, J. O., Mandrioli, J., Benatar, M., Abramzon, Y., Van Deerlin, V. M., Trojanowski, J. Q., Gibbs, J. R., Brunetti, M., Gronka, S., Wuu, J., Ding, J., McCluskey, L., and 25 others. <strong>Exome sequencing reveals VCP mutations as a cause of familial ALS.</strong> Neuron 68: 857-864, 2010. Note: Erratum: Neuron 69: 397 only, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21145000/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21145000</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21145000[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.neuron.2010.11.036" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21145000">Johnson et al. (2010)</a> identified a heterozygous c.864C-G transversion in exon 5 of the VCP gene, resulting in an arg159-to-gly (R159G) substitution in a conserved residue. The mutation was not found in 3,138 control chromosomes, and a different pathogenic mutation had previously been reported in this codon (R159H; <a href="#0007">601023.0007</a>). Two patients had classic ALS with frontotemporal dementia, and a third obligate mutation carrier had Paget disease, followed by ALS without cognitive impairment. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21145000" 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> rs387906790 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906790;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/rs387906790?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=rs387906790" 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=rs387906790" 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=RCV000023066" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000023066" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000023066</a>
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<p>In a patient with frontotemporal dementia and/or amyotrophic lateral sclerosis-6 (FTDALS6; <a href="/entry/613954">613954</a>) without FTD, <a href="#21" class="mim-tip-reference" title="Johnson, J. O., Mandrioli, J., Benatar, M., Abramzon, Y., Van Deerlin, V. M., Trojanowski, J. Q., Gibbs, J. R., Brunetti, M., Gronka, S., Wuu, J., Ding, J., McCluskey, L., and 25 others. <strong>Exome sequencing reveals VCP mutations as a cause of familial ALS.</strong> Neuron 68: 857-864, 2010. Note: Erratum: Neuron 69: 397 only, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21145000/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21145000</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21145000[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.neuron.2010.11.036" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21145000">Johnson et al. (2010)</a> identified a heterozygous c.2163G-A transition in exon 14 of the VCP gene, resulting in an asp592-to-asn (D592N) substitution in a residue directly adjacent to the central pore formed by the VCP hexamer. The mutation was not found in 3,138 control chromosomes. A maternal uncle had previously been diagnosed with ALS. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21145000" 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">rs864309501 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs864309501;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=rs864309501" 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=rs864309501" 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=RCV000202444 OR RCV002229147 OR RCV002345722" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000202444, RCV002229147, RCV002345722" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000202444...</a>
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<p>In 5 adult members of a family with autosomal dominant axonal Charcot-Marie-Tooth disease type 2Y (CMT2Y; <a href="/entry/616687">616687</a>), <a href="#14" class="mim-tip-reference" title="Gonzalez, M. A., Feely, S. M., Speziani, F., Strickland, A. V., Danzi, M., Bacon, C., Lee, Y., Chou, T.-F., Blanton, S. H., Weihl, C. C., Zuchner, S., Shy, M. E. <strong>A novel mutation in VCP causes Charcot-Marie-Tooth type 2 disease.</strong> Brain 137: 2897-2902, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25125609/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25125609</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25125609[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/brain/awu224" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25125609">Gonzalez et al. (2014)</a> identified a heterozygous c.553C-T transition (c.553C-T, NM_007126.3) in the VCP gene, resulting in a glu185-to-lys (E185K) substitution at a highly conserved residue in the L1 linker domain between the N-domain and the D1 ATPase domain. The mutation, which was found by whole-exome sequencing, segregated with the disorder in the family and was not found in the Exome Variant Server database. In vitro functional expression studies showed that the variant impaired autophagic function of VCP, leading to the accumulation of immature autophagosomes. ATPase function of the variant was normal. Intrafamilial variation was striking: 1 patient had onset in early childhood and severe disability, whereas 3 other patients had onset after age 50 and a milder phenotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25125609" 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>.0011 CHARCOT-MARIE-TOOTH DISEASE, TYPE 2Y</strong>
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VCP, GLY97GLU
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs864309502 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs864309502;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=rs864309502" 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=rs864309502" 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=RCV000202492 OR RCV001853259" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000202492, RCV001853259" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000202492...</a>
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<p>In a 60-year-old man of Dutch and Italian descent with autosomal dominant Charcot-Marie-Tooth disease type 2Y (CMT2Y; <a href="/entry/616687">616687</a>), <a href="#19" class="mim-tip-reference" title="Jerath, N. U., Crockett, C. D., Moore, S. A., Shy, M. E., Weihl, C. C., Chou, T.-F., Grider, T., Gonzalez, M. A., Zuchner, S., Swenson, A. <strong>Rare manifestation of a c.290 C-T, p.gly97glu VCP mutation.</strong> Case Rep. Genet. 2015: 239167, 2015. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25878907/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25878907</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25878907[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1155/2015/239167" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25878907">Jerath et al. (2015)</a> identified a heterozygous c.290C-T transition in the VCP gene, resulting in a gly97-to-glu (G97E) substitution. The mutation was found by exome sequencing. In vitro functional expression studies showed that the mutant protein had increased ATPase activity compared to wildtype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25878907" 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>.0012 INCLUSION BODY MYOPATHY WITHOUT EARLY-ONSET PAGET DISEASE AND FRONTOTEMPORAL DEMENTIA 1</strong>
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FRONTOTEMPORAL DEMENTIA AND/OR AMYOTROPHIC LATERAL SCLEROSIS 6, INCLUDED
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs863225291 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs863225291;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=rs863225291" 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=rs863225291" 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=RCV000201935 OR RCV001271081 OR RCV001271088 OR RCV002519583" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000201935, RCV001271081, RCV001271088, RCV002519583" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000201935...</a>
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<p>In 2 Brazilian brothers and their father with different clinical manifestations of VCP-related neurologic disease, <a href="#1" class="mim-tip-reference" title="Abrahao, A., Abath Neto, O., Kok, F., Zanoteli, E., Santos, B., de Rezende Pinto, W. B. V., Barsottini, O. G. P., Oliveira, A. S. B., Pedroso, J. L. <strong>One family, one gene and three phenotypes: a novel VCP (valosin-containing protein) mutation associated with myopathy with rimmed vacuoles, amyotrophic lateral sclerosis and frontotemporal dementia.</strong> J. Neurol. Sci. 368: 352-358, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27538664/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27538664</a>] [<a href="https://doi.org/10.1016/j.jns.2016.07.048" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27538664">Abrahao et al. (2016)</a> identified a heterozygous c.271A-T transversion in exon 3 of the VCP gene, resulting in an asn91-to-tyr (N91Y) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with a neurologic phenotype in the family. The variant was not present in the Exome Variant Server or ExAC databases, or in 1000 control Brazilian exomes. Functional studies of the variant were not performed, but it was predicted to be pathogenic. The proband presented in his forties with proximal muscle weakness associated with dystrophic features, myofibrillar disorganization, and rimmed vacuoles on muscle biopsy, consistent with a diagnosis of inclusion body myopathy (IBMPFD1; <a href="/entry/167320">167320</a>), but he had no signs of Paget disease or dementia. His affected brother presented in his late thirties with lower motor neuron-predominant amyotrophic lateral sclerosis (FTDALS6; <a href="/entry/613954">613954</a>) without signs of Paget disease or frontotemporal dementia. Their father presented at age 66 with behavioral variant frontotemporal dementia (<a href="/entry/613954">613954</a>) without signs of Paget disease, myopathy, or ALS. The findings emphasized the extreme phenotypic variability associated with VCP mutations, even within the same family. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27538664" 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> rs387906789 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906789;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/rs387906789?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=rs387906789" 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=rs387906789" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a woman (patient 2) with frontotemporal dementia without amyotrophic lateral sclerosis (FTDALS6; <a href="/entry/613954">613954</a>), <a href="#50" class="mim-tip-reference" title="Wong, T. H., Pottier, C., Hondius, D. C., Meeter, L. H. H., van Rooij, J. G. J., Melhem, S., The Netherlands Brain bank, van Minkelen, R., van Duijn, C. M., Rozemuller, A. J. M., Seelaar, H., Rademakers, R., van Swieten, J. C. <strong>Three VCP mutations in patients with frontotemporal dementia.</strong> J. Alzheimers Dis. 65: 1139-1146, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30103325/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30103325</a>] [<a href="https://doi.org/10.3233/JAD-180301" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30103325">Wong et al. (2018)</a> identified a heterozygous c.475C-A transversion in exon 5 of the VCP gene, resulting in an arg159-to-ser (R159S) substitution in the CDC48 domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in the gnomAD database. Functional studies of the variant were not performed. The patient had onset of symptoms consistent with the behavioral variant of FTD at age 56 and died at age 62. Neuropathologic examination showed prominent frontal atrophy with neuronal loss and gliosis, as well as neuronal intranuclear inclusions (NII), short dystrophic neurites (DN), and positive immunostaining for TDP43 and p62 (SQSTM1; <a href="/entry/601530">601530</a>). Several amyloid plaques were also observed, and rare NII showed VCP-positive immunostaining. The pathologic findings were consistent with FTLD-TDP subtype D. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30103325" 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>.0014 FRONTOTEMPORAL DEMENTIA WITHOUT AMYOTROPHIC LATERAL SCLEROSIS 6, WITH NEUROFIBRILLARY TANGLES</strong>
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VCP, ASP395GLY
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1828721782 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1828721782;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=rs1828721782" 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=rs1828721782" 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=RCV001271084 OR RCV004797923" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001271084, RCV004797923" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001271084...</a>
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<p>In 4 adult patients from 2 unrelated families with frontotemporal dementia without amyotrophic lateral sclerosis (FTDALS6; <a href="/entry/613954">613954</a>), <a href="#9" class="mim-tip-reference" title="Darwich, N. F., Phan, J. M., Kim, B., Suh, E., Papatriantafyllou, J. D., Changolkar, L., Nguyen, A. T., O'Rourke, C. M., He, Z., Porta, S., Gibbons, G. S., Luk, K. C., and 10 others. <strong>Autosomal dominant VCP hypomorph mutation impairs disaggregation of PHF-tau.</strong> Science 370: eaay8826, 2020. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33004675/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33004675</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=33004675[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.aay8826" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33004675">Darwich et al. (2020)</a> identified a heterozygous c.1184A-G transition (c.1184A-G, NM_007126.5) in the VCP gene, resulting in an asp395-to-gly (D395G) substitution at a conserved residue in the lid subdomain of the D1 ATPase domain. The mutation, which was found by targeted, whole-exome, or whole-genome sequencing, segregated with the disorder in both families. It was not present in the gnomAD database. The patients presented with the behavioral variant of FTD and did not have signs of myopathy, bone disease, or motor neuron disease. Neuropathologic examination of 1 patient showed frontal atrophy, neuronal vacuolization, and abundant phosphorylated tau (MAPT; <a href="/entry/157140">157140</a>) aggregates identical to neurofibrillary tangles (NFT) observed in patients with Alzheimer disease (see, e.g., AD; <a href="/entry/104300">104300</a>). The distribution of the vacuoles and NFTs were inversely related: vacuoles were more prominent in the occipital cortex, which showed minimal neurodegeneration, whereas NFTs were more prominent in frontal regions and other areas that showed cerebral atrophy, neuronal loss, and reactive gliosis. TDP43 (<a href="/entry/605078">605078</a>), beta-amyloid (APP; <a href="/entry/104760">104760</a>), SNCA (<a href="/entry/163890">163890</a>), and prion protein (PRNP; <a href="/entry/176640">176640</a>) aggregates were not observed. The pathologic tau distribution was confirmed by brain imaging studies. In vitro functional expression studies showed that the D395G mutation resulted in decreased ATPase activity with a 30% reduction in maximum enzyme velocity compared to controls, which was consistent with a hypomorphic mutation. Additional in vitro studies showed that VCP normally acts as a disaggregase for polyubiquitinated phosphorylated pathologic tau fibrils derived from brains of patients with Alzheimer disease. Cells with the D395G mutation had increased intracellular tau aggregates, suggesting that this specific mutation impairs the turnover of pathologic tau aggregates, resulting in neurodegeneration. <a href="#9" class="mim-tip-reference" title="Darwich, N. F., Phan, J. M., Kim, B., Suh, E., Papatriantafyllou, J. D., Changolkar, L., Nguyen, A. T., O'Rourke, C. M., He, Z., Porta, S., Gibbons, G. S., Luk, K. C., and 10 others. <strong>Autosomal dominant VCP hypomorph mutation impairs disaggregation of PHF-tau.</strong> Science 370: eaay8826, 2020. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33004675/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33004675</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=33004675[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.aay8826" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33004675">Darwich et al. (2020)</a> named this disease 'vacuolar tauopathy' (VT). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33004675" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>REFERENCES</strong>
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<strong>One family, one gene and three phenotypes: a novel VCP (valosin-containing protein) mutation associated with myopathy with rimmed vacuoles, amyotrophic lateral sclerosis and frontotemporal dementia.</strong>
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[<a href="https://doi.org/10.1016/j.jns.2016.07.048" target="_blank">Full Text</a>]
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<a id="Al-Obeidi2018" class="mim-anchor"></a>
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Al-Obeidi, E., Al-Tahan, S., Surampalli, A., Goyal, N., Wang, A. K., Hermann, A., Omizo, M., Smith, C., Mozaffar, T., Kimonis, V.
