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<title>
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Entry
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- *605704 - VAMP-ASSOCIATED PROTEIN B AND C; VAPB
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- OMIM
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<div id="mimSearch" class="hidden-print">
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<input type="hidden" id="mimSearchIndex" name="index" value="entry" />
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<input type="hidden" id="mimSearchStart" name="start" value="1" />
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<input type="hidden" id="mimSearchLimit" name="limit" value="10" />
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<input type="search" id="mimEntrySearch" name="search" class="form-control" value="" placeholder="Search OMIM..." maxlength="5000" autocomplete="off" autocorrect="off" autocapitalize="none" spellcheck="false" autofocus />
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Advanced Search
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<li style="margin-left: 0.5em;">
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<a href="/search/advanced/entry"> OMIM </a>
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</li>
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<li style="margin-left: 0.5em;">
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<a href="/search/advanced/clinicalSynopsis"> Clinical Synopses </a>
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<li style="margin-left: 0.5em;">
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<a href="/search/advanced/geneMap"> Gene Map </a>
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</form>
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<p />
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<div class="row">
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*605704</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<li role="presentation">
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<li role="presentation">
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneStructure">Gene Structure</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#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/605704">Table View</a>
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</li>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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</li>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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</li>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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</ul>
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</nav>
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</div>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
|
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000124164;t=ENST00000475243" 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=9217" 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=605704" 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=ENSG00000124164;t=ENST00000475243" 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_001195677,NM_004738,NR_036633,XR_001754433" 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_004738" 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=605704" 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=09300&isoform_id=09300_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/VAPB" 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/4240458,4240460,4759302,7677066,12804585,24638339,32879965,34534085,34535787,37182052,62088910,119595899,119595900,119595901,193784756,193785739,194388736,307574674" 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/O95292" 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=9217" 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=ENSG00000124164;t=ENST00000475243" 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=VAPB" 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=VAPB" 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+9217" 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/VAPB" 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:9217" 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/9217" 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=chr20&hgg_gene=ENST00000475243.6&hgg_start=58389229&hgg_end=58451101&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:12649" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=605704[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=605704[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000124164" 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=VAPB" 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=VAPB" 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=VAPB" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=VAPB&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/PA37273" 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:12649" 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/FBgn0029687.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:1928744" 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/VAPB#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:1928744" 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/9217/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=9217" 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=WBGene00018008;class=Gene" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">WBGene00018008 </a></div><div style="margin-left: 0.5em;"><a href="https://wormbase.org/db/gene/gene?name=WBGene00018354;class=Gene" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">WBGene00018354 </a></div><div style="margin-left: 0.5em;"><a href="https://wormbase.org/db/gene/gene?name=WBGene00022546;class=Gene" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">WBGene00022546 </a></div>
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</div>
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<div><a href="https://zfin.org/ZDB-GENE-030131-2348" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:9217" 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=VAPB&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> 1204350002, 784391002<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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605704
|
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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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VAMP-ASSOCIATED PROTEIN B AND C; VAPB
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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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VAPBC<br />
|
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VESICLE-ASSOCIATED MEMBRANE PROTEIN-ASSOCIATED PROTEIN B<br />
|
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VAMP-ASSOCIATED PROTEIN B<br />
|
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DVAP33A, DROSOPHILA, HOMOLOG OF
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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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<a id="includedTitles" 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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Other entities represented in this entry:
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</span>
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</p>
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</div>
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<div>
|
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<span class="h3 mim-font">
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VAMP-ASSOCIATED PROTEIN C, INCLUDED
|
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</span>
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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=VAPB" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">VAPB</a></em></strong>
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</span>
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</p>
|
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</div>
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<div>
|
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<a id="cytogeneticLocation" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
|
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<strong>
|
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<em>
|
|
Cytogenetic location: <a href="/geneMap/20/421?start=-3&limit=10&highlight=421">20q13.32</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr20:58389229-58451101&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'})">20:58,389,229-58,451,101</a> </span>
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<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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<strong>Gene-Phenotype Relationships</strong>
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Phenotype <br /> MIM number
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20q13.32
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Amyotrophic lateral sclerosis 8
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<a href="/entry/608627"> 608627 </a>
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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Spinal muscular atrophy, late-onset, Finkel type
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<a href="/entry/182980"> 182980 </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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<li><a href="/graph/linear/605704" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
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<li><a href="/graph/radial/605704" 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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<span id="mimDescriptionToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<strong>Description</strong>
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<p>The VAPB gene encodes a protein that is a member of the vesicle-associated membrane protein (VAMP)-associated protein (VAP) family. VAPB plays a role in the unfolded protein response (UPR), a process that suppresses the accumulation of unfolded proteins in the endoplasmic reticulum (ER) (<a href="#6" class="mim-tip-reference" title="Kanekura, K., Nishimoto, I., Aiso, S., Matsuoka, M. <strong>Characterization of amyotrophic lateral sclerosis-linked P56S mutation of vesicle-associated membrane protein-associated protein B (VAPB/ALS8).</strong> J. Biol. Chem. 281: 30223-30233, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16891305/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16891305</a>] [<a href="https://doi.org/10.1074/jbc.M605049200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16891305">Kanekura et al., 2006</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16891305" 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>By searching an EST database for human homologs of the Aplysia 33-kD VAMP-associated protein (Vap33), <a href="#15" class="mim-tip-reference" title="Nishimura, Y., Hayashi, M., Inada, H., Tanaka, T. <strong>Molecular cloning and characterization of mammalian homologues of vesicle-associated membrane protein-associated (VAMP-associated) proteins.</strong> Biochem. Biophys. Res. Commun. 254: 21-26, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9920726/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9920726</a>] [<a href="https://doi.org/10.1006/bbrc.1998.9876" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9920726">Nishimura et al. (1999)</a> identified cDNAs encoding VAPA (<a href="/entry/605703">605703</a>), VAPB, and VAPC. Sequence analysis predicted that the 243-amino acid VAPB protein, which is 60% homologous to VAPA, contains a conserved N-terminal domain, an alpha-helical coiled-coil domain, and a C-terminal transmembrane domain. The 99-amino acid VAPC protein is a splice variant of VAPB that retains the N-terminal 70 residues but lacks the coiled-coil and transmembrane domains. Northern blot analysis detected a major 2.5-kb VAPB transcript and 1.1- and 8.7-kb minor VAPB transcripts in all tissues tested. Expression of VAPB was less intense than that of VAPA or the 1.9-kb VAPC transcript. SDS-PAGE analysis demonstrated that the transmembrane domain of recombinant VAPA interacted with VAPA and VAPB fusion proteins. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9920726" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#5" class="mim-tip-reference" title="De Vos, K. J., Morotz, G. M., Stoica, R., Tudor, E. L., Lau, K.-F., Ackerly, S., Warley, A., Shaw, C. E., Miller, C. C. J. <strong>VAPB interacts with the mitochondrial protein PTPIP51 to regulate calcium homeostasis.</strong> Hum. Molec. Genet. 21: 1299-1311, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22131369/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22131369</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22131369[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/ddr559" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22131369">De Vos et al. (2012)</a> found that a portion of VAPB localized to mitochondria-associated membranes, a specialized ER domain in close apposition with mitochondria. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22131369" 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 immunohistochemical analysis, <a href="#9" class="mim-tip-reference" title="Larroquette, F., Seto, L., Gaub, P. L., Kamal, B., Wallis, D., Lariviere, R., Vallee, J., Robitaille, R., Tsuda, H. <strong>Vapb/amyotrophic lateral sclerosis 8 knock-in mice display slowly progressive motor behavior defects accompanying ER stress and autophagic response.</strong> Hum. Molec. Genet. 24: 6515-6529, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26362257/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26362257</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26362257[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/ddv360" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26362257">Larroquette et al. (2015)</a> found that Vapb was expressed in motor neurons of mouse spinal cord, but not in glial cells or sensory neurons. Little to no Vapb was detected in cerebellum, cerebrum, or hippocampus. In motor neurons, Vapb localized to cell bodies and dendrites and colocalized with ER markers. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26362257" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="geneStructure" class="mim-anchor"></a>
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<h4 href="#mimGeneStructureFold" id="mimGeneStructureToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<span id="mimGeneStructureToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<strong>Gene Structure</strong>
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<p><a href="#3" class="mim-tip-reference" title="Chen, H.-J., Anagnostou, G., Chai, A., Withers, J., Morris, A., Adhikaree, J., Pennetta, G., de Belleroche, J. S. <strong>Characterization of the properties of a novel mutation in VAPB in familial amyotrophic lateral sclerosis.</strong> J. Biol. Chem. 285: 40266-40281, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20940299/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20940299</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20940299[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.M110.161398" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20940299">Chen et al. (2010)</a> noted that the VAPB gene contains 6 exons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20940299" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>Mapping</strong>
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<span class="mim-text-font">
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<p>The finding by <a href="#14" class="mim-tip-reference" title="Nishimura, A. L., Mitne-Neto, M., Silva, H. C. A., Richieri-Costa, A., Middleton, S., Cascio, D., Kok, F., Oliveira, J. R. M., Gillingwater, T., Webb, J., Skehel, P., Zatz, M. <strong>A mutation in the vesicle-trafficking protein VAPB causes late-onset spinal muscular atrophy and amyotrophic lateral sclerosis.</strong> Am. J. Hum. Genet. 75: 822-831, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15372378/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15372378</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15372378[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/10.1086/425287" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15372378">Nishimura et al. (2004)</a> of a missense mutation in the VAPB gene as the cause of a form of amyotrophic lateral sclerosis (ALS8; <a href="/entry/608627">608627</a>), which had been mapped to 20q13.3, demonstrated this as the localization of the VAPB gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15372378" 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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<br />
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<a id="geneFunction" class="mim-anchor"></a>
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<h4 href="#mimGeneFunctionFold" id="mimGeneFunctionToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<p>In COS-7 cells and mouse NSC34 cells, <a href="#6" class="mim-tip-reference" title="Kanekura, K., Nishimoto, I., Aiso, S., Matsuoka, M. <strong>Characterization of amyotrophic lateral sclerosis-linked P56S mutation of vesicle-associated membrane protein-associated protein B (VAPB/ALS8).</strong> J. Biol. Chem. 281: 30223-30233, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16891305/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16891305</a>] [<a href="https://doi.org/10.1074/jbc.M605049200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16891305">Kanekura et al. (2006)</a> demonstrated that wildtype human VABP localized to the endoplasmic reticulum and that its overexpression promoted the unfolded protein response. In contrast, mutant VAPB (P56S; <a href="#0001">605704.0001</a>) was insoluble, shifted to non-ER subcellular locations, and did not induce UPR. Although the studies indicated that mutant VAPB was a loss of function mutation, cotransfection experiments showed that mutant VAPB inhibited the ability of wildtype VAPB to mediate UPR, consistent with a dominant-negative effect. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16891305" 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 immunohistochemistry and Western blot analysis, <a href="#16" class="mim-tip-reference" title="Teuling, E., Ahmed, S., Haasdijk, E., Demmers, J., Steinmetz, M. O., Akhmanova, A., Jaarsma, D., Hoogenraad, C. C. <strong>Motor neuron disease-associated mutant vesicle-associated membrane protein-associated protein (VAP) B recruits wild-type VAPs into endoplasmic reticulum-derived tubular aggregates.</strong> J. Neurosci. 27: 9801-9815, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17804640/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17804640</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17804640[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/10.1523/JNEUROSCI.2661-07.2007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17804640">Teuling et al. (2007)</a> found that VABP was widely expressed in both neuronal and nonneuronal human and mouse cell lines. The protein localized to the endoplasmic reticulum. In the CNS, the highest levels of VABP expression were found in mouse and human spinal cord motor neurons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17804640" 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 yeast 2-hybrid and coimmunoprecipitation analyses, <a href="#5" class="mim-tip-reference" title="De Vos, K. J., Morotz, G. M., Stoica, R., Tudor, E. L., Lau, K.-F., Ackerly, S., Warley, A., Shaw, C. E., Miller, C. C. J. <strong>VAPB interacts with the mitochondrial protein PTPIP51 to regulate calcium homeostasis.</strong> Hum. Molec. Genet. 21: 1299-1311, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22131369/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22131369</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22131369[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/ddr559" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22131369">De Vos et al. (2012)</a> found that endogenous human VAPB interacted with the outer mitochondrial membrane protein PTPIP51 (FAM82A2; <a href="/entry/611873">611873</a>). The cytoplasmic N-terminal domain of VAPB specifically interacted with the cytoplasmic C-terminal domain of PTPIP51. Knockdown of either VAPB or PTPIP51 in HEK293 cells delayed mitochondrial calcium uptake following IP3R (ITPR1; <a href="/entry/147265">147265</a>)-induced calcium release from ER stores, resulting in increased peak cytosolic calcium concentration. <a href="#5" class="mim-tip-reference" title="De Vos, K. J., Morotz, G. M., Stoica, R., Tudor, E. L., Lau, K.-F., Ackerly, S., Warley, A., Shaw, C. E., Miller, C. C. J. <strong>VAPB interacts with the mitochondrial protein PTPIP51 to regulate calcium homeostasis.</strong> Hum. Molec. Genet. 21: 1299-1311, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22131369/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22131369</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22131369[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/ddr559" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22131369">De Vos et al. (2012)</a> concluded that PTPIP51 directs VAPB localization to mitochondria-associated membranes and that both VAPB and PTPIP51 are involved in calcium exchange between the ER and mitochondria. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22131369" 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 spectrometry and immunoprecipitation analysis in transfected COS-7 cells, <a href="#4" class="mim-tip-reference" title="Costello, J. L., Castro, I. G., Schrader, T. A., Islinger, M., Schrader, M. <strong>Peroxisomal ACBD4 interacts with VAPB and promotes ER-peroxisome associations.</strong> Cell Cycle 16: 1039-1045, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28463579/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28463579</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28463579[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1080/15384101.2017.1314422" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28463579">Costello et al. (2017)</a> showed that ACBD4 (<a href="/entry/619968">619968</a>) isoform-2 interacted with VAPB. Coexpression of ACBD4 isoform-2 and VAPB promoted ER-peroxisome associations in COS-7 cells, suggesting a role for ACBD4 and VAPB interaction in ER-peroxisome tethering. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28463579" 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 the study of candidate genes within the region of 20q13.3 that showed linkage to an form of ALS called ALS8 (<a href="/entry/608627">608627</a>), <a href="#14" class="mim-tip-reference" title="Nishimura, A. L., Mitne-Neto, M., Silva, H. C. A., Richieri-Costa, A., Middleton, S., Cascio, D., Kok, F., Oliveira, J. R. M., Gillingwater, T., Webb, J., Skehel, P., Zatz, M. <strong>A mutation in the vesicle-trafficking protein VAPB causes late-onset spinal muscular atrophy and amyotrophic lateral sclerosis.</strong> Am. J. Hum. Genet. 75: 822-831, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15372378/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15372378</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15372378[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/10.1086/425287" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15372378">Nishimura et al. (2004)</a> identified a novel mutation in the VAPB gene (P56S; <a href="#0001">605704.0001</a>). Subsequently, they identified the same mutation in patients from 6 additional kindreds but with different clinical courses, such as ALS8, late-onset spinal muscular atrophy (<a href="/entry/182980">182980</a>), and a typical severe ALS with rapid progression. Although it was not possible to link all of these families, haplotype analysis suggested a founder effect. Members of the vesicle-associated proteins are intracellular membrane proteins that can associate with microtubules and have been shown to have a function in membrane transport. The data suggested that clinically variable motor neuron diseases may be caused by dysfunction in intracellular membrane trafficking. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15372378" 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="Kirby, J., Hewamadduma, C. A. A., Hartley, J. A., Nixon, H. C., Evans, H., Wadhwa, R. R., Kershaw, C., Ince, P. G., Shaw, P. J. <strong>Mutations in VAPB are not associated with sporadic ALS.