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[<a href="https://doi.org/10.1111/cge.13095" target="_blank">Full Text</a>]
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<a id="Ballar2007" class="mim-anchor"></a>
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Ballar, P., Zhong, Y., Nagahama, M., Tagaya, M., Shen, Y., Fang, S.
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[<a href="https://doi.org/10.1074/jbc.M704446200" target="_blank">Full Text</a>]
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<a id="Banerjee2016" class="mim-anchor"></a>
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Banerjee, S., Bartesaghi, A., Merk, A., Rao, P., Bulfer, S. L., Yan, Y., Green, N., Mroczkowski, B., Neitz, R. J., Wipf, P., Falconieri, V., Deshaies, R. J., Milne, J. L. S., Huryn, D., Arkin, M., Subramaniam, S.
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<strong>2.3 angstrom resolution cryo-EM structure of human p97 and mechanism of allosteric inhibition.</strong>
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Science 351: 871-875, 2016.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26822609/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26822609</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26822609[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26822609" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1126/science.aad7974" target="_blank">Full Text</a>]
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<a id="Clemen2010" class="mim-anchor"></a>
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Clemen, C. S., Tangavelou, K., Strucksberg, K.-H., Just, S., Gaertner, L., Regus-Leidig, H., Stumpf, M., Reimann, J., Coras, R., Morgan, R. O., Fernandez, M.-P., Hofmann, A., Muller, S., Schoser, B., Hanisch, F.-G., Rottbauer, W., Blumcke, I., von Horsten, S., Eichinger, L., Schroder, R.
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<strong>Strumpellin is a novel valosin-containing protein binding partner linking hereditary spastic paraplegia to protein aggregation diseases.</strong>
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Brain 133: 2920-2941, 2010.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20833645/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20833645</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20833645" 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/brain/awq222" target="_blank">Full Text</a>]
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<a id="Cloutier2013" class="mim-anchor"></a>
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Cloutier, P., Lavallee-Adam, M., Faubert, D., Blanchette, M., Coulombe, B.
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<strong>A newly uncovered group of distantly related lysine methyltransferases preferentially interact with molecular chaperones to regulate their activity.</strong>
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[<a href="https://doi.org/10.1371/journal.pgen.1003210" target="_blank">Full Text</a>]
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<a id="Cooney2019" class="mim-anchor"></a>
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Cooney, I., Han, H., Stewart, M. G., Carson, R. H., Hansen, D. T., Iwasa, J. H., Price, J. C., Hill, C. P., Shen, P. S.
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[<a href="https://doi.org/10.1126/science.aax0486" target="_blank">Full Text</a>]
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<a id="Custer2010" class="mim-anchor"></a>
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Custer, S. K., Neumann, M., Lu, H., Wright, A. C., Taylor, J. P.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20147319/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20147319</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20147319" 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/ddq050" target="_blank">Full Text</a>]
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<a id="Darwich2020" class="mim-anchor"></a>
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Darwich, N. F., Phan, J. M., Kim, B., Suh, E., Papatriantafyllou, J. D., Changolkar, L., Nguyen, A. T., O'Rourke, C. M., He, Z., Porta, S., Gibbons, G. S., Luk, K. C., and 10 others.
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<strong>Autosomal dominant VCP hypomorph mutation impairs disaggregation of PHF-tau.</strong>
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Science 370: eaay8826, 2020. Note: Electronic Article.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33004675/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33004675</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=33004675[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33004675" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1126/science.aay8826" target="_blank">Full Text</a>]
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<a id="De Ridder2020" class="mim-anchor"></a>
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De Ridder, W., Azmi, A., Clemen, C. S., Eichinger, L., Hofmann, A., Schroder, R., Johnson, K., Topf, A., Straub, V., De Jonghe, P., Maudsley, S., De Bleecker, J. L., Baets, J.
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<strong>Multisystem proteinopathy due to a homozygous p.Arg159His VCP mutation.</strong>
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Neurology 94: e785-e796, 2020. Note: Electronic Article.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31848255/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31848255</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31848255" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1212/WNL.0000000000008763" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1006/geno.1995.0016" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17141156/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17141156</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17141156" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.devcel.2006.10.016" target="_blank">Full Text</a>]
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<strong>Clinical heterogeneity in 3 unrelated families linked to VCP p.Arg159His.</strong>
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[<a href="https://doi.org/10.1212/WNL.0b013e3181b389d9" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1074/jbc.M116.772038" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1111/j.1399-0004.2008.00984.x" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/ng1332" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/ddi426" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/ddm037" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19380227/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19380227</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19380227[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19380227" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.nmd.2009.01.009" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33410456/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33410456</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=33410456[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33410456" 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/ddaa248" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.3233/JAD-180301" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/s41586-020-1982-9" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/414652a" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15215856/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15215856</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15215856" 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/nature02656" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/j.bbrc.2007.02.160" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1074/jbc.274.25.17806" target="_blank">Full Text</a>]
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<span class="mim-text-font">
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Bao Lige - updated : 02/25/2025
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Bao Lige - updated : 11/06/2024<br>Bao Lige - updated : 11/17/2023<br>Carol A. Bocchini - updated : 08/10/2022<br>Bao Lige - updated : 08/01/2022<br>Bao Lige - updated : 03/17/2022<br>Hilary J. Vernon - updated : 03/29/2021<br>Cassandra L. Kniffin - updated : 12/17/2020<br>Ada Hamosh - updated : 06/24/2020<br>Ada Hamosh - updated : 12/09/2019<br>Patricia A. Hartz - updated : 06/20/2017<br>Ada Hamosh - updated : 09/14/2016<br>Cassandra L. Kniffin - updated : 12/10/2015<br>Ada Hamosh - updated : 6/24/2015<br>Ada Hamosh - updated : 12/3/2014<br>Ada Hamosh - updated : 12/2/2014<br>Cassandra L. Kniffin - updated : 1/6/2014<br>Cassandra L. Kniffin - updated : 12/17/2013<br>Patricia A. Hartz - updated : 5/31/2013<br>Cassandra L. Kniffin - updated : 4/25/2012<br>Cassandra L. Kniffin - updated : 12/8/2011<br>George E. Tiller - updated : 12/1/2011<br>Cassandra L. Kniffin - updated : 5/5/2011<br>Cassandra L. Kniffin - updated : 12/21/2009<br>Patricia A. Hartz - updated : 11/10/2009<br>Cassandra L. Kniffin - updated : 10/29/2009<br>Cassandra L. Kniffin - updated : 4/23/2009<br>Cassandra L. Kniffin - updated : 3/23/2009<br>Ada Hamosh - updated : 1/24/2008<br>Cassandra L. Kniffin - updated : 2/5/2007<br>Patricia A. Hartz - updated : 1/4/2007<br>Ada Hamosh - updated : 3/8/2005<br>Ada Hamosh - updated : 7/22/2004<br>Ada Hamosh - updated : 4/2/2004<br>Paul J. Converse - updated : 1/28/2002<br>Ada Hamosh - updated : 1/2/2002<br>Victor A. McKusick - updated : 10/14/1997
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<a id="creationDate" class="mim-anchor"></a>
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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<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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Alan F. Scott : 1/30/1996
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</span>
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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mgross : 02/25/2025
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<div class="row collapse" id="mimCollapseEditHistory">
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<span class="mim-text-font">
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mgross : 11/06/2024<br>alopez : 07/09/2024<br>carol : 05/28/2024<br>mgross : 11/17/2023<br>carol : 08/11/2022<br>carol : 08/10/2022<br>alopez : 08/01/2022<br>alopez : 08/01/2022<br>mgross : 03/17/2022<br>alopez : 03/09/2022<br>carol : 03/30/2021<br>carol : 03/29/2021<br>alopez : 02/15/2021<br>carol : 12/23/2020<br>carol : 12/22/2020<br>ckniffin : 12/17/2020<br>alopez : 06/24/2020<br>carol : 01/27/2020<br>alopez : 12/09/2019<br>alopez : 04/11/2018<br>carol : 06/21/2017<br>carol : 06/21/2017<br>carol : 06/20/2017<br>alopez : 09/14/2016<br>carol : 06/24/2016<br>carol : 12/16/2015<br>carol : 12/15/2015<br>ckniffin : 12/10/2015<br>alopez : 6/24/2015<br>carol : 5/7/2015<br>carol : 2/4/2015<br>mgross : 1/22/2015<br>alopez : 12/3/2014<br>alopez : 12/2/2014<br>carol : 1/7/2014<br>ckniffin : 1/6/2014<br>carol : 12/19/2013<br>mcolton : 12/18/2013<br>ckniffin : 12/17/2013<br>mgross : 9/17/2013<br>carol : 7/26/2013<br>mgross : 5/31/2013<br>carol : 4/26/2012<br>ckniffin : 4/25/2012<br>carol : 12/16/2011<br>ckniffin : 12/8/2011<br>ckniffin : 12/8/2011<br>alopez : 12/5/2011<br>terry : 12/1/2011<br>carol : 7/6/2011<br>terry : 6/3/2011<br>carol : 6/1/2011<br>wwang : 5/18/2011<br>ckniffin : 5/5/2011<br>carol : 7/30/2010<br>wwang : 1/14/2010<br>ckniffin : 12/21/2009<br>terry : 12/1/2009<br>mgross : 11/10/2009<br>wwang : 11/5/2009<br>ckniffin : 10/29/2009<br>ckniffin : 10/29/2009<br>wwang : 5/13/2009<br>ckniffin : 4/23/2009<br>wwang : 4/7/2009<br>ckniffin : 3/23/2009<br>alopez : 2/5/2008<br>alopez : 2/5/2008<br>terry : 1/24/2008<br>carol : 5/10/2007<br>wwang : 2/9/2007<br>ckniffin : 2/5/2007<br>mgross : 1/4/2007<br>wwang : 8/9/2006<br>alopez : 3/8/2005<br>carol : 1/13/2005<br>terry : 11/3/2004<br>alopez : 7/23/2004<br>terry : 7/22/2004<br>alopez : 4/6/2004<br>terry : 4/2/2004<br>mgross : 1/28/2002<br>alopez : 1/8/2002<br>terry : 1/2/2002<br>mgross : 3/21/2000<br>mark : 10/17/1997<br>terry : 10/14/1997<br>terry : 7/28/1997<br>mark : 4/8/1997<br>terry : 3/26/1996<br>mark : 1/30/1996
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<h3>
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<span class="mim-font">
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<strong>*</strong> 601023
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<h3>
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<span class="mim-font">
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VALOSIN-CONTAINING PROTEIN; VCP