</strong> Neurology 68: 1951-1953, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17536055/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17536055</a>] [<a href="https://doi.org/10.1212/01.wnl.0000263195.50981.a6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17536055">Kirby et al. (2007)</a> did not identify mutations in the VAPB gene in 301 cases of ALS from the United Kingdom, including 23 familial and 278 sporadic cases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17536055" 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="Landers, J. E., Leclerc, A. L., Shi, L., Virkud, A., Cho, T., Maxwell, M. M., Henry, A. F., Polak, N., Glass, J. D., Kwiatkowski, T. J., Al-Chalabi, A., Shaw, C. E., Leigh, P. N., Rodriguez-Leyza, I., McKenna-Yasek, D., Sapp, P. C., Brown, R. H., Jr. <strong>New VAPB deletion variant and exclusion of VAPB mutations in familial ALS.</strong> Neurology 70: 1179-1185, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18322265/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18322265</a>] [<a href="https://doi.org/10.1212/01.wnl.0000289760.85237.4e" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18322265">Landers et al. (2008)</a> identified a P56S mutation in the VAPB gene in 1 of 80 families with ALS. The family with the mutation was of Brazilian origin. No other clearly pathogenic mutations were identified. In 1 other family, they identified a 3-bp in-frame deletion (478delCTT), resulting in loss of ser160, that was also found in 0.45% of controls. In vitro expression studies of del-ser160 VAPB showed wildtype cytoplasmic localization. <a href="#8" class="mim-tip-reference" title="Landers, J. E., Leclerc, A. L., Shi, L., Virkud, A., Cho, T., Maxwell, M. M., Henry, A. F., Polak, N., Glass, J. D., Kwiatkowski, T. J., Al-Chalabi, A., Shaw, C. E., Leigh, P. N., Rodriguez-Leyza, I., McKenna-Yasek, D., Sapp, P. C., Brown, R. H., Jr. <strong>New VAPB deletion variant and exclusion of VAPB mutations in familial ALS.</strong> Neurology 70: 1179-1185, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18322265/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18322265</a>] [<a href="https://doi.org/10.1212/01.wnl.0000289760.85237.4e" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18322265">Landers et al. (2008)</a> concluded that VAPB mutations are not a common cause of ALS and that the 3-bp deletion they identified in 1 family was not causative for the disorder. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18322265" 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 1 of 107 non-Brazilian probands with ALS, <a href="#3" class="mim-tip-reference" title="Chen, H.-J., Anagnostou, G., Chai, A., Withers, J., Morris, A., Adhikaree, J., Pennetta, G., de Belleroche, J. S. <strong>Characterization of the properties of a novel mutation in VAPB in familial amyotrophic lateral sclerosis.</strong> J. Biol. Chem. 285: 40266-40281, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20940299/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20940299</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20940299[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.M110.161398" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20940299">Chen et al. (2010)</a> identified a heterozygous mutation in the VAPB gene (T46I; <a href="#0002">605704.0002</a>). In vitro functional expression studies in COS-7 and neuronal cells showed that the T46I mutation formed intracellular protein aggregates and ubiquitin aggregates, ultimately resulting in cell death. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20940299" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#2" class="mim-tip-reference" title="Chai, A., Withers, J., Koh, Y. H., Parry, K., Bao, H., Zhang, B., Budnik, V., Pennetta, G. <strong>hVAPB, the causative gene of a heterogeneous group of motor neuron diseases in humans, is functionally interchangeable with its Drosophila homologue DVAP-33A at the neuromuscular junction.</strong> Hum. Molec. Genet. 17: 266-280, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17947296/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17947296</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17947296[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/ddm303" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17947296">Chai et al. (2008)</a> demonstrated that the Drosophila Dvap33a gene is the structural and functional homolog of the human VAPB gene. Hypomorphic and null Dvap33a alleles expressed in neurons caused a severe decrease in bouton number and an increase in bouton size. Conversely, overexpression of Dvap33a in neurons induced a highly significant increase in the number of boutons with a concomitant decrease in their size. Electrophysiologic and electron microscopic studies showed that these structural alterations were associated with compensatory changes in the physiology and ultrastructure of synapses, which maintained evoked responses within normal boundaries. These compensatory changes were determined by changes in expression of glutamate receptor subunits. Targeted expression of human VAPB in Drosophila neurons with hypomorphic or null Dvap33a alleles rescued the morphologic and electrophysiologic mutant phenotype. Transgenic expression of mutant Dvap33a in Drosophila recapitulated major hallmarks of human neuronal diseases, including locomotion defects and neuronal death with aggregate formation. The findings implicated a role for human VAPB in synaptic homeostasis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17947296" 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 transgenic mice, <a href="#1" class="mim-tip-reference" title="Aliaga, L., Lai, C., Yu, J., Chub, N., Shim, H., Sun, L., Zie, C., Yang, W.-J., Lin, X., O'Donovan, M. J., Cai, H. <strong>Amyotrophic lateral sclerosis-related VAPB P56S mutation differentially affects the function and survival of corticospinal and spinal motor neurons.</strong> Hum. Molec. Genet. 22: 4293-4305, 2013. Note: Erratum: Hum. Molec. Genet. 23: 3069 only, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23771029/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23771029</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23771029[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/ddt279" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23771029">Aliaga et al. (2013)</a> found that expression of human VAPB with the P56S mutation caused various motor behavioral abnormalities, including progressive hyperactivity. Accumulation of mutant VAPB triggered ER stress, leading to increased proapoptotic Chop (DDIT3; <a href="/entry/126337">126337</a>) expression in both corticospinal and spinal motor neurons. Mutant transgenic mice experienced significant loss of corticospinal motor neurons, but no obvious degeneration of spinal motor neurons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23771029" 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="#12" class="mim-tip-reference" title="Moustaqim-Barrette, A., Lin, Y. Q., Pradhan, S., Neely, G. G., Bellen, H. J., Tsuda, H. <strong>The amyotrophic lateral sclerosis 8 protein, VAP, is required for ER protein quality control.</strong> Hum. Molec. Genet. 23: 1975-1989, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24271015/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24271015</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24271015[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/ddt594" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24271015">Moustaqim-Barrette et al. (2014)</a> found that cortical neurons of vap-null Drosophila showed ER stress with accumulation of ubiquitinated proteins, concomitant with development of a progressive flight defect. Loss of vap also caused redistribution of oxysterol-binding protein (OSBP; <a href="/entry/167040">167040</a>) from ER to Golgi. Flies expressing vap with an ALS8 mutation (P56S) showed a less severe phenotype than vap-null flies. Expression of human OSBPL8 (<a href="/entry/606736">606736</a>), which lacks the vap-binding sequence found in Drosophila osbp, attenuated ER stress and accumulation of ubiquitinated proteins and partly rescued the flight defect in vap-null flies and flies with the ALS8 mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24271015" 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="Larroquette, F., Seto, L., Gaub, P. L., Kamal, B., Wallis, D., Lariviere, R., Vallee, J., Robitaille, R., Tsuda, H. <strong>Vapb/amyotrophic lateral sclerosis 8 knock-in mice display slowly progressive motor behavior defects accompanying ER stress and autophagic response.</strong> Hum. Molec. Genet. 24: 6515-6529, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26362257/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26362257</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26362257[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/ddv360" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26362257">Larroquette et al. (2015)</a> replaced the wildtype Vapb gene in mice with P56S mutant Vapb. Heterozygous and homozygous P56S Vapb knockin mice were obtained at the expected mendelian ratio, developed normally, and had life spans similar to wildtype mice. However, heterozygous and homozygous P56S Vapb knockin mice showed dose- and age-dependent defects in motor tasks compared with wildtype mice. P56S Vapb knockin mice also showed age- and dose-dependent cellular pathologic defects in motor neurons, with loss of P56S Vapb in the ER and accumulation of the mutant protein in cytoplasmic inclusions, where it localized with ubiquitinated proteins. P56S Vapb knockin motor neurons showed chronic mild atrophy, induction of ER stress, and autophagic response prior to onset of motor defect. Soleus muscle of P56S Vapb knockin mice showed mild partial denervation and morphologic changes at synaptic boutons at neuromuscular junctions. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26362257" 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>ALLELIC VARIANTS (<a href="/help/faq#1_4"></strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=605704[MIM]" class="btn btn-default mim-tip-hint" role="button" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs74315431 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs74315431;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/rs74315431?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=rs74315431" 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=rs74315431" 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 large white Brazilian family with amyotrophic lateral sclerosis (ALS8; <a href="/entry/608627">608627</a>), <a href="#14" class="mim-tip-reference" title="Nishimura, A. L., Mitne-Neto, M., Silva, H. C. A., Richieri-Costa, A., Middleton, S., Cascio, D., Kok, F., Oliveira, J. R. M., Gillingwater, T., Webb, J., Skehel, P., Zatz, M. <strong>A mutation in the vesicle-trafficking protein VAPB causes late-onset spinal muscular atrophy and amyotrophic lateral sclerosis.</strong> Am. J. Hum. Genet. 75: 822-831, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15372378/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15372378</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15372378[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/10.1086/425287" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15372378">Nishimura et al. (2004)</a> found a heterozygous 166C-T transition in exon 2 of the VAPB gene, leading to a pro56-to-ser (P56S) mutation. Subsequently the authors demonstrated the same mutation in patients from 6 additional kindreds in which the clinical course varied, including some with late-onset spinal muscular atrophy (Finkel type; <a href="/entry/182980">182980</a>) and some with typical severe ALS with rapid progression (see <a href="/entry/105400">105400</a>). Although it was not possible to link all of these families, haplotype analysis suggested founder effect. In vitro functional expression studies in rat hippocampal neurons and HEK293 cells showed that the P56S mutation disrupted the normal subcellular distribution of the VAPB protein and caused intracellular aggregates. Unlike the wildtype protein, the mutant P56S protein did not colocalize with either the Golgi apparatus or the endoplasmic reticulum (ER). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15372378" 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="#13" class="mim-tip-reference" title="Nishimura, A. L., Al-Chalabi, A., Zatz, M. <strong>A common founder for amyotrophic lateral sclerosis type 8 (ALS8) in the Brazilian population.</strong> Hum. Genet. 118: 499-500, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16187141/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16187141</a>] [<a href="https://doi.org/10.1007/s00439-005-0031-y" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16187141">Nishimura et al. (2005)</a> analyzed 7 polymorphic markers around the VAPB gene in an index case from each of the Brazilian families with P56S mutation previously reported by <a href="#14" class="mim-tip-reference" title="Nishimura, A. L., Mitne-Neto, M., Silva, H. C. A., Richieri-Costa, A., Middleton, S., Cascio, D., Kok, F., Oliveira, J. R. M., Gillingwater, T., Webb, J., Skehel, P., Zatz, M. <strong>A mutation in the vesicle-trafficking protein VAPB causes late-onset spinal muscular atrophy and amyotrophic lateral sclerosis.</strong> Am. J. Hum. Genet. 75: 822-831, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15372378/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15372378</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15372378[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/10.1086/425287" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15372378">Nishimura et al. (2004)</a> and in 9 Brazilian Portuguese controls. They found evidence for a common founder for all families regardless of ancestry, with a founding event 23 generations ago, consistent with the Portuguese colonization of Brazil. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15372378+16187141" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#16" class="mim-tip-reference" title="Teuling, E., Ahmed, S., Haasdijk, E., Demmers, J., Steinmetz, M. O., Akhmanova, A., Jaarsma, D., Hoogenraad, C. C. <strong>Motor neuron disease-associated mutant vesicle-associated membrane protein-associated protein (VAP) B recruits wild-type VAPs into endoplasmic reticulum-derived tubular aggregates.</strong> J. Neurosci. 27: 9801-9815, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17804640/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17804640</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17804640[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/10.1523/JNEUROSCI.2661-07.2007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17804640">Teuling et al. (2007)</a> found that the P56S mutant protein formed cytosolic aggregates in all cell types examined, including mouse and human nonneuronal cells. These aggregates did not colocalize with markers for the ER. Further studies showed that the mutant protein acted in a dominant-negative manner by recruiting wildtype VAPB to the aggregates and disrupting normal protein and cellular function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17804640" 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="Landers, J. E., Leclerc, A. L., Shi, L., Virkud, A., Cho, T., Maxwell, M. M., Henry, A. F., Polak, N., Glass, J. D., Kwiatkowski, T. J., Al-Chalabi, A., Shaw, C. E., Leigh, P. N., Rodriguez-Leyza, I., McKenna-Yasek, D., Sapp, P. C., Brown, R. H., Jr. <strong>New VAPB deletion variant and exclusion of VAPB mutations in familial ALS.</strong> Neurology 70: 1179-1185, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18322265/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18322265</a>] [<a href="https://doi.org/10.1212/01.wnl.0000289760.85237.4e" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18322265">Landers et al. (2008)</a> identified the P56S mutation in affected members of a Brazilian family with ALS. The mean age at onset was between 45 and 55 years with survival varying from 5 to 18 years. The mutation was not identified in 79 additional ALS families. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18322265" 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="Millecamps, S., Salachas, F., Cazeneuve, C., Gordon, P., Bricka, B., Camuzat, A., Guillot-Noel, L., Russaouen, O., Bruneteau, G., Pradat, P.-F., Le Forestier, N., Vandenberghe, N., and 14 others. <strong>SOD1, ANG, VAPB, TARDBP, and FUS mutations in familial amyotrophic lateral sclerosis: genotype-phenotype correlations.</strong> J. Med. Genet. 47: 554-560, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20577002/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20577002</a>] [<a href="https://doi.org/10.1136/jmg.2010.077180" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20577002">Millecamps et al. (2010)</a> identified the P56S mutation in 1 (0.6%) of 162 French probands with familial ALS. The patient was of Japanese descent, representing the first non-Brazilian reported to carry this mutation. Three other family members had motor neuron disease, suggesting autosomal dominant inheritance. The patient had long disease duration with onset in the legs during the sixth decade. <a href="#10" class="mim-tip-reference" title="Millecamps, S., Salachas, F., Cazeneuve, C., Gordon, P., Bricka, B., Camuzat, A., Guillot-Noel, L., Russaouen, O., Bruneteau, G., Pradat, P.-F., Le Forestier, N., Vandenberghe, N., and 14 others. <strong>SOD1, ANG, VAPB, TARDBP, and FUS mutations in familial amyotrophic lateral sclerosis: genotype-phenotype correlations.</strong> J. Med. Genet. 47: 554-560, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20577002/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20577002</a>] [<a href="https://doi.org/10.1136/jmg.2010.077180" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20577002">Millecamps et al. (2010)</a> suggested that the finding of the P56S mutation in a Japanese patient may reflect the Portuguese trading connection with the Far East and Brazil in the mid-16th century. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20577002" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#5" class="mim-tip-reference" title="De Vos, K. J., Morotz, G. M., Stoica, R., Tudor, E. L., Lau, K.-F., Ackerly, S., Warley, A., Shaw, C. E., Miller, C. C. J. <strong>VAPB interacts with the mitochondrial protein PTPIP51 to regulate calcium homeostasis.</strong> Hum. Molec. Genet. 21: 1299-1311, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22131369/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22131369</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22131369[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/ddr559" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22131369">De Vos et al. (2012)</a> found that VAPB with the P56S mutation showed significantly higher affinity than wildtype for the outer mitochondrial membrane protein PTPIP51 (FAM82A2; <a href="/entry/611873">611873</a>). Increased binding with PTPIP51 resulted in accumulation of VAPB at mitochondria-associated membranes in the ER and elevated calcium uptake by mitochondria following release of calcium from ER stores. Expression of human VAPB with the P56S mutation also disturbed calcium handling in cultured rat cortical neurons following depolarization. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22131369" 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 cultured embryonic rat cortical neurons, <a href="#11" class="mim-tip-reference" title="Morotz, G. M., De Vos, K. J., Vagnoni, A., Ackerley, S., Shaw, C. E., Miller, C. C. J. <strong>Amyotrophic lateral sclerosis-associated mutant VAPBP56S perturbs calcium homeostasis to disrupt axonal transport of mitochondria.</strong> Hum. Molec. Genet. 21: 1979-1988, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22258555/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22258555</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22258555[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/dds011" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22258555">Morotz et al. (2012)</a> found that expression of human VAPB with the P56S mutation (VAPB-P56S) significantly slowed anterograde axonal transport of mitochondria. Studies in rat neurons and HEK293 cells showed that expression of VAPB-P56S increased resting intracellular Ca(2+) concentration and disrupted the interaction between tubulin (see <a href="/entry/191130">191130</a>) and the mitochondrial membrane Rho GTPase MIRO1 (RHOT1; <a href="/entry/613888">613888</a>). Expression of VAPB-P56S had no effect on the amount of TRAK1 (<a href="/entry/608112">608112</a>) or kinesin-1 (see <a href="/entry/602809">602809</a>) associated with MIRO1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22258555" 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">rs281875284 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs281875284;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=rs281875284" 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=rs281875284" 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=RCV000023467 OR RCV000059634" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000023467, RCV000059634" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000023467...</a>
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<p>In a non-Brazilian patient with amyotrophic lateral sclerosis-8 (ALS8; <a href="/entry/608627">608627</a>), <a href="#3" class="mim-tip-reference" title="Chen, H.-J., Anagnostou, G., Chai, A., Withers, J., Morris, A., Adhikaree, J., Pennetta, G., de Belleroche, J. S. <strong>Characterization of the properties of a novel mutation in VAPB in familial amyotrophic lateral sclerosis.</strong> J. Biol. Chem. 285: 40266-40281, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20940299/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20940299</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20940299[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.M110.161398" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20940299">Chen et al. (2010)</a> identified a heterozygous 137C-T transition in the VAPB gene, resulting in a thr46-to-ile (T46I) substitution in a highly conserved residue important for the interaction with lipid-binding proteins. The mutation was found in 1 of 107 probands with familial ALS and was not found in 257 controls. The 73-year-old male patient presented with wasting of the small muscles of the hands. He also had fasciculations of the leg, and later developed speech and swallowing difficulties. The diagnosis was confirmed by nerve conduction studies. The patient had a brother with ALS who died within 4 months of diagnosis from pneumonia, but DNA was not available for testing. In vitro functional expression studies in COS-7 cells and neuronal showed that the T46I mutation formed intracellular protein aggregates and ubiquitin aggregates, ultimately resulting in cell death. The mutant protein was unable to activate the unfolded protein response pathway, as measured by lack of activation of IRE1 (ERN1; <a href="/entry/604033">604033</a>), and the effect was dominant-negative. Expression of the equivalent T48I mutation in Drosophila resulted in aggregate formation in neurons and nerve fibers, cell degeneration, fragmentation of the endoplasmic reticulum, and upregulation of chaperone proteins. Muscle was also adversely affected. <a href="#3" class="mim-tip-reference" title="Chen, H.-J., Anagnostou, G., Chai, A., Withers, J., Morris, A., Adhikaree, J., Pennetta, G., de Belleroche, J. S. <strong>Characterization of the properties of a novel mutation in VAPB in familial amyotrophic lateral sclerosis.</strong> J. Biol. Chem. 285: 40266-40281, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20940299/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20940299</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20940299[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.M110.161398" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20940299">Chen et al. (2010)</a> also postulated that disturbances in lipid metabolism may play a role in the pathogenesis of ALS. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20940299" 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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[<a href="https://doi.org/10.1093/hmg/ddt279" target="_blank">Full Text</a>]
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Chai, A., Withers, J., Koh, Y. H., Parry, K., Bao, H., Zhang, B., Budnik, V., Pennetta, G.