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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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<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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<h4>
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<span class="mim-font">
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CDC48, YEAST, HOMOLOG OF<br />
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p97
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: VCP</em></strong>
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<p>
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<span class="mim-text-font">
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<strong>SNOMEDCT:</strong> 1187565005;
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<p>
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<strong>
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<em>
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Cytogenetic location: 9p13.3
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Genomic coordinates <span class="small">(GRCh38)</span> : 9:35,056,064-35,072,625 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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</span>
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</p>
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</div>
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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>Gene-Phenotype Relationships</strong>
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<table class="table table-bordered table-condensed small mim-table-padding">
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<th>
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Location
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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<tbody>
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<td rowspan="3">
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<span class="mim-font">
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9p13.3
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</td>
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<td>
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<span class="mim-font">
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Charcot-Marie-Tooth disease, type 2Y
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</td>
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<td>
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<span class="mim-font">
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616687
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<span class="mim-font">
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Autosomal dominant
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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<span class="mim-font">
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Frontotemporal dementia and/or amyotrophic lateral sclerosis 6
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</td>
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<td>
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<span class="mim-font">
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613954
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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<tr>
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<td>
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<span class="mim-font">
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Inclusion body myopathy with early-onset Paget disease and frontotemporal dementia 1
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</span>
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</td>
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<td>
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<span class="mim-font">
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167320
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</td>
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</tr>
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</tbody>
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</table>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
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</span>
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</h4>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Description</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>The VCP gene encodes valosin-containing protein, a ubiquitously expressed multifunctional protein that is a member of the AAA+ (ATPase associated with various activities) protein family. It has been implicated in multiple cellular functions ranging from organelle biogenesis to ubiquitin-dependent protein degradation (summary by Weihl et al., 2009). </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Clathrin is a structural protein found in coated pits and vesicles, organelles which are important in membrane trafficking functions such as endocytosis and Golgi sorting. A 100-kD protein, designated valosin-containing protein or VCP by early investigators, is a structural protein complexed with clathrin (see 118960). VCP is the homolog of yeast cdc48p, and is a member of a family that includes putative ATP-binding proteins involved in vesicle transport and fusion, 26S proteasome function, and assembly of peroxisomes (Pleasure et al., 1993). VCP was cloned from the pig (Koller and Brownstein, 1987) and mouse (Egerton et al., 1992). Druck et al. (1995) cloned a portion of the human cDNA. </p><p>Cloutier et al. (2013) stated that the deduced 806-amino acid VCP protein contains an N-terminal domain, followed by a linker region, an ATPase domain, a second linker region, a second ATPase domain, and a C-terminal domain. The N-terminal domain consists of a double-psi-barrel superfold and 4-stranded beta barrel, and each ATPase domain consists of Walker A and B motifs and a 4-alpha-helix bundle. VCP is extensively modified by phosphorylation and acetylation, as well as by lysine methylation. </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>Biochemical Features</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>Cryoelectron Microscopy</em></strong></p><p>
|
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Banerjee et al. (2016) reported cryoelectron microscopy structures for ADP-bound, full-length, hexameric wildtype p97 in the presence and absence of an allosteric inhibitor at resolutions of 2.3 and 2.4 angstroms, respectively. Banerjee et al. (2016) also reported cryoelectron microscopy structures (at resolutions of approximately 3.3, 3.2, and 3.3 angstroms, respectively) for 3 distinct, coexisting functional states of p97 with occupancies of 0, 1, or 2 molecules of adenosine 5-prime-O-(3-thiotriphosphate) (ATP-gamma-S) per protomer. A large corkscrew-like change in molecular architecture, coupled with upward displacement of the N-terminal domain, is observed only when ATP-gamma-S is bound to both the D1 and D2 domains of the protomer. These cryoelectron microscopy structures established the sequence of nucleotide-driven structural changes in p97 at atomic resolution. They also enabled elucidation of the binding mode of an allosteric small-molecule inhibitor to p97 and illustrated how inhibitor binding at the interface between the D1 and D2 domains prevents propagation of the conformational changes necessary for p97 function. </p><p>Twomey et al. (2019) reported cryoelectron microscopy structures of the yeast Cdc48 ATPase in complex with Ufd1 (601754)/Npl4 (606590) and polyubiquitinated substrate. The structures showed that the Cdc48 complex initiates substrate processing by unfolding a ubiquitin molecule. The unfolded ubiquitin molecule binds to Npl4 and projects its N-terminal segment through both hexameric ATPase rings. Pore loops of the second ring form a staircase that acts as a conveyer belt to move the polypeptide through the central pore. </p><p>Cooney et al. (2019) reported a 3.7-angstrom-resolution structure of Cdc48 in complex with an adaptor protein and a native substrate. Cdc48 engages substrate by adopting a helical configuration of substrate-binding residues that extends through the central pore of both of the ATPase rings. Cooney et al. (2019) concluded that their findings indicated a unified hand-over-hand mechanism of protein translocation by Cdc48 and other AAA+ ATPases. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
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<strong>Gene Structure</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Johnson et al. (2010) noted that the VCP gene contains 17 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>Druck et al. (1995) used a partial human VCP cDNA to probe a panel of somatic cell hybrid DNAs and mapped the VCP gene to chromosome 9pter-q34. </p><p>By database analysis, Hoyle et al. (1997) identified a human expressed sequence tag (EST) that shares 80% identity with the mouse 3-prime untranslated region. They designed primers to this EST and amplified and sequenced a 127-bp product from total human DNA. This product detected 1 fragment only in a HindIII digest of total human DNA, indicating there is only 1 VCP sequence in the human genome. Using the 127-bp sequence to screen a human PAC library, followed by FISH analysis, they mapped the VCP gene to chromosome 9p13-p12. They mapped the mouse Vcp gene to mouse chromosome 4 and found a probable pseudogene on the mouse X chromosome. </p><p>The VCP gene maps to chromosome 9p13.3 (Johnson et al., 2010). </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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<strong>Gene Function</strong>
|
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Ye et al. (2001) demonstrated that VCP (CDC48 in yeast and p97 in mammals) is required for the export of endoplasmic reticulum (ER) into the cytosol. Whereas CDC48/p97 was known to function in a complex with the cofactor p47 in membrane fusion, Ye et al. (2001) demonstrated that its role in ER protein export requires the interacting partners UFD1 (601754) and NPL4 (606590). The AAA ATPase interacts with substrates at the ER membrane and is needed to release them as polyubiquitinated species into the cytosol. </p><p>Zhang et al. (1999) created a substrate-trapping mutant of PTPH1 (176877) that interacted primarily with VCP in vitro but not in cells. A double mutant of PTPH1 had a marked reduction in phosphotyrosine content, specifically trapped VCP in vivo, and recognized the C-terminal tyrosines of VCP. Immunoblot analysis showed that wildtype PTPH1 specifically dephosphorylated VCP. Zhang et al. (1999) concluded that PTPH1 exerts its effects on cell growth through dephosphorylation of VCP and that tyrosine phosphorylation is an important regulator of VCP function. </p><p>By yeast 2-hybrid screening, immunoprecipitation analysis and pull-down assays, Nagahama et al. (2003) showed that Svip (620965) interacted specifically with Vcp, with the interaction mediated by the coiled-coil regions of Svip and the ND1 domain of Vcp. Vcp formed a complex with p47 (NSFL1C; 606610) and Ufd1, but the Svip-Vcp complex was distinct, and formation of the 2 Vcp complexes was mutually exclusive. Expression of rat Svip induced formation of large ER-derived vacuoles in HeLa cells, and formation of large vacuoles did not appear to be due to lack of Vcp availability in Vcp-mediated pathways. </p><p>Watts et al. (2004) summarized that VCP has been associated with several essential cell protein pathways including cell cycle, homotypic membrane fusion, nuclear envelope reconstruction, postmitotic Golgi reassembly, DNA damage response, suppressor of apoptosis, and ubiquitin-dependent protein degradation. Higashiyama et al. (2002) identified a fruit fly VCP loss-of-function mutant as a dominant suppressor of expanded polyglutamine-induced neuronal degeneration. The suppressive effects of the loss-of-function mutant did not seem to result from inhibition of polyglutamine aggregate formation but rather from the degree of loss of VCP function. This suggested that a gene dosage response for VCP expression is essential to its function in expanded polyglutamine-induced neuronal degeneration. In support of this idea, transgenic fruit flies in which VCP levels were elevated experienced severe apoptotic cell death, whereas homozygous VCP loss-of-function mutants were embryonic lethal. </p><p>Ye et al. (2004) found that VIMP (607918) recruits the p97 ATPase (VCP) and its cofactor, the UFD1/NPL4 complex, to the ER for retrotranslocation of misfolded proteins into the cytosol. They noted that all pathways of retrotranslocation appear to require the function of the p97 ATPase complex, which may provide the general driving force for the movement of proteins into the cytosol. </p><p>Using a library of endoribonuclease-prepared short interfering RNAs (esiRNAs), Kittler et al. (2004) identified 37 genes required for cell division, one of which was VCP. These 37 genes included several splicing factors for which knockdown generates mitotic spindle defects. In addition, a putative nuclear-export terminator was found to speed up cell proliferation and mitotic progression after knockdown. </p><p>Uchiyama et al. (2006) found that rodent p37 (610686) formed a complex with p97 in cytosol and localized to Golgi and ER. Small interfering RNA experiments in HeLa cells revealed that p37 was required for Golgi and ER biogenesis. Injection of anti-p37 antibodies into HeLa cells at different stages of the cell cycle showed that p37 was involved in Golgi and ER maintenance during interphase and in their reassembly at the end of mitosis. In an in vitro Golgi reassembly assay, the p97/p37 complex showed membrane fusion activity that required p115 (603344)-GM130 (GOLGA2; 602580) tethering and SNARE GS15 (BET1L; 615417). VCIP135 (VCPIP1) was also required, but its deubiquitinating activity was unnecessary for p97/p37-mediated activities. </p><p>Ramadan et al. (2007) showed that p97 stimulates nucleus reformation by inactivating the chromatin-associated kinase Aurora B (604970). During mitosis, Aurora B inhibits nucleus reformation by preventing chromosome decondensation and formation of the nuclear envelope membrane. During exit from mitosis, p97 binds to Aurora B after its ubiquitylation and extracts it from chromatin. This leads to inactivation of Aurora B on chromatin, thus allowing chromatin decondensation and nuclear envelope formation. Ramadan et al. (2007) concluded that their data revealed an essential pathway that regulates reformation of the nucleus after mitosis and defined ubiquitin-dependent protein extraction as a common mechanism of Cdc48/p97 activity also during nucleus formation. </p><p>Using a chromatin immunoprecipitation assay, Zhang et al. (2007) showed that ELF2 (619798) bound specifically to the 5-prime-flanking sequence of the VCP gene in MCF7 human breast cancer cells. Knockdown of ELF2 in MCF7 cells reduced VCP expression and cell viability. Immunohistochemical analysis revealed that ELF2 expression correlated with VCP expression and proliferative activity of cells in breast cancer specimens. </p><p>By immunoprecipitation analysis, Ballar et al. (2007) showed that SVIP formed a trimeric complex with VCP and derlin-1 (DERL1; 608813). VCP and derlin-1 are also common interacting partners of GP78 (AMFR; 603243), but formation of the 2 complexes was mutually exclusive. By interacting with VCP and derlin-1, SVIP inhibited interaction of GP78 with CD3-delta (CD3D; 186790), VCP, and derlin-1, resulting in inhibition of CD3-delta ubiquitination and subsequent loading to VCP for retrotranslocation. The results suggested that SVIP is an endogenous inhibitor of ER-associated degradation (ERAD) that acts by regulating assembly of the GP78/VCP/derlin-1 complex. </p><p>Using human cell lines, Mueller et al. (2008) identified several components of a protein complex required for retrotranslocation or dislocation of misfolded proteins from the ER lumen to the cytosol for proteasome-dependent degradation. These included SEL1L (602329), HRD1 (SYVN1; 608046), derlin-2 (DERL2; 610304), the ATPase p97, PDI (P4HB; 176790), BIP (HSPA5; 138120), calnexin (CANX; 114217), AUP1 (602434), UBXD8 (FAF2), UBC6E (UBE2J1; 616175), and OS9 (609677). </p><p>By affinity purification, SDS-PAGE, and mass spectrometry, Cloutier et al. (2013) found that METTL21D (615260) expressed in HEK293 cells interacted with endogenous VCP, ASPSCR1 (606236), and UBXN6 (611946). In vitro methylation assays showed that recombinant METTL21D methylated VCP, which was abrogated by mutation of lys315 in ATPase domain 1 of VCP. Methylation reduced the activity of VCP ATPase domain 1, but it had no effect on the activity of VCP ATPase domain 2. METTL21D did not methylate ASPSRC1 or UBXN6, but the presence of ASPSRC1, but not UBXN6, enhanced METTL21D-dependent VCP methylation. </p><p>In immunoprecipitation studies, Clemen et al. (2010) identified strumpellin (KIAA0196; 601657) as a binding partner with VCP. Strumpellin was detected in pathologic protein aggregates in muscle tissue derived from patients with IBMPFD1 (167320) as well as in various myofibrillar myopathies and in cortical neurons of a mouse model of Huntington disease (HD; 143100). These findings suggested that strumpellin, like VCP, may have a role in various protein aggregate diseases. </p><p>Maric et al. (2014) showed that the CMG helicase, composed of Cdc45 (603465)/Mcm (see MCM7, 600592)/GINS (see 610608), is ubiquitylated during the final stages of chromosome replication in S. cerevisiae, specifically on its Mcm7 subunit. The yeast F-box protein Dia2 is essential in vivo for ubiquitylation of CMG, and the SCF(Dia2) ubiquitin ligase (see 603134) is also required to ubiquitylate CMG in vitro on its Mcm7 subunit in extracts of S-phase yeast cells. Maric et al. (2014) concluded that their data identified 2 key features of helicase disassembly in budding yeast. First, there is an essential role for the F-box protein Dia2, which drives ubiquitylation of the CMG helicase on its Mcm7 subunit. Second, the Cdc48 segregase is required to break ubiquitylated CMG into its component parts. Once separated from GINS and Cdc45, the Mcm2-7 hexamer is less stable, so that all of the subunits of the CMG helicase are lost from the newly replicated DNA. </p><p>Moreno et al. (2014) presented evidence consistent with the idea that polyubiquitylation of a replisome component, MCM7, leads to its disassembly at the converging terminating forks due to the action of the p97/VCP/CDC48 protein remodeler. Using Xenopus laevis egg extract, the authors showed that blocking polyubiquitylation results in the prolonged association of the active helicase with replicating chromatin. The MCM7 subunit was the only component of the active helicase found to be polyubiquitylated during replication termination. The observed polyubiquitylation was followed by disassembly of the active helicase dependent on p97/VCP. Moreno et al. (2014) concluded that their data provided insight into the mechanism of replisome disassembly during eukaryotic DNA replication termination. </p><p>Olmos et al. (2015) demonstrated that the endosomal sorting complex required for transport-III (ESCRT-III) machinery localizes to sites of annular fusion in the forming nuclear envelope in human cells, and is necessary for proper postmitotic nucleocytoplasmic compartmentalization. The ESCRT-III component CHMP2A (610893) is directed to the forming nuclear envelope through binding to CHMP4B (610897), and provides an activity essential for nuclear envelope reformation. Localization also requires the p97 complex (see 601023) member UFD1. Olmos et al. (2015) concluded that their results described a novel role for the ESCRT machinery in cell division and demonstrated a conservation of the machineries involved in topologically equivalent mitotic membrane remodeling events. </p><p>Van Haaften-Visser et al. (2017) found that human VCP interacted with ANKZF1 (617541) in the cytoplasm of U2OS osteosarcoma cells and that the complex translocated toward mitochondria following H2O2-induced oxidative stress. </p><p>Yasuda et al. (2020) demonstrated that proteasome-containing nuclear foci form under acute hyperosmotic stress. These foci are transient structures that contain ubiquitylated proteins, VCP, and multiple proteasome-interacting proteins, which collectively constitute a proteolytic center. The major substrates for degradation by these foci were ribosomal proteins that failed to properly assemble. Notably, the proteasome foci exhibited properties of liquid droplets. RAD23B (600062), a substrate-shuttling factor for the proteasome, and ubiquitylated proteins were necessary for formation of proteasome foci. In mechanistic terms, a liquid-liquid phase separation was triggered by multivalent interactions of 2 ubiquitin-associated domains of RAD23B and ubiquitin chains consisting of 4 or more ubiquitin molecules. Yasuda et al. (2020) concluded that their results suggested that ubiquitin chain-dependent phase separation induces the formation of a nuclear proteolytic compartment that promotes proteasomal degradation. </p><p>In in vitro studies, Darwich et al. (2020) found that VCP normally acts as a disaggregase for polyubiquitinated phosphorylated pathologic tau fibrils derived from brains of patients with Alzheimer disease (see, e.g., AD, 104300). This function was ATP- and polyubiquitin-dependent. </p><p>By immunoprecipitation and mass spectrometry analyses in HEK293 cells, Fielden et al. (2020) identified p97 as an interacting partner of TOP1 (126420), a protein that regulates DNA topology to ensure efficient DNA replication and transcription. By interacting with TOP1, p97 functioned as a modulator of TOP1 cleavage complex (TOP1cc) repair, as p97 ATPase activity was needed to counteract TOP1cc accumulation in human cells. The authors identified TEX264 (620608) as a p97 cofactor. TEX264 simultaneously interacted with p97 and TOP1 to form a complex to bridge recruitment of p97 specifically to TOP1cc. TEX264 knockout caused substantial TOP1cc accumulation, which led to significantly delayed DNA damage repair. This phenotype was similar to that of TDP1 (607198) depletion, as TEX264 was epistatic with TDP1 and interacted with TDP1 to promote TOP1cc repair. TEX264 function in TOP1cc repair was mediated by sumoylation. TOP1 was sumoylated, and TEX264, which contains 2 putative SUMO-interacting motifs (SIMs) in its GyrI-like domain, bound to sumoylated TOP1 for its recruitment to TOP1cc. In addition, SPRTN (616086), a metalloprotease that proteolytically cleaves TOP1, contributed to TOP1cc repair. TEX264 associated with SPRTN at the nuclear periphery and acted at replication forks. </p><p>By yeast 2-hybrid screen of a human testis cDNA library, Korner et al. (2023) demonstrated that various isoforms of both VCF1 (621109) and VCF2 (301141) interacted with p97. Mutation analysis showed that the interaction was mediated by the N domain of p97 and the C-terminal alpha helices of VCF1 and VCF2. VCF1 and VCF2 associated with specific p97 complexes in cells, including p97-UFD1-NPL4 and p97-UBXN2B, but not with all p97 complexes. Ectopic expression of VCF1 or VCF2 increased nuclear p97 levels in HeLa cells, suggesting that VCF proteins target p97 to the nucleus. Moreover, ectopic expression of VCF1 isoforms 1 and 2 induced chromatin binding of p97 in HEK293T cells. In contrast, VCF1/VCF2 double-knockout reduced nuclear p97 levels in HeLa cells, indicating that VCF1 and VCF2 modulate the nucleocytoplasmic distribution of p97. </p><p>Using pull-down analyses in transfected U2OS cells, Mirsanaye et al. (2024) identified VCF1 as a p97-interacting protein. The interaction was direct, tight, and mediated by the p97 N domain and by a distinct motif in the VCF1 C terminus. VCF1 formed joint complexes on p97 hexamers with other p97 cofactors, including UFD1-NPL4. By forming a complex with p97-UFD1-NPL4, VCF1 stimulated p97-UFD1-NPL4 recruitment to ubiquitylated substrates to facilitate their degradation. </p>
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<strong>Molecular Genetics</strong>
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<p><strong><em>Inclusion Body Myopathy with Paget Disease of Bone and Frontotemporal Dementia</em></strong></p><p>
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Watts et al. (2004) identified missense mutations in VCP as the cause of inclusion body myopathy with Paget disease of bone and frontotemporal dementia (IBMPFD; 167320). Ten of 13 families with this disorder had an amino acid change at arginine-155, either to histidine, proline, or cysteine. Arginine-155 of VCP was conserved in homologs through all species examined except in 2 C. elegans homologs, which had glutamine at that position. Arginine-191 was invariant in all species examined, and arginine-95 was substituted by histidine in only 2 species. </p><p>Watts et al. (2004) suggested that since patients with IBMPFD are viable with relatively late onset of disease, the mutations identified do not disrupt the cell cycle or apoptosis pathways. They proposed that mutations in VCP cause Paget disease of bone by compromising ubiquitin binding and target similar cellular pathways or proteins. They suggested that the progressive neuronal degeneration has to do with protein quality control and ubiquitin protein degradation pathways. Watts et al. (2004) concluded that because IBMPFD is a dominant progressive syndrome, the mutations they identified are probably relatively subtle, and aging, oxidative stress, and endoplasmic reticulum stress probably define a threshold at which the IBMPFD phenotype becomes manifest. </p><p>In vitro functional expression studies by Weihl et al. (2006) showed that cells transfected with the mutant R155H (601023.0001) and R95G (601023.0004) proteins developed a prominent increase in diffuse and aggregated ubiquitin conjugates and showed impaired function of ERAD, as well as a distorted ER structure. </p><p>In human cells with IBMPFD-associated mutations, Ju et al. (2008) found that treatment with a proteasome inhibitor resulted in increased cell death and an increase in perinuclear ubiquitinated proteins, but no clear aggresomes, compared to wildtype. Expression of an aggregate protein in mutant cells did not result in proper formation of inclusion bodies or aggresomes. A similar lack of inclusion body formation was observed in mutant mouse muscle fibers in vivo. Further studies showed that mutant VCP trapped aggregated proteins but failed to release them to aggresomes or inclusion bodies. This was reversed upon coexpression with HDAC6 (300272), a VCP-binding protein that facilitates formation of aggresomes. Ju et al. (2008) concluded that mutations in the VCP gene impaired the proper clearance of aggregated proteins. </p><p><strong><em>Frontotemporal Dementia and/or Amyotrophic Lateral Sclerosis 5</em></strong></p><p>