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<strong>hVAPB, the causative gene of a heterogeneous group of motor neuron diseases in humans, is functionally interchangeable with its Drosophila homologue DVAP-33A at the neuromuscular junction.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17947296/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17947296</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17947296[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=17947296" 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/ddm303" target="_blank">Full Text</a>]
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Chen, H.-J., Anagnostou, G., Chai, A., Withers, J., Morris, A., Adhikaree, J., Pennetta, G., de Belleroche, J. S.
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<strong>Characterization of the properties of a novel mutation in VAPB in familial amyotrophic lateral sclerosis.</strong>
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J. Biol. Chem. 285: 40266-40281, 2010.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20940299/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20940299</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20940299[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=20940299" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1074/jbc.M110.161398" target="_blank">Full Text</a>]
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Costello, J. L., Castro, I. G., Schrader, T. A., Islinger, M., Schrader, M.
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<strong>Peroxisomal ACBD4 interacts with VAPB and promotes ER-peroxisome associations.</strong>
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Cell Cycle 16: 1039-1045, 2017.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28463579/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28463579</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28463579[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=28463579" 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/10.1080/15384101.2017.1314422" target="_blank">Full Text</a>]
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De Vos, K. J., Morotz, G. M., Stoica, R., Tudor, E. L., Lau, K.-F., Ackerly, S., Warley, A., Shaw, C. E., Miller, C. C. J.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22131369/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22131369</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22131369[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=22131369" 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/ddr559" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1074/jbc.M605049200" target="_blank">Full Text</a>]
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<a id="Kirby2007" class="mim-anchor"></a>
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Kirby, J., Hewamadduma, C. A. A., Hartley, J. A., Nixon, H. C., Evans, H., Wadhwa, R. R., Kershaw, C., Ince, P. G., Shaw, P. J.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17536055/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17536055</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17536055" 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/10.1212/01.wnl.0000263195.50981.a6" target="_blank">Full Text</a>]
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Landers, J. E., Leclerc, A. L., Shi, L., Virkud, A., Cho, T., Maxwell, M. M., Henry, A. F., Polak, N., Glass, J. D., Kwiatkowski, T. J., Al-Chalabi, A., Shaw, C. E., Leigh, P. N., Rodriguez-Leyza, I., McKenna-Yasek, D., Sapp, P. C., Brown, R. H., Jr.
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<strong>New VAPB deletion variant and exclusion of VAPB mutations in familial ALS.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18322265/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18322265</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18322265" 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/10.1212/01.wnl.0000289760.85237.4e" target="_blank">Full Text</a>]
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<a id="Larroquette2015" class="mim-anchor"></a>
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Larroquette, F., Seto, L., Gaub, P. L., Kamal, B., Wallis, D., Lariviere, R., Vallee, J., Robitaille, R., Tsuda, H.
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Hum. Molec. Genet. 24: 6515-6529, 2015.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26362257/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26362257</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26362257[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=26362257" 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/ddv360" target="_blank">Full Text</a>]
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Millecamps, S., Salachas, F., Cazeneuve, C., Gordon, P., Bricka, B., Camuzat, A., Guillot-Noel, L., Russaouen, O., Bruneteau, G., Pradat, P.-F., Le Forestier, N., Vandenberghe, N., and 14 others.
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<strong>SOD1, ANG, VAPB, TARDBP, and FUS mutations in familial amyotrophic lateral sclerosis: genotype-phenotype correlations.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20577002/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20577002</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20577002" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1136/jmg.2010.077180" target="_blank">Full Text</a>]
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<a id="Morotz2012" class="mim-anchor"></a>
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Morotz, G. M., De Vos, K. J., Vagnoni, A., Ackerley, S., Shaw, C. E., Miller, C. C. J.
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<strong>Amyotrophic lateral sclerosis-associated mutant VAPBP56S perturbs calcium homeostasis to disrupt axonal transport of mitochondria.</strong>
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Hum. Molec. Genet. 21: 1979-1988, 2012.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22258555/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22258555</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22258555[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=22258555" 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/dds011" target="_blank">Full Text</a>]
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<a id="Moustaqim-Barrette2014" class="mim-anchor"></a>
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Moustaqim-Barrette, A., Lin, Y. Q., Pradhan, S., Neely, G. G., Bellen, H. J., Tsuda, H.
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<strong>The amyotrophic lateral sclerosis 8 protein, VAP, is required for ER protein quality control.</strong>
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Hum. Molec. Genet. 23: 1975-1989, 2014.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24271015/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24271015</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24271015[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=24271015" 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/ddt594" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="13" class="mim-anchor"></a>
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<a id="Nishimura2005" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Nishimura, A. L., Al-Chalabi, A., Zatz, M.
|
|
<strong>A common founder for amyotrophic lateral sclerosis type 8 (ALS8) in the Brazilian population.</strong>
|
|
Hum. Genet. 118: 499-500, 2005.
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|
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16187141/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16187141</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16187141" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1007/s00439-005-0031-y" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="14" class="mim-anchor"></a>
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<a id="Nishimura2004" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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|
Nishimura, A. L., Mitne-Neto, M., Silva, H. C. A., Richieri-Costa, A., Middleton, S., Cascio, D., Kok, F., Oliveira, J. R. M., Gillingwater, T., Webb, J., Skehel, P., Zatz, M.
|
|
<strong>A mutation in the vesicle-trafficking protein VAPB causes late-onset spinal muscular atrophy and amyotrophic lateral sclerosis.</strong>
|
|
Am. J. Hum. Genet. 75: 822-831, 2004.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15372378/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15372378</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15372378[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=15372378" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1086/425287" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="15" class="mim-anchor"></a>
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<a id="Nishimura1999" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
|
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Nishimura, Y., Hayashi, M., Inada, H., Tanaka, T.
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|
<strong>Molecular cloning and characterization of mammalian homologues of vesicle-associated membrane protein-associated (VAMP-associated) proteins.</strong>
|
|
Biochem. Biophys. Res. Commun. 254: 21-26, 1999.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9920726/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9920726</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9920726" 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/10.1006/bbrc.1998.9876" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="16" class="mim-anchor"></a>
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<a id="Teuling2007" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Teuling, E., Ahmed, S., Haasdijk, E., Demmers, J., Steinmetz, M. O., Akhmanova, A., Jaarsma, D., Hoogenraad, C. C.