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Using exome sequencing, Johnson et al. (2010) identified a heterozygous mutation in the VCP gene (R191Q; 601023.0006) in 4 affected members of an Italian family with frontotemporal dementia and/or amyotrophic lateral sclerosis-6 (FTDALS6; 613954). Screening of the VCP gene in 210 familial ALS cases and 78 autopsy-proven ALS cases identified 3 additional pathogenic VCP mutations (601023.0001, 601012.0008, and 601023.0009) in 4 patients. The findings expanded the phenotype associated with VCP mutations to include classic ALS. </p><p>In 3 unrelated adult Dutch patients with the behavioral variant of FTD without signs of myopathy or motor neuron disease (613954), Wong et al. (2018) identified heterozygous missense mutations in the VCP gene (R159S, 601023.0013, T262S, and M158V). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, were not present in the gnomAD database. Functional studies of the variants were not performed. Postmortem examination of 2 patients (patients 2 and 3) showed prominent frontal atrophy with neuronal loss and gliosis, as well as neuronal intranuclear inclusions (NII), short dystrophic neurites (DN), and positive immunostaining for TDP43 and p62 (SQSTM1; 601530). A few hyperphosphorylated tau (MAPT; 157140) deposits without amyloid plaques were observed in 1 patient, and several amyloid plaques were observed in the other patient. Rare NII showed VCP-positive immunostaining. The pathologic findings were consistent with FTLD-TDP subtype D, although the severity and distribution of the pathologic findings varied somewhat between the 2 patients. </p><p>In 4 adult patients from 2 unrelated families with the behavioral variant of FTD without signs of myopathy, bone disease, or motor neuron disease, Darwich et al. (2020) identified the same heterozygous missense mutation in (D395G; 601023.0014). The substitution occurred at a conserved residue in the lid subdomain of the D1 ATPase domain. The mutation, which was found by targeted, whole-exome, or whole-genome sequencing, segregated with the disorder in both families. It was not present in the gnomAD database. Neuropathologic examination of 1 patient showed frontal atrophy, neuronal vacuolization, and abundant phosphorylated tau (MAPT; 157140) aggregates identical to neurofibrillary tangles (NFT) observed in patients with Alzheimer disease (see, e.g., AD, 104300). MAPT mutations were absent in both families. The distribution of the vacuoles and NFTs were inversely related: vacuoles were more prominent in the occipital cortex, which showed minimal neurodegeneration, whereas NFTs were more prominent in frontal regions and other areas that showed cerebral atrophy, neuronal loss, and reactive gliosis. TDP43 (605078), beta-amyloid (APP; 104760), SNCA (163890), and prion protein (PRNP; 176640) aggregates were not observed. The pathologic tau distribution was confirmed by brain imaging studies. In vitro functional expression studies showed that the D395G mutation resulted in decreased ATPase activity with a 30% reduction in maximum enzyme velocity compared to controls, which was consistent with a hypomorphic mutation. Additional in vitro studies showed that VCP normally acts as a disaggregase for polyubiquitinated phosphorylated pathologic tau fibrils derived from brains of patients with Alzheimer disease. Cells with the D395G mutation had increased intracellular tau aggregates, suggesting that this specific mutation impairs the turnover of pathologic tau aggregates, resulting in neurodegeneration. Transgenic mice expressing this mutation showed similar pathologic tau accumulation when seeded with AD-derived tau (see ANIMAL MODEL). Darwich et al. (2020) emphasized the distinct pathogenetic mechanism associated with this mutation, and named this disease 'vacuolar tauopathy' (VT). </p><p>Tyzack et al. (2019) examined motor neurons derived from 2 human induced pluripotent stem cell (iPSC) lines with different heterozygous VCP mutations (R155C, 601023.0002 and R191Q, 601023.0006) and identified a decrease in the nuclear to cytoplasmic localization of the FUS (137070) protein during motor neuron differentiation compared to controls. Tyzack et al. (2019) also identified a reduction in the nuclear to cytoplasmic localization of the FUS protein in motor neurons from the ventral spinal cord of transgenic mice with a heterozygous mutation in the VCP gene (A232E; 601023.0003). This reduction was not seen in mice with a SOD1 (147450) G93A mutation, where FUS remained in the nucleus. Tyzack et al. (2019) next identified evidence for nuclear to cytoplasmic FUS mislocalization in postmortem spinal cord tissue from individuals with sporadic ALS compared to controls. After identifying RNA binding targets of the FUS protein, Tyzack et al. (2019) found that the FUS protein bound extensively to an aberrantly retained intron 9 within the SFPQ (605199) transcript. This aberrant SFPQ transcript was increased in the human iPSC cell lines with the heterozygous VCP mutations compared to controls. </p><p>Harley et al. (2020) identified a decreased nuclear to cytoplasmic ratio of FUS in highly enriched spinal motor neurons that were derived from human iPSC cell lines with heterozygous VCP mutations. This mislocalization of FUS extended to the neuronal processes. Harley et al. (2020) hypothesized that the nuclear loss of the FUS protein may impair its role in pre-mRNA splicing and play a role in neurodegeneration. </p><p><strong><em>Charcot-Marie-Tooth Disease Type 2Y</em></strong></p><p>
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In 5 affected members of a family with autosomal dominant axonal Charcot-Marie-Tooth disease type 2Y (CMT2Y; 616687), Gonzalez et al. (2014) identified a heterozygous missense mutation in the VCP gene (E185K; 601023.0010). The mutation, which was found by whole-exome sequencing, segregated with the disorder in the family. In vitro functional expression studies showed that the variant impaired autophagic function of VCP, leading to the accumulation of immature autophagosomes. ATPase function of the variant was normal. </p><p><strong><em>Functional Effects of VCP Mutations</em></strong></p><p>
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Cloutier et al. (2013) found that the R155H (601023.0001), R159H (601023.0007), and R191Q (601023.0006) mutations in VCP did not alter in vitro methylation of VCP by METTL21D. However, ASPSRC1 did not enhance methylation of VCP containing these mutations, as it did with wildtype VCP. </p>
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<p>Mehta et al. (2013) analyzed clinical and biochemical markers from a database of 190 individuals from 27 families harboring 10 missense mutations in the VCP gene. Among these, 145 mutation carriers were symptomatic and 45 were presymptomatic. The most common clinical feature (in 91% of patients) was onset of myopathic weakness at a mean age of 43 years. Paget disease of the bone was found in 52% of patients at a mean age of 41 years. Frontotemporal dementia occurred in 30% of patients at a mean age of 55 years. Significant genotype-phenotype correlations were difficult to establish because of small numbers. However, patients with the R155C mutation (601023.0002) had a more severe phenotype with an earlier onset of myopathy and Paget disease, as well as decreased survival, compared to those with the R155H mutation (601023.0001). A diagnosis of ALS was found in at least 13 (8.9%) individuals from the 27 families, including 10 patients with the R155H mutation, and 5 (3%) patients were diagnosed with Parkinson disease. </p><p>Al-Obeidi et al. (2018) studied 231 individuals from 36 families carrying 15 different heterozygous VCP mutations. Of these individuals, 187 were clinically symptomatic and 44 were presymptomatic carriers. The cohort of patients were of various ethnicities, including European, Brazilian, Hispanic/Apache, and an African-American. Most (90%) of symptomatic patients presented with myopathy at a mean age of 43 years (range, 20-70 years). Paget disease of bone was identified in 42% of patients with a mean age at onset of 41 years (range, 23-65 years), and dementia was diagnosed in 29.4% of patients at a mean age of 55.9 years (range, 30-80 years). When possible to ascertain, the dementia included sociobehavioral and language changes, as well as loss of executive function. Sixteen (8.6%) of patients were diagnosed with ALS associated with upper and lower motor neuron degeneration. Some patients were diagnosed with Parkinson disease (3.8%) or Alzheimer disease (2.1%). Although VCP mutations are associated with a triad of symptoms, only 10% of patients had all 3 features of myopathy, bone disease, and dementia. After stratification by mutation type, there were no apparent genotype/phenotype correlations, although the R159C mutation was associated with a slightly later age at onset of myopathy (57 years) compared to other mutations. Functional studies of the variants were not performed. The authors emphasized the enormous phenotypic heterogeneity both between and within families. </p><p>Schiava et al. (2022) reported clinical and genetic data on 234 symptomatic patients (70% male) from 194 families from 24 countries with mutations in the VCP gene. Only 7 patients (2.9%) had the classic triad of myopathy, bone disease, and dementia. Muscle weakness affecting both proximal or distal muscles of the lower and/or upper limbs was the first symptom in 90.7% of patients and was present in all but 1 patient at last assessment. Paget disease of bone occurred in 28.2%, dysautonomia in 21.2%, lower motor neuron signs in 21.2%, and frontotemporal dementia in 14.3%. Of 57 identified variants, 4 (R155H, 601023.0001; R155C, 601023.0002; R159H, 601023.0007; and R93C) accounted for 54.7% of the patients. Exons 5 and 3 represented hotspots. All but one of the mutations were missense. No mutations were exclusively associated with specific mutations, but R155C, which occurred more frequently in females, showed a more severe phenotype with an earlier onset. </p>