|
|
<strong>Motor neuron disease-associated mutant vesicle-associated membrane protein-associated protein (VAP) B recruits wild-type VAPs into endoplasmic reticulum-derived tubular aggregates.</strong>
|
|
J. Neurosci. 27: 9801-9815, 2007.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17804640/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17804640</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17804640[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=17804640" 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/10.1523/JNEUROSCI.2661-07.2007" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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</ol>
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<div>
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<br />
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</div>
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</div>
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<div>
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<a id="contributors" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="mim-text-font">
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Bao Lige - updated : 07/21/2022
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseContributors">
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<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Patricia A. Hartz - updated : 2/29/2016<br>Patricia A. Hartz - updated : 5/19/2015<br>Patricia A. Hartz - updated : 2/20/2015<br>Patricia A. Hartz - updated : 7/26/2013<br>Patricia A. Hartz - updated : 7/16/2013<br>Cassandra L. Kniffin - updated : 12/22/2010<br>Cassandra L. Kniffin - updated : 9/27/2010<br>Cassandra L. Kniffin - updated : 4/29/2009<br>Cassandra L. Kniffin - updated : 10/17/2008<br>Cassandra L. Kniffin - updated : 11/29/2007<br>Cassandra L. Kniffin - updated : 2/20/2007<br>Marla J. F. O'Neill - updated : 2/15/2006<br>Victor A. McKusick - updated : 10/21/2004
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="creationDate" class="mim-anchor"></a>
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<div class="row">
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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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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Paul J. Converse : 2/28/2001
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="editHistory" class="mim-anchor"></a>
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<div class="row">
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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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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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mgross : 07/21/2022
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseEditHistory">
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 07/20/2022<br>carol : 07/19/2022<br>alopez : 07/18/2022<br>carol : 03/31/2021<br>alopez : 08/11/2016<br>mgross : 02/29/2016<br>mgross : 2/29/2016<br>carol : 12/30/2015<br>mgross : 7/10/2015<br>mcolton : 5/19/2015<br>mgross : 3/2/2015<br>mcolton : 2/20/2015<br>mgross : 7/26/2013<br>mgross : 7/16/2013<br>mgross : 7/16/2013<br>wwang : 1/5/2011<br>ckniffin : 12/22/2010<br>wwang : 9/29/2010<br>ckniffin : 9/27/2010<br>wwang : 5/19/2009<br>ckniffin : 4/29/2009<br>wwang : 10/20/2008<br>ckniffin : 10/17/2008<br>wwang : 12/6/2007<br>ckniffin : 11/29/2007<br>wwang : 2/22/2007<br>ckniffin : 2/20/2007<br>wwang : 2/23/2006<br>terry : 2/15/2006<br>alopez : 10/25/2004<br>terry : 10/21/2004<br>mgross : 2/28/2001
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</span>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<div class="container visible-print-block">
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<div class="row">
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<div class="col-md-8 col-md-offset-1">
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<div>
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<div>
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<h3>
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<span class="mim-font">
|
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<strong>*</strong> 605704
|
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</span>
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</h3>
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</div>
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<div>
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<h3>
|
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<span class="mim-font">
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|
|
VAMP-ASSOCIATED PROTEIN B AND C; VAPB
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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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<div >
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<p>
|
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<span class="mim-font">
|
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<em>Alternative titles; symbols</em>
|
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</span>
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</p>
|
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</div>
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
VAPBC<br />
|
|
VESICLE-ASSOCIATED MEMBRANE PROTEIN-ASSOCIATED PROTEIN B<br />
|
|
VAMP-ASSOCIATED PROTEIN B<br />
|
|
DVAP33A, DROSOPHILA, HOMOLOG OF
|
|
</span>
|
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</h4>
|
|
</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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<p>
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<span class="mim-font">
|
|
Other entities represented in this entry:
|
|
</span>
|
|
</p>
|
|
</div>
|
|
<div>
|
|
<span class="h3 mim-font">
|
|
VAMP-ASSOCIATED PROTEIN C, INCLUDED
|
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</span>
|
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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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<p>
|
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<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: VAPB</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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<p>
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<span class="mim-text-font">
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|
<strong>SNOMEDCT:</strong> 1204350002, 784391002;
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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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<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: 20q13.32
|
|
|
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Genomic coordinates <span class="small">(GRCh38)</span> : 20:58,389,229-58,451,101 </span>
|
|
</em>
|
|
</strong>
|
|
<span class="small">(from NCBI)</span>
|
|
</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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<h4>
|
|
<span class="mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
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</span>
|
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</h4>
|
|
<div>
|
|
<table class="table table-bordered table-condensed small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
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<th>
|
|
Location
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</th>
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<th>
|
|
Phenotype
|
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</th>
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<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
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</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
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</th>
|
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</tr>
|
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</thead>
|
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<tbody>
|
|
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<tr>
|
|
<td rowspan="2">
|
|
<span class="mim-font">
|
|
20q13.32
|
|
</span>
|
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</td>
|
|
|
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|
|
<td>
|
|
<span class="mim-font">
|
|
Amyotrophic lateral sclerosis 8
|
|
</span>
|
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</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
608627
|
|
</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
Autosomal dominant
|
|
</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
3
|
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</span>
|
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</td>
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</tr>
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<tr>
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<td>
|
|
<span class="mim-font">
|
|
Spinal muscular atrophy, late-onset, Finkel type
|
|
</span>
|
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</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
182980
|
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</span>
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</td>
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<td>
|
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<span class="mim-font">
|
|
Autosomal dominant
|
|
</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
3
|
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</span>
|
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
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|
<h4>
|
|
<span class="mim-font">
|
|
<strong>TEXT</strong>
|
|
</span>
|
|
</h4>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Description</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
|
<span class="mim-text-font">
|
|
<p>The VAPB gene encodes a protein that is a member of the vesicle-associated membrane protein (VAMP)-associated protein (VAP) family. VAPB plays a role in the unfolded protein response (UPR), a process that suppresses the accumulation of unfolded proteins in the endoplasmic reticulum (ER) (Kanekura et al., 2006). </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
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|
|
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|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Cloning and Expression</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<span class="mim-text-font">
|
|
<p>By searching an EST database for human homologs of the Aplysia 33-kD VAMP-associated protein (Vap33), Nishimura et al. (1999) identified cDNAs encoding VAPA (605703), VAPB, and VAPC. Sequence analysis predicted that the 243-amino acid VAPB protein, which is 60% homologous to VAPA, contains a conserved N-terminal domain, an alpha-helical coiled-coil domain, and a C-terminal transmembrane domain. The 99-amino acid VAPC protein is a splice variant of VAPB that retains the N-terminal 70 residues but lacks the coiled-coil and transmembrane domains. Northern blot analysis detected a major 2.5-kb VAPB transcript and 1.1- and 8.7-kb minor VAPB transcripts in all tissues tested. Expression of VAPB was less intense than that of VAPA or the 1.9-kb VAPC transcript. SDS-PAGE analysis demonstrated that the transmembrane domain of recombinant VAPA interacted with VAPA and VAPB fusion proteins. </p><p>De Vos et al. (2012) found that a portion of VAPB localized to mitochondria-associated membranes, a specialized ER domain in close apposition with mitochondria. </p><p>Using immunohistochemical analysis, Larroquette et al. (2015) found that Vapb was expressed in motor neurons of mouse spinal cord, but not in glial cells or sensory neurons. Little to no Vapb was detected in cerebellum, cerebrum, or hippocampus. In motor neurons, Vapb localized to cell bodies and dendrites and colocalized with ER markers. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
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|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Gene Structure</strong>
|
|
</span>
|
|
</h4>
|
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</div>
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<span class="mim-text-font">