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<p>Weihl et al. (2007) found that transgenic mice overexpressing the R155H mutation became progressively weaker in a dose-dependent manner starting at 6 months of age. There was abnormal muscle pathology, with coarse internal architecture, vacuolation, and disorganized membrane morphology with reduced caveolin-3 (CAV3; 601253) expression at the sarcolemma. Even before animals displayed measurable weakness, there was an increase in ubiquitin-containing protein inclusions and high molecular weight ubiquitinated proteins. These findings suggested a dysregulation in protein degradation. </p><p>Custer et al. (2010) developed and characterized transgenic mice with ubiquitous expression of wildtype and disease-causing versions of human VCP/p97. Mice expressing VCP/p97 harboring the mutations R155H (601023.0001) or A232E (601023.0003) exhibited progressive muscle weakness, and developed inclusion body myopathy including rimmed vacuoles and TDP43 (605078) pathology. The brain showed widespread TDP43 pathology, and the skeleton exhibited severe osteopenia accompanied by focal lytic and sclerotic lesions in vertebrae and femur. In vitro studies indicated that mutant VCP caused inappropriate activation of the NF-kappa-B (see 164011) signaling cascade, which could contribute to the mechanism of pathogenesis in multiple tissues including muscle, bone, and brain. </p><p>Darwich et al. (2020) found that transgenic mice expressing the VCP D395G (601023.0014) mutation did not spontaneously develop a neurodegenerative phenotype and their brains did not show abnormal tau (MAPT; 157140) accumulation. However, when stimulated with pathologic tau derived from patients with Alzheimer disease (see, e.g., AD; 104300), transgenic mice had accumulation of pathologic tau aggregates in several brain regions. The findings suggested that neurons with this VCP mutation have increased susceptibility to pathologic tau aggregation under certain circumstances, resulting in downstream neurodegeneration. </p><p>Using mass spectroscopy analysis, Weiss et al. (2020) showed that ceramide levels were elevated in primary myoblasts from both mice homozygous for the Vcp R155H mutation and patients with VCP disease. Treatment with exogenous ceramide stimulated autophagy, a key feature of VCP disease pathology, in myoblasts from mice homozygous for the Vcp R155H mutation. Inhibition of ceramide biosynthesis mitigated VCP-associated autophagy and TDP43 pathology in patient myoblasts derived from induced pluripotent stem cells (iPSCs). </p><p>Using purified recombinant proteins, Johnson et al. (2021) showed that Drosophila Svip bound Vcp. Svip localized to lysosome tubules distributed throughout the cytosol. By binding Vcp, Svip recruited Vcp to tubular lysosomes in Drosophila. Knockout analysis revealed that Svip-dependent Vcp recruitment was essential to stabilize lysosomal structure and function in Drosophila. Synthetic recruitment of Vcp to lysosomes in Svip-knockout Drosophila was sufficient to enhance stability of a dynamic lysosomal network. Further analysis demonstrated that Svip functioned in muscle, affecting organismal motility and lifespan of Drosophila. Svip-knockout Drosophila displayed age-related muscle defects, and ultrastructural visualization showed muscle wasting in Svip-knockout Drosophila that could be rescued by muscle Svip expression. Using a biochemical screen, the authors identified a disease-causing pro134-to-leu (P134L) mutation in Vcp that impaired Svip binding and the lysosomal network in muscle in Drosophila. The Vcp P134L mutant protein aggregated in an age-dependent manner and caused muscle degeneration, mirroring many of the phenotypes in Svip-knockout Drosophila. </p>
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<strong>ALLELIC VARIANTS</strong>
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<strong>14 Selected Examples):</strong>
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<strong>.0001 INCLUSION BODY MYOPATHY WITH EARLY-ONSET PAGET DISEASE AND FRONTOTEMPORAL DEMENTIA 1</strong>
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</span>
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|
</h4>
|
|
</div>
|
|
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|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
FRONTOTEMPORAL DEMENTIA AND/OR AMYOTROPHIC LATERAL SCLEROSIS 6, INCLUDED
|
|
</span>
|
|
</div>
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<div>
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<span class="mim-text-font">
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VCP, ARG155HIS
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<br />
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SNP: rs121909329,
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ClinVar: RCV000008989, RCV000523065, RCV000540496, RCV001271089, RCV002336080
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|
|
</span>
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|
</div>
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<div>
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<span class="mim-text-font">
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<p>In 7 of 13 families with autosomal dominant inclusion body myopathy with early-onset Paget disease and frontotemporal dementia (IBMPFD1; 167320), Watts et al. (2004) identified a G-to-A transition at nucleotide 464 of the VCP gene, resulting in an arg155-to-his substitution (R155H). This mutation appears to have arisen independently on several haplotype backgrounds. </p><p>Viassolo et al. (2008) identified heterozygosity for the R155H mutation in 3 affected members of an Italian family with IBMPFD. All 3 had progressive inclusion body myopathy and rapidly progressive severe dementia, but only 1 developed Paget disease. </p><p>In vitro functional expression studies by Weihl et al. (2006) showed that R155H-mutant protein properly assembled into a hexameric structure and showed normal ATPase activity. Cell transfected with the mutant protein showed a prominent increase in diffuse and aggregated ubiquitin conjugates and impaired function of endoplasmic reticulum-associated degradation (ERAD), as well as a distorted ER structure. </p><p>Johnson et al. (2010) identified heterozygosity for the R155H mutation, which they stated resulted from an 853G-A transition in exon 5, in a member of the family reported by Watts et al. (2004). However, the family member reported by Johnson et al. (2010) had classic ALS (FTDALS6; 613954) without evidence of Paget disease, myopathy, or frontotemporal dementia. Postmortem examination of this patient showed loss of brainstem and spinal cord motor neurons with Bunina bodies in surviving neurons, TDP43 (TARDBP; 605078)-positive immunostaining, and mild pallor of the lateral descending corticospinal tracts, all features consistent with diagnosis of ALS. The findings expanded the phenotype associated with VCP mutations, even within a single family. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>.0002 INCLUSION BODY MYOPATHY WITH EARLY-ONSET PAGET DISEASE AND FRONTOTEMPORAL DEMENTIA 1</strong>
|
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</span>
|
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</h4>
|
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</div>
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<div>
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<span class="mim-text-font">
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VCP, ARG155CYS
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<br />
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SNP: rs121909330,
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ClinVar: RCV000008990, RCV000372207, RCV000685660, RCV001095424
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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|
<p>In 2 of 13 families with autosomal dominant inclusion body myopathy with early-onset Paget disease and frontotemporal dementia (IBMPFD1; 167320), Watts et al. (2004) identified a C-to-T transition at nucleotide 463 of the VCP gene, resulting in an arg155-to-cys substitution (R155C). </p><p>Kim et al. (2011) identified a heterozygous R155C mutation in 3 Korean sibs with IBMPFD. The proband developed progressive dementia presenting as fluent aphasia and language difficulties with onset at age 47. She never developed myopathy, but did develop asymptomatic Paget disease with increased serum alkaline phosphatase and lytic bone lesions on imaging. Her brother developed slowly progressive proximal muscle weakness at age 50, followed by frontotemporal dementia characterized initially by comprehension defects at age 54. He never had Paget disease, although serum alkaline phosphatase was increased. A second brother developed muscle weakness at age 47, followed by Paget disease at age 53, and dementia at age 61. Brain MRI in all patients showed asymmetric atrophy in the anterior inferior and lateral temporal lobes and inferior parietal lobule with ventricular dilatation on the affected side (2 on the left, 1 on the right). Two had glucose hypometabolism in the lateral temporal and inferior parietal areas, with less involvement of the anterior temporal and frontal lobes compared to those with typical semantic dementia. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>.0003 INCLUSION BODY MYOPATHY WITH EARLY-ONSET PAGET DISEASE AND FRONTOTEMPORAL DEMENTIA 1</strong>
|
|
</span>
|
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</h4>
|
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</div>
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<div>
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<span class="mim-text-font">
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VCP, ALA232GLU
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<br />
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SNP: rs121909331,
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ClinVar: RCV000008991, RCV001172005
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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 1 of 13 families with autosomal dominant inclusion body myopathy with early-onset Paget disease and frontotemporal dementia (IBMPFD1; 167320), Watts et al. (2004) identified a C-to-A transversion at nucleotide 695 of the VCP gene, resulting in an ala-to-glu change at codon 232 (A232E). </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>.0004 INCLUSION BODY MYOPATHY WITH EARLY-ONSET PAGET DISEASE AND FRONTOTEMPORAL DEMENTIA 1</strong>
|
|
</span>
|
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</h4>
|
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</div>
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<div>
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<span class="mim-text-font">
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VCP, ARG95GLY
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<br />
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SNP: rs121909332,
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|
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gnomAD: rs121909332,
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ClinVar: RCV000008992
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|
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|
|
|
</span>
|
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In 1 of 13 families with autosomal dominant inclusion body myopathy with early-onset Paget disease and frontotemporal dementia (IBMPFD1; 167320), Watts et al. (2004) identified a C-to-G transversion at nucleotide 283 of the VCP gene, resulting in an arg-to-gly substitution at codon 95 (R95G). </p><p>In vitro functional expression studies by Weihl et al. (2006) showed that cells transfected with R95G-mutant protein developed a prominent increased in diffuse and aggregated ubiquitin conjugates and impaired function of endoplasmic reticulum-associated degradation (ERAD), as well as a distorted ER structure. </p>
|
|
</span>
|
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</div>
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<div>
|
|
<br />
|
|
</div>
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|
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</div>
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|
|
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<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0005 INCLUSION BODY MYOPATHY WITH EARLY-ONSET PAGET DISEASE AND FRONTOTEMPORAL DEMENTIA 1</strong>
|
|
</span>
|
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</h4>
|
|
</div>
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<div>
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<span class="mim-text-font">
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VCP, ARG155PRO
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<br />
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|
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SNP: rs121909329,
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|
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ClinVar: RCV000008993, RCV001387337, RCV003137504
|
|
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|
|
</span>
|
|
</div>
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|
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In 1 of 13 families with autosomal dominant inclusion body myopathy with early-onset Paget disease and frontotemporal dementia (IBMPFD1; 167320), Watts et al. (2004) identified a G-to-C transversion at nucleotide 464 of the VCP gene, resulting in an arg-to-pro substitution at codon 155 (R155P). This family was originally reported by Tucker et al. (1982). </p>
|
|
</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>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0006 INCLUSION BODY MYOPATHY WITH EARLY-ONSET PAGET DISEASE AND FRONTOTEMPORAL DEMENTIA 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
FRONTOTEMPORAL DEMENTIA AND/OR AMYOTROPHIC LATERAL SCLEROSIS 6, INCLUDED
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
VCP, ARG191GLN
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121909334,
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|
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|
|
|
gnomAD: rs121909334,
|
|
|
|
|
|
ClinVar: RCV000008994, RCV000023064, RCV000516636, RCV000555373, RCV002496309