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<p>Chen et al. (2010) noted that the VAPB gene contains 6 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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<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>The finding by Nishimura et al. (2004) of a missense mutation in the VAPB gene as the cause of a form of amyotrophic lateral sclerosis (ALS8; 608627), which had been mapped to 20q13.3, demonstrated this as the localization of the VAPB gene. </p>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Function</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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<p>In COS-7 cells and mouse NSC34 cells, Kanekura et al. (2006) demonstrated that wildtype human VABP localized to the endoplasmic reticulum and that its overexpression promoted the unfolded protein response. In contrast, mutant VAPB (P56S; 605704.0001) was insoluble, shifted to non-ER subcellular locations, and did not induce UPR. Although the studies indicated that mutant VAPB was a loss of function mutation, cotransfection experiments showed that mutant VAPB inhibited the ability of wildtype VAPB to mediate UPR, consistent with a dominant-negative effect. </p><p>Using immunohistochemistry and Western blot analysis, Teuling et al. (2007) found that VABP was widely expressed in both neuronal and nonneuronal human and mouse cell lines. The protein localized to the endoplasmic reticulum. In the CNS, the highest levels of VABP expression were found in mouse and human spinal cord motor neurons. </p><p>Using yeast 2-hybrid and coimmunoprecipitation analyses, De Vos et al. (2012) found that endogenous human VAPB interacted with the outer mitochondrial membrane protein PTPIP51 (FAM82A2; 611873). The cytoplasmic N-terminal domain of VAPB specifically interacted with the cytoplasmic C-terminal domain of PTPIP51. Knockdown of either VAPB or PTPIP51 in HEK293 cells delayed mitochondrial calcium uptake following IP3R (ITPR1; 147265)-induced calcium release from ER stores, resulting in increased peak cytosolic calcium concentration. De Vos et al. (2012) concluded that PTPIP51 directs VAPB localization to mitochondria-associated membranes and that both VAPB and PTPIP51 are involved in calcium exchange between the ER and mitochondria. </p><p>Using mass spectrometry and immunoprecipitation analysis in transfected COS-7 cells, Costello et al. (2017) showed that ACBD4 (619968) isoform-2 interacted with VAPB. Coexpression of ACBD4 isoform-2 and VAPB promoted ER-peroxisome associations in COS-7 cells, suggesting a role for ACBD4 and VAPB interaction in ER-peroxisome tethering. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>By the study of candidate genes within the region of 20q13.3 that showed linkage to an form of ALS called ALS8 (608627), Nishimura et al. (2004) identified a novel mutation in the VAPB gene (P56S; 605704.0001). Subsequently, they identified the same mutation in patients from 6 additional kindreds but with different clinical courses, such as ALS8, late-onset spinal muscular atrophy (182980), and a typical severe ALS with rapid progression. Although it was not possible to link all of these families, haplotype analysis suggested a founder effect. Members of the vesicle-associated proteins are intracellular membrane proteins that can associate with microtubules and have been shown to have a function in membrane transport. The data suggested that clinically variable motor neuron diseases may be caused by dysfunction in intracellular membrane trafficking. </p><p>Kirby et al. (2007) did not identify mutations in the VAPB gene in 301 cases of ALS from the United Kingdom, including 23 familial and 278 sporadic cases. </p><p>Landers et al. (2008) identified a P56S mutation in the VAPB gene in 1 of 80 families with ALS. The family with the mutation was of Brazilian origin. No other clearly pathogenic mutations were identified. In 1 other family, they identified a 3-bp in-frame deletion (478delCTT), resulting in loss of ser160, that was also found in 0.45% of controls. In vitro expression studies of del-ser160 VAPB showed wildtype cytoplasmic localization. Landers et al. (2008) concluded that VAPB mutations are not a common cause of ALS and that the 3-bp deletion they identified in 1 family was not causative for the disorder. </p><p>In 1 of 107 non-Brazilian probands with ALS, Chen et al. (2010) identified a heterozygous mutation in the VAPB gene (T46I; 605704.0002). In vitro functional expression studies in COS-7 and neuronal cells showed that the T46I mutation formed intracellular protein aggregates and ubiquitin aggregates, ultimately resulting in cell death. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Animal Model</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Chai et al. (2008) demonstrated that the Drosophila Dvap33a gene is the structural and functional homolog of the human VAPB gene. Hypomorphic and null Dvap33a alleles expressed in neurons caused a severe decrease in bouton number and an increase in bouton size. Conversely, overexpression of Dvap33a in neurons induced a highly significant increase in the number of boutons with a concomitant decrease in their size. Electrophysiologic and electron microscopic studies showed that these structural alterations were associated with compensatory changes in the physiology and ultrastructure of synapses, which maintained evoked responses within normal boundaries. These compensatory changes were determined by changes in expression of glutamate receptor subunits. Targeted expression of human VAPB in Drosophila neurons with hypomorphic or null Dvap33a alleles rescued the morphologic and electrophysiologic mutant phenotype. Transgenic expression of mutant Dvap33a in Drosophila recapitulated major hallmarks of human neuronal diseases, including locomotion defects and neuronal death with aggregate formation. The findings implicated a role for human VAPB in synaptic homeostasis. </p><p>In transgenic mice, Aliaga et al. (2013) found that expression of human VAPB with the P56S mutation caused various motor behavioral abnormalities, including progressive hyperactivity. Accumulation of mutant VAPB triggered ER stress, leading to increased proapoptotic Chop (DDIT3; 126337) expression in both corticospinal and spinal motor neurons. Mutant transgenic mice experienced significant loss of corticospinal motor neurons, but no obvious degeneration of spinal motor neurons. </p><p>Moustaqim-Barrette et al. (2014) found that cortical neurons of vap-null Drosophila showed ER stress with accumulation of ubiquitinated proteins, concomitant with development of a progressive flight defect. Loss of vap also caused redistribution of oxysterol-binding protein (OSBP; 167040) from ER to Golgi. Flies expressing vap with an ALS8 mutation (P56S) showed a less severe phenotype than vap-null flies. Expression of human OSBPL8 (606736), which lacks the vap-binding sequence found in Drosophila osbp, attenuated ER stress and accumulation of ubiquitinated proteins and partly rescued the flight defect in vap-null flies and flies with the ALS8 mutation. </p><p>Larroquette et al. (2015) replaced the wildtype Vapb gene in mice with P56S mutant Vapb. Heterozygous and homozygous P56S Vapb knockin mice were obtained at the expected mendelian ratio, developed normally, and had life spans similar to wildtype mice. However, heterozygous and homozygous P56S Vapb knockin mice showed dose- and age-dependent defects in motor tasks compared with wildtype mice. P56S Vapb knockin mice also showed age- and dose-dependent cellular pathologic defects in motor neurons, with loss of P56S Vapb in the ER and accumulation of the mutant protein in cytoplasmic inclusions, where it localized with ubiquitinated proteins. P56S Vapb knockin motor neurons showed chronic mild atrophy, induction of ER stress, and autophagic response prior to onset of motor defect. Soleus muscle of P56S Vapb knockin mice showed mild partial denervation and morphologic changes at synaptic boutons at neuromuscular junctions. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>2 Selected Examples):</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0001 AMYOTROPHIC LATERAL SCLEROSIS 8</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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SPINAL MUSCULAR ATROPHY, LATE-ONSET, FINKEL TYPE, 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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VAPB, PRO56SER
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<br />
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SNP: rs74315431,
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gnomAD: rs74315431,
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ClinVar: RCV000005073, RCV000059635, RCV002254541, RCV002254542
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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 large white Brazilian family with amyotrophic lateral sclerosis (ALS8; 608627), Nishimura et al. (2004) found a heterozygous 166C-T transition in exon 2 of the VAPB gene, leading to a pro56-to-ser (P56S) mutation. Subsequently the authors demonstrated the same mutation in patients from 6 additional kindreds in which the clinical course varied, including some with late-onset spinal muscular atrophy (Finkel type; 182980) and some with typical severe ALS with rapid progression (see 105400). Although it was not possible to link all of these families, haplotype analysis suggested founder effect. In vitro functional expression studies in rat hippocampal neurons and HEK293 cells showed that the P56S mutation disrupted the normal subcellular distribution of the VAPB protein and caused intracellular aggregates. Unlike the wildtype protein, the mutant P56S protein did not colocalize with either the Golgi apparatus or the endoplasmic reticulum (ER). </p><p>Nishimura et al. (2005) analyzed 7 polymorphic markers around the VAPB gene in an index case from each of the Brazilian families with P56S mutation previously reported by Nishimura et al. (2004) and in 9 Brazilian Portuguese controls. They found evidence for a common founder for all families regardless of ancestry, with a founding event 23 generations ago, consistent with the Portuguese colonization of Brazil. </p><p>Teuling et al. (2007) found that the P56S mutant protein formed cytosolic aggregates in all cell types examined, including mouse and human nonneuronal cells. These aggregates did not colocalize with markers for the ER. Further studies showed that the mutant protein acted in a dominant-negative manner by recruiting wildtype VAPB to the aggregates and disrupting normal protein and cellular function. </p><p>Landers et al. (2008) identified the P56S mutation in affected members of a Brazilian family with ALS. The mean age at onset was between 45 and 55 years with survival varying from 5 to 18 years. The mutation was not identified in 79 additional ALS families. </p><p>Millecamps et al. (2010) identified the P56S mutation in 1 (0.6%) of 162 French probands with familial ALS. The patient was of Japanese descent, representing the first non-Brazilian reported to carry this mutation. Three other family members had motor neuron disease, suggesting autosomal dominant inheritance. The patient had long disease duration with onset in the legs during the sixth decade. Millecamps et al. (2010) suggested that the finding of the P56S mutation in a Japanese patient may reflect the Portuguese trading connection with the Far East and Brazil in the mid-16th century. </p><p>De Vos et al. (2012) found that VAPB with the P56S mutation showed significantly higher affinity than wildtype for the outer mitochondrial membrane protein PTPIP51 (FAM82A2; 611873). Increased binding with PTPIP51 resulted in accumulation of VAPB at mitochondria-associated membranes in the ER and elevated calcium uptake by mitochondria following release of calcium from ER stores. Expression of human VAPB with the P56S mutation also disturbed calcium handling in cultured rat cortical neurons following depolarization. </p><p>Using cultured embryonic rat cortical neurons, Morotz et al. (2012) found that expression of human VAPB with the P56S mutation (VAPB-P56S) significantly slowed anterograde axonal transport of mitochondria. Studies in rat neurons and HEK293 cells showed that expression of VAPB-P56S increased resting intracellular Ca(2+) concentration and disrupted the interaction between tubulin (see 191130) and the mitochondrial membrane Rho GTPase MIRO1 (RHOT1; 613888). Expression of VAPB-P56S had no effect on the amount of TRAK1 (608112) or kinesin-1 (see 602809) associated with MIRO1. </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>.0002 AMYOTROPHIC LATERAL SCLEROSIS 8</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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VAPB, THR46ILE
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<br />
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SNP: rs281875284,
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ClinVar: RCV000023467, RCV000059634
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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 non-Brazilian patient with amyotrophic lateral sclerosis-8 (ALS8; 608627), Chen et al. (2010) identified a heterozygous 137C-T transition in the VAPB gene, resulting in a thr46-to-ile (T46I) substitution in a highly conserved residue important for the interaction with lipid-binding proteins. The mutation was found in 1 of 107 probands with familial ALS and was not found in 257 controls. The 73-year-old male patient presented with wasting of the small muscles of the hands. He also had fasciculations of the leg, and later developed speech and swallowing difficulties. The diagnosis was confirmed by nerve conduction studies. The patient had a brother with ALS who died within 4 months of diagnosis from pneumonia, but DNA was not available for testing. In vitro functional expression studies in COS-7 cells and neuronal showed that the T46I mutation formed intracellular protein aggregates and ubiquitin aggregates, ultimately resulting in cell death. The mutant protein was unable to activate the unfolded protein response pathway, as measured by lack of activation of IRE1 (ERN1; 604033), and the effect was dominant-negative. Expression of the equivalent T48I mutation in Drosophila resulted in aggregate formation in neurons and nerve fibers, cell degeneration, fragmentation of the endoplasmic reticulum, and upregulation of chaperone proteins. Muscle was also adversely affected. Chen et al. (2010) also postulated that disturbances in lipid metabolism may play a role in the pathogenesis of ALS. </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>REFERENCES</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<ol>
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<li>
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<p class="mim-text-font">
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Aliaga, L., Lai, C., Yu, J., Chub, N., Shim, H., Sun, L., Zie, C., Yang, W.-J., Lin, X., O'Donovan, M. J., Cai, H.