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 1 of 13 families with autosomal dominant inclusion body myopathy with early-onset Paget disease and frontotemporal dementia (IBMPFD1; 167320), Watts et al. (2004) identified a G-to-C transversion at nucleotide 572 of the VCP gene, resulting in an arg-to-gln substitution at codon 191 (R191Q). </p><p>Using exome sequencing, Johnson et al. (2010) identified heterozygosity for the R191Q mutation in the VCP gene, which they stated resulted from a 961G-A transition in exon 5, in 4 affected members of an Italian family with frontotemporal dementia and/or amyotrophic lateral sclerosis-6 (FTDALS6; 613954). Affected individuals presented in adulthood with limb-onset motor neuron symptoms that rapidly progressed to involve all 4 limbs and the bulbar musculature, consistent with a classical ALS phenotype. All patients had unequivocal upper and lower motor signs, and none had evidence of Paget disease. One patient showed mild frontotemporal dementia. Autopsy material was not available. A parent of the proband had died at age 58 with dementia, parkinsonism, Paget disease, and upper limb weakness, suggesting IBMPFD. The findings indicated an expanded phenotypic spectrum for VCP mutations. </p><p>Sacconi et al. (2012) identified a heterozygous R191Q mutation in 2 unrelated men in their fifties who presented with a phenotype consistent with IBMPFD. One had scapuloperoneal weakness without facial involvement and increased serum creatine kinase. The second patient had facial weakness, shoulder and pelvic girdle weakness, and anterior foreleg weakness. Creatine kinase was increased 4-fold. Muscle biopsies of both patients showed mild dystrophic changes, but no inclusion bodies. EMG showed myopathic patterns. One patient was later found to have a mild dysexecutive syndrome, but neither had evidence of Paget disease. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 INCLUSION BODY MYOPATHY WITH EARLY-ONSET PAGET DISEASE AND FRONTOTEMPORAL DEMENTIA 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
VCP, ARG159HIS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121909335,
|
|
|
|
|
|
gnomAD: rs121909335,
|
|
|
|
|
|
ClinVar: RCV000008995, RCV000276565, RCV000639653, RCV003335021, RCV004532314
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 4 affected sibs of an Austrian family with autosomal dominant inclusion body myopathy and Paget disease but without dementia (IBMPFD1; 167320), Haubenberger et al. (2005) identified a heterozygous 688G-A transition in exon 5 of the VCP gene, resulting in an arg159-to-his (R159H) substitution. The mutation occurred in a highly conserved region close to the codon 155 hotspot described by Watts et al. (2004) and was not present in 384 control chromosomes. None of the 4 affected sibs demonstrated frontotemporal dementia even though all were over 60 years of age. Haubenberger et al. (2005) noted that only approximately 30% of patients with VCP mutations develop dementia, illustrating phenotypic variability. In a follow-up of this family, van der Zee et al. (2009) noted that 1 patient had developed dementia at age 64. Van der Zee et al. (2009) also identified the R159H mutation in affected members of 2 unrelated Belgian families. In 1 family, patients presented with frontotemporal lobar degeneration only, whereas in the other family, patients developed frontotemporal lobar degeneration, Paget disease of the bone, or both without signs of inclusion body myopathy for any of the mutation carriers. Haplotype analysis showed that the 2 families and the Austrian family reported by Haubenberger et al. (2005) were unrelated. Autopsy data of 3 patients from the 2 Belgian families showed frontotemporal lobar degeneration with numerous ubiquitin-immunoreactive, intranuclear inclusions and dystrophic neurites staining positive for TDP43 (TARDBP; 605078) protein. Van der Zee et al. (2009) commented on the high degree of clinical heterogeneity and incomplete penetrance of the disorder in different families carrying the same mutation. </p><p>De Ridder et al. (2020) reported a 36-year-old Belgian man with onset of IBMPFD1 at age 29 years who carried a homozygous R159H mutation in the VCP gene. His 63-year-old father, who carried the mutation in heterozygous state, had a similar myopathic phenotype with later onset at age 58. His 60-year-old mother, who was also heterozygous for the mutation, was clinically unaffected. The proband presented with progressive proximal muscle weakness with possible neurogenic features and high serum creatine kinase; an asymptomatic Paget bone lesion was later identified. Neither patient had dementia. Functional studies of the variant were not performed, but proteomic analysis of skeletal muscle from the proband and his father, as well as from 3 additional patients with VCP-related myopathy, showed changes in upstream regulators involved in myogenesis, muscle regeneration, oxidative stress, endoplasmic reticulum stress, stress granules, and the unfolded protein response. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0008 FRONTOTEMPORAL DEMENTIA AND/OR AMYOTROPHIC LATERAL SCLEROSIS 6</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
VCP, ARG159GLY
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs387906789,
|
|
|
|
|
|
gnomAD: rs387906789,
|
|
|
|
|
|
ClinVar: RCV000023065
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members of a family with frontotemporal dementia and/or amyotrophic lateral sclerosis-6 (FTDALS6; 613954), Johnson et al. (2010) identified a heterozygous c.864C-G transversion in exon 5 of the VCP gene, resulting in an arg159-to-gly (R159G) substitution in a conserved residue. The mutation was not found in 3,138 control chromosomes, and a different pathogenic mutation had previously been reported in this codon (R159H; 601023.0007). Two patients had classic ALS with frontotemporal dementia, and a third obligate mutation carrier had Paget disease, followed by ALS without cognitive impairment. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0009 FRONTOTEMPORAL DEMENTIA AND/OR AMYOTROPHIC LATERAL SCLEROSIS 6</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
VCP, ASP592ASN
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs387906790,
|
|
|
|
|
|
gnomAD: rs387906790,
|
|
|
|
|
|
ClinVar: RCV000023066
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with frontotemporal dementia and/or amyotrophic lateral sclerosis-6 (FTDALS6; 613954) without FTD, Johnson et al. (2010) identified a heterozygous c.2163G-A transition in exon 14 of the VCP gene, resulting in an asp592-to-asn (D592N) substitution in a residue directly adjacent to the central pore formed by the VCP hexamer. The mutation was not found in 3,138 control chromosomes. A maternal uncle had previously been diagnosed with ALS. </p>
|
|
</span>
|
|
</div>
|
|
|
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<div>
|
|
<br />
|
|
</div>
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|
|
|
</div>
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|
|
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<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 CHARCOT-MARIE-TOOTH DISEASE, TYPE 2Y</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
VCP, GLU185LYS
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|
|
|
|
<br />
|
|
|
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SNP: rs864309501,
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|
|
ClinVar: RCV000202444, RCV002229147, RCV002345722
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|
|
|
|
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</span>
|
|
</div>
|
|
|
|
|
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In 5 adult members of a family with autosomal dominant axonal Charcot-Marie-Tooth disease type 2Y (CMT2Y; 616687), Gonzalez et al. (2014) identified a heterozygous c.553C-T transition (c.553C-T, NM_007126.3) in the VCP gene, resulting in a glu185-to-lys (E185K) substitution at a highly conserved residue in the L1 linker domain between the N-domain and the D1 ATPase domain. The mutation, which was found by whole-exome sequencing, segregated with the disorder in the family and was not found in the Exome Variant Server database. In vitro functional expression studies showed that the variant impaired autophagic function of VCP, leading to the accumulation of immature autophagosomes. ATPase function of the variant was normal. Intrafamilial variation was striking: 1 patient had onset in early childhood and severe disability, whereas 3 other patients had onset after age 50 and a milder phenotype. </p>
|
|
</span>
|
|
</div>
|
|
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<div>
|
|
<br />
|
|
</div>
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|
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</div>
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<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0011 CHARCOT-MARIE-TOOTH DISEASE, TYPE 2Y</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
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<span class="mim-text-font">
|
|
|
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VCP, GLY97GLU
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|
|
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<br />
|
|
|
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SNP: rs864309502,
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|
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ClinVar: RCV000202492, RCV001853259
|
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|
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</span>
|
|
</div>
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|
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 60-year-old man of Dutch and Italian descent with autosomal dominant Charcot-Marie-Tooth disease type 2Y (CMT2Y; 616687), Jerath et al. (2015) identified a heterozygous c.290C-T transition in the VCP gene, resulting in a gly97-to-glu (G97E) substitution. The mutation was found by exome sequencing. In vitro functional expression studies showed that the mutant protein had increased ATPase activity compared to wildtype. </p>
|
|
</span>
|
|
</div>
|
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|
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<div>
|
|
<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0012 INCLUSION BODY MYOPATHY WITHOUT EARLY-ONSET PAGET DISEASE AND FRONTOTEMPORAL DEMENTIA 1</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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FRONTOTEMPORAL DEMENTIA AND/OR AMYOTROPHIC LATERAL SCLEROSIS 6, 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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VCP, ASN91TYR
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<br />
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SNP: rs863225291,
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ClinVar: RCV000201935, RCV001271081, RCV001271088, RCV002519583
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In 2 Brazilian brothers and their father with different clinical manifestations of VCP-related neurologic disease, Abrahao et al. (2016) identified a heterozygous c.271A-T transversion in exon 3 of the VCP gene, resulting in an asn91-to-tyr (N91Y) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with a neurologic phenotype in the family. The variant was not present in the Exome Variant Server or ExAC databases, or in 1000 control Brazilian exomes. Functional studies of the variant were not performed, but it was predicted to be pathogenic. The proband presented in his forties with proximal muscle weakness associated with dystrophic features, myofibrillar disorganization, and rimmed vacuoles on muscle biopsy, consistent with a diagnosis of inclusion body myopathy (IBMPFD1; 167320), but he had no signs of Paget disease or dementia. His affected brother presented in his late thirties with lower motor neuron-predominant amyotrophic lateral sclerosis (FTDALS6; 613954) without signs of Paget disease or frontotemporal dementia. Their father presented at age 66 with behavioral variant frontotemporal dementia (613954) without signs of Paget disease, myopathy, or ALS. The findings emphasized the extreme phenotypic variability associated with VCP mutations, even within the same family. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0013 FRONTOTEMPORAL DEMENTIA WITHOUT AMYOTROPHIC LATERAL SCLEROSIS 6</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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VCP, ARG159SER
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<br />
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SNP: rs387906789,
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gnomAD: rs387906789,
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ClinVar: RCV001271083
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a woman (patient 2) with frontotemporal dementia without amyotrophic lateral sclerosis (FTDALS6; 613954), Wong et al. (2018) identified a heterozygous c.475C-A transversion in exon 5 of the VCP gene, resulting in an arg159-to-ser (R159S) substitution in the CDC48 domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in the gnomAD database. Functional studies of the variant were not performed. The patient had onset of symptoms consistent with the behavioral variant of FTD at age 56 and died at age 62. Neuropathologic examination showed prominent frontal atrophy with neuronal loss and gliosis, as well as neuronal intranuclear inclusions (NII), short dystrophic neurites (DN), and positive immunostaining for TDP43 and p62 (SQSTM1; 601530). Several amyloid plaques were also observed, and rare NII showed VCP-positive immunostaining. The pathologic findings were consistent with FTLD-TDP subtype D. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0014 FRONTOTEMPORAL DEMENTIA WITHOUT AMYOTROPHIC LATERAL SCLEROSIS 6, WITH NEUROFIBRILLARY TANGLES</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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VCP, ASP395GLY
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<br />
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SNP: rs1828721782,
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ClinVar: RCV001271084, RCV004797923
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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 4 adult patients from 2 unrelated families with frontotemporal dementia without amyotrophic lateral sclerosis (FTDALS6; 613954), Darwich et al. (2020) identified a heterozygous c.1184A-G transition (c.1184A-G, NM_007126.5) in the VCP gene, resulting in an asp395-to-gly (D395G) substitution at a conserved residue in the lid subdomain of the D1 ATPase domain. The mutation, which was found by targeted, whole-exome, or whole-genome sequencing, segregated with the disorder in both families. It was not present in the gnomAD database. The patients presented with the behavioral variant of FTD and did not have signs of myopathy, bone disease, or motor neuron disease. Neuropathologic examination of 1 patient showed frontal atrophy, neuronal vacuolization, and abundant phosphorylated tau (MAPT; 157140) aggregates identical to neurofibrillary tangles (NFT) observed in patients with Alzheimer disease (see, e.g., AD; 104300). The distribution of the vacuoles and NFTs were inversely related: vacuoles were more prominent in the occipital cortex, which showed minimal neurodegeneration, whereas NFTs were more prominent in frontal regions and other areas that showed cerebral atrophy, neuronal loss, and reactive gliosis. TDP43 (605078), beta-amyloid (APP; 104760), SNCA (163890), and prion protein (PRNP; 176640) aggregates were not observed. The pathologic tau distribution was confirmed by brain imaging studies. In vitro functional expression studies showed that the D395G mutation resulted in decreased ATPase activity with a 30% reduction in maximum enzyme velocity compared to controls, which was consistent with a hypomorphic mutation. Additional in vitro studies showed that VCP normally acts as a disaggregase for polyubiquitinated phosphorylated pathologic tau fibrils derived from brains of patients with Alzheimer disease. Cells with the D395G mutation had increased intracellular tau aggregates, suggesting that this specific mutation impairs the turnover of pathologic tau aggregates, resulting in neurodegeneration. Darwich et al. (2020) named this disease 'vacuolar tauopathy' (VT). </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>REFERENCES</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<ol>
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<li>
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<strong>One family, one gene and three phenotypes: a novel VCP (valosin-containing protein) mutation associated with myopathy with rimmed vacuoles, amyotrophic lateral sclerosis and frontotemporal dementia.</strong>
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<strong>2.3 angstrom resolution cryo-EM structure of human p97 and mechanism of allosteric inhibition.</strong>
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Cloutier, P., Lavallee-Adam, M., Faubert, D., Blanchette, M., Coulombe, B.
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<strong>A newly uncovered group of distantly related lysine methyltransferases preferentially interact with molecular chaperones to regulate their activity.</strong>
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<strong>Structure of the Cdc48 segregase in the act of unfolding an authentic substrate.</strong>
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Science 365: 502-505, 2019.
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Custer, S. K., Neumann, M., Lu, H., Wright, A. C., Taylor, J. P.
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Darwich, N. F., Phan, J. M., Kim, B., Suh, E., Papatriantafyllou, J. D., Changolkar, L., Nguyen, A. T., O'Rourke, C. M., He, Z., Porta, S., Gibbons, G. S., Luk, K. C., and 10 others.
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<strong>Autosomal dominant VCP hypomorph mutation impairs disaggregation of PHF-tau.</strong>
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Egerton, M., Ashe, O. R., Chen, D., Druker, B. J., Burgess, W. H., Samelson, L. E.
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<strong>VCP, the mammalian homolog of cdc48, is tyrosine phosphorylated in response to T cell antigen receptor activation.</strong>
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Fielden, J., Wiseman, K., Torrecilla, I., Li, S., Hume, S., Chiang, S. C., Ruggiano, A., Narayan Singh, A., Freire, R., Hassanieh, S., Domingo, E., Vendrell, I., Fischer, R., Kessler, B. M., Maughan, T. S., El-Khamisy, S. F., Ramadan, K.
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Gonzalez, M. A., Feely, S. M., Speziani, F., Strickland, A. V., Danzi, M., Bacon, C., Lee, Y., Chou, T.-F., Blanton, S. H., Weihl, C. C., Zuchner, S., Shy, M. E.
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<strong>A novel mutation in VCP causes Charcot-Marie-Tooth type 2 disease.</strong>
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|
Brain 137: 2897-2902, 2014.
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[PubMed: 25125609]
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[Full Text: https://doi.org/10.1093/brain/awu224]
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<p class="mim-text-font">
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Harley, J., Hagemann, C., Serio, A., Patani, R.
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<strong>FUS is lost from nuclei and gained in neurites of motor neurons in a human stem cell model of VCP-related ALS. (Letter)</strong>
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[PubMed: 33253377]
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[Full Text: https://doi.org/10.1093/brain/awaa339]
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<p class="mim-text-font">
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Haubenberger, D., Bittner, R. E., Rauch-Shorny, S., Zimprich, F., Mannhalter, C., Wagner, L., Mineva, I., Vass, K., Auff, E., Zimprich, A.
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|
<strong>Inclusion body myopathy and Paget disease is linked to a novel mutation in the VCP gene.</strong>
|
|
Neurology 65: 1304-1305, 2005.
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[PubMed: 16247064]
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<li>
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<p class="mim-text-font">
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Higashiyama, H., Hirose, F., Yamaguchi, M., Inoue, Y. H., Fujikake, N., Matsukage, A., Kakizuka, A.
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<strong>Identification of ter94, Drosophila VCP, as a modulator of polyglutamine-induced neurodegeneration.</strong>
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<p class="mim-text-font">
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Hoyle, J., Tan, K. H., Fisher, E. M. C.
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<strong>Mapping the valosin-containing protein (VCP) gene on human chromosome 9 and mouse chromosome 4, and a likely pseudogene on the mouse X chromosome.</strong>
|
|
Mammalian Genome 8: 778-780, 1997.
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[PubMed: 9321476]
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[Full Text: https://doi.org/10.1007/s003359900566]
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</p>
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<li>
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<p class="mim-text-font">
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Jerath, N. U., Crockett, C. D., Moore, S. A., Shy, M. E., Weihl, C. C., Chou, T.-F., Grider, T., Gonzalez, M. A., Zuchner, S., Swenson, A.
|
|
<strong>Rare manifestation of a c.290 C-T, p.gly97glu VCP mutation.</strong>
|
|
Case Rep. Genet. 2015: 239167, 2015. Note: Electronic Article.
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[PubMed: 25878907]
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[Full Text: https://doi.org/10.1155/2015/239167]
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</p>
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<li>
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<p class="mim-text-font">
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Johnson, A. E., Orr, B. O., Fetter, R. D., Moughamian, A. J., Primeaux, L. A., Geier, E. G., Yokoyama, J. S., Miller, B. L., Davis, G. W.
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|
<strong>SVIP is a molecular determinant of lysosomal dynamic stability, neurodegeneration and lifespan.</strong>
|
|
Nature Commun. 12: 513, 2021.
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[PubMed: 33479240]
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[Full Text: https://doi.org/10.1038/s41467-020-20796-8]
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</p>
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</li>
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Ye, Y., Shibata, Y., Yun, C., Ron, D., Rapoport, T. A.
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<strong>A membrane protein complex mediates retro-translocation from the ER lumen into the cytosol.</strong>
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Zhang, B., Tomita, Y., Qiu, Y., He, J., Morii, E., Noguchi, S., Aozasa, K.
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<strong>E74-like factor 2 regulates vasolin-containing protein expression.</strong>
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Zhang, S.-H., Liu, J., Kobayashi, R., Tonks, N. K.
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<strong>Identification of the cell cycle regulator VCP (p97/CDC48) as a substrate of the band 4.1-related protein-tyrosine phosphatase PTPH1.</strong>
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Contributors:
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Bao Lige - updated : 02/25/2025<br>Bao Lige - updated : 11/06/2024<br>Bao Lige - updated : 11/17/2023<br>Carol A. Bocchini - updated : 08/10/2022<br>Bao Lige - updated : 08/01/2022<br>Bao Lige - updated : 03/17/2022<br>Hilary J. Vernon - updated : 03/29/2021<br>Cassandra L. Kniffin - updated : 12/17/2020<br>Ada Hamosh - updated : 06/24/2020<br>Ada Hamosh - updated : 12/09/2019<br>Patricia A. Hartz - updated : 06/20/2017<br>Ada Hamosh - updated : 09/14/2016<br>Cassandra L. Kniffin - updated : 12/10/2015<br>Ada Hamosh - updated : 6/24/2015<br>Ada Hamosh - updated : 12/3/2014<br>Ada Hamosh - updated : 12/2/2014<br>Cassandra L. Kniffin - updated : 1/6/2014<br>Cassandra L. Kniffin - updated : 12/17/2013<br>Patricia A. Hartz - updated : 5/31/2013<br>Cassandra L. Kniffin - updated : 4/25/2012<br>Cassandra L. Kniffin - updated : 12/8/2011<br>George E. Tiller - updated : 12/1/2011<br>Cassandra L. Kniffin - updated : 5/5/2011<br>Cassandra L. Kniffin - updated : 12/21/2009<br>Patricia A. Hartz - updated : 11/10/2009<br>Cassandra L. Kniffin - updated : 10/29/2009<br>Cassandra L. Kniffin - updated : 4/23/2009<br>Cassandra L. Kniffin - updated : 3/23/2009<br>Ada Hamosh - updated : 1/24/2008<br>Cassandra L. Kniffin - updated : 2/5/2007<br>Patricia A. Hartz - updated : 1/4/2007<br>Ada Hamosh - updated : 3/8/2005<br>Ada Hamosh - updated : 7/22/2004<br>Ada Hamosh - updated : 4/2/2004<br>Paul J. Converse - updated : 1/28/2002<br>Ada Hamosh - updated : 1/2/2002<br>Victor A. McKusick - updated : 10/14/1997
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Alan F. Scott : 1/30/1996
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