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<strong>Amyotrophic lateral sclerosis-related VAPB P56S mutation differentially affects the function and survival of corticospinal and spinal motor neurons.</strong>
|
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Hum. Molec. Genet. 22: 4293-4305, 2013. Note: Erratum: Hum. Molec. Genet. 23: 3069 only, 2014.
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[PubMed: 23771029]
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[Full Text: https://doi.org/10.1093/hmg/ddt279]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Chai, A., Withers, J., Koh, Y. H., Parry, K., Bao, H., Zhang, B., Budnik, V., Pennetta, G.
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<strong>hVAPB, the causative gene of a heterogeneous group of motor neuron diseases in humans, is functionally interchangeable with its Drosophila homologue DVAP-33A at the neuromuscular junction.</strong>
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Hum. Molec. Genet. 17: 266-280, 2008.
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[PubMed: 17947296]
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[Full Text: https://doi.org/10.1093/hmg/ddm303]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Chen, H.-J., Anagnostou, G., Chai, A., Withers, J., Morris, A., Adhikaree, J., Pennetta, G., de Belleroche, J. S.
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<strong>Characterization of the properties of a novel mutation in VAPB in familial amyotrophic lateral sclerosis.</strong>
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J. Biol. Chem. 285: 40266-40281, 2010.
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[PubMed: 20940299]
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[Full Text: https://doi.org/10.1074/jbc.M110.161398]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Costello, J. L., Castro, I. G., Schrader, T. A., Islinger, M., Schrader, M.
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<strong>Peroxisomal ACBD4 interacts with VAPB and promotes ER-peroxisome associations.</strong>
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Cell Cycle 16: 1039-1045, 2017.
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[PubMed: 28463579]
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[Full Text: https://doi.org/10.1080/15384101.2017.1314422]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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De Vos, K. J., Morotz, G. M., Stoica, R., Tudor, E. L., Lau, K.-F., Ackerly, S., Warley, A., Shaw, C. E., Miller, C. C. J.
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<strong>VAPB interacts with the mitochondrial protein PTPIP51 to regulate calcium homeostasis.</strong>
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Hum. Molec. Genet. 21: 1299-1311, 2012.
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[PubMed: 22131369]
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[Full Text: https://doi.org/10.1093/hmg/ddr559]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Kanekura, K., Nishimoto, I., Aiso, S., Matsuoka, M.
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<strong>Characterization of amyotrophic lateral sclerosis-linked P56S mutation of vesicle-associated membrane protein-associated protein B (VAPB/ALS8).</strong>
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J. Biol. Chem. 281: 30223-30233, 2006.
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[PubMed: 16891305]
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[Full Text: https://doi.org/10.1074/jbc.M605049200]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Kirby, J., Hewamadduma, C. A. A., Hartley, J. A., Nixon, H. C., Evans, H., Wadhwa, R. R., Kershaw, C., Ince, P. G., Shaw, P. J.
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<strong>Mutations in VAPB are not associated with sporadic ALS.</strong>
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Neurology 68: 1951-1953, 2007.
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[PubMed: 17536055]
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[Full Text: https://doi.org/10.1212/01.wnl.0000263195.50981.a6]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Landers, J. E., Leclerc, A. L., Shi, L., Virkud, A., Cho, T., Maxwell, M. M., Henry, A. F., Polak, N., Glass, J. D., Kwiatkowski, T. J., Al-Chalabi, A., Shaw, C. E., Leigh, P. N., Rodriguez-Leyza, I., McKenna-Yasek, D., Sapp, P. C., Brown, R. H., Jr.
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<strong>New VAPB deletion variant and exclusion of VAPB mutations in familial ALS.</strong>
|
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Neurology 70: 1179-1185, 2008.
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[PubMed: 18322265]
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[Full Text: https://doi.org/10.1212/01.wnl.0000289760.85237.4e]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Larroquette, F., Seto, L., Gaub, P. L., Kamal, B., Wallis, D., Lariviere, R., Vallee, J., Robitaille, R., Tsuda, H.
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<strong>Vapb/amyotrophic lateral sclerosis 8 knock-in mice display slowly progressive motor behavior defects accompanying ER stress and autophagic response.</strong>
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Hum. Molec. Genet. 24: 6515-6529, 2015.
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[PubMed: 26362257]
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[Full Text: https://doi.org/10.1093/hmg/ddv360]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Millecamps, S., Salachas, F., Cazeneuve, C., Gordon, P., Bricka, B., Camuzat, A., Guillot-Noel, L., Russaouen, O., Bruneteau, G., Pradat, P.-F., Le Forestier, N., Vandenberghe, N., and 14 others.
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<strong>SOD1, ANG, VAPB, TARDBP, and FUS mutations in familial amyotrophic lateral sclerosis: genotype-phenotype correlations.</strong>
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J. Med. Genet. 47: 554-560, 2010.
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[PubMed: 20577002]
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[Full Text: https://doi.org/10.1136/jmg.2010.077180]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Morotz, G. M., De Vos, K. J., Vagnoni, A., Ackerley, S., Shaw, C. E., Miller, C. C. J.
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<strong>Amyotrophic lateral sclerosis-associated mutant VAPBP56S perturbs calcium homeostasis to disrupt axonal transport of mitochondria.</strong>
|
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Hum. Molec. Genet. 21: 1979-1988, 2012.
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[PubMed: 22258555]
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[Full Text: https://doi.org/10.1093/hmg/dds011]
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Moustaqim-Barrette, A., Lin, Y. Q., Pradhan, S., Neely, G. G., Bellen, H. J., Tsuda, H.
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<strong>The amyotrophic lateral sclerosis 8 protein, VAP, is required for ER protein quality control.</strong>
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Nishimura, A. L., Al-Chalabi, A., Zatz, M.
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<strong>A common founder for amyotrophic lateral sclerosis type 8 (ALS8) in the Brazilian population.</strong>
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Nishimura, A. L., Mitne-Neto, M., Silva, H. C. A., Richieri-Costa, A., Middleton, S., Cascio, D., Kok, F., Oliveira, J. R. M., Gillingwater, T., Webb, J., Skehel, P., Zatz, M.
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<strong>A mutation in the vesicle-trafficking protein VAPB causes late-onset spinal muscular atrophy and amyotrophic lateral sclerosis.</strong>
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Nishimura, Y., Hayashi, M., Inada, H., Tanaka, T.
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<strong>Molecular cloning and characterization of mammalian homologues of vesicle-associated membrane protein-associated (VAMP-associated) proteins.</strong>
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Teuling, E., Ahmed, S., Haasdijk, E., Demmers, J., Steinmetz, M. O., Akhmanova, A., Jaarsma, D., Hoogenraad, C. C.
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Bao Lige - updated : 07/21/2022<br>Patricia A. Hartz - updated : 2/29/2016<br>Patricia A. Hartz - updated : 5/19/2015<br>Patricia A. Hartz - updated : 2/20/2015<br>Patricia A. Hartz - updated : 7/26/2013<br>Patricia A. Hartz - updated : 7/16/2013<br>Cassandra L. Kniffin - updated : 12/22/2010<br>Cassandra L. Kniffin - updated : 9/27/2010<br>Cassandra L. Kniffin - updated : 4/29/2009<br>Cassandra L. Kniffin - updated : 10/17/2008<br>Cassandra L. Kniffin - updated : 11/29/2007<br>Cassandra L. Kniffin - updated : 2/20/2007<br>Marla J. F. O'Neill - updated : 2/15/2006<br>Victor A. McKusick - updated : 10/21/2004
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